C H APT E R

Endocrine Disease 23
RUSSELL T. WALL, III

endogenous glucose production via glycogenolysis and gluco-

neogenesis. Following a meal, plasma glucose level increases,
Diabetes Mellitus which stimulates an increase in plasma insulin secretion that
Signs and Symptoms promotes glucose utilization. Late in the postprandial period
Diagnosis (2–4 hours after eating) when glucose utilization exceeds glu-
Treatment cose production, a transition from exogenous glucose delivery
Complications to endogenous production becomes necessary to maintain a
Management of Anesthesia normal plasma glucose level. Approximately 70%–80% of glu-
Insulinoma cose released by the liver is metabolized by insulin-insensitive
Thyroid Disease tissues such as the brain, gastrointestinal (GI) tract, and red
Diagnosis blood cells. During this time, diminished insulin secretion is
Hyperthyroidism fundamental to maintenance of a normal plasma glucose con-
Hypothyroidism centration. Hyperglycemia-producing hormones (glucagon,
Goiter and Thyroid Tumors epinephrine, growth hormone, cortisol) comprise the glucose
Complications of Thyroid Surgery counterregulatory system and support glucose production.
Pheochromocytoma Glucagon plays a primary role by stimulating glycogenolysis
Signs and Symptoms and gluconeogenesis and inhibiting glycolysis.
Diagnosis Diabetes mellitus results from an inadequate supply of
Management of Anesthesia insulin and/or an inadequate tissue response to insulin. This
Adrenal Gland Dysfunction leads to increased circulating glucose levels with eventual
Hypercortisolism (Cushing Syndrome) microvascular and macrovascular complications. Type 1a dia-
Primary Hyperaldosteronism (Conn Syndrome) betes is caused by autoimmune destruction of beta cells within
Hypoaldosteronism
Adrenal Insufficiency 200
Parathyroid Gland Dysfunction Liver 100 Brain
Plasma
Hyperparathyroidism   glucose
Hypoparathyroidism
Pituitary Gland Dysfunction Insulin Glucagon
Acromegaly Nonglucose
Diabetes Insipidus stimuli
Syndrome of Inappropriate Antidiuretic Hormone Secretion
(SIADH)
Key Points Pancreatic Fat and
Insulin
islet  muscle
FIG. 23.1  The pancreatic islets act as glucose sensors to balance
hepatic glucose release to insulin-insensitive tissues (brain) and
DIABETES MELLITUS insulin-sensitive tissues (fat, muscle). Insulin inhibits glucose release
by the liver and stimulates glucose utilization by insulin-sensitive tis-
Normal glucose physiology is marked by a balance between sues. With hyperglycemia, insulin secretion increases. With hypogly-
glucose utilization and endogenous production or dietary cemia, the reverse occurs. (Adapted from Porte D Jr. Beta-cells in
delivery (Fig. 23.1). The liver is the primary source of type II diabetes mellitus. Diabetes. 1991;40:166-180.)

449
450 STOELTING’S ANESTHESIA AND CO-EXISTING DISEASE
Liver
Increased glucose
production
Impaired insulin
secretion
FIG. 23.2  Abnormalities in type 2 diabetes. (Adapted from Inzucchi S, ed. The Diabetes Mel-
litus Manual: A Primary Care Companion to Ellenberg and Rifkin’s Sixth Edition. New York:
McGraw-Hill; 2005:79.)
pancreatic islets, resulting in complete absence or minimal
circulating levels of insulin. Type 1b diabetes is a rare disease
of absolute insulin deficiency that is not immune mediated.
Type 2 diabetes also is not immune mediated and results from
defects in insulin receptors and postreceptor intracellular sig-
naling pathways.
Signs and Symptoms
Type 1 Diabetes
Between 5% and 10% of all cases of diabetes are type 1. There
are 1.4 million individuals with type 1 diabetes in the United
States and 10–20 million globally. Currently the incidence is
increasing by 3%–5% per year. The disorder is usually diag-
nosed before the age of 40 and is one of the most common
chronic childhood illnesses.
Type 1 diabetes is caused by T cell–mediated autoimmune
destruction of beta cells in the pancreas. The exact cause is
unknown, although environmental triggers such as viruses
(especially enteroviruses), dietary proteins, or drugs or chemi-
cals may initiate the autoimmune process in genetically sus-
ceptible hosts. At least 80%–90% of beta cell function must be
lost before hyperglycemia occurs.
The presentation of clinical disease is often sudden and
severe, secondary to loss of a critical mass of beta cells. Patients
demonstrate hyperglycemia over several days to weeks associ-
ated with fatigue, weight loss, polyuria, polydipsia, blurring of
vision, and signs of intravascular volume depletion. The diag-
nosis is based on the presence of a random blood glucose level
higher than 200 mg/dL and a hemoglobin (Hb)A1c level above
Peripheral
tissues
(muscle)
Receptor
+
postreceptor
defect
Glucose
Pancreas
7.0%. The presence of ketoacidosis indicates severe insulin
deficiency and unrestrained lipolysis. 
Type 2 Diabetes
Type 2 diabetes is responsible for 90% of all cases of diabe-
tes mellitus in the world. In 2000 there were approximately
150 million individuals with type 2 diabetes globally, and the
number is expected to double by 2025. Patients with type 2
diabetes are typically in the middle to older age group and are
overweight, although there has been a significant increase in
younger patients and even children with type 2 diabetes over
the past decade.
Type 2 diabetes is characterized by relative beta cell insuf-
ficiency and insulin resistance. In the initial stages of the dis-
ease, an insensitivity to insulin on the part of peripheral tissues
leads to an increase in pancreatic insulin secretion to maintain
normal plasma glucose levels. As the disease progresses and
pancreatic cell function decreases, insulin levels are unable
to compensate and hyperglycemia occurs. Three important
defects are seen in type 2 diabetes: (1) an increased rate of
hepatic glucose release, (2) impaired basal and stimulated
insulin secretion, and (3) inefficient use of glucose by periph-
eral tissues (i.e., insulin resistance) (Fig. 23.2). Although
relative beta cell insufficiency is significant, type 2 diabetes
is characterized by insulin resistance in skeletal muscle, adi-
pose tissue, and the liver. It appears that insulin resistance is
an inherited component of type 2 diabetes, with obesity and
a sedentary lifestyle being acquired and contributing factors.
Impaired glucose tolerance is associated with an increase in
body weight, a decrease in insulin secretion, and a reduction

TABLE 23.1   Diagnostic Features of Metabolic
Syndrome
  
At least three of the following:
Fasting plasma glucose level ≥ 110 mg/dL
Abdominal obesity (waist girth > 40 inches in men, >35 inches
in women)
Serum triglyceride level ≥ 150 mg/dL
Serum high-density lipoprotein cholesterol level < 40 mg/dL in
men, <50 mg/dL in women
Blood pressure ≥ 130/85 mm Hg
Adapted from Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults: Executive summary of the third report of the National Cho-
lesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA.
2001;285:2486-2497.
TABLE 23.2   Diagnostic Criteria for Diabetes Mellitus
  
Symptoms of diabetes (polyuria, polydipsia, unexplained weight
loss) plus a random plasma glucose concentration ≥ 200 mg/dL
or
Fasting (no caloric intake for ≥ 8 hr) plasma glucose level ≥ 126
mg/dL
or
2-hr plasma glucose level > 200 mg/dL during an oral glucose
tolerance test
Adapted from Diagnosis and classification of diabetes mellitus. American Diabetes
Association. Diabetes Care. 2010;33(Suppl 1):S62.
in peripheral insulin action. The transition to clinical diabe-
tes is characterized by these same factors plus an increase in
hepatic glucose production.
The increasing prevalence of type 2 diabetes among chil-
dren and adolescents appears related to obesity, since 85% of
affected children are overweight or obese at the time of diagno-
sis. Obese patients exhibit a compensatory hyperinsulinemia
to maintain normoglycemia. These increased insulin levels
may desensitize target tissues, causing a reduced response to
insulin. The mechanisms for hyperinsulinemia and insulin
resistance from weight gain remain elusive.
Metabolic syndrome, or insulin-resistance syndrome, is a
constellation of clinical and biochemical characteristics fre-
quently seen in patients who have or are at risk of developing
type 2 diabetes (Table 23.1). This syndrome combines insulin
resistance with hypertension, dyslipidemia, a procoagulant
state, and obesity and is associated with premature atheroscle-
rosis and subsequent cardiovascular disease. This syndrome
affects at least 25% of people in the United States.  ing insulin secretion from pancreatic beta cells; they can also
Diagnosis
The American Diabetes Association (ADA) has established
diagnostic criteria for diabetes mellitus (Table 23.2). Mea-
surement of fasting plasma glucose level is the recommended
screening test for diabetes mellitus. The upper limit for normal
fasting glucose level is 100 mg/dL. Hyperglycemia not suffi-
cient to meet the diagnostic criteria for diabetes is classified as
Chapter 23  Endocrine Disease 451
either impaired fasting glucose or impaired glucose tolerance,
depending on whether it is identified through measurement of
fasting plasma glucose level or an oral glucose tolerance test.
Any fasting glucose level between 101 and 125 mg/dL is cat-
egorized as impaired fasting glucose. Glucose levels, especially
in type 2 diabetics, usually increase over years to decades, pro-
gressing from the normal range to the impaired glucose toler-
ance range and finally to clinical diabetes.
The HbA1c test provides a valuable measure of long-term
glycemic control. Hemoglobin is nonenzymatically glyco-
sylated by glucose, which freely crosses red blood cell mem-
branes. The percentage of hemoglobin molecules participating
in this reaction is proportional to the average plasma glucose
concentration during the preceding 60–90 days. The normal
range for HbA1c is 4%–6%. Increased risk of microvascular
and macrovascular disease begins when the HbA1c proportion
is 6.5% or higher. Measurement of HbA1c is recommended at
least twice a year and more frequently (every 3 months) if gly-
cemic control is inadequate or therapy has changed. 
Treatment
The cornerstones of treatment for type 2 diabetes are dietary
adjustments along with weight loss, exercise therapy, and oral
antidiabetic drugs. Reduction of body weight through diet
and exercise is the first therapeutic measure to control type
2 diabetes. The decrease in adiposity improves hepatic and
peripheral tissue insulin sensitivity, enhances postreceptor
insulin action, and may possibly increase insulin secretion.
Nutritional guidelines of the ADA emphasize maintenance of
optimal plasma glucose and lipid levels.
Oral Antidiabetic Drugs
The four major classes of oral antidiabetic medications are
(1) the secretagogues (sulfonylureas, meglitinides), which
increase insulin availability; (2) the biguanides (metformin),
which suppress excessive hepatic glucose release; (3) the thia-
zolidinediones or glitazones (rosiglitazone, pioglitazone),
which improve insulin sensitivity; and (4) the α-glucosidase
inhibitors (acarbose, miglitol), which delay GI glucose absorp-
tion (Fig. 23.3). These agents are used to maintain glucose con-
trol, which is defined as a fasting glucose level of 90–130 mg/
dL, peak postprandial glucose level below 180 mg/dL, and
HbA1c level below 7% in the initial stages of the disease.
The sulfonylureas are usually the initial pharmacologic
treatment for type 2 diabetes mellitus. They act by stimulat-
enhance insulin-stimulated peripheral tissue utilization of
glucose. The second-generation agents (glyburide, glipizide,
glimepiride) are more potent and have fewer side effects than
their predecessors. Unfortunately, because of the natural his-
tory of type 2 diabetes characterized by decreasing beta cell
function, these drugs are not effective indefinitely. Hypogly-
cemia is the most common side effect. Whether or not harm-
ful cardiac effects from sulfonylureas have been demonstrated
is controversial. Another class of insulin secretagogues act as
452 STOELTING’S ANESTHESIA AND CO-EXISTING DISEASE

Delay
carbohydrate
absorption

Reduce excessive
hepatic glucose output Stimulate impaired
insulin secretion
-Glucosidase
inhibitors
Sulfonylureas
Reduce
Biguanides hyperglycemia Meglitinides

Glitazones Biguanides

Decreased
Increased
Improve peripheral
insulin action
FIG. 23.3  Sites of action of oral antidiabetic agents. (Adapted from Inzucchi S, ed. The Diabetes
Mellitus Manual: A Primary Care Companion to Ellenberg and Rifkin’s Sixth Edition. New York:
McGraw-Hill; 2005:168.)

GLP-1 (glucagon-like peptide 1) agonists or enhance endog-
enous GLP-1 activity in the gut. Exenatide and liraglutide are
examples and have been approved for treatment for type 2
diabetes. These agents (incretins) increase glucose-stimulated
insulin secretion, suppress glucagon, and slow gastric empty-
ing. Dipeptidyl peptidase-4 inhibitors (saxagliptin, sitagliptin,
vildagliptin) inhibit the degradation of native GLP-1 and thus
enhance glucose-stimulated insulin secretion.
The biguanides decrease hepatic gluconeogenesis and
to a lesser degree enhance utilization of glucose by skeletal
muscle and adipose tissue by increasing glucose transport
across cell membranes. In addition to lowering glucose
levels, they decrease plasma levels of triglycerides and
low-density lipoprotein cholesterol and reduce postpran-
dial hyperlipidemia and plasma free fatty acids. The risk
of hypoglycemia is less than that with the sulfonylureas.
Lactic acidosis is a rare but serious side effect of the bigu-
anides; the risk is particularly high in patients with renal
insufficiency. It is much less common with metformin than
with its predecessor phenformin.
The thiazolidinediones or glitazones are insulin sensitiz-
ers that decrease insulin resistance by binding to peroxisome
proliferator–activated receptors located in skeletal muscle,
liver, and adipose tissue. These drugs influence the expression
of genes encoding proteins for glucose and lipid metabolism,
endothelial function, and atherogenesis; as a result, they may
influence diabetic dyslipidemia in addition to hyperglycemia.
The α-glucosidase inhibitors inhibit α-glucosidase enzymes
in the brush border of enterocytes in the proximal small intes-
tine, which results in a delay in intraluminal production and
subsequent absorption of glucose. They are administered
before a main meal to ensure their presence at the site of action.
In most patients, therapy is initiated with a sulfonylurea or big-
uanide and titrated to achieve fasting and peak postprandial glu-
cose levels recommended by the ADA (Fig. 23.4). Combination
therapy with oral agents directed at more than one mechanism is
often effective. If combination oral therapy is unsuccessful, a bed-
time dose of intermediate-acting insulin is added, since hepatic
glucose overproduction is typically highest at night. If oral agents
plus single-dose insulin therapy is ineffective, type 2 diabetic
patients are switched to insulin therapy alone.
Tight control of type 2 diabetes provides significant ben-
efits in preventing and slowing the progression of microvascu-
lar disease and possibly macrovascular disease. Not only must
hyperglycemia be treated, but all abnormalities of insulin resis-
tance (metabolic syndrome) must be managed, with the goals
of therapy including an HbA1c level below 7%, a low-density
lipoprotein level below 100 mg/dL, a high-density lipoprotein
level higher than 40 mg/dL in men and higher than 50 mg/dL
in women, a triglyceride level below 200 mg/dL, and a blood
pressure lower than 130/80 mm Hg. 
Insulin
Insulin is necessary to manage all cases of type 1 diabetes
and many cases of type 2 diabetes (Table 23.3). In the United
States, 30% of patients with type 2 diabetes are treated with
insulin. Conventional insulin therapy uses twice-daily injec-
tions. Intensive insulin therapy requires three or more daily
injections or a continuous infusion (Figs. 23.5–23.9).
The various forms of insulin include basal insulins, which
are intermediate acting (NPH, Lente, lispro protamine, aspart
protamine) and administered twice daily or long acting (Ultra-
lente, glargine, detemir) and administered once daily; and
insulins that are short acting (regular) or rapid acting (lispro,
 Chapter 23  Endocrine Disease 453

Glycemic goals
Fasting and preprandial plasma glucose: 90 -130 mg/dL
Peak postprandial plasma glucose: 180 mg/dL
Glycosylated hemoglobin: 7%

Diagnosis of type 2 diabetes

Lifelong diet, exercise, weight management

Glycemic goals not achieved • Severe symptoms • Ketosis

• Severe hyperglycemia • Pregnancy

Oral agent monotherapy

Lean, insulinopenic Secretagogues
Obese, insulin resistant Biguanides
Insulin resistant, renal impairment Glitazones
Postprandial hyperglycemia -Glucosidase inhibitor
Meglitinide

Glycemic goals
not achieved

Oral agent combination therapy Insulin regimens

Secretagogue  glitazone Combination of intermediate–long acting*
Secretagogue  biguanide and short-acting insulin*
Secretagogue  -glucosidase inhibitor (two or more injections)
Biguanide  glitazone Continuous SC insulin infusion pump
Biguanide  glitazone  secretagogue (may continue/add sensitizer/
secretagogue to reduce insulin
*Not all above combinations are FDA approved requirements)
*Lispro/glargine are not FDA approved
for use in pregnancy
OR

