You are on page 1of 29

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

Peripheral
tissues
(muscle)

Receptor
+
postreceptor
defect

Glucose

Liver

Increased glucose
production

Pancreas

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 7.0%. The presence of ketoacidosis indicates severe insulin
circulating levels of insulin. Type 1b diabetes is a rare disease deficiency and unrestrained lipolysis. 
of absolute insulin deficiency that is not immune mediated.
Type 2 diabetes also is not immune mediated and results from Type 2 Diabetes
defects in insulin receptors and postreceptor intracellular sig- Type 2 diabetes is responsible for 90% of all cases of diabe-
naling pathways. 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
Signs and Symptoms
diabetes are typically in the middle to older age group and are
Type 1 Diabetes overweight, although there has been a significant increase in
Between 5% and 10% of all cases of diabetes are type 1. There younger patients and even children with type 2 diabetes over
are 1.4 million individuals with type 1 diabetes in the United the past decade.
States and 10–20 million globally. Currently the incidence is Type 2 diabetes is characterized by relative beta cell insuf-
increasing by 3%–5% per year. The disorder is usually diag- ficiency and insulin resistance. In the initial stages of the dis-
nosed before the age of 40 and is one of the most common ease, an insensitivity to insulin on the part of peripheral tissues
chronic childhood illnesses. leads to an increase in pancreatic insulin secretion to maintain
Type 1 diabetes is caused by T cell–mediated autoimmune normal plasma glucose levels. As the disease progresses and
destruction of beta cells in the pancreas. The exact cause is pancreatic cell function decreases, insulin levels are unable
unknown, although environmental triggers such as viruses to compensate and hyperglycemia occurs. Three important
(especially enteroviruses), dietary proteins, or drugs or chemi- defects are seen in type 2 diabetes: (1) an increased rate of
cals may initiate the autoimmune process in genetically sus- hepatic glucose release, (2) impaired basal and stimulated
ceptible hosts. At least 80%–90% of beta cell function must be insulin secretion, and (3) inefficient use of glucose by periph-
lost before hyperglycemia occurs. eral tissues (i.e., insulin resistance) (Fig. 23.2). Although
The presentation of clinical disease is often sudden and relative beta cell insufficiency is significant, type 2 diabetes
severe, secondary to loss of a critical mass of beta cells. Patients is characterized by insulin resistance in skeletal muscle, adi-
demonstrate hyperglycemia over several days to weeks associ- pose tissue, and the liver. It appears that insulin resistance is
ated with fatigue, weight loss, polyuria, polydipsia, blurring of an inherited component of type 2 diabetes, with obesity and
vision, and signs of intravascular volume depletion. The diag- a sedentary lifestyle being acquired and contributing factors.
nosis is based on the presence of a random blood glucose level Impaired glucose tolerance is associated with an increase in
higher than 200 mg/dL and a hemoglobin (Hb)A1c level above body weight, a decrease in insulin secretion, and a reduction
Chapter 23  Endocrine Disease 451

either impaired fasting glucose or impaired glucose tolerance,


TABLE 23.1   Diagnostic Features of Metabolic
Syndrome
depending on whether it is identified through measurement of
   fasting plasma glucose level or an oral glucose tolerance test.
At least three of the following: Any fasting glucose level between 101 and 125 mg/dL is cat-
Fasting plasma glucose level ≥ 110 mg/dL egorized as impaired fasting glucose. Glucose levels, especially
Abdominal obesity (waist girth > 40 inches in men, >35 inches in type 2 diabetics, usually increase over years to decades, pro-
in women)
Serum triglyceride level ≥ 150 mg/dL
gressing from the normal range to the impaired glucose toler-
Serum high-density lipoprotein cholesterol level < 40 mg/dL in ance range and finally to clinical diabetes.
men, <50 mg/dL in women The HbA1c test provides a valuable measure of long-term
Blood pressure ≥ 130/85 mm Hg glycemic control. Hemoglobin is nonenzymatically glyco-
Adapted from Expert Panel on Detection, Evaluation, and Treatment of High Blood
sylated by glucose, which freely crosses red blood cell mem-
Cholesterol in Adults: Executive summary of the third report of the National Cho- branes. The percentage of hemoglobin molecules participating
lesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and in this reaction is proportional to the average plasma glucose
Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA.
2001;285:2486-2497.
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
TABLE 23.2   Diagnostic Criteria for Diabetes Mellitus is 6.5% or higher. Measurement of HbA1c is recommended at
   least twice a year and more frequently (every 3 months) if gly-
Symptoms of diabetes (polyuria, polydipsia, unexplained weight cemic control is inadequate or therapy has changed. 
loss) plus a random plasma glucose concentration ≥ 200 mg/dL
or
Fasting (no caloric intake for ≥ 8 hr) plasma glucose level ≥ 126 Treatment
mg/dL
or The cornerstones of treatment for type 2 diabetes are dietary
2-hr plasma glucose level > 200 mg/dL during an oral glucose adjustments along with weight loss, exercise therapy, and oral
tolerance test antidiabetic drugs. Reduction of body weight through diet
Adapted from Diagnosis and classification of diabetes mellitus. American Diabetes and exercise is the first therapeutic measure to control type
Association. Diabetes Care. 2010;33(Suppl 1):S62. 2 diabetes. The decrease in adiposity improves hepatic and
peripheral tissue insulin sensitivity, enhances postreceptor
in peripheral insulin action. The transition to clinical diabe- insulin action, and may possibly increase insulin secretion.
tes is characterized by these same factors plus an increase in Nutritional guidelines of the ADA emphasize maintenance of
hepatic glucose production. optimal plasma glucose and lipid levels.
The increasing prevalence of type 2 diabetes among chil-
dren and adolescents appears related to obesity, since 85% of Oral Antidiabetic Drugs
affected children are overweight or obese at the time of diagno- The four major classes of oral antidiabetic medications are
sis. Obese patients exhibit a compensatory hyperinsulinemia (1) the secretagogues (sulfonylureas, meglitinides), which
to maintain normoglycemia. These increased insulin levels increase insulin availability; (2) the biguanides (metformin),
may desensitize target tissues, causing a reduced response to which suppress excessive hepatic glucose release; (3) the thia-
insulin. The mechanisms for hyperinsulinemia and insulin zolidinediones or glitazones (rosiglitazone, pioglitazone),
resistance from weight gain remain elusive. which improve insulin sensitivity; and (4) the α-glucosidase
Metabolic syndrome, or insulin-resistance syndrome, is a inhibitors (acarbose, miglitol), which delay GI glucose absorp-
constellation of clinical and biochemical characteristics fre- tion (Fig. 23.3). These agents are used to maintain glucose con-
quently seen in patients who have or are at risk of developing trol, which is defined as a fasting glucose level of 90–130 mg/
type 2 diabetes (Table 23.1). This syndrome combines insulin dL, peak postprandial glucose level below 180 mg/dL, and
resistance with hypertension, dyslipidemia, a procoagulant HbA1c level below 7% in the initial stages of the disease.
state, and obesity and is associated with premature atheroscle- The sulfonylureas are usually the initial pharmacologic
rosis and subsequent cardiovascular disease. This syndrome treatment for type 2 diabetes mellitus. They act by stimulat-
affects at least 25% of people in the United States.  ing insulin secretion from pancreatic beta cells; they can also
enhance insulin-stimulated peripheral tissue utilization of
glucose. The second-generation agents (glyburide, glipizide,
Diagnosis
glimepiride) are more potent and have fewer side effects than
The American Diabetes Association (ADA) has established their predecessors. Unfortunately, because of the natural his-
diagnostic criteria for diabetes mellitus (Table 23.2). Mea- tory of type 2 diabetes characterized by decreasing beta cell
surement of fasting plasma glucose level is the recommended function, these drugs are not effective indefinitely. Hypogly-
screening test for diabetes mellitus. The upper limit for normal cemia is the most common side effect. Whether or not harm-
fasting glucose level is 100 mg/dL. Hyperglycemia not suffi- ful cardiac effects from sulfonylureas have been demonstrated
cient to meet the diagnostic criteria for diabetes is classified as 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- In most patients, therapy is initiated with a sulfonylurea or big-
enous GLP-1 activity in the gut. Exenatide and liraglutide are uanide and titrated to achieve fasting and peak postprandial glu-
examples and have been approved for treatment for type 2 cose levels recommended by the ADA (Fig. 23.4). Combination
diabetes. These agents (incretins) increase glucose-stimulated therapy with oral agents directed at more than one mechanism is
insulin secretion, suppress glucagon, and slow gastric empty- often effective. If combination oral therapy is unsuccessful, a bed-
ing. Dipeptidyl peptidase-4 inhibitors (saxagliptin, sitagliptin, time dose of intermediate-acting insulin is added, since hepatic
vildagliptin) inhibit the degradation of native GLP-1 and thus glucose overproduction is typically highest at night. If oral agents
enhance glucose-stimulated insulin secretion. plus single-dose insulin therapy is ineffective, type 2 diabetic
The biguanides decrease hepatic gluconeogenesis and patients are switched to insulin therapy alone.
to a lesser degree enhance utilization of glucose by skeletal Tight control of type 2 diabetes provides significant ben-
muscle and adipose tissue by increasing glucose transport efits in preventing and slowing the progression of microvascu-
across cell membranes. In addition to lowering glucose lar disease and possibly macrovascular disease. Not only must
levels, they decrease plasma levels of triglycerides and hyperglycemia be treated, but all abnormalities of insulin resis-
low-density lipoprotein cholesterol and reduce postpran- tance (metabolic syndrome) must be managed, with the goals
dial hyperlipidemia and plasma free fatty acids. The risk of therapy including an HbA1c level below 7%, a low-density
of hypoglycemia is less than that with the sulfonylureas. lipoprotein level below 100 mg/dL, a high-density lipoprotein
Lactic acidosis is a rare but serious side effect of the bigu- level higher than 40 mg/dL in men and higher than 50 mg/dL
anides; the risk is particularly high in patients with renal in women, a triglyceride level below 200 mg/dL, and a blood
insufficiency. It is much less common with metformin than pressure lower than 130/80 mm Hg. 
with its predecessor phenformin.
The thiazolidinediones or glitazones are insulin sensitiz- Insulin
ers that decrease insulin resistance by binding to peroxisome Insulin is necessary to manage all cases of type 1 diabetes
proliferator–activated receptors located in skeletal muscle, and many cases of type 2 diabetes (Table 23.3). In the United
liver, and adipose tissue. These drugs influence the expression States, 30% of patients with type 2 diabetes are treated with
of genes encoding proteins for glucose and lipid metabolism, insulin. Conventional insulin therapy uses twice-daily injec-
endothelial function, and atherogenesis; as a result, they may tions. Intensive insulin therapy requires three or more daily
influence diabetic dyslipidemia in addition to hyperglycemia. injections or a continuous infusion (Figs. 23.5–23.9).
The α-glucosidase inhibitors inhibit α-glucosidase enzymes The various forms of insulin include basal insulins, which
in the brush border of enterocytes in the proximal small intes- are intermediate acting (NPH, Lente, lispro protamine, aspart
tine, which results in a delay in intraluminal production and protamine) and administered twice daily or long acting (Ultra-
subsequent absorption of glucose. They are administered lente, glargine, detemir) and administered once daily; and
before a main meal to ensure their presence at the site of action. 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- Hypoglycemia is the most frequent and dangerous com-
times. Rapid-acting insulins are preferred over regular insu- plication of insulin therapy. The hypoglycemic effect can
lin for prandial coverage. Insulin glargine has a later onset of be exacerbated by simultaneous administration of alcohol,
action, longer duration of action, a less pronounced peak of sulfonylureas, biguanides, thiazolidinediones, angiotensin-
action, and a lower incidence of hypoglycemia, especially at converting enzyme (ACE) inhibitors, monoamine oxidase
night. A long-acting insulin is usually prescribed with a short- inhibitors, and nonselective β-blockers.
acting insulin to mimic physiologic insulin release with meals. Repetitive episodes of hypoglycemia, especially at night,
In general, patients with type 1 diabetes require 0.5–1 U/kg/ can result in hypoglycemia unawareness, a condition in which
day divided into multiple doses, with approximately 50% the patient does not respond with the appropriate autonomic
given as basal insulin. warning symptoms before neuroglycopenia. The diagnosis
Regular insulin is preferred over insulin analogues for intra- in adults requires a plasma glucose level below 50 mg/dL.
venous (IV) infusions because it is less expensive and equally Symptoms are adrenergic (sweating, tachycardia, palpitations,
effective. Sliding scale short-acting insulin alone is inadequate restlessness, pallor) and neuroglycopenic (fatigue, confu-
for inpatient glucose management and should not be used. 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.
Chapter 23  Endocrine Disease 455

Morning Afternoon Evening Night


TABLE 23.5   Diagnostic Features of Hyperglycemic
Hyperosmolar Syndrome
  
Insulin effect
Meal Meal Meal Basal
bolus bolus bolus infusion Glucose level (mg/dL) ≥600
pH ≥7.3
HCO3− (mEq/L) ≥15
Serum osmolarity (mOsm/L) ≥350

B is initiated. Insulin administration must be continued until a


B L S HS
normal acid-base status is achieved. The insulin rate is reduced
Meals
when hyperglycemia is controlled, blood pH is higher than
FIG. 23.9  Insulin effect of continuous subcutaneous infusion of 7.3, and bicarbonate level exceeds 18 mEq/L. Potassium and
short- or rapid-acting insulin before meals and snacks. ↑, Time of
phosphate are replaced with KCl and K2PO4. Magnesium
insulin injection; B, breakfast; HS, bedtime; L, lunch; S, supper.
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
TABLE 23.4   Diagnostic Features of Diabetic of hyperglycemia without simultaneous correction of serum
Ketoacidosis sodium level. 
  