Oral agent/insulin combination therapy

Bedtime intermediate-acting insulin (start with 10 -15 U HS
and adjust to maintain AM FPG 140 mg/dL)

If daytime glycemia not achieved

FIG. 23.4  Algorithm for treatment of type 2 diabetes. FDA, US Food and Drug Administration;
FPG, fasting plasma glucose level; HS, at bedtime; SC, subcutaneous. (Adapted from Inzucchi S,
ed. The Diabetes Mellitus Manual: A Primary Care Companion to Ellenberg and Rifkin’s Sixth
Edition. New York: McGraw-Hill; 2005:193.)

aspart, glulisine), which provide glycemic control at meal-
times. Rapid-acting insulins are preferred over regular insu-
lin for prandial coverage. Insulin glargine has a later onset of
action, longer duration of action, a less pronounced peak of
action, and a lower incidence of hypoglycemia, especially at
night. A long-acting insulin is usually prescribed with a short-
acting insulin to mimic physiologic insulin release with meals.
In general, patients with type 1 diabetes require 0.5–1 U/kg/
day divided into multiple doses, with approximately 50%
given as basal insulin.
Regular insulin is preferred over insulin analogues for intra-
venous (IV) infusions because it is less expensive and equally
effective. Sliding scale short-acting insulin alone is inadequate
for inpatient glucose management and should not be used.
Hypoglycemia is the most frequent and dangerous com-
plication of insulin therapy. The hypoglycemic effect can
be exacerbated by simultaneous administration of alcohol,
sulfonylureas, biguanides, thiazolidinediones, angiotensin-
converting enzyme (ACE) inhibitors, monoamine oxidase
inhibitors, and nonselective β-blockers.
Repetitive episodes of hypoglycemia, especially at night,
can result in hypoglycemia unawareness, a condition in which
the patient does not respond with the appropriate autonomic
warning symptoms before neuroglycopenia. The diagnosis
in adults requires a plasma glucose level below 50 mg/dL.
Symptoms are adrenergic (sweating, tachycardia, palpitations,
restlessness, pallor) and neuroglycopenic (fatigue, confu-
sion, headache, somnolence, convulsions, coma). Treatment
454 STOELTING’S ANESTHESIA AND CO-EXISTING DISEASE

TABLE 23.3   Insulin Preparations

  
Insulin Onset Peak Duration
RAPID ACTING
Lispro (Humalog) 10–15 min 1–2 h 3–6 h
Aspart (NovoLog) 10–15 min 1–2 h 3–6 h
Glulisine (Apidra) 20–30 min 30–90 min 1–2.5 h

SHORT ACTING
Human regular 30 min 2–4 h 5–8 h

INTERMEDIATE
Human NPH 1–2 h 6–10 h 10–20 h
Lente 1–2 h 6–10 h 10–20 h

LONG ACTING
Ultralente 4–6 h 8–20 h 24–48 h
Glargine (Lantus) 1–2 h — 24 h
Detemir (Levemir) 1–2 h 6–8 h 24 h

Morning Afternoon Evening Night Morning Afternoon Evening Night

Insulin effect
Insulin effect

Reg Reg Reg Reg

NPH/Lente NPH/Lente NPH/Lente NPH/Lente

B L S HS B B L S HS B
Meals Meals
FIG. 23.5  Insulin effect of two daily doses of NPH/Lente plus regu- FIG. 23.6  Insulin effect of a regimen of three injections per day:
lar insulin. ↑, Time of insulin injection; B, breakfast; L, lunch; S, sup- NPH/Lente plus regular insulin in morning, regular insulin before sup-
per; HS, bedtime. (Adapted from Hirsch IB, Farkas-Hirsch R, Skyler per, NPH/Lente at bedtime. ↑, Time of insulin injection; B, breakfast;
JS. Intensive insulin therapy for treatment of type I diabetes. Diabe- HS, bedtime; L, lunch; S, supper.
tes Care. 1990;13:1265-1283.)

Morning Afternoon Evening Night

Morning Afternoon Evening Night
Insulin effect

Insulin effect

Rapid Rapid Rapid

Reg Reg Reg

NPH/Lente Insulin glargine

B L S HS B
Meals B L S HS (Glargine)
FIG. 23.7  Insulin effect of a regimen of four injections per day: FIG. 23.8  Insulin effect of a multiple-dose regimen: three pre-
short-acting insulin before each meal and NPH/Lente at bedtime. meal doses of rapid-acting insulin (lispro/aspart) plus basal insulin
↑, Time of insulin injection; B, breakfast; HS, bedtime; L, lunch; S, (glargine). ↑, Time of insulin injection; B, breakfast; HS, bedtime; L,
supper. lunch; S, supper.

Morning Afternoon Evening Night
Insulin effect
Meal Meal Meal Basal
bolus bolus bolus infusion
B is initiated. Insulin administration must be continued until a
B L S HS
Meals
FIG. 23.9  Insulin effect of continuous subcutaneous infusion of
short- or rapid-acting insulin before meals and snacks. ↑, Time of
insulin injection; B, breakfast; HS, bedtime; L, lunch; S, supper.
TABLE 23.4   Diagnostic Features of Diabetic
Ketoacidosis
Serum glucose level (mg/dL) ≥300
pH ≤7.3
HCO3− (mEq/L) ≤18
Serum osmolarity (mOsm/L) <320
Serum and urine ketone levels Moderate to high
includes administration of sugar in the form of sugar cubes,
glucose tablets, or soft drinks if the patient is conscious; and
glucose 0.5 g/kg IV or glucagon 0.5–1 mg IV, intramuscularly,
or subcutaneously if the patient is unconscious.  tion or coma (Table 23.5). Patients may have some degree of
Complications
Diabetic Ketoacidosis
Diabetic ketoacidosis (DKA) is a complication of decom-
pensated diabetes mellitus. The signs and symptoms of DKA
are primarily the result of abnormalities in carbohydrate and
fat metabolism. Episodes of DKA occur more commonly in
patients with type 1 diabetes and are precipitated by infec-
tion or acute illness. High glucose levels exceed the thresh-
old for renal tubular absorption, which creates a significant
osmotic diuresis with marked hypovolemia. A tight metabolic
coupling between hepatic gluconeogenesis and ketogenesis
leads to overproduction of ketoacids by the liver. An increase
in production of ketoacids (β-hydroxybutyrate, acetoacetate,
acetone) creates an anion-gap metabolic acidosis (Table 23.4).
Substantial deficits of water, potassium, and phosphorus exist,
although laboratory values of these electrolytes may be normal
or increased. Hyponatremia results from the effect of hyper-
glycemia and hyperosmolarity on water distribution. The defi-
cit of potassium is usually substantial (3–5 mEq/kg), and the
deficit of phosphorus can lead to diaphragmatic and skeletal
muscle dysfunction and impaired myocardial contractility.
Treatment of DKA consists of administration of large
amounts of normal saline, effective doses of insulin, and elec-
trolyte supplementation. An IV loading dose of 0.1 unit/kg of
regular insulin plus a low-dose insulin infusion of 0.1 unit/kg/h
Chapter 23  Endocrine Disease 455
TABLE 23.5   Diagnostic Features of Hyperglycemic
Hyperosmolar Syndrome
Glucose level (mg/dL) ≥600
pH ≥7.3
HCO3− (mEq/L) ≥15
Serum osmolarity (mOsm/L) ≥350
normal acid-base status is achieved. The insulin rate is reduced
when hyperglycemia is controlled, blood pH is higher than
7.3, and bicarbonate level exceeds 18 mEq/L. Potassium and
phosphate are replaced with KCl and K2PO4. Magnesium
is replaced as needed. Sodium bicarbonate is administered
if blood pH is less than 7.1. The infrequent but devastating
development of cerebral edema can result from correction
of hyperglycemia without simultaneous correction of serum
sodium level. 
Hyperglycemic Hyperosmolar Syndrome
Hyperglycemic hyperosmolar syndrome is characterized by
severe hyperglycemia, hyperosmolarity, and dehydration. It
usually occurs in the context of an acute illness in patients with
type 2 diabetes who are older than 60 years. The syndrome
evolves over days to weeks, with a persistent glycosuric diure-
sis. The patient experiences polyuria, polydipsia, hypovolemia,
hypotension, tachycardia, and organ hypoperfusion. Hyperos-
molarity (>340 mOsm/L) is responsible for mental obtunda-
metabolic acidosis but do not demonstrate ketoacidosis.
Treatment includes significant fluid resuscitation, insulin
administration, and electrolyte supplementation. If plasma
osmolarity is greater than 320 mOsm/L, large volumes of
hypotonic saline (1000–1500 mL/h) should be administered
until the osmolarity is less than 320 mOsm/L, at which time
large volumes of isotonic saline (1000–1500 mL/h) can be
given. Insulin therapy is initiated with an IV bolus of 15 units
of regular insulin followed by a 0.1-unit/kg/h infusion. The
insulin infusion is decreased to 2–3 units/h when the glucose
level decreases to approximately 250–300 mg/dL. Electrolyte
deficits are significant but usually less severe than in DKA. 
Microvascular Complications
Microvascular dysfunction is unique to diabetes and char-
acterized by nonocclusive microcirculatory disease and
impaired autoregulation of blood flow and vascular tone.
Chronic hyperglycemia is essential for development of these
changes, and intensive glycemic control delays the onset and
slows the progression of microvascular effects.
Nephropathy
Approximately 30%–40% of individuals with type 1 diabetes
and 5%–10% of those with type 2 diabetes develop end-stage
renal disease. The clinical course is characterized by hyper-
tension, albuminuria, peripheral edema, and a progressive
decrease in glomerular filtration rate (GFR). When the GFR
456 STOELTING’S ANESTHESIA AND CO-EXISTING DISEASE
decreases to less than 15–20 mL/min, the ability of the kid-
neys to excrete potassium and acids is impaired, and patients
develop hyperkalemia and metabolic acidosis. Hypertension,
hyperglycemia, hypercholesterolemia, and microalbumin-
uria accelerate the decrease in GFR. Treatment of hyperten-
sion can markedly slow the progression of renal dysfunction.
ACE inhibitors are particularly beneficial in diabetic patients
because they retard the progression of proteinuria and the
decrease in GFR.  nomic neuropathy.
Peripheral Neuropathy
More than 50% of patients who have had diabetes for lon-
ger than 25 years develop a peripheral neuropathy. A distal
symmetric diffuse sensorimotor polyneuropathy is the most
common form. Sensory deficits usually overshadow motor
abnormalities and appear in the toes or feet and progress
proximally toward the chest in a “stocking-glove” distribution.
Loss of large sensory and motor fibers produces loss of light
touch and proprioception as well as muscle weakness. Loss of
small fibers decreases the perception of pain and temperature
and produces dysesthesia, paresthesia, and neuropathic pain.
Foot ulcers develop from mechanical and traumatic injury as
a result of loss of cutaneous sensitivity to pain and tempera-
ture and impaired perfusion. Significant morbidity results
from recurrent infection, foot fractures (Charcot joint), and
subsequent amputations. Treatment of peripheral neuropathy
includes optimal glucose control as well as use of nonsteroidal
antiinflammatory drugs, antidepressants, and anticonvulsants
for pain control.  present, and stress testing should be considered in patients
Retinopathy
Diabetic retinopathy results from a variety of microvascular
changes. Visual impairment can range from minor changes
in color vision to total blindness. Strict glycemic control and
blood pressure control can reduce the risk of development and
progression of retinopathy.  hypotension. In addition, loss of compensatory sympathetic
Autonomic Neuropathy
Diabetic autonomic neuropathy can affect any part of the
autonomic nervous system. Symptomatic autonomic neu-
ropathy is rare and present in fewer than 5% of diabetics. The
pathogenesis is not completely understood but may involve
metabolic, microvascular, and/or autonomic abnormalities.
Cardiovascular signs of autonomic neuropathy include abnor-
malities in heart rate control as well as central and peripheral
vascular dynamics. A heart rate that fails to respond to exer-
cise is indicative of significant cardiac denervation and is likely
to result in substantially reduced exercise tolerance. The heart
may demonstrate systolic and diastolic dysfunction with a
reduced ejection fraction. Dysrhythmias may be responsible
for sudden death. The presence of cardiovascular autonomic
neuropathy can be demonstrated by measuring orthostatic
changes in heart rate and blood pressure and the hemody-
namic response to exercise.
Diabetic autonomic neuropathy may also impair gastric
secretion and gastric motility, eventually causing gastroparesis
diabeticorum in approximately 25% of diabetic patients.
Although it is often clinically silent, symptomatic patients will
have nausea, vomiting, early satiety, bloating, and epigastric
pain. Treatment of gastroparesis includes strict blood glucose
control, consumption of multiple small meals, reduction of
the fat content of meals, and use of prokinetic agents such as
metoclopramide. Diarrhea and constipation are also common
among diabetic patients and may be related to diabetic auto-
 
Macrovascular Complications
Cardiovascular disease is a major cause of morbidity and the
leading cause of mortality in diabetic individuals. Patients
with poorly controlled diabetes demonstrate elevated triglyc-
eride levels, low levels of high-density lipoprotein cholesterol,
and an abnormally small, dense, more atherogenic low-density
lipoprotein cholesterol. Measures to prevent coronary artery
disease include maintaining lipid levels, glucose level, and
blood pressure within normal limits. Aspirin and statin therapy
should be considered for all diabetic patients. 
Management of Anesthesia
Preoperative Evaluation
Preoperative evaluation should emphasize the cardiovascular,
renal, neurologic, and musculoskeletal systems. The index of
suspicion should be high for myocardial ischemia and infarc-
tion. Silent ischemia is possible if autonomic neuropathy is
with multiple cardiac risk factors and poor or indeterminate
exercise tolerance. For renal disease, control of hypertension is
important. Meticulous attention to hydration status, avoidance
of nephrotoxins, and preservation of renal blood flow are also
essential. The presence of autonomic neuropathy predisposes
the patient to perioperative dysrhythmias and intraoperative
responses interferes with detection and treatment of hemody-
namic insults. Preoperative evaluation of the musculoskeletal
system should look for limited joint mobility caused by nonen-
zymatic glycosylation of proteins and abnormal cross-linking
of collagen. Gastroparesis may increase the risk of aspiration,
regardless of nothing-by-mouth status.
Management of insulin in the preoperative period depends
on the type of insulin the patient takes and the timing of
dosing. If a patient takes subcutaneous insulin each night at
bedtime, two-thirds of this dose (NPH and regular) should
be administered the night before surgery, and one-half of
the usual morning NPH dose should be given on the day of
surgery. The daily morning dose of regular insulin should be
held. If the patient uses an insulin pump, the overnight rate
should be decreased by 30%. On the morning of surgery, the
pump can be kept infusing at the basal rate or discontinued
and replaced with a continuous insulin infusion at the same
rate. Alternatively the patient can be given subcutaneous
glargine and the pump discontinued 60–90 minutes after
administration. If the patient uses glargine and lispro or aspart
 Chapter 23  Endocrine Disease 457

TABLE 23.6   Inpatient Insulin Algorithm

  
Goal BG: ________________ mg/dL
Standard drip: Regular insulin 100 units/100 mL 0.9% NaCl via infusion device
Initiation of infusion:
Bolus dose: Regular insulin 0.1 unit/kg = ________________ units
Algorithm 1: Start here for most patients.
Algorithm 2: Start here if patient has undergone CABG, solid organ transplant, or islet cell transplant; is receiving glucocorticoids or
vasopressors; or is diabetic and receiving >80 units/day of insulin as an outpatient.

Algorithm 1 Algorithm 2 Algorithm 3 Algorithm 4

BG Units/h BG Units/h BG Units/h BG Units/h
<60 = Hypoglycemia (see below for treatment)
<70 Off <70 Off <70 Off <70 Off
70–109 0.2 70–109 0.5 70–109 1 70–109 1.5
110–119 0.5 110–119 1 110–119 2 110–119 3
120–149 1 120–149 1.5 120–149 3 120–149 5
150–179 1.5 150–179 2 150–179 4 150–179 7
180–209 2 180–209 3 180–209 5 180–209 9
210–239 2 210–239 4 210–239 6 210–239 12
240–269 3 240–269 5 240–269 8 240–269 16
270–299 3 270–299 6 270–299 10 270–299 20
300–329 4 300–329 7 300–329 12 300–329 24
330–359 4 330–359 8 330–359 14 >330 28
>360 6 >360 12 >360 16

MOVING FROM ALGORITHM TO ALGORITHM

Moving up: Move to higher algorithm when current algorithm fails, defined as BG outside goal range for 2 h (see above goal) and failure of
level to change by at least 60 mg/dL within 1 h.
Moving down: Move to lower algorithm when BG is <70 mg/dL for two checks OR BG decreases by >100 mg/dL in 1 h.
Tube feeds or TPN: Decrease infusion by 50% if nutrition (tube feeds or TPN) is discontinued or significantly reduced. Reinstitute hourly BG
checks every 4 h.
Patient monitoring: Check capillary BG every hour until it is within goal range for 4 h, then decrease to every 2 h for 4 h, and if it remains at
goal, may decrease to every 4 h.

TREATMENT OF HYPOGLYCEMIA (BG < 60 mg/dL)

Discontinue insulin drip
   and
Give D50W IV
 Patient conscious: 25 mL (½ amp)
 Patient unconscious: 50 mL (1 amp)
  Recheck BG every 20 min and repeat 25 min of D50W IV if <60 mg/dL. Restart drip once BG is >70 mg/dL for two checks. Restart drip
with lower algorithm (see Moving Down).

INTRAVENOUS FLUIDS
Most patients will need 5–10 g of glucose per hour (D5W or D5 ½ NS at 100-200 mL/h or equivalent [TPN, enteral feeds]).
amp, Ampule; BG, blood glucose; CABG, coronary artery bypass graft; D5W, 5% dextrose in water; D5 ½ NS, 5% dextrose in half-normal saline; D50W, 50% dextrose in
water; IV, intravenously; TPN, total parenteral nutrition.

for daily glycemic control, he or she should take two-thirds
of the glargine dose and the entire lispro or aspart dose the
night before surgery and hold all morning dosing. Oral hypo-
glycemics should be discontinued 24–48 hours preoperatively.
It is advised that sulfonylureas be avoided during the entire
perioperative period because they block the myocardial potas-
sium adenosine triphosphate (ATP) channels responsible for
ischemia- and anesthetic-induced preconditioning.  cal rate is 0.02 unit/kg/h, or 1.4 units/h in a 70-kg patient. An
Intraoperative Management
Aggressive glycemic control is important intraoperatively
(Table 23.6). Ideally a continuous infusion of insulin should be
initiated at least 2 hours before surgery. Intraoperative serum
glucose levels should be maintained between 120 and 180 mg/dL.
Levels above 200 mg/dL are likely to cause glycosuria and
dehydration and to inhibit wound healing. Typically 1 unit of
insulin lowers glucose approximately 25–30 mg/dL. The ini-
tial hourly rate for a continuous insulin infusion is determined
by dividing the total daily insulin requirement by 24. A typi-
insulin infusion can be prepared by mixing 100 units of regular
insulin in 100 mL of normal saline (1 unit/mL). Insulin infu-
sion requirements are higher for patients undergoing coronary
artery bypass graft surgery, patients receiving steroids, patients
458 STOELTING’S ANESTHESIA AND CO-EXISTING DISEASE
with severe infection, and patients receiving hyperalimenta-
tion or vasopressor infusions. An insulin infusion should be
accompanied by an infusion of 5% dextrose in half-normal
saline with 20 mEq KCl at 100–150 mL/h to provide enough
carbohydrate (at least 150 g/day) to inhibit hepatic glucose pro-
duction and protein catabolism. Serum glucose levels should
be monitored at least every hour and even every 30 minutes in
patients undergoing coronary artery bypass surgery or patients
with high insulin requirements. Glucose determination is pref-
erentially made using venous plasma or serum samples; arte-
rial and capillary blood yields glucose values approximately
7% higher than those for venous blood, and whole-blood
determinations are usually 15% lower than plasma or serum
values. Urine glucose monitoring is not reliable.
Avoidance of hypoglycemia is especially critical, since rec-
ognition of hypoglycemia may be delayed in patients receiving
anesthetics, sedatives, analgesics, β-blockers, or sympatholyt-
ics and in those with autonomic neuropathy. If hypoglycemia
does occur, treatment consists of administration of 50 mL of
50% dextrose in water, which typically increases the glucose
level 100 mg/dL or 2 mg/dL/mL.  A pair of parathyroid glands is located on the posterior aspect
Postoperative Care
Postoperative management of diabetic patients requires
meticulous monitoring of insulin requirements. Hypergly-
cemia has been associated with poor outcomes in postop-
erative and critically ill patients. However, the optimal target
for blood glucose level in the perioperative period has not
yet been defined. In addition, this target may be different for
patients with newly diagnosed hyperglycemia than for those
with preexisting diabetes. The risks of hypoglycemia must also
be considered. Currently the ADA recommends that glucose
levels be maintained between 140 and 180 mg/dL in critically
ill patients and that insulin treatment be initiated if serum glu-
cose levels exceed 180 mg/dL.  transported from the plasma into thyroid follicular cells (Fig.
INSULINOMA
Insulinomas are rare, benign, insulin-secreting pancreatic
islet cell tumors. They usually occur as an isolated finding but
may present as part of multiple endocrine neoplasia syndrome
type I (MEN I; insulinoma, hyperparathyroidism, and a pitu-
itary tumor). They occur in women twice as often as in men
and usually in the fifth or sixth decade of life. The diagnosis
is made by demonstrating Whipple’s triad: (1) symptoms of
hypoglycemia with fasting, (2) a glucose level below 50 mg/dL
with symptoms, and (3) relief of symptoms with administra-
tion of glucose. An inappropriately high insulin level (>5–10
microunits/mL) during a 48- to 72-hour fast confirms the
diagnosis.
Preoperatively, patients are often managed with diazox-
ide, an agent that directly inhibits insulin release from beta
cells. Other medical therapies include verapamil, phenytoin,
propranolol, glucocorticoids, and the somatostatin ana-
logues octreotide and lanreotide. Surgical treatment is cura-
tive. Ninety percent of insulinomas are benign, and tumor
enucleation is the procedure of choice. Laparoscopic resection
is used in selected cases.
Profound hypoglycemia can occur intraoperatively, par-
ticularly during manipulation of the tumor; however, marked
hyperglycemia can follow removal of the tumor. In a few med-
ical centers, an artificial pancreas that continuously analyzes
the blood glucose concentration and automatically infuses
insulin or glucose has been used for intraoperative manage-
ment of these patients. In most cases, serial blood glucose
measurements (every 15 minutes) are taken using a standard
glucometer. Since evidence of hypoglycemia may be masked
under anesthesia, it is probably wise to include glucose in
intravenously administered fluids. 
THYROID DISEASE
The thyroid gland weighs approximately 20 g and is composed
of two lobes joined by an isthmus. The gland is closely affixed
to the anterior and lateral aspects of the trachea, with the upper
border of the isthmus located just below the cricoid cartilage.
of each lobe. The gland is innervated by the adrenergic and
cholinergic nervous systems. The recurrent laryngeal nerve
and external motor branch of the superior laryngeal nerve are
in intimate proximity to the gland. Histologically the thyroid
is composed of numerous follicles filled with proteinaceous
colloid. The major constituent of colloid is thyroglobulin, an
iodinated glycoprotein that serves as the substrate for thyroid
hormone synthesis. The thyroid gland also contains parafol-
licular C cells that produce calcitonin.
Production of normal quantities of thyroid hormones
depends on the availability of exogenous iodine. The diet is
the primary source of iodine. Iodine is reduced to iodide in
the GI tract, rapidly absorbed into the blood, then actively
23.10). Binding of iodine to thyroglobulin (i.e., organifica-
tion) is catalyzed by an iodinase enzyme and yields inactive
monoiodotyrosine and diiodotyrosine. Approximately 25% of
the monoiodotyrosine and diiodotyrosine undergo coupling
via thyroid peroxidase to form the active compounds triiodo-
thyronine (T3) and thyroxine (T4). The remaining 75% never
becomes hormones, and eventually the iodine is cleaved and
recycled. T3 and T4 remain attached to thyroglobulin and are
stored as colloid until they are released into the circulation.
Since the thyroid contains a large store of hormones and has a
low turnover rate, there is protection against depletion if syn-
thesis is impaired or discontinued.
The T4:T3 ratio of secreted hormones is 10:1. Upon entering
the blood, T4 and T3 bind reversibly to three major proteins:
thyroxine-binding globulin (80% of binding), prealbumin
(10%–15%), and albumin (5%–10%). Only the small amount
of free fraction of hormone, however, is biologically active.
Although only 10% of thyroid hormone secretion is T3, T3 is
three to four times more active than T4 per unit of weight and
may be the only active thyroid hormone in peripheral tissues.
Thyroid hormones stimulate virtually all metabolic processes.
 Chapter 23  Endocrine Disease 459

Thyroid follicular cell

Plasma
tyr Colloid
Thyroglobulin tyr tyr I
synthesis T
tyr tyr I I I
tyr I I tyr DIT
1
2 tyr T
I I I2O
Peroxidase Iodinase T T-T3 T-T4
H2O2 tyr T
T-T4 T-T3 T-T3
I tyr MIT
I T-T3 T-T3 T-T4
25% T-T4 T-T3
3 thyroid
peroxidase
T-T3 T-T3
T3 (10%) T-T3
T-T4 T-T4
T4 (90%) T-T4
Proteases Phagocytosis
peptidases

1 Iodide trapping 2 Organification 3 Coupling Colloid

Thyroid follicular cell Plasma

Thyroid gland
FIG. 23.10  Thyroid follicular cell. DIT, Diiodotyrosine; MIT, monoiodotyrosine; T, thyroglobulin; T3,
3,5,3′-triiodothyronine (triiodothyronine); T4, 3,5,3′,5′-tetraiodothyronine (thyroxine); tyr, tyrosine.

They influence growth and maturation of tissues, enhance
tissue function, and stimulate protein synthesis and carbohy-
drate and lipid metabolism.
Thyroid hormone acts directly on cardiac myocytes and
vascular smooth muscle cells. Thyroid hormone increases
myocardial contractility directly, decreases systemic vascular
resistance via direct vasodilation, and increases intravascular
volume. Most recent studies emphasize the direct effects of T3
on the heart and vascular smooth muscle as responsible for the
exaggerated hemodynamic effects of hyperthyroidism.
Regulation of thyroid function is controlled by the hypo-
thalamus, pituitary, and thyroid glands, which participate in
a classic feedback control system. Thyrotropin-releasing hor-
mone (TRH) is secreted from the hypothalamus, traverses the
pituitary stalk, and promotes release of thyrotropin-stimulat-
ing hormone (TSH) from the anterior pituitary. TSH binds to
specific receptors on the thyroid cell membrane and enhances
all processes of synthesis and secretion of T4 and T3. A
decrease in TSH causes a reduction in synthesis and secretion
of T4 and T3, a decrease in follicular cell size, and a decrease in
the gland’s vascularity. An increase in TSH yields an increase
in hormone production and release and an increase in gland
cellularity and vascularity. TSH secretion is also influenced
by plasma levels of T4 and T3 via a negative feedback loop.
In addition to the feedback system, the thyroid gland has an
autoregulatory mechanism that maintains a consistent level of
hormone stores.
Diagnosis
The third generation of the TSH assay is now the single best
test of thyroid hormone action at the cellular level. Small
changes in thyroid function cause significant changes in TSH
secretion. The normal level of TSH is 0.4–5.0 milliunits/L. A
TSH level of 0.1–0.4 milliunits/L with normal levels of free T3
(FT3) and free T4 (FT4) is diagnostic of subclinical hyperthy-
roidism. A TSH level below 0.03 milliunits/L with elevated
T3 and T4 is diagnostic of overt hyperthyroidism. A TSH
level of 5.0–10 milliunits/L with normal levels of FT3 and
FT4 is diagnostic of subclinical hypothyroidism. A TSH level
higher than 20 milliunits/L (may be as high as 200 or even
400 milliunits/L) with reduced levels of T3 and T4 is diagnostic
of overt hypothyroidism.
The TRH stimulation test assesses the functional state of
the TSH-secreting mechanism in response to TRH and is
used to test pituitary function. Thyroid scans using iodine 123
(123I) or technetium 99m (99mTc) evaluate thyroid nodules as
“warm” (normally functioning), “hot” (hyperfunctioning), or
“cold” (hypofunctioning). Ultrasonography is 90%–95% accu-
rate in determining whether a lesion is cystic, solid, or mixed. 
Hyperthyroidism
Signs and Symptoms
Hyperthyroidism refers to hyperfunctioning of the thyroid
gland, with excessive secretion of active thyroid hormones.
The majority of cases of hyperthyroidism result from one of
three pathologic processes: Graves disease, toxic multinodular
goiter, or a toxic adenoma. Regardless of the cause, the signs
and symptoms of hyperthyroidism are those of a hypermeta-
bolic state. The patient is anxious, restless, and hyperkinetic
and may be emotionally unstable. The skin is warm and moist,
the face is flushed, the hair is fine, and the nails are soft and
fragile. The patient may demonstrate increased sweating and
460 STOELTING’S ANESTHESIA AND CO-EXISTING DISEASE
complain of heat intolerance. The eyes exhibit a wide-eyed
stare, with retraction of the upper eyelids (exophthalmos or
proptosis) resulting from an infiltrative process that involves
retrobulbar fat and the eyelids. Wasting, weakness, and fatigue
of the proximal limb muscles are common. The patient usu-
ally complains of extreme fatigue but an inability to sleep.
Increased bone turnover and osteoporosis may occur. A fine
tremor of the hands and hyperactive tendon reflexes are com-
mon. Weight loss despite an increased appetite occurs second-
ary to increased calorigenesis. Bowel movements are frequent
and diarrhea is not uncommon.
The cardiovascular system is most threatened by hyper-
metabolism of peripheral tissues, increased cardiac work
with tachycardia, dysrhythmias (commonly atrial) and pal-
pitations, a hyperdynamic circulation, increased myocardial
contractility and cardiac output, and cardiomegaly. The car-
diac responses are due to the direct effects of T3 on the myo-
cardium and peripheral vasculature. Graves disease, or toxic
diffuse goiter, occurs in 0.4% of the US population and is the
leading cause of hyperthyroidism. The disease typically occurs
in females (female/male ratio is 7:1) between the ages of 20
and 40 years. Although the etiology is unknown, Graves dis-
ease appears to be a systemic autoimmune disease caused by
thyroid-stimulating antibodies that bind to TSH receptors in
the thyroid, activating adenylcyclase and stimulating thyroid
growth, vascularity, and hypersecretion of T4 and T3. The
thyroid is usually diffusely enlarged, becoming two to three
times its normal size. An ophthalmopathy occurs in 30% of
cases and may include upper lid retraction, a wide-eyed stare,
muscle weakness, proptosis, and an increase in intraocular
pressure. The diagnosis of Graves disease is confirmed by the
presence of thyroid-stimulating antibodies in the context of a
low TSH level and elevated T4 and T3 levels.
Toxic multinodular goiter usually arises from long-stand-
ing simple goiter and occurs mostly in patients older than
age 50. It may present with extreme thyroid enlargement
that can cause dysphagia, globus sensation, and possibly
inspiratory stridor from tracheal compression. The latter is
especially common when the mass extends into the thoracic
inlet behind the sternum. In severe cases, superior vena cava
obstruction syndrome may also be present. The diagnosis is
confirmed by a thyroid scan demonstrating “hot” patchy foci
throughout the gland or one or two “hot” nodules. Radio-
active iodine uptake and serum T4 and T3 levels may only
be slightly elevated. The goiter must be differentiated from
a neoplasm, and a computed tomography (CT) scan and
biopsy may be necessary.  ter and hypothyroidism. Long-term use of propranolol during
Treatment
The first line of treatment for hyperthyroidism is an antithy-
roid drug, either methimazole or propylthiouracil (PTU).
These agents interfere with the synthesis of thyroid hormones
by inhibiting organification and coupling. PTU has the added
advantage of inhibiting the peripheral conversion of T4 to T3.
A euthyroid state can almost always be achieved in 6–8 weeks
with either drug if a sufficient dosage is used.
Iodide in high concentrations inhibits release of hormones
from the hyperfunctioning gland. High concentrations of
iodide decrease all phases of thyroid synthesis and release
and result in reduced gland size and possibly a decrease in
vascularity. Its effects occur immediately but are short-lived.
Therefore iodide is usually reserved for preparing hyperthy-
roid patients for surgery, managing patients with actual or
impending thyroid storm, and treating patients with severe
thyrocardiac disease. There is no need to delay surgery in a
patient with otherwise well-controlled thyrotoxicosis in order
to initiate iodide therapy.
Iodide is administered orally as a saturated solution of potas-
sium iodide (SSKI), 3 drops PO every 8 hours for 10–14 days.
The radiographic contrast dye ipodate or iopanoic acid (0.5–3.0 g
every day) contains iodide and demonstrates beneficial effects
similar to those of inorganic iodide. In addition, ipodate inhib-
its the peripheral conversion of T4 to T3 and may also antago-
nize thyroid hormone binding to receptors. Antithyroid drug
therapy should precede initiation of iodide treatment, because
administration of iodide alone will increase thyroid hormone
stores and exacerbate the thyrotoxic state. Lithium carbonate
300 mg PO every 6 hours may be given in place of potassium
iodide or ipodate to patients who are allergic to iodide.
β-Adrenergic antagonists do not affect the underlying thyroid
abnormality but may relieve signs and symptoms of increased
adrenergic activity such as anxiety, sweating, heat intolerance,
tremors, and tachycardia. Propranolol offers the added features
of impairing the peripheral conversion of T4 to T3.
Ablative therapy with radioactive iodine 131 (131I) or surgery
is recommended for patients with Graves disease for whom
medical management has failed, as well as for patients with toxic
multinodular goiter or a toxic adenoma. The remission rate is
80%–98%. A major disadvantage of therapy is that 40%–70% of
treated patients become hypothyroid within 10 years.
Surgery (i.e., subtotal thyroidectomy or possibly total thy-
roidectomy) results in prompt control of disease and is asso-
ciated with a lower incidence of hypothyroidism (10%–30%)
than radioactive iodine therapy. Subtotal thyroidectomy cor-
rects thyrotoxicosis in over 95% of patients.
Hyperthyroidism during pregnancy is treated with low
dosages of antithyroid drugs. However, these drugs do cross
the placenta and can cause fetal hypothyroidism. If the mother
remains euthyroid while taking small dosages of an antithy-
roid drug, the occurrence of fetal hypothyroidism is rare.
Radioactive iodine treatment is contraindicated during preg-
nancy, as is oral iodide therapy, because it can cause fetal goi-
pregnancy is controversial, since intrauterine growth retarda-
tion has been attributed to its use. Thyroid storm occurring
in pregnancy is managed in the same way as in nonpregnant
patients. 
Management of Anesthesia
In hyperthyroid patients undergoing surgery, euthyroidism
should definitely be established preoperatively. In elective
cases this may mean waiting a substantial time (6–8 weeks)