Serum glucose level (mg/dL) ≥300 Hyperglycemic Hyperosmolar Syndrome
pH ≤7.3
HCO3− (mEq/L) ≤18
Hyperglycemic hyperosmolar syndrome is characterized by
Serum osmolarity (mOsm/L) <320 severe hyperglycemia, hyperosmolarity, and dehydration. It
Serum and urine ketone levels Moderate to high 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-
includes administration of sugar in the form of sugar cubes, sis. The patient experiences polyuria, polydipsia, hypovolemia,
glucose tablets, or soft drinks if the patient is conscious; and hypotension, tachycardia, and organ hypoperfusion. Hyperos-
glucose 0.5 g/kg IV or glucagon 0.5–1 mg IV, intramuscularly, molarity (>340 mOsm/L) is responsible for mental obtunda-
or subcutaneously if the patient is unconscious.  tion or coma (Table 23.5). Patients may have some degree of
metabolic acidosis but do not demonstrate ketoacidosis.
Treatment includes significant fluid resuscitation, insulin
Complications
administration, and electrolyte supplementation. If plasma
Diabetic Ketoacidosis osmolarity is greater than 320 mOsm/L, large volumes of
Diabetic ketoacidosis (DKA) is a complication of decom- hypotonic saline (1000–1500 mL/h) should be administered
pensated diabetes mellitus. The signs and symptoms of DKA until the osmolarity is less than 320 mOsm/L, at which time
are primarily the result of abnormalities in carbohydrate and large volumes of isotonic saline (1000–1500 mL/h) can be
fat metabolism. Episodes of DKA occur more commonly in given. Insulin therapy is initiated with an IV bolus of 15 units
patients with type 1 diabetes and are precipitated by infec- of regular insulin followed by a 0.1-unit/kg/h infusion. The
tion or acute illness. High glucose levels exceed the thresh- insulin infusion is decreased to 2–3 units/h when the glucose
old for renal tubular absorption, which creates a significant level decreases to approximately 250–300 mg/dL. Electrolyte
osmotic diuresis with marked hypovolemia. A tight metabolic deficits are significant but usually less severe than in DKA. 
coupling between hepatic gluconeogenesis and ketogenesis
leads to overproduction of ketoacids by the liver. An increase Microvascular Complications
in production of ketoacids (β-hydroxybutyrate, acetoacetate, Microvascular dysfunction is unique to diabetes and char-
acetone) creates an anion-gap metabolic acidosis (Table 23.4). acterized by nonocclusive microcirculatory disease and
Substantial deficits of water, potassium, and phosphorus exist, impaired autoregulation of blood flow and vascular tone.
although laboratory values of these electrolytes may be normal Chronic hyperglycemia is essential for development of these
or increased. Hyponatremia results from the effect of hyper- changes, and intensive glycemic control delays the onset and
glycemia and hyperosmolarity on water distribution. The defi- slows the progression of microvascular effects.
cit of potassium is usually substantial (3–5 mEq/kg), and the
deficit of phosphorus can lead to diaphragmatic and skeletal Nephropathy
muscle dysfunction and impaired myocardial contractility. Approximately 30%–40% of individuals with type 1 diabetes
Treatment of DKA consists of administration of large and 5%–10% of those with type 2 diabetes develop end-stage
amounts of normal saline, effective doses of insulin, and elec- renal disease. The clinical course is characterized by hyper-
trolyte supplementation. An IV loading dose of 0.1 unit/kg of tension, albuminuria, peripheral edema, and a progressive
regular insulin plus a low-dose insulin infusion of 0.1 unit/kg/h 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- diabeticorum in approximately 25% of diabetic patients.
neys to excrete potassium and acids is impaired, and patients Although it is often clinically silent, symptomatic patients will
develop hyperkalemia and metabolic acidosis. Hypertension, have nausea, vomiting, early satiety, bloating, and epigastric
hyperglycemia, hypercholesterolemia, and microalbumin- pain. Treatment of gastroparesis includes strict blood glucose
uria accelerate the decrease in GFR. Treatment of hyperten- control, consumption of multiple small meals, reduction of
sion can markedly slow the progression of renal dysfunction. the fat content of meals, and use of prokinetic agents such as
ACE inhibitors are particularly beneficial in diabetic patients metoclopramide. Diarrhea and constipation are also common
because they retard the progression of proteinuria and the among diabetic patients and may be related to diabetic auto-
decrease in GFR.  nomic neuropathy. 

Peripheral Neuropathy Macrovascular Complications


More than 50% of patients who have had diabetes for lon- Cardiovascular disease is a major cause of morbidity and the
ger than 25 years develop a peripheral neuropathy. A distal leading cause of mortality in diabetic individuals. Patients
symmetric diffuse sensorimotor polyneuropathy is the most with poorly controlled diabetes demonstrate elevated triglyc-
common form. Sensory deficits usually overshadow motor eride levels, low levels of high-density lipoprotein cholesterol,
abnormalities and appear in the toes or feet and progress and an abnormally small, dense, more atherogenic low-density
proximally toward the chest in a “stocking-glove” distribution. lipoprotein cholesterol. Measures to prevent coronary artery
Loss of large sensory and motor fibers produces loss of light disease include maintaining lipid levels, glucose level, and
touch and proprioception as well as muscle weakness. Loss of blood pressure within normal limits. Aspirin and statin therapy
small fibers decreases the perception of pain and temperature should be considered for all diabetic patients. 
and produces dysesthesia, paresthesia, and neuropathic pain.
Foot ulcers develop from mechanical and traumatic injury as
Management of Anesthesia
a result of loss of cutaneous sensitivity to pain and tempera-
ture and impaired perfusion. Significant morbidity results Preoperative Evaluation
from recurrent infection, foot fractures (Charcot joint), and Preoperative evaluation should emphasize the cardiovascular,
subsequent amputations. Treatment of peripheral neuropathy renal, neurologic, and musculoskeletal systems. The index of
includes optimal glucose control as well as use of nonsteroidal suspicion should be high for myocardial ischemia and infarc-
antiinflammatory drugs, antidepressants, and anticonvulsants tion. Silent ischemia is possible if autonomic neuropathy is
for pain control.  present, and stress testing should be considered in patients
with multiple cardiac risk factors and poor or indeterminate
Retinopathy exercise tolerance. For renal disease, control of hypertension is
Diabetic retinopathy results from a variety of microvascular important. Meticulous attention to hydration status, avoidance
changes. Visual impairment can range from minor changes of nephrotoxins, and preservation of renal blood flow are also
in color vision to total blindness. Strict glycemic control and essential. The presence of autonomic neuropathy predisposes
blood pressure control can reduce the risk of development and the patient to perioperative dysrhythmias and intraoperative
progression of retinopathy.  hypotension. In addition, loss of compensatory sympathetic
responses interferes with detection and treatment of hemody-
Autonomic Neuropathy namic insults. Preoperative evaluation of the musculoskeletal
Diabetic autonomic neuropathy can affect any part of the system should look for limited joint mobility caused by nonen-
autonomic nervous system. Symptomatic autonomic neu- zymatic glycosylation of proteins and abnormal cross-linking
ropathy is rare and present in fewer than 5% of diabetics. The of collagen. Gastroparesis may increase the risk of aspiration,
pathogenesis is not completely understood but may involve regardless of nothing-by-mouth status.
metabolic, microvascular, and/or autonomic abnormalities. Management of insulin in the preoperative period depends
Cardiovascular signs of autonomic neuropathy include abnor- on the type of insulin the patient takes and the timing of
malities in heart rate control as well as central and peripheral dosing. If a patient takes subcutaneous insulin each night at
vascular dynamics. A heart rate that fails to respond to exer- bedtime, two-thirds of this dose (NPH and regular) should
cise is indicative of significant cardiac denervation and is likely be administered the night before surgery, and one-half of
to result in substantially reduced exercise tolerance. The heart the usual morning NPH dose should be given on the day of
may demonstrate systolic and diastolic dysfunction with a surgery. The daily morning dose of regular insulin should be
reduced ejection fraction. Dysrhythmias may be responsible held. If the patient uses an insulin pump, the overnight rate
for sudden death. The presence of cardiovascular autonomic should be decreased by 30%. On the morning of surgery, the
neuropathy can be demonstrated by measuring orthostatic pump can be kept infusing at the basal rate or discontinued
changes in heart rate and blood pressure and the hemody- and replaced with a continuous insulin infusion at the same
namic response to exercise. rate. Alternatively the patient can be given subcutaneous
Diabetic autonomic neuropathy may also impair gastric glargine and the pump discontinued 60–90 minutes after
secretion and gastric motility, eventually causing gastroparesis 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 initiated at least 2 hours before surgery. Intraoperative serum
of the glargine dose and the entire lispro or aspart dose the glucose levels should be maintained between 120 and 180 mg/dL.
night before surgery and hold all morning dosing. Oral hypo- Levels above 200 mg/dL are likely to cause glycosuria and
glycemics should be discontinued 24–48 hours preoperatively. dehydration and to inhibit wound healing. Typically 1 unit of
It is advised that sulfonylureas be avoided during the entire insulin lowers glucose approximately 25–30 mg/dL. The ini-
perioperative period because they block the myocardial potas- tial hourly rate for a continuous insulin infusion is determined
sium adenosine triphosphate (ATP) channels responsible for by dividing the total daily insulin requirement by 24. A typi-
ischemia- and anesthetic-induced preconditioning.  cal rate is 0.02 unit/kg/h, or 1.4 units/h in a 70-kg patient. An
insulin infusion can be prepared by mixing 100 units of regular
Intraoperative Management insulin in 100 mL of normal saline (1 unit/mL). Insulin infu-
Aggressive glycemic control is important intraoperatively sion requirements are higher for patients undergoing coronary
(Table 23.6). Ideally a continuous infusion of insulin should be artery bypass graft surgery, patients receiving steroids, patients
458 STOELTING’S ANESTHESIA AND CO-EXISTING DISEASE

with severe infection, and patients receiving hyperalimenta- enucleation is the procedure of choice. Laparoscopic resection
tion or vasopressor infusions. An insulin infusion should be is used in selected cases.
accompanied by an infusion of 5% dextrose in half-normal Profound hypoglycemia can occur intraoperatively, par-
saline with 20 mEq KCl at 100–150 mL/h to provide enough ticularly during manipulation of the tumor; however, marked
carbohydrate (at least 150 g/day) to inhibit hepatic glucose pro- hyperglycemia can follow removal of the tumor. In a few med-
duction and protein catabolism. Serum glucose levels should ical centers, an artificial pancreas that continuously analyzes
be monitored at least every hour and even every 30 minutes in the blood glucose concentration and automatically infuses
patients undergoing coronary artery bypass surgery or patients insulin or glucose has been used for intraoperative manage-
with high insulin requirements. Glucose determination is pref- ment of these patients. In most cases, serial blood glucose
erentially made using venous plasma or serum samples; arte- measurements (every 15 minutes) are taken using a standard
rial and capillary blood yields glucose values approximately glucometer. Since evidence of hypoglycemia may be masked
7% higher than those for venous blood, and whole-blood under anesthesia, it is probably wise to include glucose in
determinations are usually 15% lower than plasma or serum intravenously administered fluids. 
values. Urine glucose monitoring is not reliable.
Avoidance of hypoglycemia is especially critical, since rec-
THYROID DISEASE
ognition of hypoglycemia may be delayed in patients receiving
anesthetics, sedatives, analgesics, β-blockers, or sympatholyt- The thyroid gland weighs approximately 20 g and is composed
ics and in those with autonomic neuropathy. If hypoglycemia of two lobes joined by an isthmus. The gland is closely affixed
does occur, treatment consists of administration of 50 mL of to the anterior and lateral aspects of the trachea, with the upper
50% dextrose in water, which typically increases the glucose border of the isthmus located just below the cricoid cartilage.
level 100 mg/dL or 2 mg/dL/mL.  A pair of parathyroid glands is located on the posterior aspect
of each lobe. The gland is innervated by the adrenergic and
Postoperative Care cholinergic nervous systems. The recurrent laryngeal nerve
Postoperative management of diabetic patients requires and external motor branch of the superior laryngeal nerve are
meticulous monitoring of insulin requirements. Hypergly- in intimate proximity to the gland. Histologically the thyroid
cemia has been associated with poor outcomes in postop- is composed of numerous follicles filled with proteinaceous
erative and critically ill patients. However, the optimal target colloid. The major constituent of colloid is thyroglobulin, an
for blood glucose level in the perioperative period has not iodinated glycoprotein that serves as the substrate for thyroid
yet been defined. In addition, this target may be different for hormone synthesis. The thyroid gland also contains parafol-
patients with newly diagnosed hyperglycemia than for those licular C cells that produce calcitonin.
with preexisting diabetes. The risks of hypoglycemia must also Production of normal quantities of thyroid hormones
be considered. Currently the ADA recommends that glucose depends on the availability of exogenous iodine. The diet is
levels be maintained between 140 and 180 mg/dL in critically the primary source of iodine. Iodine is reduced to iodide in
ill patients and that insulin treatment be initiated if serum glu- the GI tract, rapidly absorbed into the blood, then actively
cose levels exceed 180 mg/dL.  transported from the plasma into thyroid follicular cells (Fig.
23.10). Binding of iodine to thyroglobulin (i.e., organifica-
tion) is catalyzed by an iodinase enzyme and yields inactive
INSULINOMA
monoiodotyrosine and diiodotyrosine. Approximately 25% of
Insulinomas are rare, benign, insulin-secreting pancreatic the monoiodotyrosine and diiodotyrosine undergo coupling
islet cell tumors. They usually occur as an isolated finding but via thyroid peroxidase to form the active compounds triiodo-
may present as part of multiple endocrine neoplasia syndrome thyronine (T3) and thyroxine (T4). The remaining 75% never
type I (MEN I; insulinoma, hyperparathyroidism, and a pitu- becomes hormones, and eventually the iodine is cleaved and
itary tumor). They occur in women twice as often as in men recycled. T3 and T4 remain attached to thyroglobulin and are
and usually in the fifth or sixth decade of life. The diagnosis stored as colloid until they are released into the circulation.
is made by demonstrating Whipple’s triad: (1) symptoms of Since the thyroid contains a large store of hormones and has a
hypoglycemia with fasting, (2) a glucose level below 50 mg/dL low turnover rate, there is protection against depletion if syn-
with symptoms, and (3) relief of symptoms with administra- thesis is impaired or discontinued.
tion of glucose. An inappropriately high insulin level (>5–10 The T4:T3 ratio of secreted hormones is 10:1. Upon entering
microunits/mL) during a 48- to 72-hour fast confirms the the blood, T4 and T3 bind reversibly to three major proteins:
diagnosis. thyroxine-binding globulin (80% of binding), prealbumin
Preoperatively, patients are often managed with diazox- (10%–15%), and albumin (5%–10%). Only the small amount
ide, an agent that directly inhibits insulin release from beta of free fraction of hormone, however, is biologically active.
cells. Other medical therapies include verapamil, phenytoin, Although only 10% of thyroid hormone secretion is T3, T3 is
propranolol, glucocorticoids, and the somatostatin ana- three to four times more active than T4 per unit of weight and
logues octreotide and lanreotide. Surgical treatment is cura- may be the only active thyroid hormone in peripheral tissues.
tive. Ninety percent of insulinomas are benign, and tumor 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 changes in thyroid function cause significant changes in TSH
tissue function, and stimulate protein synthesis and carbohy- secretion. The normal level of TSH is 0.4–5.0 milliunits/L. A
drate and lipid metabolism. TSH level of 0.1–0.4 milliunits/L with normal levels of free T3
Thyroid hormone acts directly on cardiac myocytes and (FT3) and free T4 (FT4) is diagnostic of subclinical hyperthy-
vascular smooth muscle cells. Thyroid hormone increases roidism. A TSH level below 0.03 milliunits/L with elevated
myocardial contractility directly, decreases systemic vascular T3 and T4 is diagnostic of overt hyperthyroidism. A TSH
resistance via direct vasodilation, and increases intravascular level of 5.0–10 milliunits/L with normal levels of FT3 and
volume. Most recent studies emphasize the direct effects of T3 FT4 is diagnostic of subclinical hypothyroidism. A TSH level
on the heart and vascular smooth muscle as responsible for the higher than 20 milliunits/L (may be as high as 200 or even
exaggerated hemodynamic effects of hyperthyroidism. 400 milliunits/L) with reduced levels of T3 and T4 is diagnostic
Regulation of thyroid function is controlled by the hypo- of overt hypothyroidism.
thalamus, pituitary, and thyroid glands, which participate in The TRH stimulation test assesses the functional state of
a classic feedback control system. Thyrotropin-releasing hor- the TSH-secreting mechanism in response to TRH and is
mone (TRH) is secreted from the hypothalamus, traverses the used to test pituitary function. Thyroid scans using iodine 123
pituitary stalk, and promotes release of thyrotropin-stimulat- (123I) or technetium 99m (99mTc) evaluate thyroid nodules as
ing hormone (TSH) from the anterior pituitary. TSH binds to “warm” (normally functioning), “hot” (hyperfunctioning), or
specific receptors on the thyroid cell membrane and enhances “cold” (hypofunctioning). Ultrasonography is 90%–95% accu-
all processes of synthesis and secretion of T4 and T3. A rate in determining whether a lesion is cystic, solid, or mixed. 
decrease in TSH causes a reduction in synthesis and secretion
of T4 and T3, a decrease in follicular cell size, and a decrease in
Hyperthyroidism
the gland’s vascularity. An increase in TSH yields an increase
in hormone production and release and an increase in gland Signs and Symptoms
cellularity and vascularity. TSH secretion is also influenced Hyperthyroidism refers to hyperfunctioning of the thyroid
by plasma levels of T4 and T3 via a negative feedback loop. gland, with excessive secretion of active thyroid hormones.
In addition to the feedback system, the thyroid gland has an The majority of cases of hyperthyroidism result from one of
autoregulatory mechanism that maintains a consistent level of three pathologic processes: Graves disease, toxic multinodular
hormone stores. 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
Diagnosis
and may be emotionally unstable. The skin is warm and moist,
The third generation of the TSH assay is now the single best the face is flushed, the hair is fine, and the nails are soft and
test of thyroid hormone action at the cellular level. Small 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 Iodide in high concentrations inhibits release of hormones
stare, with retraction of the upper eyelids (exophthalmos or from the hyperfunctioning gland. High concentrations of
proptosis) resulting from an infiltrative process that involves iodide decrease all phases of thyroid synthesis and release
retrobulbar fat and the eyelids. Wasting, weakness, and fatigue and result in reduced gland size and possibly a decrease in
of the proximal limb muscles are common. The patient usu- vascularity. Its effects occur immediately but are short-lived.
ally complains of extreme fatigue but an inability to sleep. Therefore iodide is usually reserved for preparing hyperthy-
Increased bone turnover and osteoporosis may occur. A fine roid patients for surgery, managing patients with actual or
tremor of the hands and hyperactive tendon reflexes are com- impending thyroid storm, and treating patients with severe
mon. Weight loss despite an increased appetite occurs second- thyrocardiac disease. There is no need to delay surgery in a
ary to increased calorigenesis. Bowel movements are frequent patient with otherwise well-controlled thyrotoxicosis in order
and diarrhea is not uncommon. to initiate iodide therapy.
The cardiovascular system is most threatened by hyper- Iodide is administered orally as a saturated solution of potas-
metabolism of peripheral tissues, increased cardiac work sium iodide (SSKI), 3 drops PO every 8 hours for 10–14 days.
with tachycardia, dysrhythmias (commonly atrial) and pal- The radiographic contrast dye ipodate or iopanoic acid (0.5–3.0 g
pitations, a hyperdynamic circulation, increased myocardial every day) contains iodide and demonstrates beneficial effects
contractility and cardiac output, and cardiomegaly. The car- similar to those of inorganic iodide. In addition, ipodate inhib-
diac responses are due to the direct effects of T3 on the myo- its the peripheral conversion of T4 to T3 and may also antago-
cardium and peripheral vasculature. Graves disease, or toxic nize thyroid hormone binding to receptors. Antithyroid drug
diffuse goiter, occurs in 0.4% of the US population and is the therapy should precede initiation of iodide treatment, because
leading cause of hyperthyroidism. The disease typically occurs administration of iodide alone will increase thyroid hormone
in females (female/male ratio is 7:1) between the ages of 20 stores and exacerbate the thyrotoxic state. Lithium carbonate
and 40 years. Although the etiology is unknown, Graves dis- 300 mg PO every 6 hours may be given in place of potassium
ease appears to be a systemic autoimmune disease caused by iodide or ipodate to patients who are allergic to iodide.
thyroid-stimulating antibodies that bind to TSH receptors in β-Adrenergic antagonists do not affect the underlying thyroid
the thyroid, activating adenylcyclase and stimulating thyroid abnormality but may relieve signs and symptoms of increased
growth, vascularity, and hypersecretion of T4 and T3. The adrenergic activity such as anxiety, sweating, heat intolerance,
thyroid is usually diffusely enlarged, becoming two to three tremors, and tachycardia. Propranolol offers the added features
times its normal size. An ophthalmopathy occurs in 30% of of impairing the peripheral conversion of T4 to T3.
cases and may include upper lid retraction, a wide-eyed stare, Ablative therapy with radioactive iodine 131 (131I) or surgery
muscle weakness, proptosis, and an increase in intraocular is recommended for patients with Graves disease for whom
pressure. The diagnosis of Graves disease is confirmed by the medical management has failed, as well as for patients with toxic
presence of thyroid-stimulating antibodies in the context of a multinodular goiter or a toxic adenoma. The remission rate is
low TSH level and elevated T4 and T3 levels. 80%–98%. A major disadvantage of therapy is that 40%–70% of
Toxic multinodular goiter usually arises from long-stand- treated patients become hypothyroid within 10 years.
ing simple goiter and occurs mostly in patients older than Surgery (i.e., subtotal thyroidectomy or possibly total thy-
age 50. It may present with extreme thyroid enlargement roidectomy) results in prompt control of disease and is asso-
that can cause dysphagia, globus sensation, and possibly ciated with a lower incidence of hypothyroidism (10%–30%)
inspiratory stridor from tracheal compression. The latter is than radioactive iodine therapy. Subtotal thyroidectomy cor-
especially common when the mass extends into the thoracic rects thyrotoxicosis in over 95% of patients.
inlet behind the sternum. In severe cases, superior vena cava Hyperthyroidism during pregnancy is treated with low
obstruction syndrome may also be present. The diagnosis is dosages of antithyroid drugs. However, these drugs do cross
confirmed by a thyroid scan demonstrating “hot” patchy foci the placenta and can cause fetal hypothyroidism. If the mother
throughout the gland or one or two “hot” nodules. Radio- remains euthyroid while taking small dosages of an antithy-
active iodine uptake and serum T4 and T3 levels may only roid drug, the occurrence of fetal hypothyroidism is rare.
be slightly elevated. The goiter must be differentiated from Radioactive iodine treatment is contraindicated during preg-
a neoplasm, and a computed tomography (CT) scan and nancy, as is oral iodide therapy, because it can cause fetal goi-
biopsy may be necessary.  ter and hypothyroidism. Long-term use of propranolol during
pregnancy is controversial, since intrauterine growth retarda-
Treatment tion has been attributed to its use. Thyroid storm occurring
The first line of treatment for hyperthyroidism is an antithy- in pregnancy is managed in the same way as in nonpregnant
roid drug, either methimazole or propylthiouracil (PTU). patients. 
These agents interfere with the synthesis of thyroid hormones
by inhibiting organification and coupling. PTU has the added Management of Anesthesia
advantage of inhibiting the peripheral conversion of T4 to T3. In hyperthyroid patients undergoing surgery, euthyroidism
A euthyroid state can almost always be achieved in 6–8 weeks should definitely be established preoperatively. In elective
with either drug if a sufficient dosage is used. cases this may mean waiting a substantial time (6–8 weeks)
Chapter 23  Endocrine Disease 461

for antithyroid drugs to become effective. In emergency cases managed with IV administration of glucose-containing crys-
the use of an IV β-blocker, ipodate, glucocorticoids, and PTU talloid solutions, and cooling measures (e.g., cooling blanket,
is usually necessary. No IV preparation of PTU is available, ice packs, administration of cool humidified oxygen) are used
so the drug must be taken orally, via a nasogastric tube, or to counter the fever. β-Blockers should be titrated to decrease
rectally. Glucocorticoids (dexamethasone 2 mg IV every heart rate to less than 90 beats per minute. Dexamethasone
6 hours) should be administered to decrease hormone release 2 mg every 6 hours or cortisol 100–200 mg every 8 hours can
and reduce the peripheral conversion of T4 to T3. be used to decrease hormone release and conversion of T4 to
Evaluation of the upper airway for evidence of tracheal T3. Antithyroid drugs (PTU 200–400 mg every 8 hours) may be
compression or deviation caused by a goiter is an important administered through a nasogastric tube, orally, or rectally. If
part of the preoperative evaluation. Examination of chest circulatory shock is present, IV administration of a direct vaso-
radiographs and CT scans is often helpful in this regard. Intra- pressor (phenylephrine) is indicated. A β-adrenergic blocker or
operatively the need for invasive monitoring is determined digitalis is recommended for atrial fibrillation accompanied by
on an individual basis and depends on the type of surgery a fast ventricular response. Serum thyroid hormone levels
to be performed and the medical condition of the patient. generally return to normal within 24–48 hours, and recovery
Controlled studies in hyperthyroid animals demonstrate no occurs within 1 week. The mortality rate for thyroid storm
clinically significant increase in anesthetic requirements (i.e., remains surprisingly high at approximately 20%. 
minimum alveolar concentration). Establishment of adequate
anesthetic depth is extremely important to avoid exaggerated
Hypothyroidism
sympathetic nervous system responses. Drugs that stimulate
the sympathetic nervous system (i.e., ketamine, pancuronium, Signs and Symptoms
atropine, ephedrine, epinephrine) should be avoided. Eye pro- Hypothyroidism, or myxedema, is a relatively common dis-
tection (eyedrops, lubricant, eye pads) is critical, especially for ease affecting 0.5%–0.8% of the adult population. Primary
patients with proptosis. hypothyroidism results in decreased production of thyroid
For maintenance of anesthesia, any of the potent inhala- hormones despite adequate or increased levels of TSH and
tion agents may be used. A concern in hyperthyroid patients accounts for 95% of all cases of hypothyroidism. The most
is organ toxicity secondary to an increase in drug metabolism. common cause in the United States is ablation of the gland by
Nitrous oxide and opioids are safe and effective in hyperthy- radioactive iodine or surgery. The second most common type
roid patients. Hyperthyroid patients may have co-existing of hypothyroidism is idiopathic and probably autoimmune in
muscle disease (e.g., myasthenia gravis) with reduced require- origin, with autoantibodies blocking TSH receptors in the thy-
ments for the nondepolarizing muscle relaxants; therefore roid. Hashimoto thyroiditis is an autoimmune disorder char-
careful titration is required. For treatment of intraoperative acterized by goitrous enlargement and hypothyroidism that
hypotension, a direct-acting vasopressor (phenylephrine) usually affects middle-aged women.
is preferred. Ephedrine, epinephrine, norepinephrine, and In adults, hypothyroidism has a slow, insidious, progressive
dopamine should be avoided or administered in extremely course. There is gradual slowing of mental and physical activ-
low doses to prevent exaggerated hemodynamic responses. ity. In mild cases, patients tire easily and experience weight
Regional anesthesia can be safely performed and in fact may gain. In moderate to severe cases, patients develop fatigue,
be a preferred technique. Epinephrine-containing local anes- lethargy, apathy, and listlessness. Speech becomes slow and
thetic solutions should be avoided. the intellect becomes dull. With time, patients experience cold
Removal of the thyrotoxic gland does not mean immedi- intolerance, decreased sweating, constipation, menorrhagia,
ate resolution of thyrotoxicosis. The half-life of T4 is 7–8 days; and slowing of motor function secondary to muscle stiffness
therefore β-blocker therapy may need to be continued in the and cramping. They gain weight despite a decrease in appetite.
postoperative period.  Physically they demonstrate dry thickened skin, coarse facial
features, dry brittle hair, a large tongue, a deep hoarse voice,
Thyroid Storm and periorbital and peripheral edema.
Thyroid storm is a life-threatening exacerbation of hyperthy- Physiologically, cardiac output is decreased secondary
roidism precipitated by trauma, infection, medical illness, or to reductions in stroke volume and heart rate. Barorecep-
surgery. Thyroid storm and malignant hyperthermia can pres- tor function is also impaired. The electrocardiogram (ECG)
ent with similar intraoperative and postoperative signs and in patients with overt hypothyroidism shows flattened or
symptoms (i.e., hyperpyrexia, tachycardia, hypermetabolism); inverted T waves, low-amplitude P waves and QRS complexes,
differentiation between the two may be extremely difficult. and sinus bradycardia; ventricular dysrhythmias may also be
Thyroid storm most often occurs in the postoperative present. Peripheral vascular resistance is increased and blood
period in untreated or inadequately treated hyperthyroid volume is reduced, which results in pale, cool skin. Pericar-
patients after emergency surgery. Patients manifest extreme dial effusions are common. Hypothyroid patients usually have
anxiety, fever, tachycardia, cardiovascular instability, and hypercholesterolemia and hypertriglyceridemia and may have
altered consciousness. Treatment includes rapid alleviation coronary artery disease. Hyponatremia and impairment of
of thyrotoxicosis and general supportive care. Dehydration is free water excretion are also common, related to inappropriate
462 STOELTING’S ANESTHESIA AND CO-EXISTING DISEASE