for antithyroid drugs to become effective. In emergency cases
the use of an IV β-blocker, ipodate, glucocorticoids, and PTU
is usually necessary. No IV preparation of PTU is available,
so the drug must be taken orally, via a nasogastric tube, or
rectally. Glucocorticoids (dexamethasone 2 mg IV every
6 hours) should be administered to decrease hormone release
and reduce the peripheral conversion of T4 to T3.
Evaluation of the upper airway for evidence of tracheal
compression or deviation caused by a goiter is an important
part of the preoperative evaluation. Examination of chest
radiographs and CT scans is often helpful in this regard. Intra-
operatively the need for invasive monitoring is determined
on an individual basis and depends on the type of surgery
to be performed and the medical condition of the patient.
Controlled studies in hyperthyroid animals demonstrate no
clinically significant increase in anesthetic requirements (i.e.,
minimum alveolar concentration). Establishment of adequate
anesthetic depth is extremely important to avoid exaggerated
sympathetic nervous system responses. Drugs that stimulate
the sympathetic nervous system (i.e., ketamine, pancuronium,
atropine, ephedrine, epinephrine) should be avoided. Eye pro-
tection (eyedrops, lubricant, eye pads) is critical, especially for
patients with proptosis.
For maintenance of anesthesia, any of the potent inhala-
tion agents may be used. A concern in hyperthyroid patients
is organ toxicity secondary to an increase in drug metabolism.
Nitrous oxide and opioids are safe and effective in hyperthy-
roid patients. Hyperthyroid patients may have co-existing
muscle disease (e.g., myasthenia gravis) with reduced require-
ments for the nondepolarizing muscle relaxants; therefore
careful titration is required. For treatment of intraoperative
hypotension, a direct-acting vasopressor (phenylephrine)
is preferred. Ephedrine, epinephrine, norepinephrine, and
dopamine should be avoided or administered in extremely
low doses to prevent exaggerated hemodynamic responses.
Regional anesthesia can be safely performed and in fact may
be a preferred technique. Epinephrine-containing local anes-
thetic solutions should be avoided.
Removal of the thyrotoxic gland does not mean immedi-
ate resolution of thyrotoxicosis. The half-life of T4 is 7–8 days;
therefore β-blocker therapy may need to be continued in the
postoperative period.  Physically they demonstrate dry thickened skin, coarse facial
Thyroid Storm
Thyroid storm is a life-threatening exacerbation of hyperthy-
roidism precipitated by trauma, infection, medical illness, or
surgery. Thyroid storm and malignant hyperthermia can pres-
ent with similar intraoperative and postoperative signs and
symptoms (i.e., hyperpyrexia, tachycardia, hypermetabolism);
differentiation between the two may be extremely difficult.
Thyroid storm most often occurs in the postoperative
period in untreated or inadequately treated hyperthyroid
patients after emergency surgery. Patients manifest extreme
anxiety, fever, tachycardia, cardiovascular instability, and
altered consciousness. Treatment includes rapid alleviation
of thyrotoxicosis and general supportive care. Dehydration is
Chapter 23  Endocrine Disease 461
managed with IV administration of glucose-containing crys-
talloid solutions, and cooling measures (e.g., cooling blanket,
ice packs, administration of cool humidified oxygen) are used
to counter the fever. β-Blockers should be titrated to decrease
heart rate to less than 90 beats per minute. Dexamethasone
2 mg every 6 hours or cortisol 100–200 mg every 8 hours can
be used to decrease hormone release and conversion of T4 to
T3. Antithyroid drugs (PTU 200–400 mg every 8 hours) may be
administered through a nasogastric tube, orally, or rectally. If
circulatory shock is present, IV administration of a direct vaso-
pressor (phenylephrine) is indicated. A β-adrenergic blocker or
digitalis is recommended for atrial fibrillation accompanied by
a fast ventricular response. Serum thyroid hormone levels
generally return to normal within 24–48 hours, and recovery
occurs within 1 week. The mortality rate for thyroid storm
remains surprisingly high at approximately 20%. 
Hypothyroidism
Signs and Symptoms
Hypothyroidism, or myxedema, is a relatively common dis-
ease affecting 0.5%–0.8% of the adult population. Primary
hypothyroidism results in decreased production of thyroid
hormones despite adequate or increased levels of TSH and
accounts for 95% of all cases of hypothyroidism. The most
common cause in the United States is ablation of the gland by
radioactive iodine or surgery. The second most common type
of hypothyroidism is idiopathic and probably autoimmune in
origin, with autoantibodies blocking TSH receptors in the thy-
roid. Hashimoto thyroiditis is an autoimmune disorder char-
acterized by goitrous enlargement and hypothyroidism that
usually affects middle-aged women.
In adults, hypothyroidism has a slow, insidious, progressive
course. There is gradual slowing of mental and physical activ-
ity. In mild cases, patients tire easily and experience weight
gain. In moderate to severe cases, patients develop fatigue,
lethargy, apathy, and listlessness. Speech becomes slow and
the intellect becomes dull. With time, patients experience cold
intolerance, decreased sweating, constipation, menorrhagia,
and slowing of motor function secondary to muscle stiffness
and cramping. They gain weight despite a decrease in appetite.
features, dry brittle hair, a large tongue, a deep hoarse voice,
and periorbital and peripheral edema.
Physiologically, cardiac output is decreased secondary
to reductions in stroke volume and heart rate. Barorecep-
tor function is also impaired. The electrocardiogram (ECG)
in patients with overt hypothyroidism shows flattened or
inverted T waves, low-amplitude P waves and QRS complexes,
and sinus bradycardia; ventricular dysrhythmias may also be
present. Peripheral vascular resistance is increased and blood
volume is reduced, which results in pale, cool skin. Pericar-
dial effusions are common. Hypothyroid patients usually have
hypercholesterolemia and hypertriglyceridemia and may have
coronary artery disease. Hyponatremia and impairment of
free water excretion are also common, related to inappropriate
462 STOELTING’S ANESTHESIA AND CO-EXISTING DISEASE
secretion of antidiuretic hormone (ADH). Gastrointestinal
function is slow, and an adynamic ileus may occur. Deep ten-
don reflexes demonstrate a prolonged relaxation phase.
Twenty percent of women older than 60 years have subclin-
ical hypothyroidism. Subclinical disease is associated with an
increased risk of coronary heart disease in patients with a TSH
level above 10 milliunits/L. Even though changes are revers-
ible with l-thyroxine therapy, use of thyroid replacement for
subclinical disease remains controversial.
Secondary hypothyroidism is diagnosed by reduced levels
of FT4, T4, and T3, as well as a reduced TSH level. A TRH stim-
ulation test can confirm pituitary abnormality as the cause. In
primary hypothyroidism, basal levels of TSH are elevated, and
the elevation is exaggerated after TRH administration. With
pituitary dysfunction there is a blunted or absent response to
TRH.
Euthyroid sick syndrome is the occurrence of abnor-
mal results on thyroid function tests in critically ill patients
with significant nonthyroidal illness. Characteristic findings
include low levels of T3 and T4 and a normal TSH level. As
illness increases in severity, T3 and T4 levels decrease further.
The etiology of this response is not understood. Euthyroid sick
syndrome may be a physiologic response to stress, and it can
be induced by surgery. No treatment for thyroid function is
necessary. Differentiating hypothyroidism from euthyroid sick
syndrome can be extremely difficult. A serum TSH level is the
best aid. Levels higher than 10 milliunits/L indicate hypothy-
roidism, whereas levels lower than 5.0 milliunits/L indicate
euthyroidism.
Changes in thyroid function test results have also been doc-
umented following uncomplicated acute myocardial infarc-
tions, congestive heart failure, and cardiopulmonary bypass.
Significant depression of T3 levels occurs, but administration
of T3 does not appear efficacious. In addition, the use of T3 as
an inotrope has not been shown to result in any substantial
improvement in cardiac performance.  sion may require supplemental steroid administration.
Treatment
l-Thyroxine (levothyroxine sodium) is usually administered
for the treatment of hypothyroidism. The first evidence of a
therapeutic response to thyroid hormone is sodium and water
diuresis and a reduction in the TSH level. In patients with
hypothyroid cardiomyopathy, a measurable improvement in
myocardial function is often achieved with therapy.
Although angina is uncommon in hypothyroidism, it can
appear or worsen during treatment of the hypothyroid state
with thyroid hormone. Medical management of such patients
is particularly difficult.  a peak basal metabolic rate seen in 36–72 hours. l-Thyrox-
Management of Anesthesia
Hypothyroid patients may be at increased risk for a number
of reasons when undergoing either general or regional anes-
thesia. Airway compromise secondary to a swollen oral cavity,
edematous vocal cords, or goitrous enlargement may be pres-
ent. Decreased gastric emptying increases the risk of regurgi-
tation and aspiration. A hypodynamic cardiovascular system
characterized by decreased cardiac output, stroke volume,
heart rate, baroreceptor reflexes, and intravascular volume
may be compromised by surgical stress and cardiac-depres-
sant anesthetic agents. Decreased ventilatory responsiveness
to hypoxia and hypercarbia is enhanced by anesthetic agents.
Hypothermia occurs quickly and is difficult to treat. Hema-
tologic abnormalities such as anemia (25%–50% of patients)
and dysfunction of platelets and coagulation factors (espe-
cially factor VIII), electrolyte imbalances (hyponatremia),
and hypoglycemia are common and require close monitor-
ing intraoperatively. Decreased neuromuscular excitability is
exacerbated by anesthetic drugs.
These patients can be extremely sensitive to narcotics and
sedatives and may even be lethargic secondary to their disease;
therefore preoperative sedation should be undertaken with
caution. Hypothyroid patients also appear to have an increased
sensitivity to anesthetic drugs, although the effect of thyroid
activity on the minimum alveolar concentration of volatile
anesthetics is negligible. Increased sensitivity is probably sec-
ondary to reduced cardiac output, decreased blood volume,
abnormal baroreceptor function, decreased hepatic metabo-
lism, and decreased renal excretion of drugs. In patients with
a hypodynamic cardiovascular system, invasive monitoring
and/or transesophageal echocardiography may be needed to
monitor intravascular volume and cardiac status.
General anesthetics should be administered through an
endotracheal tube following either rapid-sequence induction
or awake intubation if a difficult airway is present. Hypothy-
roid patients are very sensitive to the myocardial-depressant
effects of the potent inhalational agents. Vasodilation in the
presence of possible hypovolemia and impaired barorecep-
tor activity can produce significant hypotension. Pharmaco-
logic support for intraoperative hypotension is best provided
with ephedrine, dopamine, or epinephrine and not a pure
α-adrenergic agonist (phenylephrine). Unresponsive hypoten-
Controlled ventilation is recommended in all cases, since
these patients tend to hypoventilate if allowed to breathe spon-
taneously. Dextrose in normal saline is the recommended IV
fluid to avoid hypoglycemia and minimize hyponatremia sec-
ondary to impaired free water clearance.
If emergency surgery is necessary, the potential for severe
intraoperative cardiovascular instability and myxedema coma
in the postoperative period is high. Intravenous thyroid
replacement therapy should be initiated as soon as possible.
Although IV l-thyroxine takes 10–12 days to yield a peak basal
metabolic rate, IV triiodothyronine is effective in 6 hours, with
ine 300–500 μg IV or l-triiodothyronine 25–50 μg IV is an
acceptable initial dose. Steroid coverage with hydrocortisone
or dexamethasone is necessary, since decreased adrenal corti-
cal function often accompanies hypothyroidism. Phosphodi-
esterase inhibitors such as milrinone may be effective in the
treatment of reduced myocardial contractility, because their
mechanism of action does not depend on β receptors, whose
number and sensitivity may be reduced in hypothyroidism. 