secretion of antidiuretic hormone (ADH). Gastrointestinal characterized by decreased cardiac output, stroke volume,
function is slow, and an adynamic ileus may occur. Deep ten- heart rate, baroreceptor reflexes, and intravascular volume
don reflexes demonstrate a prolonged relaxation phase. may be compromised by surgical stress and cardiac-depres-
Twenty percent of women older than 60 years have subclin- sant anesthetic agents. Decreased ventilatory responsiveness
ical hypothyroidism. Subclinical disease is associated with an to hypoxia and hypercarbia is enhanced by anesthetic agents.
increased risk of coronary heart disease in patients with a TSH Hypothermia occurs quickly and is difficult to treat. Hema-
level above 10 milliunits/L. Even though changes are revers- tologic abnormalities such as anemia (25%–50% of patients)
ible with l-thyroxine therapy, use of thyroid replacement for and dysfunction of platelets and coagulation factors (espe-
subclinical disease remains controversial. cially factor VIII), electrolyte imbalances (hyponatremia),
Secondary hypothyroidism is diagnosed by reduced levels and hypoglycemia are common and require close monitor-
of FT4, T4, and T3, as well as a reduced TSH level. A TRH stim- ing intraoperatively. Decreased neuromuscular excitability is
ulation test can confirm pituitary abnormality as the cause. In exacerbated by anesthetic drugs.
primary hypothyroidism, basal levels of TSH are elevated, and These patients can be extremely sensitive to narcotics and
the elevation is exaggerated after TRH administration. With sedatives and may even be lethargic secondary to their disease;
pituitary dysfunction there is a blunted or absent response to therefore preoperative sedation should be undertaken with
TRH. caution. Hypothyroid patients also appear to have an increased
Euthyroid sick syndrome is the occurrence of abnor- sensitivity to anesthetic drugs, although the effect of thyroid
mal results on thyroid function tests in critically ill patients activity on the minimum alveolar concentration of volatile
with significant nonthyroidal illness. Characteristic findings anesthetics is negligible. Increased sensitivity is probably sec-
include low levels of T3 and T4 and a normal TSH level. As ondary to reduced cardiac output, decreased blood volume,
illness increases in severity, T3 and T4 levels decrease further. abnormal baroreceptor function, decreased hepatic metabo-
The etiology of this response is not understood. Euthyroid sick lism, and decreased renal excretion of drugs. In patients with
syndrome may be a physiologic response to stress, and it can a hypodynamic cardiovascular system, invasive monitoring
be induced by surgery. No treatment for thyroid function is and/or transesophageal echocardiography may be needed to
necessary. Differentiating hypothyroidism from euthyroid sick monitor intravascular volume and cardiac status.
syndrome can be extremely difficult. A serum TSH level is the General anesthetics should be administered through an
best aid. Levels higher than 10 milliunits/L indicate hypothy- endotracheal tube following either rapid-sequence induction
roidism, whereas levels lower than 5.0 milliunits/L indicate or awake intubation if a difficult airway is present. Hypothy-
euthyroidism. roid patients are very sensitive to the myocardial-depressant
Changes in thyroid function test results have also been doc- effects of the potent inhalational agents. Vasodilation in the
umented following uncomplicated acute myocardial infarc- presence of possible hypovolemia and impaired barorecep-
tions, congestive heart failure, and cardiopulmonary bypass. tor activity can produce significant hypotension. Pharmaco-
Significant depression of T3 levels occurs, but administration logic support for intraoperative hypotension is best provided
of T3 does not appear efficacious. In addition, the use of T3 as with ephedrine, dopamine, or epinephrine and not a pure
an inotrope has not been shown to result in any substantial α-adrenergic agonist (phenylephrine). Unresponsive hypoten-
improvement in cardiac performance.  sion may require supplemental steroid administration.
Controlled ventilation is recommended in all cases, since
Treatment these patients tend to hypoventilate if allowed to breathe spon-
l-Thyroxine (levothyroxine sodium) is usually administered taneously. Dextrose in normal saline is the recommended IV
for the treatment of hypothyroidism. The first evidence of a fluid to avoid hypoglycemia and minimize hyponatremia sec-
therapeutic response to thyroid hormone is sodium and water ondary to impaired free water clearance.
diuresis and a reduction in the TSH level. In patients with If emergency surgery is necessary, the potential for severe
hypothyroid cardiomyopathy, a measurable improvement in intraoperative cardiovascular instability and myxedema coma
myocardial function is often achieved with therapy. in the postoperative period is high. Intravenous thyroid
Although angina is uncommon in hypothyroidism, it can replacement therapy should be initiated as soon as possible.
appear or worsen during treatment of the hypothyroid state Although IV l-thyroxine takes 10–12 days to yield a peak basal
with thyroid hormone. Medical management of such patients metabolic rate, IV triiodothyronine is effective in 6 hours, with
is particularly difficult.  a peak basal metabolic rate seen in 36–72 hours. l-Thyrox-
ine 300–500 μg IV or l-triiodothyronine 25–50 μg IV is an
Management of Anesthesia acceptable initial dose. Steroid coverage with hydrocortisone
Hypothyroid patients may be at increased risk for a number or dexamethasone is necessary, since decreased adrenal corti-
of reasons when undergoing either general or regional anes- cal function often accompanies hypothyroidism. Phosphodi-
thesia. Airway compromise secondary to a swollen oral cavity, esterase inhibitors such as milrinone may be effective in the
edematous vocal cords, or goitrous enlargement may be pres- treatment of reduced myocardial contractility, because their
ent. Decreased gastric emptying increases the risk of regurgi- mechanism of action does not depend on β receptors, whose
tation and aspiration. A hypodynamic cardiovascular system number and sensitivity may be reduced in hypothyroidism. 
Chapter 23  Endocrine Disease 463

Myxedema Coma If the mass extends into the substernal regional (i.e., ante-
Myxedema coma is a rare severe form of hypothyroidism rior mediastinal mass), superior vena cava obstruction, major
characterized by delirium or unconsciousness, hypoventila- airway obstruction, and/or cardiac compression may occur.
tion, hypothermia (80% of patients), bradycardia, hypoten- The latter two may become apparent only upon induction of
sion, and a severe dilutional hyponatremia. It occurs most general anesthesia. Airway obstruction appears to result from
commonly in elderly women with a long history of hypo- changes in lung and chest wall mechanics that occur with
thyroidism. Infection, trauma, cold, and central nervous changes in patient position or with the onset of muscle paraly-
system (CNS) depressants predispose hypothyroid patients sis. During spontaneous respiration, the larger airways are
to myxedema coma. Ironically most patients are not coma- supported by negative intrathoracic pressure, and the effects of
tose. Hypothermia (as low as 27°C) is a cardinal feature and extrinsic compression may be apparent in only the most severe
results from impaired thermoregulation caused by defec- cases. With cessation of spontaneous respiration, compensa-
tive function of the hypothalamus (a target tissue of thyroid tory mechanisms are removed and airway obstruction occurs.
hormone). Myxedema coma is a medical emergency with a In addition, positive pressure ventilation may demonstrate
mortality rate higher than 50%. Intravenous l-thyroxine or total airway occlusion. A preoperative history of dyspnea in
l-triiodothyronine is the treatment of choice. Intravenous the upright or supine position is predictive of possible airway
hydration with glucose-containing saline solutions, temper- obstruction during general anesthesia. A CT scan must be
ature regulation, correction of electrolyte imbalances, and examined to assess the extent of the tumor. Echocardiography
stabilization of the cardiac and pulmonary systems are nec- with the patient in the upright and supine positions can indi-
essary. Mechanical ventilation is frequently required. Heart cate the degree of cardiac compression.
rate, blood pressure, and temperature usually improve within If practical, local anesthesia is recommended for patients
24 hours, and a relative euthyroid state is achieved in 3–5 requiring surgery. If general anesthesia is necessary, preopera-
days. Hydrocortisone 100–300 mg/day IV is also prescribed tive shrinkage of a thyroid tumor by radiation or chemother-
to treat possible adrenal insufficiency.  apy is recommended unless the altered histologic appearance
would prevent an accurate diagnosis, as when a biopsy speci-
men is required for diagnosis. Unfortunately, goiters are not
Goiter and Thyroid Tumors
sensitive to radiation therapy. In such patients an awake intu-
A goiter is a swelling of the thyroid gland that results from bation with fiberoptic bronchoscopy using an anode tube is
compensatory hypertrophy and hyperplasia of follicular epi- recommended. The patient is placed in semi-Fowler posi-
thelium secondary to a reduction in thyroid hormone output. tion, and volatile anesthetic with nitrous oxide and oxygen is
The cause may be a deficient intake of iodine, ingestion of a administered using spontaneous ventilation. Muscle relaxants
dietary (e.g., cassava) or pharmacologic (e.g., phenylbutazone, are avoided. It must be possible to change the patient’s position.
lithium) goitrogen, or a defect in the hormonal biosynthetic Following tumor resection the airway should be exam-
pathway. The size of the goiter is determined by the level and ined by fiberoptic bronchoscopy to detect tracheomalacia and
duration of hormone insufficiency. In most cases a goiter is determine whether and when tracheal extubation is appropri-
associated with a euthyroid state, with the increased mass and ate. A rigid bronchoscope should be available to reestablish
cellular activity eventually overcoming the impairment in the airway if collapse occurs. Cardiopulmonary bypass equip-
hormone synthesis. However, hypothyroidism or hyperthy- ment should be on standby during the case. 
roidism occurs in some cases. Patients with simple nontoxic
goiter are euthyroid. Nevertheless, simple nontoxic goiter is a
Complications of Thyroid Surgery
forerunner of toxic multinodular goiter. In the United States,
most cases of simple nontoxic goiter are of unknown cause Morbidity from thyroid surgery approaches 13%. Recur-
and are treated with l-thyroxine. Surgery is indicated only if rent laryngeal nerve injury may be unilateral or bilateral and
medical therapy is ineffective and the goiter is compromising temporary or permanent. The injury may result from excess
the airway or is cosmetically unacceptable. trauma to the nerve(s) (abductor and/or adductor fibers of
Anesthetic management of a patient undergoing surgical the recurrent laryngeal nerve), inadvertent ligation, or tran-
removal of a large goiter or thyroid mass that compromises the section. When paralysis of the abductor muscles to the vocal
airway presents a major challenge. Examination of a CT scan of cord occurs, the involved cord assumes a median or parame-
the neck will demonstrate anatomic abnormalities. Sedatives dian position. If trauma is unilateral, the patient experiences
and narcotics should be avoided or used with great caution hoarseness but no airway obstruction, and function usually
before and during endotracheal tube placement. Awake intu- returns in 3–6 months. Ligation or transection of the nerve
bation with an armored (anode) tube using fiberoptic bron- results in permanent hoarseness. Bilateral involvement is more
choscopy is probably the safest method to assess the degree serious, since the patient usually experiences airway obstruc-
of obstruction and establish the airway. Surgical removal of tion and problems with coughing and respiratory toilet.
the mass may reveal underlying tracheomalacia and a collaps- Depending on the degree of damage, a temporary or perma-
ible airway. Tracheal extubation should be performed with as nent tracheostomy is usually necessary. Injury to the adductor
much caution and concern as intubation. 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 medullary carcinoma of the thyroid, alimentary tract ganglio-
aspiration. Injury to the motor branch of the superior laryn- neuromatosis, thickened corneal nerves, and a marfanoid hab-
geal nerve, which innervates the inferior pharyngeal constric- itus. Almost 100% of patients with MEN II have or will develop
tor and cricothyroid muscles, can also occur during thyroid bilateral benign adrenal medullary pheochromocytomas.
dissection. This injury results in weakening of the voice and Eighty percent of pheochromocytomas are located in the
inability to create high tones. adrenal medulla. The organ of Zuckerkandl near the aortic
Hypoparathyroidism is also a complication of thyroid sur- bifurcation is the most common extraadrenal site. Two per-
gery. It usually results from damage to the blood supply of cent of extraadrenal pheochromocytomas occur in the neck
the parathyroid glands rather than inadvertent removal. One and thorax. Most extraadrenal pheochromocytomas follow
functioning parathyroid gland with an adequate blood sup- a benign course. Malignant pheochromocytomas usually
ply is all that is necessary to avoid hypoparathyroidism. The spread via venous and lymphatic channels, with a predilection
signs and symptoms of hypocalcemia occur in the first 24–48 for liver and bone. The 5-year survival rate for patients with
hours postoperatively. Anxiety, circumoral numbness, tingling malignancy is 44%. Following resection of benign tumors,
of the fingertips, muscle cramping, and positive Chvostek and 5%–10% of patients have a benign recurrence.
Trousseau signs are indicative of hypocalcemia. Stridor can Most pheochromocytomas secrete norepinephrine, either
occur and can proceed to laryngospasm. Immediate treatment alone or, more commonly, in combination with a smaller
with IV calcium gluconate (1 g, 10 mL of a 10% solution) or amount of epinephrine in a ratio of 85:15—the inverse of the
calcium chloride (1 g, 10 mL of a 10% solution) is necessary. A secretion ratio in the normal adrenal gland. Approximately
continuous infusion of calcium for several days is also recom- 15% of tumors secrete predominantly epinephrine.
mended. For long-term management, oral calcium and vita-
min D3 are prescribed, or autotransplantation of parathyroid
Signs and Symptoms
tissue may be performed.
Tracheal compression from an expanding hematoma may The clinical presentation of pheochromocytoma is variable;
cause rapid respiratory compromise in the period immedi- attacks range from infrequent (i.e., once a month or fewer) to
ately after thyroid surgery. Immediate hematoma evacuation numerous (i.e., many times per day) and may last from less
is the first line of treatment. If time permits, the patient should than a minute to several hours. They may occur spontane-
be returned to the operating room. If necessary, the wound ously or be precipitated by physical injury, emotional stress, or
should be opened at the bedside, clots evacuated, and bleed- medications. Hypertension, either continuous or paroxysmal,
ing vessels secured to relieve airway obstruction. A thyroid is the most frequent manifestation of pheochromocytoma.
tray including a tracheostomy set should always be available Headache, sweating, pallor, and palpitations are other classic
at the bedside during the postoperative period so that sutures signs and symptoms. Orthostatic hypotension is also a com-
or clips can be removed and the wound opened emergently.  mon finding and is considered to be secondary to hypovole-
mia and impaired vasoconstrictor reflex responses.
Hemodynamic signs depend on the predominant catechol-
PHEOCHROMOCYTOMA
amine secreted. With norepinephrine, α-adrenergic effects
Pheochromocytomas are catecholamine-secreting tumors that predominate and patients usually have systolic and diastolic
arise from chromaffin cells of the sympathoadrenal system. hypertension and a reflex bradycardia. With epinephrine,
Although pheochromocytomas account for fewer than 0.1% β-adrenergic effects predominate and patients usually have
of all cases of hypertension in adults, their detection is impera- systolic hypertension, diastolic hypotension, and tachycardia.
tive, since they have lethal potential and are one of the few Despite the 10-fold higher levels of circulating catecholamines,
truly curable forms of hypertension. Uncontrolled catechol- the hemodynamics are not greatly different in patients with
amine release can result in malignant hypertension, cerebro- pheochromocytomas and those with essential hypertension.
vascular accident, and myocardial infarction. Cardiomyopathy is a complication of pheochromocytoma.
The precise cause of a pheochromocytoma is unknown. In addition, high catecholamine levels result in coronary vaso-
Pheochromocytomas are usually an isolated finding (90% of constriction through α-adrenergic pathways, which reduces
cases); 10% are inherited (familial) as an autosomal dominant coronary blood flow and potentially creates ischemia. Dilated
trait. Familial pheochromocytomas usually occur as bilateral and hypertrophic cardiomyopathies as well as left ventricu-
adrenal tumors or as extraadrenal tumors that appear in the lar outflow tract obstruction have been demonstrated echo-
same anatomic site over successive generations. Both sexes cardiographically. ECG abnormalities may include elevation
are equally affected, and the peak incidence is in the third to or depression of the ST segment, flattening or inversion of
fifth decades of life. Familial pheochromocytomas can also be T waves, prolongation of the QT interval, high or peaked P
part of the MEN syndromes and can occur in association with waves, left axis deviation, and dysrhythmias. The cardiomy-
several neuroectodermal dysplasias (e.g., von Hippel-Lindau opathy appears reversible if catecholamine stimulation is
syndrome). Patients with MEN IIA have a pheochromocy- removed early before fibrosis has occurred. Pheochromocy-
toma, medullary carcinoma of the thyroid, and hyperparathy- toma patients may also develop cardiac hypertrophy with con-
roidism. Patients with MEN IIB have a pheochromocytoma, gestive heart failure secondary to sustained hypertension.
Chapter 23  Endocrine Disease 465

Although pheochromocytoma patients rarely have primary


TABLE 23.7   Pattern of Catecholamine Production by
diabetes, most have an elevated blood glucose level secondary Site of Pheochromocytoma
to catecholamine stimulation of glycogenolysis and inhibition   
of insulin release.  Adrenal +
Adrenal Extraadrenal Extraadrenal

Diagnosis Norepinephrine 61% 31% 8%


Epinephrine 100% — —
When a pheochromocytoma is clinically suspected, excess Norepinephrine + 95% — 5%
catecholamine secretion must be demonstrated. For patients epinephrine
with a low probability of having a pheochromocytoma, a Adapted from Kaser H. Clinical and diagnostic findings in patients with chromaffin
24-hour urine collection for measurement of metanephrines tumors: pheochromocytomas, pheochromoblastomas. Recent Results Cancer
and catecholamines is a useful screening test. However, the Res. 1990;118:97-105.

most sensitive test for patients at high risk (familial pheochro-


mocytoma or classic symptoms) is measurement of plasma lower blood pressure, increase intravascular volume, prevent
free metanephrines. Catecholamines are metabolized to free paroxysmal hypertensive episodes, allow resensitization of
metanephrines within tumor cells, and these metabolites adrenergic receptors, and decrease myocardial dysfunction.
are continuously released into the circulation. A plasma free Although a significantly reduced intravascular volume may
normetanephrine level higher than 400 pg/mL and/or a meta- accompany a pheochromocytoma, the majority of patients
nephrine level higher than 220 pg/mL confirms the diagnosis have a normal or only slightly decreased intravascular volume.
of pheochromocytoma. A pheochromocytoma is excluded α-Blockade appears to protect myocardial performance and
if the normetanephrine level is less than 112 pg/mL and the tissue oxygenation from the adverse effects of catecholamines.
metanephrine level is less than 61 pg/mL. Phenoxybenzamine is the most frequently prescribed
Results are equivocal in 5%–10% of patients, and in these α-blocker for preoperative use. It is a noncompetitive α1-
cases the clonidine suppression test may be used. In patients antagonist with some α2-blocking properties. Because it is a
with a pheochromocytoma, increased plasma catecholamines noncompetitive blocker, it is difficult for excess catecholamines
result from tumor release that bypasses normal storage and to overcome the blockade. Its long duration of action permits
release mechanisms. Clonidine acts to lower plasma cat- oral dosing only twice daily. The goal of therapy is normoten-
echolamine levels in patients without a pheochromocytoma sion, resolution of symptoms, elimination of ST-segment and
but has no effect on catecholamine levels in patients with a T-wave changes on the ECG, and elimination of dysrhythmias.
pheochromocytoma. Overtreatment can result in severe orthostatic hypotension.
In the past, provocative testing with histamine or tyramine The optimal duration of α-blockade therapy is undetermined
was used to elicit excess catecholamine release from the tumor. and may range from 3 days to 2 weeks or longer. Because of
However, owing to the relatively high incidence of morbidity, the prolonged effect of phenoxybenzamine on α receptors, the
these tests have been abandoned. A glucagon stimulation test recommendation has been to discontinue its use 24–48 hours
is now considered to be the safest and most specific provoca- before surgery to avoid vascular unresponsiveness immedi-
tive test. Glucagon acts directly on the tumor to induce release ately following removal of the tumor. Some anesthesiologists
of catecholamines. A positive response to the test yields a administer only one-half to two-thirds of the morning dose
plasma catecholamine increase of at least three times the base- preceding surgery to address similar concerns. Some surgeons
line values or more than 2000 pg/mL within 1–3 minutes of request its discontinuation 48 hours preoperatively so they can
glucagon administration. This test should be performed only use hypertensive episodes intraoperatively as cues in local-
in patients with a diastolic blood pressure below 100 mm Hg. izing areas of metastasis. Prazosin and doxazosin, pure α1-
Tumor location can be predicted by the pattern of catechol- competitive blockers, are alternatives to phenoxybenzamine.
amine production (Table 23.7). CT detects more than 95% of They are shorter acting, cause less tachycardia, and are easier
adrenal masses larger than 1 cm in diameter. Magnetic resonance to titrate to a desired end point than phenoxybenzamine.
imaging (MRI) offers advantages over CT, including better iden- If tachycardia (i.e., heart rates > 120 beats per minute) or other
tification of small adrenal lesions, better differentiation of various dysrhythmias result after α-blockade with phenoxybenzamine,
types of adrenal lesions, no need for IV contrast, and lack of radi- a β-adrenergic blocker is prescribed. A nonselective β-blocker
ation exposure. Positron emission scanning and selective venous should never be administered before α-blockade, because block-
catheterization with sampling of catecholamines from the adrenal ade of vasodilatory β2-receptors results in unopposed α-agonism,
veins and other sites are additional useful tests.  leading to vasoconstriction and hypertensive crises. The degree
of α- and β-blockade provided by labetalol (i.e., β effects exceed
α effects) may not be appropriate for certain pheochromocytoma
Management of Anesthesia
patients. In very rare circumstances, β-blockade may be initiated
Preoperative Management before α-blockade. A patient with a pheochromocytoma secret-
Since most pheochromocytomas secrete predominantly nor- ing solely epinephrine and with coronary artery disease may
epinephrine, medical therapy has depended on α-blockade to benefit greatly from the β1-selective antagonist esmolol.
466 STOELTING’S ANESTHESIA AND CO-EXISTING DISEASE

α-Methylparatyrosine (metyrosine) inhibits the rate-lim- succinylcholine are examples of vagolytic or sympathomimetic
iting enzyme tyrosine hydroxylase of the catecholamine syn- drugs that may stimulate the sympathetic nervous system.
thetic pathway and may decrease catecholamine production Virtually all patients exhibit increases in systolic arterial
by 50%–80%. In combination with phenoxybenzamine, it has pressure in excess of 200 mm Hg for periods of time intraop-
been shown to facilitate intraoperative hemodynamic man- eratively, irrespective of preoperative initiation of α-blockade.
agement. It is especially useful for malignant and inoperable A number of antihypertensive drugs must be prepared and
tumors. Side effects that include extrapyramidal reactions and ready for immediate administration. Sodium nitroprusside (if
crystalluria have limited its application. available), a direct vasodilator, is the agent of choice because
Calcium channel blockers and ACE inhibitors may also of its potency, immediate onset of action, and short duration
be used to control hypertension. Calcium is a trigger for cat- of action. Phentolamine, a competitive α-adrenergic blocker
echolamine release from the tumor, and excess calcium entry and direct vasodilator, is effective, although tachyphylaxis and
into myocardial cells contributes to a catecholamine-mediated tachycardia are associated with its use. Nitroglycerin is effec-
cardiomyopathy. Nifedipine, diltiazem, and verapamil have all tive, but large doses are often required and may cause tachy-
been used to control preoperative hypertension, as has capto- cardia. Labetalol, with more β- than α-blocking properties, is
pril. An α1-blocker plus a calcium channel blocker is an effec- preferred for predominantly epinephrine-secreting tumors.
tive combination in treatment-resistant cases.  Magnesium sulfate inhibits release of catecholamines from the
adrenal medulla and peripheral nerve terminals, reduces sen-
Intraoperative Management sitivity of α receptors to catecholamines, is a direct vasodilator,
Optimal preparation for pheochromocytoma resection and is an antidysrhythmic. However, like all antihypertensive
involves preoperative administration of an α-adrenergic medications, it is suboptimal in controlling hypertension dur-
blocker with or without a β-blocker with or without ing tumor manipulation. Mixtures of antihypertensive drugs
α-methylparatyrosine, as well as correction of possible hypo- such as nitroprusside (if available), esmolol, diltiazem, and
volemia. Intraoperative goals include avoidance of drugs or phentolamine have been recommended to control refractory
maneuvers that may provoke catecholamine release or poten- hypertension. Increasing the depth of anesthesia is also an
tiate catecholamine actions, and maintenance of cardiovascu- option, although this approach may accentuate the hypoten-
lar stability, preferably with short-acting drugs. Hypertension sion accompanying tumor vein ligation.
frequently occurs during pneumoperitoneum, as well as dur- Dysrhythmias are usually ventricular in origin and are man-
ing tumor manipulation. On the other hand, significant hypo- aged with either lidocaine or β-blockers. Lidocaine is short
tension may develop following ligation of the tumor’s venous acting and has minimal negative inotropic action. Although
drainage. Intraoperative monitoring should include standard propranolol has been widely used, esmolol, a selective β1-
plus invasive monitoring methods. An arterial catheter enables blocker, offers several advantages. Esmolol has a rapid onset
monitoring of blood pressure on a beat-to-beat basis. A cen- and is short acting, which allows adequate control of heart rate;
tral venous pressure catheter is usually sufficient for patients it may also provide protection against catecholamine-induced
without cardiac symptoms or other clinical evidence of cardiac ischemia and development of postoperative hypoglycemia.
involvement. A pulmonary artery catheter or transesophageal Amiodarone, an antidysrhythmic agent that prolongs the dura-
echocardiography may be necessary to manage the large fluid tion of the action potential of atrial and ventricular muscle, has
requirements, major volume shifts, and possible underlying been used as an alternative to β-blockers to treat supraventricu-
myocardial dysfunction in patients with very active tumors. lar tachycardia associated with hypercatecholaminemia.
A large positive fluid balance is usually required to manage Hypotension following tumor vein ligation is usually sig-
hypotension and keep intravascular volumes within a normal nificant and occurs secondary to a combination of factors,
range. including an immediate decrease in plasma catecholamine
Intraoperative ultrasonography can be used to localize levels (half-lives of norepinephrine and epinephrine are ≈1–2
small functional tumors and perform adrenal-sparing proce- minutes), vasodilation from residual α-blockade with phenoxy-
dures or partial adrenalectomies. Adrenal-sparing procedures benzamine, intraoperative fluid and blood loss, and increased
are particularly valuable when bilateral adrenal pheochro- anesthetic depth. Hypotension with systolic pressures in the
mocytomas must be removed. Laparoscopy can be used for range of 70–79 mm Hg is not infrequent. To prevent precipi-
tumors smaller than 4–5 cm and is becoming the surgical tous hypotension, volume expansion should be attained before
approach of choice for many endocrine surgeons. tumor vein ligation. Lactated Ringer solution and physiologic
Factors that stimulate catecholamine release (e.g., fear, saline are the recommended fluids for use before tumor removal.
stress, pain, shivering, hypoxia, hypercarbia) must be mini- Vasopressors and inotropes should be viewed as a secondary
mized in the perioperative period. Although all anesthetic treatment modality. Residual α-adrenergic blockade and down-
drugs have been used with some degree of success, certain regulation of receptors make patients relatively less responsive
drugs should theoretically be avoided to prevent possible to vasopressors. Intraoperative administration of blood salvage
adverse hemodynamic responses. Morphine and atracurium products has resulted in postresection hypertension second-
can cause histamine release, which may provoke release of ary to the catecholamine content of the blood. A decrease in
catecholamines from the tumor. Atropine, pancuronium, and anesthetic depth will also aid in controlling hypotension. With a
Chapter 23  Endocrine Disease 467