Myxedema Coma
Myxedema coma is a rare severe form of hypothyroidism
characterized by delirium or unconsciousness, hypoventila-
tion, hypothermia (80% of patients), bradycardia, hypoten-
sion, and a severe dilutional hyponatremia. It occurs most
commonly in elderly women with a long history of hypo-
thyroidism. Infection, trauma, cold, and central nervous
system (CNS) depressants predispose hypothyroid patients
to myxedema coma. Ironically most patients are not coma-
tose. Hypothermia (as low as 27°C) is a cardinal feature and
results from impaired thermoregulation caused by defec-
tive function of the hypothalamus (a target tissue of thyroid
hormone). Myxedema coma is a medical emergency with a
mortality rate higher than 50%. Intravenous l-thyroxine or
l-triiodothyronine is the treatment of choice. Intravenous
hydration with glucose-containing saline solutions, temper-
ature regulation, correction of electrolyte imbalances, and
stabilization of the cardiac and pulmonary systems are nec-
essary. Mechanical ventilation is frequently required. Heart
rate, blood pressure, and temperature usually improve within
24 hours, and a relative euthyroid state is achieved in 3–5
days. Hydrocortisone 100–300 mg/day IV is also prescribed
to treat possible adrenal insufficiency.  apy is recommended unless the altered histologic appearance
Goiter and Thyroid Tumors
A goiter is a swelling of the thyroid gland that results from
compensatory hypertrophy and hyperplasia of follicular epi-
thelium secondary to a reduction in thyroid hormone output.
The cause may be a deficient intake of iodine, ingestion of a
dietary (e.g., cassava) or pharmacologic (e.g., phenylbutazone,
lithium) goitrogen, or a defect in the hormonal biosynthetic
pathway. The size of the goiter is determined by the level and
duration of hormone insufficiency. In most cases a goiter is
associated with a euthyroid state, with the increased mass and
cellular activity eventually overcoming the impairment in
hormone synthesis. However, hypothyroidism or hyperthy-
roidism occurs in some cases. Patients with simple nontoxic
goiter are euthyroid. Nevertheless, simple nontoxic goiter is a
forerunner of toxic multinodular goiter. In the United States,
most cases of simple nontoxic goiter are of unknown cause
and are treated with l-thyroxine. Surgery is indicated only if
medical therapy is ineffective and the goiter is compromising
the airway or is cosmetically unacceptable.
Anesthetic management of a patient undergoing surgical
removal of a large goiter or thyroid mass that compromises the
airway presents a major challenge. Examination of a CT scan of
the neck will demonstrate anatomic abnormalities. Sedatives
and narcotics should be avoided or used with great caution
before and during endotracheal tube placement. Awake intu-
bation with an armored (anode) tube using fiberoptic bron-
choscopy is probably the safest method to assess the degree
of obstruction and establish the airway. Surgical removal of
the mass may reveal underlying tracheomalacia and a collaps-
ible airway. Tracheal extubation should be performed with as
much caution and concern as intubation.
Chapter 23  Endocrine Disease 463
If the mass extends into the substernal regional (i.e., ante-
rior mediastinal mass), superior vena cava obstruction, major
airway obstruction, and/or cardiac compression may occur.
The latter two may become apparent only upon induction of
general anesthesia. Airway obstruction appears to result from
changes in lung and chest wall mechanics that occur with
changes in patient position or with the onset of muscle paraly-
sis. During spontaneous respiration, the larger airways are
supported by negative intrathoracic pressure, and the effects of
extrinsic compression may be apparent in only the most severe
cases. With cessation of spontaneous respiration, compensa-
tory mechanisms are removed and airway obstruction occurs.
In addition, positive pressure ventilation may demonstrate
total airway occlusion. A preoperative history of dyspnea in
the upright or supine position is predictive of possible airway
obstruction during general anesthesia. A CT scan must be
examined to assess the extent of the tumor. Echocardiography
with the patient in the upright and supine positions can indi-
cate the degree of cardiac compression.
If practical, local anesthesia is recommended for patients
requiring surgery. If general anesthesia is necessary, preopera-
tive shrinkage of a thyroid tumor by radiation or chemother-
would prevent an accurate diagnosis, as when a biopsy speci-
men is required for diagnosis. Unfortunately, goiters are not
sensitive to radiation therapy. In such patients an awake intu-
bation with fiberoptic bronchoscopy using an anode tube is
recommended. The patient is placed in semi-Fowler posi-
tion, and volatile anesthetic with nitrous oxide and oxygen is
administered using spontaneous ventilation. Muscle relaxants
are avoided. It must be possible to change the patient’s position.
Following tumor resection the airway should be exam-
ined by fiberoptic bronchoscopy to detect tracheomalacia and
determine whether and when tracheal extubation is appropri-
ate. A rigid bronchoscope should be available to reestablish
the airway if collapse occurs. Cardiopulmonary bypass equip-
ment should be on standby during the case. 
Complications of Thyroid Surgery
Morbidity from thyroid surgery approaches 13%. Recur-
rent laryngeal nerve injury may be unilateral or bilateral and
temporary or permanent. The injury may result from excess
trauma to the nerve(s) (abductor and/or adductor fibers of
the recurrent laryngeal nerve), inadvertent ligation, or tran-
section. When paralysis of the abductor muscles to the vocal
cord occurs, the involved cord assumes a median or parame-
dian position. If trauma is unilateral, the patient experiences
hoarseness but no airway obstruction, and function usually
returns in 3–6 months. Ligation or transection of the nerve
results in permanent hoarseness. Bilateral involvement is more
serious, since the patient usually experiences airway obstruc-
tion and problems with coughing and respiratory toilet.
Depending on the degree of damage, a temporary or perma-
nent tracheostomy is usually necessary. Injury to the adductor
fibers of the recurrent laryngeal nerve(s) results in paralysis of
464 STOELTING’S ANESTHESIA AND CO-EXISTING DISEASE
the adductor muscle(s) and increases the risk of pulmonary
aspiration. Injury to the motor branch of the superior laryn-
geal nerve, which innervates the inferior pharyngeal constric-
tor and cricothyroid muscles, can also occur during thyroid
dissection. This injury results in weakening of the voice and
inability to create high tones.
Hypoparathyroidism is also a complication of thyroid sur-
gery. It usually results from damage to the blood supply of
the parathyroid glands rather than inadvertent removal. One
functioning parathyroid gland with an adequate blood sup-
ply is all that is necessary to avoid hypoparathyroidism. The
signs and symptoms of hypocalcemia occur in the first 24–48
hours postoperatively. Anxiety, circumoral numbness, tingling
of the fingertips, muscle cramping, and positive Chvostek and
Trousseau signs are indicative of hypocalcemia. Stridor can
occur and can proceed to laryngospasm. Immediate treatment
with IV calcium gluconate (1 g, 10 mL of a 10% solution) or
calcium chloride (1 g, 10 mL of a 10% solution) is necessary. A
continuous infusion of calcium for several days is also recom-
mended. For long-term management, oral calcium and vita-
min D3 are prescribed, or autotransplantation of parathyroid
tissue may be performed.
Tracheal compression from an expanding hematoma may
cause rapid respiratory compromise in the period immedi-
ately after thyroid surgery. Immediate hematoma evacuation
is the first line of treatment. If time permits, the patient should
be returned to the operating room. If necessary, the wound
should be opened at the bedside, clots evacuated, and bleed-
ing vessels secured to relieve airway obstruction. A thyroid
tray including a tracheostomy set should always be available
at the bedside during the postoperative period so that sutures
or clips can be removed and the wound opened emergently.  mon finding and is considered to be secondary to hypovole-
PHEOCHROMOCYTOMA
Pheochromocytomas are catecholamine-secreting tumors that
arise from chromaffin cells of the sympathoadrenal system.
Although pheochromocytomas account for fewer than 0.1%
of all cases of hypertension in adults, their detection is impera-
tive, since they have lethal potential and are one of the few
truly curable forms of hypertension. Uncontrolled catechol-
amine release can result in malignant hypertension, cerebro-
vascular accident, and myocardial infarction.
The precise cause of a pheochromocytoma is unknown.
Pheochromocytomas are usually an isolated finding (90% of
cases); 10% are inherited (familial) as an autosomal dominant
trait. Familial pheochromocytomas usually occur as bilateral
adrenal tumors or as extraadrenal tumors that appear in the
same anatomic site over successive generations. Both sexes
are equally affected, and the peak incidence is in the third to
fifth decades of life. Familial pheochromocytomas can also be
part of the MEN syndromes and can occur in association with
several neuroectodermal dysplasias (e.g., von Hippel-Lindau
syndrome). Patients with MEN IIA have a pheochromocy-
toma, medullary carcinoma of the thyroid, and hyperparathy-
roidism. Patients with MEN IIB have a pheochromocytoma,
medullary carcinoma of the thyroid, alimentary tract ganglio-
neuromatosis, thickened corneal nerves, and a marfanoid hab-
itus. Almost 100% of patients with MEN II have or will develop
bilateral benign adrenal medullary pheochromocytomas.
Eighty percent of pheochromocytomas are located in the
adrenal medulla. The organ of Zuckerkandl near the aortic
bifurcation is the most common extraadrenal site. Two per-
cent of extraadrenal pheochromocytomas occur in the neck
and thorax. Most extraadrenal pheochromocytomas follow
a benign course. Malignant pheochromocytomas usually
spread via venous and lymphatic channels, with a predilection
for liver and bone. The 5-year survival rate for patients with
malignancy is 44%. Following resection of benign tumors,
5%–10% of patients have a benign recurrence.
Most pheochromocytomas secrete norepinephrine, either
alone or, more commonly, in combination with a smaller
amount of epinephrine in a ratio of 85:15—the inverse of the
secretion ratio in the normal adrenal gland. Approximately
15% of tumors secrete predominantly epinephrine.
Signs and Symptoms
The clinical presentation of pheochromocytoma is variable;
attacks range from infrequent (i.e., once a month or fewer) to
numerous (i.e., many times per day) and may last from less
than a minute to several hours. They may occur spontane-
ously or be precipitated by physical injury, emotional stress, or
medications. Hypertension, either continuous or paroxysmal,
is the most frequent manifestation of pheochromocytoma.
Headache, sweating, pallor, and palpitations are other classic
signs and symptoms. Orthostatic hypotension is also a com-
mia and impaired vasoconstrictor reflex responses.
Hemodynamic signs depend on the predominant catechol-
amine secreted. With norepinephrine, α-adrenergic effects
predominate and patients usually have systolic and diastolic
hypertension and a reflex bradycardia. With epinephrine,
β-adrenergic effects predominate and patients usually have
systolic hypertension, diastolic hypotension, and tachycardia.
Despite the 10-fold higher levels of circulating catecholamines,
the hemodynamics are not greatly different in patients with
pheochromocytomas and those with essential hypertension.
Cardiomyopathy is a complication of pheochromocytoma.
In addition, high catecholamine levels result in coronary vaso-
constriction through α-adrenergic pathways, which reduces
coronary blood flow and potentially creates ischemia. Dilated
and hypertrophic cardiomyopathies as well as left ventricu-
lar outflow tract obstruction have been demonstrated echo-
cardiographically. ECG abnormalities may include elevation
or depression of the ST segment, flattening or inversion of
T waves, prolongation of the QT interval, high or peaked P
waves, left axis deviation, and dysrhythmias. The cardiomy-
opathy appears reversible if catecholamine stimulation is
removed early before fibrosis has occurred. Pheochromocy-
toma patients may also develop cardiac hypertrophy with con-
gestive heart failure secondary to sustained hypertension.

Although pheochromocytoma patients rarely have primary
diabetes, most have an elevated blood glucose level secondary
to catecholamine stimulation of glycogenolysis and inhibition
of insulin release.  Adrenal +
Diagnosis
When a pheochromocytoma is clinically suspected, excess
catecholamine secretion must be demonstrated. For patients
with a low probability of having a pheochromocytoma, a
24-hour urine collection for measurement of metanephrines
and catecholamines is a useful screening test. However, the
most sensitive test for patients at high risk (familial pheochro-
mocytoma or classic symptoms) is measurement of plasma
free metanephrines. Catecholamines are metabolized to free
metanephrines within tumor cells, and these metabolites
are continuously released into the circulation. A plasma free
normetanephrine level higher than 400 pg/mL and/or a meta-
nephrine level higher than 220 pg/mL confirms the diagnosis
of pheochromocytoma. A pheochromocytoma is excluded
if the normetanephrine level is less than 112 pg/mL and the
metanephrine level is less than 61 pg/mL.
Results are equivocal in 5%–10% of patients, and in these
cases the clonidine suppression test may be used. In patients
with a pheochromocytoma, increased plasma catecholamines
result from tumor release that bypasses normal storage and
release mechanisms. Clonidine acts to lower plasma cat-
echolamine levels in patients without a pheochromocytoma
but has no effect on catecholamine levels in patients with a
pheochromocytoma.
In the past, provocative testing with histamine or tyramine
was used to elicit excess catecholamine release from the tumor.
However, owing to the relatively high incidence of morbidity,
these tests have been abandoned. A glucagon stimulation test
is now considered to be the safest and most specific provoca-
tive test. Glucagon acts directly on the tumor to induce release
of catecholamines. A positive response to the test yields a
plasma catecholamine increase of at least three times the base-
line values or more than 2000 pg/mL within 1–3 minutes of
glucagon administration. This test should be performed only
in patients with a diastolic blood pressure below 100 mm Hg.
Tumor location can be predicted by the pattern of catechol-
amine production (Table 23.7). CT detects more than 95% of
adrenal masses larger than 1 cm in diameter. Magnetic resonance
imaging (MRI) offers advantages over CT, including better iden-
tification of small adrenal lesions, better differentiation of various
types of adrenal lesions, no need for IV contrast, and lack of radi-
ation exposure. Positron emission scanning and selective venous
catheterization with sampling of catecholamines from the adrenal
veins and other sites are additional useful tests.  leading to vasoconstriction and hypertensive crises. The degree
Management of Anesthesia
Preoperative Management
Since most pheochromocytomas secrete predominantly nor-
epinephrine, medical therapy has depended on α-blockade to
Chapter 23  Endocrine Disease 465
TABLE 23.7   Pattern of Catecholamine Production by
Site of Pheochromocytoma
  
Adrenal Extraadrenal Extraadrenal
Norepinephrine 61% 31% 8%
Epinephrine 100% — —
Norepinephrine + 95% — 5%
epinephrine
Adapted from Kaser H. Clinical and diagnostic findings in patients with chromaffin
tumors: pheochromocytomas, pheochromoblastomas. Recent Results Cancer
Res. 1990;118:97-105.
lower blood pressure, increase intravascular volume, prevent
paroxysmal hypertensive episodes, allow resensitization of
adrenergic receptors, and decrease myocardial dysfunction.
Although a significantly reduced intravascular volume may
accompany a pheochromocytoma, the majority of patients
have a normal or only slightly decreased intravascular volume.
α-Blockade appears to protect myocardial performance and
tissue oxygenation from the adverse effects of catecholamines.
Phenoxybenzamine is the most frequently prescribed
α-blocker for preoperative use. It is a noncompetitive α1-
antagonist with some α2-blocking properties. Because it is a
noncompetitive blocker, it is difficult for excess catecholamines
to overcome the blockade. Its long duration of action permits
oral dosing only twice daily. The goal of therapy is normoten-
sion, resolution of symptoms, elimination of ST-segment and
T-wave changes on the ECG, and elimination of dysrhythmias.
Overtreatment can result in severe orthostatic hypotension.
The optimal duration of α-blockade therapy is undetermined
and may range from 3 days to 2 weeks or longer. Because of
the prolonged effect of phenoxybenzamine on α receptors, the
recommendation has been to discontinue its use 24–48 hours
before surgery to avoid vascular unresponsiveness immedi-
ately following removal of the tumor. Some anesthesiologists
administer only one-half to two-thirds of the morning dose
preceding surgery to address similar concerns. Some surgeons
request its discontinuation 48 hours preoperatively so they can
use hypertensive episodes intraoperatively as cues in local-
izing areas of metastasis. Prazosin and doxazosin, pure α1-
competitive blockers, are alternatives to phenoxybenzamine.
They are shorter acting, cause less tachycardia, and are easier
to titrate to a desired end point than phenoxybenzamine.
If tachycardia (i.e., heart rates > 120 beats per minute) or other
dysrhythmias result after α-blockade with phenoxybenzamine,
a β-adrenergic blocker is prescribed. A nonselective β-blocker
should never be administered before α-blockade, because block-
ade of vasodilatory β2-receptors results in unopposed α-agonism,
of α- and β-blockade provided by labetalol (i.e., β effects exceed
α effects) may not be appropriate for certain pheochromocytoma
patients. In very rare circumstances, β-blockade may be initiated
before α-blockade. A patient with a pheochromocytoma secret-
ing solely epinephrine and with coronary artery disease may
benefit greatly from the β1-selective antagonist esmolol.
466 STOELTING’S ANESTHESIA AND CO-EXISTING DISEASE
α-Methylparatyrosine (metyrosine) inhibits the rate-lim-
iting enzyme tyrosine hydroxylase of the catecholamine syn-
thetic pathway and may decrease catecholamine production
by 50%–80%. In combination with phenoxybenzamine, it has
been shown to facilitate intraoperative hemodynamic man-
agement. It is especially useful for malignant and inoperable
tumors. Side effects that include extrapyramidal reactions and
crystalluria have limited its application.
Calcium channel blockers and ACE inhibitors may also
be used to control hypertension. Calcium is a trigger for cat-
echolamine release from the tumor, and excess calcium entry
into myocardial cells contributes to a catecholamine-mediated
cardiomyopathy. Nifedipine, diltiazem, and verapamil have all
been used to control preoperative hypertension, as has capto-
pril. An α1-blocker plus a calcium channel blocker is an effec-
tive combination in treatment-resistant cases.  Magnesium sulfate inhibits release of catecholamines from the
Intraoperative Management
Optimal preparation for pheochromocytoma resection
involves preoperative administration of an α-adrenergic
blocker with or without a β-blocker with or without
α-methylparatyrosine, as well as correction of possible hypo-
volemia. Intraoperative goals include avoidance of drugs or
maneuvers that may provoke catecholamine release or poten-
tiate catecholamine actions, and maintenance of cardiovascu-
lar stability, preferably with short-acting drugs. Hypertension
frequently occurs during pneumoperitoneum, as well as dur-
ing tumor manipulation. On the other hand, significant hypo-
tension may develop following ligation of the tumor’s venous
drainage. Intraoperative monitoring should include standard
plus invasive monitoring methods. An arterial catheter enables
monitoring of blood pressure on a beat-to-beat basis. A cen-
tral venous pressure catheter is usually sufficient for patients
without cardiac symptoms or other clinical evidence of cardiac
involvement. A pulmonary artery catheter or transesophageal
echocardiography may be necessary to manage the large fluid
requirements, major volume shifts, and possible underlying
myocardial dysfunction in patients with very active tumors.
A large positive fluid balance is usually required to manage
hypotension and keep intravascular volumes within a normal
range.
Intraoperative ultrasonography can be used to localize
small functional tumors and perform adrenal-sparing proce-
dures or partial adrenalectomies. Adrenal-sparing procedures
are particularly valuable when bilateral adrenal pheochro-
mocytomas must be removed. Laparoscopy can be used for
tumors smaller than 4–5 cm and is becoming the surgical
approach of choice for many endocrine surgeons.
Factors that stimulate catecholamine release (e.g., fear,
stress, pain, shivering, hypoxia, hypercarbia) must be mini-
mized in the perioperative period. Although all anesthetic
drugs have been used with some degree of success, certain
drugs should theoretically be avoided to prevent possible
adverse hemodynamic responses. Morphine and atracurium
can cause histamine release, which may provoke release of
catecholamines from the tumor. Atropine, pancuronium, and
succinylcholine are examples of vagolytic or sympathomimetic
drugs that may stimulate the sympathetic nervous system.
Virtually all patients exhibit increases in systolic arterial
pressure in excess of 200 mm Hg for periods of time intraop-
eratively, irrespective of preoperative initiation of α-blockade.
A number of antihypertensive drugs must be prepared and
ready for immediate administration. Sodium nitroprusside (if
available), a direct vasodilator, is the agent of choice because
of its potency, immediate onset of action, and short duration
of action. Phentolamine, a competitive α-adrenergic blocker
and direct vasodilator, is effective, although tachyphylaxis and
tachycardia are associated with its use. Nitroglycerin is effec-
tive, but large doses are often required and may cause tachy-
cardia. Labetalol, with more β- than α-blocking properties, is
preferred for predominantly epinephrine-secreting tumors.
adrenal medulla and peripheral nerve terminals, reduces sen-
sitivity of α receptors to catecholamines, is a direct vasodilator,
and is an antidysrhythmic. However, like all antihypertensive
medications, it is suboptimal in controlling hypertension dur-
ing tumor manipulation. Mixtures of antihypertensive drugs
such as nitroprusside (if available), esmolol, diltiazem, and
phentolamine have been recommended to control refractory
hypertension. Increasing the depth of anesthesia is also an
option, although this approach may accentuate the hypoten-
sion accompanying tumor vein ligation.
Dysrhythmias are usually ventricular in origin and are man-
aged with either lidocaine or β-blockers. Lidocaine is short
acting and has minimal negative inotropic action. Although
propranolol has been widely used, esmolol, a selective β1-
blocker, offers several advantages. Esmolol has a rapid onset
and is short acting, which allows adequate control of heart rate;
it may also provide protection against catecholamine-induced
ischemia and development of postoperative hypoglycemia.
Amiodarone, an antidysrhythmic agent that prolongs the dura-
tion of the action potential of atrial and ventricular muscle, has
been used as an alternative to β-blockers to treat supraventricu-
lar tachycardia associated with hypercatecholaminemia.
Hypotension following tumor vein ligation is usually sig-
nificant and occurs secondary to a combination of factors,
including an immediate decrease in plasma catecholamine
levels (half-lives of norepinephrine and epinephrine are ≈1–2
minutes), vasodilation from residual α-blockade with phenoxy-
benzamine, intraoperative fluid and blood loss, and increased
anesthetic depth. Hypotension with systolic pressures in the
range of 70–79 mm Hg is not infrequent. To prevent precipi-
tous hypotension, volume expansion should be attained before
tumor vein ligation. Lactated Ringer solution and physiologic
saline are the recommended fluids for use before tumor removal.
Vasopressors and inotropes should be viewed as a secondary
treatment modality. Residual α-adrenergic blockade and down-
regulation of receptors make patients relatively less responsive
to vasopressors. Intraoperative administration of blood salvage
products has resulted in postresection hypertension second-
ary to the catecholamine content of the blood. A decrease in
anesthetic depth will also aid in controlling hypotension. With a