decrease in plasma catecholamine levels immediately following Surgery is one of the most potent and best-studied activa-
resection, insulin levels increase and hypoglycemia may occur. tors of the hypothalamic-pituitary-adrenal (HPA) axis. The
Therefore dextrose-containing solutions should be added after degree of activation of the axis depends on the magnitude
tumor removal. Glucocorticoid therapy should be administered and duration of surgery and the type and depth of anesthe-
if a bilateral adrenalectomy is performed or if hypoadrenalism sia. Deep general anesthesia or regional anesthesia blunts but
is a possibility.  does not eliminate this response. Increases in ACTH begin
with surgical incision and remain elevated during surgery,
Postoperative Management with the peak level occurring with pharmacologic reversal of
The majority of patients become normotensive following com- muscle relaxants and extubation of the patient at the end of the
plete tumor resection. However, plasma catecholamine levels procedure. Hormone levels remain elevated for several days
do not return to normal until 7–10 days after surgery because postoperatively.
of a slow release of stored catecholamines from peripheral
nerves. Fifty percent of patients are hypertensive for several
Hypercortisolism (Cushing Syndrome)
days after surgery, and 25%–30% remain hypertensive indefi-
nitely. In these patients, hypertension is sustained rather than Cushing syndrome results from chronic exposure to excess
paroxysmal, lower than before surgery, and not accompanied glucocorticoids. The disorder may be ACTH dependent,
by the classic features of hypercatecholaminemia. The differ- ACTH independent, or iatrogenic. ACTH-dependent eti-
ential diagnosis of persistent hypertension includes a missed ologies include pituitary corticotrope adenomas (known as
pheochromocytoma, surgical complications with subsequent Cushing disease) and ectopic secretion of ACTH from nonpi-
renal ischemia, and underlying essential hypertension. tuitary tumors (predominantly carcinoid tumors, especially
Hypotension is the most frequent cause of death in the lung). ACTH-independent etiologies include adrenocortical
period immediately after surgery. Large volumes of fluid are adenomas and carcinomas or adrenal hyperplasia. Medical
necessary, since the peripheral vasculature is poorly respon- use of glucocorticoids for immunosuppression or treatment of
sive to reduced levels of catecholamines. Vasopressors are a inflammatory disorders represents the iatrogenic cause. Medi-
secondary consideration. Steroid supplementation may be cal use of glucocorticoids aside, the majority of patients with
necessary if hypoadrenalism is present. Dextrose-containing Cushing syndrome have an ACTH-producing corticotrope
solutions should be included as part of the fluid therapy, and adenoma of the pituitary. Only 10% of patients with Cush-
plasma glucose levels should be monitored for 24 hours.  ing syndrome have a primary adrenal (autonomous release of
cortisol) cause of their disease. Cushing syndrome generally
occurs in the third or fourth decade of life. On clinical presen-
ADRENAL GLAND DYSFUNCTION
tation, patients demonstrate an upregulation of gluconeogen-
Each adrenal gland consists of two components, the adrenal esis, lipolysis, and protein catabolism. They also demonstrate
cortex and the adrenal medulla. The adrenal cortex is respon- signs of mineralocorticoid excess. Signs and symptoms include
sible for synthesis of three groups of hormones, classified as glu- obesity (central adiposity), hyperglycemia (overt diabetes in
cocorticoids, mineralocorticoids (aldosterone), and androgens. <20%), diastolic hypertension, hirsutism, amenorrhea, osteo-
Corticotropin (ACTH) is secreted by the anterior pituitary gland porosis, and emotional liability and depression, with unique/
in response to corticotropin-releasing hormone (CRH), which specific features of fragile skin, easy bruising, broad purple
is synthesized in the hypothalamus and carried to the anterior striae, and signs of proximal myopathy with thin extremities.
pituitary in the portal blood. ACTH stimulates the adrenal cor- Diagnosis is made by first excluding exogenous glucocorti-
tex to produce cortisol. Maintenance of systemic blood pressure coid use and demonstrating an elevated 24-hour urinary free
by cortisol reflects the importance of this hormone in facilitat- cortisol level. Patients also demonstrate a failure to suppress
ing conversion of norepinephrine to epinephrine in the adre- morning cortisol after overnight exposure to dexamethasone,
nal medulla. Hyperglycemia in response to cortisol secretion and loss of diurnal cortisol secretion with high levels at mid-
reflects gluconeogenesis and inhibition of the peripheral use of night. A plasma ACTH level follows; if normal or elevated,
glucose by cells. Retention of sodium and excretion of potas- the patient has ACTH-dependent Cushing syndrome. Further
sium are facilitated by cortisol. The antiinflammatory effects of testing will include a pituitary MRI, chest CT, corticotropin-
cortisol and other glucocorticoids (cortisone, prednisone, meth- releasing hormone (CRH) test, and high-dose dexamethasone
ylprednisolone, dexamethasone, triamcinolone) are particularly test. These patients demonstrate a decrease in cortisol and
apparent in the presence of high serum concentrations of these 17-hydroxycorticosteroid levels after high-dose dexametha-
hormones. Aldosterone secretion is regulated by the renin- sone because the pituitary tumor retains some negative feed-
angiotensin system and serum concentrations of potassium. back control, which adrenal tumors do not possess. A low
The adrenal medulla is a specialized part of the sympathetic ACTH level confirms the diagnosis of ACTH-independent
nervous system that is capable of synthesizing norepinephrine Cushing syndrome, and a CT scan of the adrenal glands is
and epinephrine. The only important disease process associ- performed.
ated with the adrenal medulla is pheochromocytoma. Adrenal Treatment for Cushing disease requires removal of
medullary insufficiency is not known to occur. the pituitary corticotrope tumor via a transsphenoidal
468 STOELTING’S ANESTHESIA AND CO-EXISTING DISEASE

hypophysectomy. Treatment for ACTH-independent disease used, and other invasive monitors should be determined on a
requires removal of the adrenal tumor. Preoperative medical case-by-case basis. Patients with Conn syndrome have a high
control of excess cortisol includes metyrapone (which inhib- incidence of ischemic heart disease. Surgical excision of a soli-
its cortisol synthesis), ketoconazole (which inhibits steroido- tary adrenal adenoma should not require exogenous cortisol
genesis), mitotane (which is an adrenolytic agent and reduces administration, but bilateral manipulation of the adrenal glands
cortisol), and a low-dose IV infusion of etomidate. A hydro- to excise multiple functional tumors may require supplemental
cortisone replacement regimen is initiated at the time of sur- cortisol if transient hypocortisolism is a consideration. 
gery and slowly tapered postoperatively.
There are no specific anesthetic techniques or medications
Hypoaldosteronism
recommended for these cases. Muscle relaxants should be
used cautiously when significant skeletal muscle weakness is Hyperkalemia in the absence of renal insufficiency suggests the
present. Perioperative management of hypertension, hyper- presence of hypoaldosteronism. Hyperchloremic metabolic
glycemia, intravascular fluid volume (usually elevated), and acidosis is a predictable finding in the presence of hypoaldo-
electrolytes (hypokalemia is common) is extremely impor- steronism. Heart block secondary to hyperkalemia, orthostatic
tant. Preoperative diuresis with spironolactone is helpful. hypotension, and hyponatremia may also be present.
The patient’s cardiac reserve dictates the use of intraoperative Isolated deficiency of aldosterone secretion may reflect
invasive monitoring. A pneumothorax is possible during adre- congenital deficiency of aldosterone synthetase or hyporenin-
nal surgery. Careful positioning is necessary for osteopenic emia, resulting from defects in the juxtaglomerular apparatus,
patients. If bilateral adrenalectomy is performed, fludrocorti- or treatment with ACE inhibitors, leading to loss of angioten-
sone will be necessary in the postoperative period (usually day sin stimulation. Hyporeninemic hypoaldosteronism typically
3–5) to provide mineralocorticoid activity. Delayed wound occurs in patients older than age 45 with chronic renal dis-
healing and increased susceptibility to infection can result ease and/or diabetes mellitus. Treatment of hypoaldosteron-
from increased levels of glucocorticoids.  ism includes liberal sodium intake and daily administration
of fludrocortisone. 
Primary Hyperaldosteronism (Conn Syndrome)
Adrenal Insufficiency
Primary hyperaldosteronism, or Conn syndrome, is the most
common cause of mineralocorticoid (aldosterone) excess. Signs and Symptoms
Bilateral micronodular adrenal hyperplasia is a more com- There are two types of adrenal insufficiency (AI): primary and
mon cause (60%) than unilateral adrenal adenoma (40%). secondary. In primary disease (Addison’s disease) the adrenal
Rarely, adrenocortical carcinoma is responsible. Hypokalemic glands are unable to elaborate sufficient quantities of gluco-
hypertension is the common presentation. Clinical features corticoid, mineralocorticoid, and androgen hormones. The
include sodium retention, potassium depletion, hydrogen most common cause of this rare endocrinopathy is bilateral
depletion with metabolic alkalosis, and cardiac remodeling. adrenal destruction from autoimmune disease. More than
Muscle weakness and cramps occur secondary to hypokale- 90% of the glands must be involved before signs of AI appear.
mia. The diagnosis is made by demonstrating an elevated level The insidious onset of Addison’s disease is characterized by
of plasma aldosterone and low plasma renin (renin secretion fatigue, weakness, anorexia, nausea and vomiting, cutaneous
is inhibited by the high aldosterone levels). A specific aldoste- and mucosal hyperpigmentation, hypovolemia, hyponatre-
rone-renin ratio (ARR) confirms the diagnosis. Localization mia, and hyperkalemia. Secondary AI results from a failure
studies include adrenal CT and MRI and adrenal vein sam- in production of CRH or ACTH caused by hypothalamic-
pling. A unilateral adrenal lesion is treated surgically. Bilat- pituitary disease or suppression of the hypothalamic-pituitary
eral adrenal hyperplasia is managed with spironolactone and axis. Unlike in Addison’s disease, there is only a glucocorticoid
eplerenone (competitive aldosterone antagonist) or amiloride. deficiency in secondary disease. In the majority of cases the
An adrenocortical carcinoma (ACC) is rare, highly malignant, cause is iatrogenic, such as pituitary surgery, pituitary irradia-
requires staging, and carries a poor prognosis. With success- tion, or most commonly the use of synthetic glucocorticoids.
ful surgical removal, adjuvant treatment with mitotane is These patients lack cutaneous hyperpigmentation and may
necessary. demonstrate only mild electrolyte abnormalities.
Anesthetic management requires preoperative restoration of Cortisol is one of the few hormones essential for life. It par-
intravascular volume, electrolyte levels, renal function, and con- ticipates in carbohydrate and protein metabolism, fatty acid
trol of hypertension. Restricting sodium intake and administer- mobilization, electrolyte and water balance, and the antiin-
ing spironolactone (an aldosterone antagonist) and potassium flammatory response. It facilitates catecholamine synthesis
(significant total deficit) are necessary. A preoperative echo- and action; modulates β-receptor synthesis, regulation, cou-
cardiogram will determine the effects of long-standing hyper- pling, and responsiveness; and contributes to normal vascular
tension. Excess preoperative diuresis may render the patient permeability, tone, and cardiac contractility. Cortisol accounts
hypovolemic. No specific anesthetic technique or medications for 95% of the adrenal gland’s glucocorticoid activity, with cor-
are recommended for these cases. An arterial line should be 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 prednisone for more than 3 weeks within the previous year is
The most common cause of AI is exogenous steroids (Table at risk of AI and should receive perioperative supplementa-
23.8). Those who take steroids long term may exhibit signs tion. Patients receiving dosages of steroids between these two
and symptoms of AI during periods of stress, such as sur- extremes may have HPA axis suppression and should prob-
gery or acute illness. For patients with a history of long-term ably receive supplementation. Similarly, patients receiving
steroid use, it may take 6–12 months from the time of dis- more than 2 g/day of topical steroids or more than 0.8 mg/
continuation of the steroids for the adrenal glands to recover day of inhaled steroids on a long-term basis should probably
full function. Recovery from short courses of steroids may receive supplementation.
take several days. Preoperative glucocorticoid coverage Patients with known or suspected adrenal suppression or
should be provided for patients with a positive result on the AI should receive their baseline steroid therapy plus supple-
ACTH stimulation test, Cushing syndrome, or AI, as well mentation in the perioperative period. Supplementation is
as for those at risk of HPA axis suppression or AI based on individualized based on the surgery (Table 23.9). When more
prior glucocorticoid therapy. Adrenal suppression is much than 100 mg/day of hydrocortisone is administered, it may be
more common than AI and is of concern because overt AI, wise to consider substituting methylprednisolone for hydro-
although uncommon, may occur under the stressful condi- cortisone; given its lower mineralocorticoid activity, it is less
tions of surgery and anesthesia. Patients taking prednisone likely to cause fluid retention, edema, and hypokalemia. 
in dosages of less than 5 mg/day (morning dose) for any
length of time, even years, do not demonstrate clinically Management of Anesthesia
significant HPA axis suppression and do not require periop- Acute AI should be considered in the differential diagnosis of
erative supplementation, although they should receive their hemodynamic instability, especially in patients unresponsive
normal daily steroid dose. Any patient who received a gluco- to the usual therapeutic interventions. Therapy includes treat-
corticoid in dosages equivalent to more than 20 mg/day of ment of the cause, repletion of circulating glucocorticoids,
470 STOELTING’S ANESTHESIA AND CO-EXISTING DISEASE

and replacement of water and sodium deficits. Glucocorticoid hyperparathyroidism cases. Hyperplasia, with all four glands
replacement may include IV hydrocortisone, methylpredniso- hyperfunctioning, is present in 15% of cases; it is usually
lone, or dexamethasone. A bolus of 100 mg of hydrocortisone hereditary and may be associated with other endocrine abnor-
followed by a continuous infusion at 10 mg/h is a recom- malities (MEN I and MEN IIA). Adenomas are mostly located
mended prescription. A 100-mg bolus of hydrocortisone in the inferior parathyroid glands. They are 0.5–5 grams in size
every 6 hours is also an acceptable option. When the patient’s (normal gland weighs 25 mg). Although over 50% of patients
condition stabilizes, the steroid dosage is reduced, with even- are asymptomatic, manifestations of hypercalcemia involve
tual conversion to an oral preparation. Volume deficits may primarily the kidneys and skeletal system. Renal pathology
be substantial (2–3 L), and 5% dextrose in normal saline is includes calcium deposits in renal parenchyma or recurrent
the replacement fluid of choice. Hemodynamic support with nephrolithiasis, and skeletal pathology. Signs and symptoms
vasopressors may be necessary. Metabolic acidosis and hyper- of hypercalcemia include CNS (confusion, depression), neu-
kalemia usually resolve with fluid and steroid administration. romuscular (weakness, fatigue), and GI (anorexia, nausea,
In primary disease, administration of the mineralocorticoid vomiting, constipation, peptic ulcer disease) manifestations
fludrocortisone is not necessary acutely because isotonic (Table 23.10). Symptoms are more common at calcium levels
saline replaces sodium loss. above 2.9–3 mmol/L (11.5–12 mg/dL).
No specific anesthetic agent(s) and/or technique(s) are Diagnostic tests include a third-generation PTH immuno-
recommended in managing patients with or at risk of AI. metric assay and a simultaneous calcium level. Patients with
However, etomidate transiently inhibits cortisol synthesis hyperparathyroidism have increased PTH and serum cal-
and should be avoided in this patient population. Patients cium. Localization studies can include a 99mTc sestamibi scan
with untreated AI undergoing emergency surgery should be with single-photon emission CT scan. Surgical excision of the
managed aggressively with invasive monitoring, IV corticoste- abnormal parathyroid tissue is the definitive treatment. Medi-
roids, and fluid and electrolyte resuscitation. Minimal doses of cal management can be safely followed in patients with mild
anesthetic agents and drugs are recommended, since myocar- asymptomatic disease by quarterly monitoring of blood pres-
dial depression and skeletal muscle weakness are frequently sure, serum calcium and creatinine, and bone density. For an
part of the clinical presentation.  adenoma, the one abnormal gland is removed and a second
parathyroid gland is sought, biopsied, and confirmed to be
histologically normal (without hyperplasia) to conclude the
PARATHYROID GLAND DYSFUNCTION
operation. An intraoperative PTH assay is measured before
Four parathyroid glands are located on the posterior aspect and at 5-minute intervals after adenoma removal to confirm a
of the thyroid gland. They produce and release parathormone rapid fall to normal. For multiple-gland hyperplasia, all glands
(PTH), the primary regulator of extracellular fluid calcium must be identified and either: (1) three are removed, with
concentration. PTH secretion is determined by the ionized partial excision of the fourth (leaving a good blood supply),
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- TABLE 23.10   Signs and Symptoms of Hypercalcemia
tion via 1,25 dihydroxyvitamin D). Serum PTH levels are Due to Hyperparathyroidism
tightly regulated by a negative feedback loop. Low ionized cal-   
cium and vitamin D levels increase PTH synthesis and release, Organ System Signs and Symptoms
and vice versa. An immediate increase in blood calcium Neuromuscular Skeletal muscle weakness
occurs secondary to PTH effects on bone resorption and, to a Renal Polyuria and polydipsia
lesser extent, on renal absorption. Maintenance of steady-state Decreased glomerular filtration rate
calcium balance is provided by GI absorption. Continuous Kidney stones
exposure to elevated PTH levels, usually from a parathyroid Hematopoietic Anemia
Cardiac Prolonged PR interval
adenoma or hyperplasia, results in osteoclast-mediated bone Shortened QT interval
resorption and hypercalcemia. Systemic hypertension
Gastrointestinal Vomiting
Abdominal pain
Hyperparathyroidism Peptic ulcer
Pancreatitis
Hyperparathyroidism is characterized by excess produc- Skeletal Skeletal demineralization
tion of PTH. It is the most common cause of hypercalcemia, Collapse of vertebral bodies
defined as total serum calcium above 10.4 mg/dL. Hyperpara- Pathologic fractures
thyroidism may be primary, secondary, or ectopic. Primary Nervous Somnolence
hyperparathyroidism is most common and usually results Decreased pain sensation
Psychosis
from a parathyroid adenoma or parathyroid hyperplasia. Ocular Calcifications (band keratopathy)
Peak incidence is between the third and fifth decades of life. Conjunctivitis
A solitary benign adenoma is responsible for 80% of primary
Chapter 23  Endocrine Disease 471

or (2) total parathyroidectomy is performed, with immediate 4.75–5.7 mg/dL (1.19–1.33 mmol/L). Approximately 50%
transplantation of a removed, minced parathyroid gland into of serum calcium is bound to albumin, 40% is ionized,
the forearm muscles. There is no preferred anesthetic tech- and 10% is bound to chelating agents (phosphate, citrate,
nique and no special intraoperative monitoring. The effects of sulfate). If the serum protein concentration decreases, so
neuromuscular blocking agents are unpredictable secondary does the total serum calcium concentration. An increase in
to hypercalcemia. Careful positioning is necessary to avoid serum proteins yields an increase in serum calcium. Acido-
bone injuries. Postoperative complications are similar to thy- sis increases serum calcium, and alkalosis decreases serum
roid surgery (recurrent laryngeal nerve injury, hematoma, calcium.
hypocalcemia). A decline in serum calcium occurs within 24 The most common cause of acquired hypoparathyroid-
hours postoperatively. Acute hypocalcemia should occur only ism is iatrogenic (i.e., inadvertent removal of all parathyroid
if severe bone deficits are present or injury to all normal para- glands during thyroid or parathyroid surgery). Clinical signs
thyroid glands occurred during surgery. In such cases, paren- of hypocalcemia include neuronal irritability, skeletal muscle
teral calcium is necessary at 0.5–2 mg/kg/h for several days, spasms, tetany, and possibly seizures. Fatigue and mental status
with possible addition of a vitamin D analogue (calcitriol) changes including depression are common symptoms. Acute
and/or oral calcium. Hypophosphatemia and hypomagnese- hypocalcemia can present with stridor and apnea. Conges-
mia may also occur postoperatively and require phosphate tive heart failure, hypotension, and decreased responsiveness
and magnesium. to β-agonists may occur. A prolonged QT interval is present
Parathyroid carcinoma is rare and usually not aggressive. on ECG. There are a number of other causes of hypoparathy-
Calcium values are frequently high (3.5–3.7 mmol/L [14–15 roidism (Table 23.11). Treatment for hypoparathyroidism is
mg/dL]) and provide a preoperative clue for carcinoma, which electrolyte replacement. Calcium supplements and vitamin D
requires removal of the entire gland with capsule intact. analogues are the primary treatment of hypocalcemia. Hypo-
The most common cause of hypercalcemia in hospitalized magnesemia is managed with oral or IV magnesium. Hyper-
patients is malignancy (occurs in as many as 20% of cancer phosphatemia is treated with phosphate-binding resins and
patients). Breast cancer accounts for 25%–50% of malig- possibly dialysis. Severe symptomatic hypocalcemia requires
nancy-related hypercalcemia. Unlike hypercalcemia from 10–20 mL of 10% calcium gluconate or 3–5 mL of 10% cal-
primary hyperparathyroidism, which is usually detected cium chloride followed by a continuous infusion of calcium
coincidentally on laboratory testing, the symptoms of malig- (1–2 mg/kg/h).
nancy bring the patient to medical attention, and hypercal- Hypoparathyroid patients may present to the operat-
cemia is then detected. In addition to a significant elevation ing room for an unrelated surgical condition. Patients with
in serum calcium, patients have a low PTH and an elevated symptomatic hypocalcemia must be treated aggressively
PTH-related peptide (PTHrP) assay and require localization preoperatively. Calcium, phosphate, and magnesium lev-
studies to include chest x-ray, CT of the chest and abdomen, els should be measured preoperatively and postoperatively.
and a bone scan. Less than 10% of cases of hypercalcemia Serum ionized calcium levels should maintained in the low-
are caused by disorders other than hyperparathyroidism and normal range intraoperatively. The QT interval may be used
malignancy. as an indirect guide of the serum calcium level. No specific
Medical treatment of hypercalcemia varies with its sever- anesthetic agents or techniques are recommended. Respira-
ity. Mild hypercalcemia (<3 mmol/L [12 mg/dL]) is managed tory alkalosis must be avoided because it lowers ionized cal-
with hydration. Moderate to severe hypercalcemia (3.2–3.7 cium levels. 
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 TABLE 23.11   Causes of Hypoparathyroidism
hours. Phosphate should be given to treat hypophosphate-   
mia. Bisphosphonates (pamidronate, zolendronate), calcito- DECREASED OR ABSENT PARATHYROID HORMONE
Accidental removal of parathyroid glands during thyroidectomy
nin, glucocorticoids, phosphates, mithramycin, plicamycin,
Parathyroidectomy to treat hyperplasia
and dialysis are also valuable. Bisphosphonates are powerful Idiopathic (DiGeorge syndrome)
inhibitors of bone resorption, and calcitonin is a hypocalcemic
hormone.  RESISTANCE OF PERIPHERAL TISSUES TO EFFECTS OF
PARATHYROID HORMONE
Congenital
Hypoparathyroidism  Pseudohypoparathyroidism
Acquired
Hypoparathyroidism results from absence or deficiency in  Hypomagnesemia
PTH secretion or resistance of peripheral tissues to the effects   Chronic renal failure
of the hormone. The clinical features of hypoparathyroidism  Malabsorption
  Anticonvulsive therapy (phenytoin)
are those of hypocalcemia.
 Osteoblastic metastases
Normal total (bound and free) serum calcium con-   Acute pancreatitis
centration is 9.5–10.5 mg/dL. Normal ionized calcium is
472 STOELTING’S ANESTHESIA AND CO-EXISTING DISEASE

TABLE 23.12   Hypothalamic and Related Pituitary Hormones


  
Pituitary Hormone or Organ
Hypothalamic Hormone Action Affected Action

Corticotropin-releasing hormone Stimulatory Corticotropin Stimulates secretion of cortisol and androgens


Thyrotropin-releasing hormone Stimulatory Thyrotropin Stimulates secretion of thyroxine and
triiodothyronine
Gonadotropin-releasing hormone Stimulatory Follicle-stimulating hormone, Stimulate secretion of estradiol and progesterone,a
luteinizing hormone stimulate ovulation,a stimulate secretion of
testosterone,b stimulate spermatogenesisb
Growth hormone–releasing Stimulatory Growth hormone Stimulates production of insulinlike growth factor
hormone
Dopamine Inhibitory Prolactin Stimulates lactationa
Somatostatin Inhibitory Pituitary, gastrointestinal Inhibits secretion of growth hormone and thyroid-
tract, pancreas stimulating hormone, suppresses release of
gastrointestinal and pancreatic hormones
Vasopressin (antidiuretic hormone) Stimulatory Kidneys Stimulates free water reabsorption
Oxytocin Stimulatory Uterus Stimulates uterine contractionsa
Breasts Stimulates milk ejectiona
aActionsin females.
bActionsin males.
Adapted from Vance ML. Hypopituitarism. N Engl J Med. 1994;330:1651-1662.

and the patient’s age. Gonadotropin deficiency (amenorrhea,


PITUITARY GLAND DYSFUNCTION
impotence) is typically the first manifestation of global pitu-
The pituitary gland, located in the sella turcica at the base of the itary dysfunction. Hypocortisolism occurs 4–14 days after
brain, consists of the anterior pituitary and posterior pituitary. hypophysectomy, whereas hypothyroidism is not likely to
The anterior pituitary secretes six hormones under the control of manifest before 4 weeks. CT and MRI are useful for radio-
the hypothalamus (Table 23.12). The hypothalamus controls the graphic assessment of the pituitary gland.
function of the anterior pituitary by means of vascular connec-
tions (hormones travel via the hypophyseal portal veins to reach
Acromegaly
the anterior pituitary). The hypothalamic–anterior pituitary–
target organ axis is composed of tightly coordinated systems in Acromegaly is due to excessive secretion of growth hormone
which hormonal signals from the hypothalamus stimulate or in adults, most often by an adenoma in the anterior pituitary
inhibit secretion of anterior pituitary hormones, which in turn gland. Failure of plasma growth hormone concentrations to
act on target organs and modulate hypothalamic and anterior decrease 1–2 hours after ingestion of 75–100 g of glucose is
pituitary activity (closed-loop, negative feedback system). The presumptive evidence of acromegaly, as are growth hormone
posterior pituitary is composed of terminal neuron endings that concentrations higher than 3 ng/mL. A skull radiograph and
originate in the hypothalamus. Vasopressin (ADH) and oxyto- CT are useful for detecting enlargement of the sella turcica,
cin are synthesized in the hypothalamus and are subsequently which is characteristic of anterior pituitary adenomas.
transported along the hypothalamic neuronal axons for storage
in the posterior pituitary. The stimulus for the release of these Signs and Symptoms
hormones from the posterior pituitary arises from osmorecep- Manifestations of acromegaly reflect parasellar extension of the
tors in the hypothalamus that sense plasma osmolarity. anterior pituitary adenoma and peripheral effects produced by
Overproduction of anterior pituitary hormones is most the presence of excess growth hormone (Table 23.13). Head-
often associated with hypersecretion of ACTH (Cushing syn- ache and papilledema reflect increased intracranial pressure
drome) by anterior pituitary adenomas. Hypersecretion of resulting from expansion of the anterior pituitary adenoma.
other tropic hormones rarely occurs. Underproduction of a Visual disturbances are due to compression of the optic chi-
single anterior pituitary hormone is less common than gen- asm by the expanding overgrowth of surrounding tissues.
eralized pituitary hypofunction (panhypopituitarism). The Overgrowth of soft tissues of the upper airway (enlargement
anterior pituitary gland is the only endocrine gland in which a of the tongue and epiglottis) makes patients susceptible to upper
tumor, most often a chromophobe adenoma, causes destruc- airway obstruction. Hoarseness and abnormal movement of
tion by compressing the gland against the bony confines of the vocal cords or paralysis of a recurrent laryngeal nerve may
the sella turcica. Metastatic tumor, most often from the breast result from stretching caused by overgrowth of the surrounding
or lung, also occasionally produces pituitary hypofunction. cartilaginous structures. In addition, involvement of the crico-
Endocrine features of panhypopituitarism are highly vari- arytenoid joints can result in alterations in the patient’s voice
able and depend on the rate at which the deficiency develops resulting from impaired movement of the vocal cords.
Chapter 23  Endocrine Disease 473

be predicted based on the patient’s age and size. Nasal turbi-


TABLE 23.13   Manifestations of Acromegaly
   nate enlargement may preclude the passage of nasopharyngeal
PARASELLAR TUMOR or nasotracheal airways. A preoperative history of dyspnea
Enlarged sella turcica on exertion or the presence of hoarseness or stridor suggests
Headache involvement of the larynx by acromegaly. In this instance,
Visual field defects
indirect laryngoscopy may be indicated to quantitate the
Rhinorrhea
extent of vocal cord dysfunction. When a catheter is placed
EXCESS GROWTH HORMONE in the radial artery, it is important to consider the possibil-
Skeletal overgrowth (prognathism) ity of inadequate collateral circulation at the wrist. Monitor-
Soft tissue overgrowth (lips, tongue, epiglottis, vocal cords) ing blood glucose concentrations is useful if diabetes mellitus
Connective tissue overgrowth (recurrent laryngeal nerve paralysis) or glucose intolerance accompanies acromegaly. Peripheral
Peripheral neuropathy (carpal tunnel syndrome)
Visceromegaly
nerve stimulation is used to guide dosing of nondepolariz-
Glucose intolerance ing muscle relaxants, particularly if skeletal muscle weakness
Osteoarthritis is present. Skeletal changes associated with acromegaly may
Osteoporosis make use of regional anesthesia technically difficult or unre-
Hyperhidrosis liable. There is no evidence that hemodynamic instability or
Skeletal muscle weakness
alterations in pulmonary gas exchange accompany anesthesia
in acromegalic patients. 