decrease in plasma catecholamine levels immediately following
resection, insulin levels increase and hypoglycemia may occur.
Therefore dextrose-containing solutions should be added after
tumor removal. Glucocorticoid therapy should be administered
if a bilateral adrenalectomy is performed or if hypoadrenalism
is a possibility.  does not eliminate this response. Increases in ACTH begin
Postoperative Management
The majority of patients become normotensive following com-
plete tumor resection. However, plasma catecholamine levels
do not return to normal until 7–10 days after surgery because
of a slow release of stored catecholamines from peripheral
nerves. Fifty percent of patients are hypertensive for several
days after surgery, and 25%–30% remain hypertensive indefi-
nitely. In these patients, hypertension is sustained rather than
paroxysmal, lower than before surgery, and not accompanied
by the classic features of hypercatecholaminemia. The differ-
ential diagnosis of persistent hypertension includes a missed
pheochromocytoma, surgical complications with subsequent
renal ischemia, and underlying essential hypertension.
Hypotension is the most frequent cause of death in the
period immediately after surgery. Large volumes of fluid are
necessary, since the peripheral vasculature is poorly respon-
sive to reduced levels of catecholamines. Vasopressors are a
secondary consideration. Steroid supplementation may be
necessary if hypoadrenalism is present. Dextrose-containing
solutions should be included as part of the fluid therapy, and
plasma glucose levels should be monitored for 24 hours.  ing syndrome have a primary adrenal (autonomous release of
ADRENAL GLAND DYSFUNCTION
Each adrenal gland consists of two components, the adrenal
cortex and the adrenal medulla. The adrenal cortex is respon-
sible for synthesis of three groups of hormones, classified as glu-
cocorticoids, mineralocorticoids (aldosterone), and androgens.
Corticotropin (ACTH) is secreted by the anterior pituitary gland
in response to corticotropin-releasing hormone (CRH), which
is synthesized in the hypothalamus and carried to the anterior
pituitary in the portal blood. ACTH stimulates the adrenal cor-
tex to produce cortisol. Maintenance of systemic blood pressure
by cortisol reflects the importance of this hormone in facilitat-
ing conversion of norepinephrine to epinephrine in the adre-
nal medulla. Hyperglycemia in response to cortisol secretion
reflects gluconeogenesis and inhibition of the peripheral use of
glucose by cells. Retention of sodium and excretion of potas-
sium are facilitated by cortisol. The antiinflammatory effects of
cortisol and other glucocorticoids (cortisone, prednisone, meth-
ylprednisolone, dexamethasone, triamcinolone) are particularly
apparent in the presence of high serum concentrations of these
hormones. Aldosterone secretion is regulated by the renin-
angiotensin system and serum concentrations of potassium.
The adrenal medulla is a specialized part of the sympathetic
nervous system that is capable of synthesizing norepinephrine
and epinephrine. The only important disease process associ-
ated with the adrenal medulla is pheochromocytoma. Adrenal
medullary insufficiency is not known to occur.
Chapter 23  Endocrine Disease 467
Surgery is one of the most potent and best-studied activa-
tors of the hypothalamic-pituitary-adrenal (HPA) axis. The
degree of activation of the axis depends on the magnitude
and duration of surgery and the type and depth of anesthe-
sia. Deep general anesthesia or regional anesthesia blunts but
with surgical incision and remain elevated during surgery,
with the peak level occurring with pharmacologic reversal of
muscle relaxants and extubation of the patient at the end of the
procedure. Hormone levels remain elevated for several days
postoperatively.
Hypercortisolism (Cushing Syndrome)
Cushing syndrome results from chronic exposure to excess
glucocorticoids. The disorder may be ACTH dependent,
ACTH independent, or iatrogenic. ACTH-dependent eti-
ologies include pituitary corticotrope adenomas (known as
Cushing disease) and ectopic secretion of ACTH from nonpi-
tuitary tumors (predominantly carcinoid tumors, especially
lung). ACTH-independent etiologies include adrenocortical
adenomas and carcinomas or adrenal hyperplasia. Medical
use of glucocorticoids for immunosuppression or treatment of
inflammatory disorders represents the iatrogenic cause. Medi-
cal use of glucocorticoids aside, the majority of patients with
Cushing syndrome have an ACTH-producing corticotrope
adenoma of the pituitary. Only 10% of patients with Cush-
cortisol) cause of their disease. Cushing syndrome generally
occurs in the third or fourth decade of life. On clinical presen-
tation, patients demonstrate an upregulation of gluconeogen-
esis, lipolysis, and protein catabolism. They also demonstrate
signs of mineralocorticoid excess. Signs and symptoms include
obesity (central adiposity), hyperglycemia (overt diabetes in
<20%), diastolic hypertension, hirsutism, amenorrhea, osteo-
porosis, and emotional liability and depression, with unique/
specific features of fragile skin, easy bruising, broad purple
striae, and signs of proximal myopathy with thin extremities.
Diagnosis is made by first excluding exogenous glucocorti-
coid use and demonstrating an elevated 24-hour urinary free
cortisol level. Patients also demonstrate a failure to suppress
morning cortisol after overnight exposure to dexamethasone,
and loss of diurnal cortisol secretion with high levels at mid-
night. A plasma ACTH level follows; if normal or elevated,
the patient has ACTH-dependent Cushing syndrome. Further
testing will include a pituitary MRI, chest CT, corticotropin-
releasing hormone (CRH) test, and high-dose dexamethasone
test. These patients demonstrate a decrease in cortisol and
17-hydroxycorticosteroid levels after high-dose dexametha-
sone because the pituitary tumor retains some negative feed-
back control, which adrenal tumors do not possess. A low
ACTH level confirms the diagnosis of ACTH-independent
Cushing syndrome, and a CT scan of the adrenal glands is
performed.
Treatment for Cushing disease requires removal of
the pituitary corticotrope tumor via a transsphenoidal
468 STOELTING’S ANESTHESIA AND CO-EXISTING DISEASE
hypophysectomy. Treatment for ACTH-independent disease
requires removal of the adrenal tumor. Preoperative medical
control of excess cortisol includes metyrapone (which inhib-
its cortisol synthesis), ketoconazole (which inhibits steroido-
genesis), mitotane (which is an adrenolytic agent and reduces
cortisol), and a low-dose IV infusion of etomidate. A hydro-
cortisone replacement regimen is initiated at the time of sur-
gery and slowly tapered postoperatively.
There are no specific anesthetic techniques or medications
recommended for these cases. Muscle relaxants should be
used cautiously when significant skeletal muscle weakness is
present. Perioperative management of hypertension, hyper-
glycemia, intravascular fluid volume (usually elevated), and
electrolytes (hypokalemia is common) is extremely impor-
tant. Preoperative diuresis with spironolactone is helpful.
The patient’s cardiac reserve dictates the use of intraoperative
invasive monitoring. A pneumothorax is possible during adre-
nal surgery. Careful positioning is necessary for osteopenic
patients. If bilateral adrenalectomy is performed, fludrocorti-
sone will be necessary in the postoperative period (usually day
3–5) to provide mineralocorticoid activity. Delayed wound
healing and increased susceptibility to infection can result
from increased levels of glucocorticoids.  ism includes liberal sodium intake and daily administration
Primary Hyperaldosteronism (Conn Syndrome)
Primary hyperaldosteronism, or Conn syndrome, is the most
common cause of mineralocorticoid (aldosterone) excess.
Bilateral micronodular adrenal hyperplasia is a more com-
mon cause (60%) than unilateral adrenal adenoma (40%).
Rarely, adrenocortical carcinoma is responsible. Hypokalemic
hypertension is the common presentation. Clinical features
include sodium retention, potassium depletion, hydrogen
depletion with metabolic alkalosis, and cardiac remodeling.
Muscle weakness and cramps occur secondary to hypokale-
mia. The diagnosis is made by demonstrating an elevated level
of plasma aldosterone and low plasma renin (renin secretion
is inhibited by the high aldosterone levels). A specific aldoste-
rone-renin ratio (ARR) confirms the diagnosis. Localization
studies include adrenal CT and MRI and adrenal vein sam-
pling. A unilateral adrenal lesion is treated surgically. Bilat-
eral adrenal hyperplasia is managed with spironolactone and
eplerenone (competitive aldosterone antagonist) or amiloride.
An adrenocortical carcinoma (ACC) is rare, highly malignant,
requires staging, and carries a poor prognosis. With success-
ful surgical removal, adjuvant treatment with mitotane is
necessary.
Anesthetic management requires preoperative restoration of
intravascular volume, electrolyte levels, renal function, and con-
trol of hypertension. Restricting sodium intake and administer-
ing spironolactone (an aldosterone antagonist) and potassium
(significant total deficit) are necessary. A preoperative echo-
cardiogram will determine the effects of long-standing hyper-
tension. Excess preoperative diuresis may render the patient
hypovolemic. No specific anesthetic technique or medications
are recommended for these cases. An arterial line should be
used, and other invasive monitors should be determined on a
case-by-case basis. Patients with Conn syndrome have a high
incidence of ischemic heart disease. Surgical excision of a soli-
tary adrenal adenoma should not require exogenous cortisol
administration, but bilateral manipulation of the adrenal glands
to excise multiple functional tumors may require supplemental
cortisol if transient hypocortisolism is a consideration. 
Hypoaldosteronism
Hyperkalemia in the absence of renal insufficiency suggests the
presence of hypoaldosteronism. Hyperchloremic metabolic
acidosis is a predictable finding in the presence of hypoaldo-
steronism. Heart block secondary to hyperkalemia, orthostatic
hypotension, and hyponatremia may also be present.
Isolated deficiency of aldosterone secretion may reflect
congenital deficiency of aldosterone synthetase or hyporenin-
emia, resulting from defects in the juxtaglomerular apparatus,
or treatment with ACE inhibitors, leading to loss of angioten-
sin stimulation. Hyporeninemic hypoaldosteronism typically
occurs in patients older than age 45 with chronic renal dis-
ease and/or diabetes mellitus. Treatment of hypoaldosteron-
of fludrocortisone. 
Adrenal Insufficiency
Signs and Symptoms
There are two types of adrenal insufficiency (AI): primary and
secondary. In primary disease (Addison’s disease) the adrenal
glands are unable to elaborate sufficient quantities of gluco-
corticoid, mineralocorticoid, and androgen hormones. The
most common cause of this rare endocrinopathy is bilateral
adrenal destruction from autoimmune disease. More than
90% of the glands must be involved before signs of AI appear.
The insidious onset of Addison’s disease is characterized by
fatigue, weakness, anorexia, nausea and vomiting, cutaneous
and mucosal hyperpigmentation, hypovolemia, hyponatre-
mia, and hyperkalemia. Secondary AI results from a failure
in production of CRH or ACTH caused by hypothalamic-
pituitary disease or suppression of the hypothalamic-pituitary
axis. Unlike in Addison’s disease, there is only a glucocorticoid
deficiency in secondary disease. In the majority of cases the
cause is iatrogenic, such as pituitary surgery, pituitary irradia-
tion, or most commonly the use of synthetic glucocorticoids.
These patients lack cutaneous hyperpigmentation and may
demonstrate only mild electrolyte abnormalities.
Cortisol is one of the few hormones essential for life. It par-
ticipates in carbohydrate and protein metabolism, fatty acid
mobilization, electrolyte and water balance, and the antiin-
flammatory response. It facilitates catecholamine synthesis
and action; modulates β-receptor synthesis, regulation, cou-
pling, and responsiveness; and contributes to normal vascular
permeability, tone, and cardiac contractility. Cortisol accounts
for 95% of the adrenal gland’s glucocorticoid activity, with cor-
ticosterone and cortisone contributing some activity. 
 Chapter 23  Endocrine Disease 469

TABLE 23.8   Glucocorticoid Preparations

  
Potency
Steroid Antiinflammatory (Glucocorticoid) Na+ Retention (Mineralocorticoid) Equivalent Dose (Oral or IV, mg)
SHORT ACTING
Cortisol (hydrocortisone) 1 1 20
Cortisone 0.8 0.8 25

INTERMEDIATE ACTING
Prednisone 4 0.8 5
Prednisolone 4 0.8 5
Methylprednisolone 5 0.5 4
Triamcinolone 5 0 4

LONG ACTING
Dexamethasone 30–40 0 0.75

Adapted from Stoelting RK, Dierdorf SF. Endocrine disease. In: Stoelting RK, ed. Anesthesia and Co-Existing Disease. New York, NY: Churchill Livingstone; 1993:358.
IV, Intravenous.

Diagnosis
The classic definition of AI includes a baseline plasma corti- TABLE 23.9   Perioperative Steroid (Hydrocortisone)
Supplementation
sol concentration of less than 20 μg/dL and a cortisol level of   
less than 20 μg/dL after ACTH stimulation. The short 250-μg Superficial surgery None
ACTH stimulation test is a reliable test of the integrity of the (e.g., dental surgery, biopsy)
entire HPA axis. All steroids except dexamethasone must be Minor surgery 25 mg IV
(e.g., inguinal hernia repair)
discontinued for 24 hours before testing. A normal ACTH
Moderate surgery (e.g., 50–75 mg IV, taper 1–2
stimulation test result is a plasma cortisol level greater than 25 cholecystectomy, colon resection) days
μg/dL. A positive test finding demonstrates a poor response Major surgery (e.g., cardiovascular 100–150 mg IV, taper 1–2
to ACTH and indicates an impairment of the adrenal cortex. surgery, Whipple procedure) days
Absolute AI is characterized by a low baseline cortisol level Intensive care unit 50–100 mg q6–8h for 2
(e.g., sepsis, shock) days to 1 week, fol-
and a positive result on the ACTH stimulation test. Relative AI
lowed by slow taper
is indicated when the baseline cortisol level is higher, but the
result on the ACTH stimulation test is positive.  IV, Intravenous.