Peripheral neuropathy is common and likely reflects trap-


Diabetes Insipidus
ping of nerves by skeletal, connective, and soft tissue over-
growth. Flow through the ulnar artery may be compromised The posterior pituitary gland produces antidiuretic hormone
in patients exhibiting symptoms of carpal tunnel syndrome. (ADH). Secretion is regulated by the osmotic pressure of the
Even in the absence of such symptoms, approximately half intravascular volume. ADH increases permeability of cells lin-
of patients with acromegaly have inadequate collateral blood ing the distal tubule and medullary collecting ducts of the kid-
flow through the ulnar artery in one or both hands. ney to promote water absorption.
Glucose intolerance and, on occasion, diabetes mellitus Diabetes insipidus (DI) occurs from a decrease of syn-
requiring treatment with insulin reflect the effects of growth thesis and release of vasopressin (neurogenic DI) or from
hormone on carbohydrate metabolism. The incidence of sys- a resistance or insensitivity of renal tubules to vasopres-
temic hypertension, ischemic heart disease, osteoarthritis, sin (nephrogenic DI). Secretion or action of vasopressin is
and osteoporosis seems to be increased in these patients. Lung decreased 80%–85% below normal. Neurogenic DI can be
volumes are increased, and ventilation/perfusion mismatch- differentiated from nephrogenic DI based on response to
ing may be present. The patient’s skin becomes thick and oily, desmopressin (DDAVP [1-deamino-8-d-arginine-vasopres-
skeletal muscle weakness may be prominent, and complaints sin]). This vasopressin analogue concentrates urine in the
of fatigue are common.  presence of neurogenic DI but not nephrogenic DI. Neuro-
genic DI often occurs following damage or destruction to
Treatment the pituitary gland by trauma, infiltrating lesions, or surgery.
Transsphenoidal surgical excision of pituitary adenomas is Patients present with polydipsia, hypernatremia, and high
the preferred initial therapy. When adenomas have extended output of poorly concentrated urine despite increased serum
beyond the sella turcica, surgery or radiation therapy is no osmolality. Clinically, patients demonstrate altered mental
longer feasible; medical treatment with suppressant drugs status/seizures, fatigue, weakness, and hemodynamic insta-
(bromocriptine) may be an option in these cases.  bility. Hypernatremia and hypovolemia can become severe
enough to be life threatening. A 24-hour urine collection
Management of Anesthesia is required to make the diagnosis. The 24-hour urine vol-
Management of anesthesia in patients with acromegaly is com- ume must exceed 50 mL/kg of body weight, and the urine
plicated by changes induced by excessive secretion of growth osmolality must be less than 300 mOsm/L to confirm DI. An
hormone. Particularly important are changes in the upper air- increase in plasma osmolality (normal = 283–285 mOsm/L)
way. Distorted facial anatomy may interfere with placement of also occurs. DI from pituitary surgery usually appears within
an anesthesia face mask. Enlargement of the tongue and epi- 24 hours and may last a few days to 6 months. Desmopressin
glottis predisposes to upper airway obstruction and interferes (DDAVP) is the treatment for neurogenic DI. During sur-
with visualization of the vocal cords by direct laryngoscopy. gery an IV infusion of 100–200 m U/h is administered in
The distance between the lips and vocal cords is increased combination with an isotonic crystalloid solution. Frequent
secondary to overgrowth of the mandible. The glottic opening monitoring of serum Na and plasma osmolality is required.
may be narrowed because of enlargement of the vocal cords. DDAVP can also be administered IM or intranasally. Treat-
This, in addition to subglottic narrowing, may necessitate use ments for nephrogenic DI include chlorpropamide, clofi-
of a tracheal tube with a smaller internal diameter than would brate, and thiazide diuretics.
474 STOELTING’S ANESTHESIA AND CO-EXISTING DISEASE

Anesthetic management includes continuous monitoring have low urine output and can demonstrate delayed awaken-
of urine output and hourly measurement of serum Na and ing or awakening with mental confusion. Measurement of
plasma osmolality. The goal for plasma osmolality is less than intravascular volume status with a central venous pressure
290 mOsm/L. Patients with complete DI and a total lack of catheter may be indicated. Cautious fluid resuscitation with
ADH require a preoperative dose of desmopressin intranasally normal saline is recommended. Frequent measures of urine
or an IV bolus of 100 mU (0.1 unit) of aqueous vasopressin osmolality, plasma osmolality, and serum Na are necessary
followed by a continuous infusion of 100–200 mU/h (0.1–0.2 perioperatively. It is not unusual to see patients in the neuro-
units/h). Isotonic fluids should be used for volume resuscita- surgical intensive care unit with this syndrome. 
tion. If plasma osmolality exceeds 290 mOsm/L, hypotonic
fluid should be used for resuscitation and the vasopressin
KEY POINTS
infusion should be increased above 200 mU/h. Since vasopres-
sin causes vasoconstriction of arteriolar beds, close monitor- • Diabetes mellitus results from inadequate supply of and/
ing for myocardial ischemia is recommended.  or inadequate tissue response to insulin, which leads to
increased circulating glucose levels.
• The effects of chronic hyperglycemia are many and include
Syndrome of Inappropriate Antidiuretic
hypertension, coronary artery disease, congestive heart
Hormone Secretion (SIADH)
failure, peripheral vascular disease, cerebrovascular acci-
Inappropriate (i.e., excessive) secretion of antidiuretic hor- dent, chronic renal failure, and autonomic neuropathy.
mone yields hyponatremia (Na < 135 mEq/L) from the • Aggressive perioperative glucose control has been shown to
expansion of intravascular fluid volume secondary to hor- limit infection risk, improve wound healing, and result in
mone-induced resorption of water by renal tubules. Ectopic overall reductions in morbidity and mortality.
production of vasopressin by tumors is a common cause of • The direct effects of T3 on the heart and vascular smooth
SIADH. Small cell lung carcinoma (50% of these patients muscle are responsible for the exaggerated hemodynamic
develop SIADH) and carcinoid tumors are the most common effects of hyperthyroidism.
sources. Other types of lung cancer and tumors of the CNS, • The third-generation TSH assay is the single best test of
head and neck, GI tract, genitourinary tract, and ovary can thyroid hormone action at the cellular level.
also produce vasopressin. CNS trauma, infections, certain • Every effort should be made to render patients euthyroid
medications (chlorpropamide, clofibrate, thiazides, antineo- before surgery. When caring for surgical patients with
plastic agents), hypothyroidism, and major surgery can also hyperthyroidism or hypothyroidism, the clinician must
result in SIADH. Most patients are asymptomatic. Clinical be prepared to manage thyroid storm or myxedema coma
signs and symptoms may include nausea, weakness, lethargy, during the perioperative period.
confusion, depressed mental status, and seizures. Although • 
Since most pheochromocytomas secrete predominantly
hyponatremia usually develops slowly (over weeks to months), norepinephrine, preoperative α-blockade is necessary to
the rapidity of onset and degree of hyponatremia determine lower blood pressure, increase intravascular volume, pre-
the severity of symptoms. The diagnosis is made by demon- vent paroxysmal hypertensive episodes, allow resensiti-
strating hyponatremia (<130 mEq/L), reduced serum osmo- zation of adrenergic receptors, and decrease myocardial
lality (<270 mOsm/L), normal or increased urine Na excretion dysfunction.
(>20 mEq/L), and inappropriately normal or increased urine • 
During surgical excision of a pheochromocytoma, the
osmolality (hypertonic relative to plasma). patient often exhibits an exaggerated hypertensive response
SIADH is a diagnosis of exclusion, and other causes of hypo- to anesthetic induction, intubation, surgical excision, and
natremia should be excluded first. SIADH is corrected gradu- particularly tumor manipulation. Conversely, hypotension
ally unless mental status is altered and/or the patient appears may occur following ligation of the tumor’s venous drainage.
at risk for seizures. Treatment of the malignancy is primary. • The physiologic response to surgical stress is an increase in
Free water restriction is required. Fluid intake is limited to CRH, ACTH, and cortisol secretion that begins at surgical
500–1000 mL/day. Demeclocycline inhibits the action of ADH incision and continues into the postoperative period.
on the renal distal tubule. Conivaptan, a vasopressin-2 recep- • The most common cause of AI is administration of exog-
tor (V2R) antagonist, may be effective. Severe hyponatremia enous steroids.
(Na < 115 mEq/L) may require 3% hypertonic saline or normal • Patients who received glucocorticoids in dosages equivalent
saline plus furosemide. The rate of sodium correction should to more than 20 mg/day of prednisone for longer than 3 weeks
be slow (0.5 mEq/L/h) until Na concentration is 125 mEq/L, within the previous year are considered to have adrenal sup-
then proceed more slowly to prevent central pontine myelinoly- pression and are at increased risk of AI. Such patients require
sis and possibly permanent brain damage. perioperative corticosteroid supplementation.
Anesthetic management of patients with SIADH involves • Hydrocortisone 200–300 mg/day for a minimum of 5–7
careful administration and monitoring of fluids and electro- days, followed by a tapering regimen over 5–7 days, results
lytes. If SIADH results from malignancy, anemia and malnu- in overall improvement in patients with vasopressor-
trition may be present. Perioperatively, these patients usually dependent septic shock.
Chapter 23  Endocrine Disease 475

• Primary hyperparathyroidism is the most common cause of Bravo EL. Evolving concepts in the pathophysiology, diagnosis, and treatment
hypercalcemia in the general population and usually results of pheochromocytoma. Endocr Rev. 1994;15:356-368.
Burch HB, Wartofsky L. Life-threatening thyrotoxicosis: thyroid storm. Endo-
from a benign parathyroid adenoma. Hypercalcemia can crinol Metab Clin North Am. 1993;22:263-277.
be treated medically by saline infusion, furosemide, and/or Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N
bisphosphonates before surgery. Engl J Med. 2003;348:727-734.
• Overproduction of anterior pituitary hormones is most com- DeWitt DE, Hirsch IB. Outpatient insulin therapy in type 1 and type 2 diabe-
monly manifested as Cushing syndrome caused by ACTH tes mellitus. JAMA. 2003;289:2254-2264.
Inzucchi S. The Diabetes Mellitus Manual: a Primary Care Companion to El-
hypersecretion by an adenoma in the anterior pituitary. lenberg and Rifkin’s Sixth Edition. New York: McGraw-Hill; 2005.
• SIADH is common in the postoperative period and usually Klein I, Ojamma K. Thyroid hormone and the cardiovascular system. N Engl
responds to fluid restriction. J Med. 2001;344:501-509.
Mathur A, Gorden P, Libutti SK. Insulinoma. Surg Clin North Am.
2009;89:1105-1121.
RESOURCES Stathatos N, Wartofsky L. Perioperative management of patients with hypo-
Akhtar S, Barash PG, Inzucchi SE. Scientific principles and clinical impli- thyroidism. Endocrinol Metab Clin North Am. 2003;32:503-518.
cations of perioperative glucose regulation and control. Anesth Analg. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: scientific re-
2010;110:478-497. view and guidelines for diagnosis and management. JAMA. 2004;291:228-
Axelrod L. Perioperative management of patients treated with glucocorti- 238.
coids. Endocrinol Metab Clin North Am. 2003;32:367-383.
This page intentionally left blank

     
C H APT E R

Hematologic Disorders 24
ADRIANA D. OPREA

Physiology of Anemia Hemostatic Disorders Affecting Coagulation Factors of the


The Transfusion Trigger Propagation Phase
Management of Anesthesia: General Concepts for Anemia Arterial Coagulation
Evaluation and Classification of Anemia Disorders Affecting Platelet Number
Microcytic Anemias Congenital Disorders Resulting in Platelet Production
Defects
Normocytic Anemias
Acquired Disorders Resulting in Platelet Production
Macrocytic/Megaloblastic Anemias
Defects
Other Hemoglobin-Related Disorders
Nonimmune Platelet Destruction Disorders
Hemoglobins With Increased Oxygen Affinity
Autoimmune Platelet Destruction Disorders
Hemoglobins With Decreased Oxygen Affinity
Qualitative Platelet Disorders
Polycythemia
Hypercoagulable Disorders
Physiology of Polycythemia
Heritable Causes of Hypercoagulability
Polycythemia Vera
Acquired Causes of Hypercoagulability
Secondary Polycythemia Due to Hypoxia
Management of Anesthesia in Venous Hypercoagulable
Secondary Polycythemia Due to Increased Erythropoietin Disorders
Production
Acquired Hypercoagulability of the Arterial Vasculature
Disorders of Hemostasis
Key Points
Normal Hemostasis
Hemostatic Disorders Affecting Coagulation Factors of the
Initiation Phase

Disease states related to erythrocytes include anemia and anemia as Hb concentration less than 12 g/dL for women
polycythemia. Anemia is characterized by a decrease in the and less than 13 g/dL for men. In pregnancy a decreased Hct
red cell mass, with the main adverse effect being a decrease in reflects the increase in plasma volume in relationship to the
the oxygen-carrying capacity of blood. Polycythemia (erythro- RBC mass (physiologic anemia). However, Hb less than 11 g/dL
cytosis) represents an increase in hematocrit (Hct). Its conse- in a pregnant patient is considered truly anemic. In acute
quences are primarily related to an expanded red cell mass and blood loss the Hct may initially be unchanged. Decreases in
a resulting increase in blood viscosity. 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-
PHYSIOLOGY OF ANEMIA
tion in arterial oxygen concentration and the potential for
Anemia is a disease sign manifesting clinically as a reduced decreased tissue oxygen delivery. For example, a decrease in
absolute number of circulating red blood cells (RBCs). Hb concentration from 15 g/dL to 10 g/dL result in a 33%
Although a decrease in Hct is used most often as an indicator, decrease in arterial oxygen content. The initial compensation
anemia has been defined as a reduction in one or more of the for this decrease in oxygen content is an increase in cardiac
major RBC indices: hemoglobin (Hb) concentration, Hct, and output. This occurs via enhanced sympathetic nervous system
RBC count. In adults the World Health Organization defines activity and the decrease in blood viscosity that accompanies

477