Treatment
The most common cause of AI is exogenous steroids (Table
23.8). Those who take steroids long term may exhibit signs
and symptoms of AI during periods of stress, such as sur-
gery or acute illness. For patients with a history of long-term
steroid use, it may take 6–12 months from the time of dis-
continuation of the steroids for the adrenal glands to recover
full function. Recovery from short courses of steroids may
take several days. Preoperative glucocorticoid coverage
should be provided for patients with a positive result on the
ACTH stimulation test, Cushing syndrome, or AI, as well
as for those at risk of HPA axis suppression or AI based on
prior glucocorticoid therapy. Adrenal suppression is much
more common than AI and is of concern because overt AI,
although uncommon, may occur under the stressful condi-
tions of surgery and anesthesia. Patients taking prednisone
in dosages of less than 5 mg/day (morning dose) for any
length of time, even years, do not demonstrate clinically
significant HPA axis suppression and do not require periop-
erative supplementation, although they should receive their
normal daily steroid dose. Any patient who received a gluco-
corticoid in dosages equivalent to more than 20 mg/day of
prednisone for more than 3 weeks within the previous year is
at risk of AI and should receive perioperative supplementa-
tion. Patients receiving dosages of steroids between these two
extremes may have HPA axis suppression and should prob-
ably receive supplementation. Similarly, patients receiving
more than 2 g/day of topical steroids or more than 0.8 mg/
day of inhaled steroids on a long-term basis should probably
receive supplementation.
Patients with known or suspected adrenal suppression or
AI should receive their baseline steroid therapy plus supple-
mentation in the perioperative period. Supplementation is
individualized based on the surgery (Table 23.9). When more
than 100 mg/day of hydrocortisone is administered, it may be
wise to consider substituting methylprednisolone for hydro-
cortisone; given its lower mineralocorticoid activity, it is less
likely to cause fluid retention, edema, and hypokalemia. 
Management of Anesthesia
Acute AI should be considered in the differential diagnosis of
hemodynamic instability, especially in patients unresponsive
to the usual therapeutic interventions. Therapy includes treat-
ment of the cause, repletion of circulating glucocorticoids,
470 STOELTING’S ANESTHESIA AND CO-EXISTING DISEASE
and replacement of water and sodium deficits. Glucocorticoid
replacement may include IV hydrocortisone, methylpredniso-
lone, or dexamethasone. A bolus of 100 mg of hydrocortisone
followed by a continuous infusion at 10 mg/h is a recom-
mended prescription. A 100-mg bolus of hydrocortisone
every 6 hours is also an acceptable option. When the patient’s
condition stabilizes, the steroid dosage is reduced, with even-
tual conversion to an oral preparation. Volume deficits may
be substantial (2–3 L), and 5% dextrose in normal saline is
the replacement fluid of choice. Hemodynamic support with
vasopressors may be necessary. Metabolic acidosis and hyper-
kalemia usually resolve with fluid and steroid administration.
In primary disease, administration of the mineralocorticoid
fludrocortisone is not necessary acutely because isotonic
saline replaces sodium loss.
No specific anesthetic agent(s) and/or technique(s) are
recommended in managing patients with or at risk of AI.
However, etomidate transiently inhibits cortisol synthesis
and should be avoided in this patient population. Patients
with untreated AI undergoing emergency surgery should be
managed aggressively with invasive monitoring, IV corticoste-
roids, and fluid and electrolyte resuscitation. Minimal doses of
anesthetic agents and drugs are recommended, since myocar-
dial depression and skeletal muscle weakness are frequently
part of the clinical presentation.  adenoma, the one abnormal gland is removed and a second
PARATHYROID GLAND DYSFUNCTION
Four parathyroid glands are located on the posterior aspect
of the thyroid gland. They produce and release parathormone
(PTH), the primary regulator of extracellular fluid calcium
concentration. PTH secretion is determined by the ionized
fraction of calcium in blood. PTH increases calcium levels by
interacting with bone (increases resorption), kidney (increases
renal tubular absorption), and the GI tract (increases absorp-
tion via 1,25 dihydroxyvitamin D). Serum PTH levels are
tightly regulated by a negative feedback loop. Low ionized cal-
cium and vitamin D levels increase PTH synthesis and release,
and vice versa. An immediate increase in blood calcium
occurs secondary to PTH effects on bone resorption and, to a
lesser extent, on renal absorption. Maintenance of steady-state
calcium balance is provided by GI absorption. Continuous
exposure to elevated PTH levels, usually from a parathyroid
adenoma or hyperplasia, results in osteoclast-mediated bone
resorption and hypercalcemia.
Hyperparathyroidism
Hyperparathyroidism is characterized by excess produc-
tion of PTH. It is the most common cause of hypercalcemia,
defined as total serum calcium above 10.4 mg/dL. Hyperpara-
thyroidism may be primary, secondary, or ectopic. Primary
hyperparathyroidism is most common and usually results
from a parathyroid adenoma or parathyroid hyperplasia.
Peak incidence is between the third and fifth decades of life.
A solitary benign adenoma is responsible for 80% of primary
hyperparathyroidism cases. Hyperplasia, with all four glands
hyperfunctioning, is present in 15% of cases; it is usually
hereditary and may be associated with other endocrine abnor-
malities (MEN I and MEN IIA). Adenomas are mostly located
in the inferior parathyroid glands. They are 0.5–5 grams in size
(normal gland weighs 25 mg). Although over 50% of patients
are asymptomatic, manifestations of hypercalcemia involve
primarily the kidneys and skeletal system. Renal pathology
includes calcium deposits in renal parenchyma or recurrent
nephrolithiasis, and skeletal pathology. Signs and symptoms
of hypercalcemia include CNS (confusion, depression), neu-
romuscular (weakness, fatigue), and GI (anorexia, nausea,
vomiting, constipation, peptic ulcer disease) manifestations
(Table 23.10). Symptoms are more common at calcium levels
above 2.9–3 mmol/L (11.5–12 mg/dL).
Diagnostic tests include a third-generation PTH immuno-
metric assay and a simultaneous calcium level. Patients with
hyperparathyroidism have increased PTH and serum cal-
cium. Localization studies can include a 99mTc sestamibi scan
with single-photon emission CT scan. Surgical excision of the
abnormal parathyroid tissue is the definitive treatment. Medi-
cal management can be safely followed in patients with mild
asymptomatic disease by quarterly monitoring of blood pres-
sure, serum calcium and creatinine, and bone density. For an
parathyroid gland is sought, biopsied, and confirmed to be
histologically normal (without hyperplasia) to conclude the
operation. An intraoperative PTH assay is measured before
and at 5-minute intervals after adenoma removal to confirm a
rapid fall to normal. For multiple-gland hyperplasia, all glands
must be identified and either: (1) three are removed, with
partial excision of the fourth (leaving a good blood supply),
TABLE 23.10   Signs and Symptoms of Hypercalcemia
Due to Hyperparathyroidism
  
Organ System Signs and Symptoms
Neuromuscular Skeletal muscle weakness
Renal Polyuria and polydipsia
Decreased glomerular filtration rate
Kidney stones
Hematopoietic Anemia
Cardiac Prolonged PR interval
Shortened QT interval
Systemic hypertension
Gastrointestinal Vomiting
Abdominal pain
Peptic ulcer
Pancreatitis
Skeletal Skeletal demineralization
Collapse of vertebral bodies
Pathologic fractures
Nervous Somnolence
Decreased pain sensation
Psychosis
Ocular Calcifications (band keratopathy)
Conjunctivitis

or (2) total parathyroidectomy is performed, with immediate
transplantation of a removed, minced parathyroid gland into
the forearm muscles. There is no preferred anesthetic tech-
nique and no special intraoperative monitoring. The effects of
neuromuscular blocking agents are unpredictable secondary
to hypercalcemia. Careful positioning is necessary to avoid
bone injuries. Postoperative complications are similar to thy-
roid surgery (recurrent laryngeal nerve injury, hematoma,
hypocalcemia). A decline in serum calcium occurs within 24
hours postoperatively. Acute hypocalcemia should occur only
if severe bone deficits are present or injury to all normal para-
thyroid glands occurred during surgery. In such cases, paren-
teral calcium is necessary at 0.5–2 mg/kg/h for several days,
with possible addition of a vitamin D analogue (calcitriol)
and/or oral calcium. Hypophosphatemia and hypomagnese-
mia may also occur postoperatively and require phosphate
and magnesium.
Parathyroid carcinoma is rare and usually not aggressive.
Calcium values are frequently high (3.5–3.7 mmol/L [14–15
mg/dL]) and provide a preoperative clue for carcinoma, which
requires removal of the entire gland with capsule intact.
The most common cause of hypercalcemia in hospitalized
patients is malignancy (occurs in as many as 20% of cancer
patients). Breast cancer accounts for 25%–50% of malig-
nancy-related hypercalcemia. Unlike hypercalcemia from
primary hyperparathyroidism, which is usually detected
coincidentally on laboratory testing, the symptoms of malig-
nancy bring the patient to medical attention, and hypercal-
cemia is then detected. In addition to a significant elevation
in serum calcium, patients have a low PTH and an elevated
PTH-related peptide (PTHrP) assay and require localization
studies to include chest x-ray, CT of the chest and abdomen,
and a bone scan. Less than 10% of cases of hypercalcemia
are caused by disorders other than hyperparathyroidism and
malignancy.
Medical treatment of hypercalcemia varies with its sever-
ity. Mild hypercalcemia (<3 mmol/L [12 mg/dL]) is managed
with hydration. Moderate to severe hypercalcemia (3.2–3.7
mmol/L [13–15 mg/dL]) is aggressively treated with IV saline
hydration and furosemide or ethacrynic acid to promote a
Na/Ca diuresis. Serum calcium usually falls 1–3 mg/dL in 24
hours. Phosphate should be given to treat hypophosphate-
mia. Bisphosphonates (pamidronate, zolendronate), calcito-
nin, glucocorticoids, phosphates, mithramycin, plicamycin,
and dialysis are also valuable. Bisphosphonates are powerful
inhibitors of bone resorption, and calcitonin is a hypocalcemic
hormone.  RESISTANCE OF PERIPHERAL TISSUES TO EFFECTS OF
Hypoparathyroidism
Hypoparathyroidism results from absence or deficiency in
PTH secretion or resistance of peripheral tissues to the effects
of the hormone. The clinical features of hypoparathyroidism
are those of hypocalcemia.
Normal total (bound and free) serum calcium con-
centration is 9.5–10.5 mg/dL. Normal ionized calcium is
Chapter 23  Endocrine Disease 471
4.75–5.7 mg/dL (1.19–1.33 mmol/L). Approximately 50%
of serum calcium is bound to albumin, 40% is ionized,
and 10% is bound to chelating agents (phosphate, citrate,
sulfate). If the serum protein concentration decreases, so
does the total serum calcium concentration. An increase in
serum proteins yields an increase in serum calcium. Acido-
sis increases serum calcium, and alkalosis decreases serum
calcium.
The most common cause of acquired hypoparathyroid-
ism is iatrogenic (i.e., inadvertent removal of all parathyroid
glands during thyroid or parathyroid surgery). Clinical signs
of hypocalcemia include neuronal irritability, skeletal muscle
spasms, tetany, and possibly seizures. Fatigue and mental status
changes including depression are common symptoms. Acute
hypocalcemia can present with stridor and apnea. Conges-
tive heart failure, hypotension, and decreased responsiveness
to β-agonists may occur. A prolonged QT interval is present
on ECG. There are a number of other causes of hypoparathy-
roidism (Table 23.11). Treatment for hypoparathyroidism is
electrolyte replacement. Calcium supplements and vitamin D
analogues are the primary treatment of hypocalcemia. Hypo-
magnesemia is managed with oral or IV magnesium. Hyper-
phosphatemia is treated with phosphate-binding resins and
possibly dialysis. Severe symptomatic hypocalcemia requires
10–20 mL of 10% calcium gluconate or 3–5 mL of 10% cal-
cium chloride followed by a continuous infusion of calcium
(1–2 mg/kg/h).
Hypoparathyroid patients may present to the operat-
ing room for an unrelated surgical condition. Patients with
symptomatic hypocalcemia must be treated aggressively
preoperatively. Calcium, phosphate, and magnesium lev-
els should be measured preoperatively and postoperatively.
Serum ionized calcium levels should maintained in the low-
normal range intraoperatively. The QT interval may be used
as an indirect guide of the serum calcium level. No specific
anesthetic agents or techniques are recommended. Respira-
tory alkalosis must be avoided because it lowers ionized cal-
cium levels. 
TABLE 23.11   Causes of Hypoparathyroidism
  
DECREASED OR ABSENT PARATHYROID HORMONE
Accidental removal of parathyroid glands during thyroidectomy
Parathyroidectomy to treat hyperplasia
Idiopathic (DiGeorge syndrome)
PARATHYROID HORMONE
Congenital
 Pseudohypoparathyroidism
Acquired
 Hypomagnesemia
  Chronic renal failure
 Malabsorption
  Anticonvulsive therapy (phenytoin)
 Osteoblastic metastases
  Acute pancreatitis
472 STOELTING’S ANESTHESIA AND CO-EXISTING DISEASE
TABLE 23.12   Hypothalamic and Related Pituitary Hormones
Pituitary Hormone or Organ
Hypothalamic Hormone Action Affected
Corticotropin-releasing hormone Stimulatory Corticotropin
Thyrotropin-releasing hormone Stimulatory Thyrotropin
Gonadotropin-releasing hormone Stimulatory Follicle-stimulating hormone,
luteinizing hormone
Growth hormone–releasing Stimulatory Growth hormone
hormone
Dopamine Inhibitory Prolactin
Somatostatin Inhibitory Pituitary, gastrointestinal
tract, pancreas
Vasopressin (antidiuretic hormone) Stimulatory Kidneys
Oxytocin Stimulatory Uterus
Breasts
aActionsin females.
bActionsin males.
Adapted from Vance ML. Hypopituitarism. N Engl J Med. 1994;330:1651-1662.
PITUITARY GLAND DYSFUNCTION
The pituitary gland, located in the sella turcica at the base of the
brain, consists of the anterior pituitary and posterior pituitary.
The anterior pituitary secretes six hormones under the control of
the hypothalamus (Table 23.12). The hypothalamus controls the
function of the anterior pituitary by means of vascular connec-
tions (hormones travel via the hypophyseal portal veins to reach
the anterior pituitary). The hypothalamic–anterior pituitary–
target organ axis is composed of tightly coordinated systems in
which hormonal signals from the hypothalamus stimulate or
inhibit secretion of anterior pituitary hormones, which in turn
act on target organs and modulate hypothalamic and anterior
pituitary activity (closed-loop, negative feedback system). The
posterior pituitary is composed of terminal neuron endings that
originate in the hypothalamus. Vasopressin (ADH) and oxyto-
cin are synthesized in the hypothalamus and are subsequently
transported along the hypothalamic neuronal axons for storage
in the posterior pituitary. The stimulus for the release of these
hormones from the posterior pituitary arises from osmorecep-
tors in the hypothalamus that sense plasma osmolarity.
Overproduction of anterior pituitary hormones is most
often associated with hypersecretion of ACTH (Cushing syn-
drome) by anterior pituitary adenomas. Hypersecretion of
other tropic hormones rarely occurs. Underproduction of a
single anterior pituitary hormone is less common than gen-
eralized pituitary hypofunction (panhypopituitarism). The
anterior pituitary gland is the only endocrine gland in which a
tumor, most often a chromophobe adenoma, causes destruc-
tion by compressing the gland against the bony confines of
the sella turcica. Metastatic tumor, most often from the breast
or lung, also occasionally produces pituitary hypofunction.
Endocrine features of panhypopituitarism are highly vari-
able and depend on the rate at which the deficiency develops
Action
Stimulates secretion of cortisol and androgens
Stimulates secretion of thyroxine and
triiodothyronine
Stimulate secretion of estradiol and progesterone,a
stimulate ovulation,a stimulate secretion of
testosterone,b stimulate spermatogenesisb
Stimulates production of insulinlike growth factor
Stimulates lactationa
Inhibits secretion of growth hormone and thyroid-
stimulating hormone, suppresses release of
gastrointestinal and pancreatic hormones
Stimulates free water reabsorption
Stimulates uterine contractionsa
Stimulates milk ejectiona
and the patient’s age. Gonadotropin deficiency (amenorrhea,
impotence) is typically the first manifestation of global pitu-
itary dysfunction. Hypocortisolism occurs 4–14 days after
hypophysectomy, whereas hypothyroidism is not likely to
manifest before 4 weeks. CT and MRI are useful for radio-
graphic assessment of the pituitary gland.
Acromegaly
Acromegaly is due to excessive secretion of growth hormone
in adults, most often by an adenoma in the anterior pituitary
gland. Failure of plasma growth hormone concentrations to
decrease 1–2 hours after ingestion of 75–100 g of glucose is
presumptive evidence of acromegaly, as are growth hormone
concentrations higher than 3 ng/mL. A skull radiograph and
CT are useful for detecting enlargement of the sella turcica,
which is characteristic of anterior pituitary adenomas.
Signs and Symptoms
Manifestations of acromegaly reflect parasellar extension of the
anterior pituitary adenoma and peripheral effects produced by
the presence of excess growth hormone (Table 23.13). Head-
ache and papilledema reflect increased intracranial pressure
resulting from expansion of the anterior pituitary adenoma.
Visual disturbances are due to compression of the optic chi-
asm by the expanding overgrowth of surrounding tissues.
Overgrowth of soft tissues of the upper airway (enlargement
of the tongue and epiglottis) makes patients susceptible to upper
airway obstruction. Hoarseness and abnormal movement of
the vocal cords or paralysis of a recurrent laryngeal nerve may
result from stretching caused by overgrowth of the surrounding
cartilaginous structures. In addition, involvement of the crico-
arytenoid joints can result in alterations in the patient’s voice
resulting from impaired movement of the vocal cords.

TABLE 23.13   Manifestations of Acromegaly
  
PARASELLAR TUMOR
Enlarged sella turcica
Headache
Visual field defects
Rhinorrhea
EXCESS GROWTH HORMONE
Skeletal overgrowth (prognathism)
Soft tissue overgrowth (lips, tongue, epiglottis, vocal cords)
Connective tissue overgrowth (recurrent laryngeal nerve paralysis)
Peripheral neuropathy (carpal tunnel syndrome)
Visceromegaly
Glucose intolerance
Osteoarthritis
Osteoporosis
Hyperhidrosis
Skeletal muscle weakness
Peripheral neuropathy is common and likely reflects trap-
ping of nerves by skeletal, connective, and soft tissue over-
growth. Flow through the ulnar artery may be compromised
in patients exhibiting symptoms of carpal tunnel syndrome.
Even in the absence of such symptoms, approximately half
of patients with acromegaly have inadequate collateral blood
flow through the ulnar artery in one or both hands.
Glucose intolerance and, on occasion, diabetes mellitus
requiring treatment with insulin reflect the effects of growth
hormone on carbohydrate metabolism. The incidence of sys-
temic hypertension, ischemic heart disease, osteoarthritis,
and osteoporosis seems to be increased in these patients. Lung
volumes are increased, and ventilation/perfusion mismatch-
ing may be present. The patient’s skin becomes thick and oily,
skeletal muscle weakness may be prominent, and complaints
of fatigue are common.  presence of neurogenic DI but not nephrogenic DI. Neuro-
Treatment
Transsphenoidal surgical excision of pituitary adenomas is
the preferred initial therapy. When adenomas have extended
beyond the sella turcica, surgery or radiation therapy is no
longer feasible; medical treatment with suppressant drugs
(bromocriptine) may be an option in these cases.  bility. Hypernatremia and hypovolemia can become severe
Management of Anesthesia
Management of anesthesia in patients with acromegaly is com-
plicated by changes induced by excessive secretion of growth
hormone. Particularly important are changes in the upper air-
way. Distorted facial anatomy may interfere with placement of
an anesthesia face mask. Enlargement of the tongue and epi-
glottis predisposes to upper airway obstruction and interferes
with visualization of the vocal cords by direct laryngoscopy.
The distance between the lips and vocal cords is increased
secondary to overgrowth of the mandible. The glottic opening
may be narrowed because of enlargement of the vocal cords.
This, in addition to subglottic narrowing, may necessitate use
of a tracheal tube with a smaller internal diameter than would
Chapter 23  Endocrine Disease 473
be predicted based on the patient’s age and size. Nasal turbi-
nate enlargement may preclude the passage of nasopharyngeal
or nasotracheal airways. A preoperative history of dyspnea
on exertion or the presence of hoarseness or stridor suggests
involvement of the larynx by acromegaly. In this instance,
indirect laryngoscopy may be indicated to quantitate the
extent of vocal cord dysfunction. When a catheter is placed
in the radial artery, it is important to consider the possibil-
ity of inadequate collateral circulation at the wrist. Monitor-
ing blood glucose concentrations is useful if diabetes mellitus
or glucose intolerance accompanies acromegaly. Peripheral
nerve stimulation is used to guide dosing of nondepolariz-
ing muscle relaxants, particularly if skeletal muscle weakness
is present. Skeletal changes associated with acromegaly may
make use of regional anesthesia technically difficult or unre-
liable. There is no evidence that hemodynamic instability or
alterations in pulmonary gas exchange accompany anesthesia
in acromegalic patients. 
Diabetes Insipidus
The posterior pituitary gland produces antidiuretic hormone
(ADH). Secretion is regulated by the osmotic pressure of the
intravascular volume. ADH increases permeability of cells lin-
ing the distal tubule and medullary collecting ducts of the kid-
ney to promote water absorption.
Diabetes insipidus (DI) occurs from a decrease of syn-
thesis and release of vasopressin (neurogenic DI) or from
a resistance or insensitivity of renal tubules to vasopres-
sin (nephrogenic DI). Secretion or action of vasopressin is
decreased 80%–85% below normal. Neurogenic DI can be
differentiated from nephrogenic DI based on response to
desmopressin (DDAVP [1-deamino-8-d-arginine-vasopres-
sin]). This vasopressin analogue concentrates urine in the
genic DI often occurs following damage or destruction to
the pituitary gland by trauma, infiltrating lesions, or surgery.
Patients present with polydipsia, hypernatremia, and high
output of poorly concentrated urine despite increased serum
osmolality. Clinically, patients demonstrate altered mental
status/seizures, fatigue, weakness, and hemodynamic insta-
enough to be life threatening. A 24-hour urine collection
is required to make the diagnosis. The 24-hour urine vol-
ume must exceed 50 mL/kg of body weight, and the urine
osmolality must be less than 300 mOsm/L to confirm DI. An
increase in plasma osmolality (normal = 283–285 mOsm/L)
also occurs. DI from pituitary surgery usually appears within
24 hours and may last a few days to 6 months. Desmopressin
(DDAVP) is the treatment for neurogenic DI. During sur-
gery an IV infusion of 100–200 m U/h is administered in
combination with an isotonic crystalloid solution. Frequent
monitoring of serum Na and plasma osmolality is required.
DDAVP can also be administered IM or intranasally. Treat-
ments for nephrogenic DI include chlorpropamide, clofi-
brate, and thiazide diuretics.
474 STOELTING’S ANESTHESIA AND CO-EXISTING DISEASE
Anesthetic management includes continuous monitoring
of urine output and hourly measurement of serum Na and
plasma osmolality. The goal for plasma osmolality is less than
290 mOsm/L. Patients with complete DI and a total lack of
ADH require a preoperative dose of desmopressin intranasally
or an IV bolus of 100 mU (0.1 unit) of aqueous vasopressin
followed by a continuous infusion of 100–200 mU/h (0.1–0.2
units/h). Isotonic fluids should be used for volume resuscita-
tion. If plasma osmolality exceeds 290 mOsm/L, hypotonic
fluid should be used for resuscitation and the vasopressin
infusion should be increased above 200 mU/h. Since vasopres-
sin causes vasoconstriction of arteriolar beds, close monitor-
ing for myocardial ischemia is recommended.  or inadequate tissue response to insulin, which leads to
Syndrome of Inappropriate Antidiuretic
Hormone Secretion (SIADH)
Inappropriate (i.e., excessive) secretion of antidiuretic hor-
mone yields hyponatremia (Na < 135 mEq/L) from the
expansion of intravascular fluid volume secondary to hor-
mone-induced resorption of water by renal tubules. Ectopic
production of vasopressin by tumors is a common cause of
SIADH. Small cell lung carcinoma (50% of these patients
develop SIADH) and carcinoid tumors are the most common
sources. Other types of lung cancer and tumors of the CNS,
head and neck, GI tract, genitourinary tract, and ovary can
also produce vasopressin. CNS trauma, infections, certain
medications (chlorpropamide, clofibrate, thiazides, antineo-
plastic agents), hypothyroidism, and major surgery can also
result in SIADH. Most patients are asymptomatic. Clinical
signs and symptoms may include nausea, weakness, lethargy,
confusion, depressed mental status, and seizures. Although
hyponatremia usually develops slowly (over weeks to months),
the rapidity of onset and degree of hyponatremia determine
the severity of symptoms. The diagnosis is made by demon-
strating hyponatremia (<130 mEq/L), reduced serum osmo-
lality (<270 mOsm/L), normal or increased urine Na excretion
(>20 mEq/L), and inappropriately normal or increased urine
osmolality (hypertonic relative to plasma).
SIADH is a diagnosis of exclusion, and other causes of hypo-
natremia should be excluded first. SIADH is corrected gradu-
ally unless mental status is altered and/or the patient appears
at risk for seizures. Treatment of the malignancy is primary.
Free water restriction is required. Fluid intake is limited to
500–1000 mL/day. Demeclocycline inhibits the action of ADH
on the renal distal tubule. Conivaptan, a vasopressin-2 recep-
tor (V2R) antagonist, may be effective. Severe hyponatremia
(Na < 115 mEq/L) may require 3% hypertonic saline or normal
saline plus furosemide. The rate of sodium correction should
be slow (0.5 mEq/L/h) until Na concentration is 125 mEq/L,
then proceed more slowly to prevent central pontine myelinoly-
sis and possibly permanent brain damage.
Anesthetic management of patients with SIADH involves
careful administration and monitoring of fluids and electro-
lytes. If SIADH results from malignancy, anemia and malnu-
trition may be present. Perioperatively, these patients usually
have low urine output and can demonstrate delayed awaken-
ing or awakening with mental confusion. Measurement of
intravascular volume status with a central venous pressure
catheter may be indicated. Cautious fluid resuscitation with
normal saline is recommended. Frequent measures of urine
osmolality, plasma osmolality, and serum Na are necessary
perioperatively. It is not unusual to see patients in the neuro-
surgical intensive care unit with this syndrome. 
KEY POINTS
• Diabetes mellitus results from inadequate supply of and/
increased circulating glucose levels.
• The effects of chronic hyperglycemia are many and include
hypertension, coronary artery disease, congestive heart
failure, peripheral vascular disease, cerebrovascular acci-
dent, chronic renal failure, and autonomic neuropathy.
• Aggressive perioperative glucose control has been shown to
limit infection risk, improve wound healing, and result in
overall reductions in morbidity and mortality.
• The direct effects of T3 on the heart and vascular smooth
muscle are responsible for the exaggerated hemodynamic
effects of hyperthyroidism.
• The third-generation TSH assay is the single best test of
thyroid hormone action at the cellular level.
• Every effort should be made to render patients euthyroid
before surgery. When caring for surgical patients with
hyperthyroidism or hypothyroidism, the clinician must
be prepared to manage thyroid storm or myxedema coma
during the perioperative period.
• 
Since most pheochromocytomas secrete predominantly
norepinephrine, preoperative α-blockade is necessary to
lower blood pressure, increase intravascular volume, pre-
vent paroxysmal hypertensive episodes, allow resensiti-
zation of adrenergic receptors, and decrease myocardial
dysfunction.
• 
During surgical excision of a pheochromocytoma, the
patient often exhibits an exaggerated hypertensive response
to anesthetic induction, intubation, surgical excision, and
particularly tumor manipulation. Conversely, hypotension
may occur following ligation of the tumor’s venous drainage.
• The physiologic response to surgical stress is an increase in
CRH, ACTH, and cortisol secretion that begins at surgical
incision and continues into the postoperative period.
• The most common cause of AI is administration of exog-
enous steroids.
• Patients who received glucocorticoids in dosages equivalent
to more than 20 mg/day of prednisone for longer than 3 weeks
within the previous year are considered to have adrenal sup-
pression and are at increased risk of AI. Such patients require
perioperative corticosteroid supplementation.
• Hydrocortisone 200–300 mg/day for a minimum of 5–7
days, followed by a tapering regimen over 5–7 days, results
in overall improvement in patients with vasopressor-
dependent septic shock.

• Primary hyperparathyroidism is the most common cause of
hypercalcemia in the general population and usually results
from a benign parathyroid adenoma. Hypercalcemia can
be treated medically by saline infusion, furosemide, and/or
bisphosphonates before surgery.
• Overproduction of anterior pituitary hormones is most com-
monly manifested as Cushing syndrome caused by ACTH
hypersecretion by an adenoma in the anterior pituitary.
• SIADH is common in the postoperative period and usually
responds to fluid restriction.
RESOURCES
Akhtar S, Barash PG, Inzucchi SE. Scientific principles and clinical impli-
cations of perioperative glucose regulation and control. Anesth Analg.
2010;110:478-497.
Axelrod L. Perioperative management of patients treated with glucocorti-
coids. Endocrinol Metab Clin North Am. 2003;32:367-383.
Chapter 23  Endocrine Disease 475
Bravo EL. Evolving concepts in the pathophysiology, diagnosis, and treatment
of pheochromocytoma. Endocr Rev. 1994;15:356-368.
Burch HB, Wartofsky L. Life-threatening thyrotoxicosis: thyroid storm. Endo-
crinol Metab Clin North Am. 1993;22:263-277.
Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N
Engl J Med. 2003;348:727-734.
DeWitt DE, Hirsch IB. Outpatient insulin therapy in type 1 and type 2 diabe-
tes mellitus. JAMA. 2003;289:2254-2264.
Inzucchi S. The Diabetes Mellitus Manual: a Primary Care Companion to El-
lenberg and Rifkin’s Sixth Edition. New York: McGraw-Hill; 2005.
Klein I, Ojamma K. Thyroid hormone and the cardiovascular system. N Engl
J Med. 2001;344:501-509.
Mathur A, Gorden P, Libutti SK. Insulinoma. Surg Clin North Am.
2009;89:1105-1121.
Stathatos N, Wartofsky L. Perioperative management of patients with hypo-
thyroidism. Endocrinol Metab Clin North Am. 2003;32:503-518.
Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: scientific re-
view and guidelines for diagnosis and management. JAMA. 2004;291:228-
238.
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Hematologic Disorders
Physiology of Anemia
The Transfusion Trigger
Management of Anesthesia: General Concepts for Anemia
Evaluation and Classification of Anemia
Microcytic Anemias
Normocytic Anemias
Macrocytic/Megaloblastic Anemias
Other Hemoglobin-Related Disorders
Hemoglobins With Increased Oxygen Affinity
Hemoglobins With Decreased Oxygen Affinity
Polycythemia
Physiology of Polycythemia
Polycythemia Vera
Secondary Polycythemia Due to Hypoxia
Secondary Polycythemia Due to Increased Erythropoietin
Production
Disorders of Hemostasis
Normal Hemostasis
Hemostatic Disorders Affecting Coagulation Factors of the
Initiation Phase
Disease states related to erythrocytes include anemia and
polycythemia. Anemia is characterized by a decrease in the
red cell mass, with the main adverse effect being a decrease in
the oxygen-carrying capacity of blood. Polycythemia (erythro-
cytosis) represents an increase in hematocrit (Hct). Its conse-
quences are primarily related to an expanded red cell mass and
a resulting increase in blood viscosity.
PHYSIOLOGY OF ANEMIA
Anemia is a disease sign manifesting clinically as a reduced
absolute number of circulating red blood cells (RBCs).
Although a decrease in Hct is used most often as an indicator,
anemia has been defined as a reduction in one or more of the
major RBC indices: hemoglobin (Hb) concentration, Hct, and
RBC count. In adults the World Health Organization defines
C H APT E R
24
ADRIANA D. OPREA
Hemostatic Disorders Affecting Coagulation Factors of the
Propagation Phase
Arterial Coagulation
Disorders Affecting Platelet Number
Congenital Disorders Resulting in Platelet Production
Defects
Acquired Disorders Resulting in Platelet Production
Defects
Nonimmune Platelet Destruction Disorders
Autoimmune Platelet Destruction Disorders
Qualitative Platelet Disorders
Hypercoagulable Disorders
Heritable Causes of Hypercoagulability
Acquired Causes of Hypercoagulability
Management of Anesthesia in Venous Hypercoagulable
Disorders
Acquired Hypercoagulability of the Arterial Vasculature
Key Points
anemia as Hb concentration less than 12 g/dL for women
and less than 13 g/dL for men. In pregnancy a decreased Hct
reflects the increase in plasma volume in relationship to the
RBC mass (physiologic anemia). However, Hb less than 11 g/dL
in a pregnant patient is considered truly anemic. In acute
blood loss the Hct may initially be unchanged. Decreases in
Hct that exceed 1% every 24 hours can only be explained by
acute blood loss or intravascular hemolysis.
The most important adverse effect of anemia is the reduc-
tion in arterial oxygen concentration and the potential for
decreased tissue oxygen delivery. For example, a decrease in
Hb concentration from 15 g/dL to 10 g/dL result in a 33%
decrease in arterial oxygen content. The initial compensation
for this decrease in oxygen content is an increase in cardiac
output. This occurs via enhanced sympathetic nervous system
activity and the decrease in blood viscosity that accompanies
477