Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

CHAPTER 13 – Diseases of the Endocrine System

Michael F. Roizen, MD,
Nader M. Enany, MD

  

 

Parathyroid Glands

  

 

Physiology

  

 

Hypercalcemia

  

 

Hypocalcemia

  

 

Summary

  

 

Thyroid Gland

  

 

Physiology

  

 

Thyroid Function Tests

  

 

Pathophysiology of Thyroid Disease

  

 

Intraoperative Anesthetic Considerations and Postoperative Problems in Patients with Thyroid Disease

  

 

Summary

  

 

Pituitary Gland

  

 

Physiology

  

 

Diseases of the Anterior Pituitary Gland

  

 

Disorders of the Posterior Pituitary Gland

  

 

Anesthetic Considerations for Patients With ADH Abnormalities

  

 

Summary

  

 

Adrenal Cortex

  

 

Physiology

  

 

Excessive Adrenocortical Hormones: Hyperplasia, Adenoma, Carcinoma

  

 

Adrenocortical Hormone Deficiency

  

 

Patients Taking Corticosteroids for Medical Conditions

  

 

Summary

  

 

Adrenal Medulla: Pheochromocytoma

  

 

Physiology and Diagnosis

  

 

Anesthetic Considerations for Patients with Pheochromocytoma

  

 

Summary

  

 

Pancreas

  

 

Physiology

  

 

Hypoglycemia and Hyperinsulinism (Islet Cell Tumors of the Pancreas)

  

 

Anesthetic Considerations for Patients with Hypoglycemia

  

 

Diabetes Mellitus

  

 

Perioperative Considerations for Patients with Diabetes

  

 

Summary

A crucial factor in successful surgical treatment of endocrine diseases is a complete and accurate preoperative diagnosis. Sometimes the differential diagnosis is difficult, and often it requires the expertise of the endocrinologist, radiologist, and clinical pathologist. Armed with a complete and accurate diagnosis, the anesthesiologist and surgeon can offer the patient better relief of his or her symptoms and a more optimistic prognosis. Perioperative outcome in many of these conditions involves an understanding by the anesthesiologist of what the surgeon is trying to accomplish and, equally important, the end organ effect of the endocrine disorder. For example, diabetics often have renal and cardiac disease and peripheral and autonomic neuropathies. Understanding these consequences of diabetes and optimizing their treatment is crucial to the perioperative management of the diabetic, more so than is the finesse of managing insulin requirements by one of the many schemes available.

PARATHYROID GLANDS

Physiology

Total (bound and free) serum calcium concentration is maintained at the normal level of 9.5 to 10.5 mg/dL by the effects of parathyroid hormone (PTH), calcitonin, and vitamin D.[1] When the ionized calcium concentration decreases or the serum phosphate level rises, release of PTH is stimulated. PTH is secreted by the four parathyroid glands, which are usually located posterior to the upper and lower poles of the thyroid gland.[2] PTH increases tubular reabsorption of calcium and decreases tubular reabsorption of phosphate to raise the serum calcium concentration. A renal phosphate leak is the result of excessive PTH secretion. Calcitonin (produced in the C cells of the thyroid gland) antagonizes the effects of PTH and is released in response to high serum ionized calcium. Approximately 50% of the serum calcium is bound to serum proteins (albumin). Forty percent of the serum calcium is ionized, and the remaining 10% is bound to such chelating agents as citrate. If the serum protein concentration decreases, the total serum calcium concentration will also decrease. The rule of thumb is that for every 1-g decrement in albumin, a 0.8-mg/dL decrement in total serum calcium concentration occurs. Likewise, if the serum proteins increase (as in myeloma), total serum calcium level will increase. Acidosis tends to increase the ionized calcium, whereas alkalosis tends to decrease it. There may be a slight tendency for the serum calcium level to decrease with age, with a concomitant elevation of the serum PTH, perhaps contributing to the osteoporosis associated with the aging process.[3]

Vitamin D plays an important role in calcium homeostasis. Cholecalciferol is synthesized in the skin by the effects of ultraviolet light. Cholecalciferol is hydroxylated in the liver to form 25-hydroxycholecalciferol. The 25-hydroxy derivative is further hydroxylated in the kidney to form 1,25-dihydroxycholecalciferol (1,25[OH]2D3). The 1,25-dihydroxy derivative is by far the most potent vitamin D compound yet discovered. 1,25(OH)2D3 stimulates absorption of both calcium and phosphorus from the gastrointestinal tract.[4] Thus, vitamin D provides the substrates for the formation of mineralized bone. 1,25(OH)2D3 may also directly enhance mineralization of newly formed osteoid matrix in bone. Vitamin D derivatives also seem to work synergistically with PTH in bringing about increased resorption of bone. Clinically, this is an important point because immobilization alone increases bone reabsorption, and if the patient is receiving a vitamin D derivative, bone reabsorption may be increased further. Evidence now indicates that the hydroxylation of 25-hydroxycholecalciferol is controlled in the kidney by PTH and the phosphorus level. Elevated PTH and hypophosphatemia tend to accentuate the synthesis of 1,25(OH)2D3, whereas low levels of PTH and high levels of phosphate turn off the synthesis of 1,25(OH)2D3 in the kidney. PTH maintains a normal calcium level in blood by increasing calcium reabsorption from bone and by promoting synthesis of 1,25(OH)2D3, which in turn enhances calcium reabsorption from the gut. Finally, PTH directly increases calcium reabsorption from the renal tubule.

Thus, PTH accelerates the breakdown of bone by a complex mechanism that includes a fast component and a slow component (involving protein synthesis and cellular proliferation). In addition, PTH has an anabolic effect on bone formation, and in tissue culture it increases the number of active osteoblasts, the maturation of cartilage, and osteoid formation within the bone shaft.

Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Copyright © 2005 Saunders, An Imprint of Elsevier

Hypercalcemia

Patients with hypercalcemia present with a variety of symptoms that are often nonspecific because calcium is important to many functions: free intracellular calcium initiates and/or regulates muscle contraction, release of neurotransmitters, secretion of hormones, enzyme action, and energy metabolism. The level of blood calcium is frequently related to the degree and severity of symptoms. With calcium levels above 14 mg/dL, signs and symptoms such as anorexia, nausea, vomiting, abdominal pain, constipation, polyuria, tachycardia, and dehydration may occur. [1] [5] Psychosis and obtundation are usually the end results of severe and prolonged hypercalcemia. Band keratopathy is a most unusual physical finding. Patients with hyperparathyroidism occasionally present with a history of calcium-containing kidney stones or peptic ulcers. Nephrolithiasis occurs in 60% to 70% of patients with hyperparathyroidism. Sustained hypercalcemia can result in tubular and glomerular disorders. Polyuria and polydipsia are common complaints. Bone disease in hyperparathyroidism, such as subperiosteal resorption, can also be seen in radiographs of the teeth and hands.[6] Severe bone disease in hyperparathyroidism, such as osteitis fibrosa cystica, is only very rarely seen and usually only in older patients who have had long-standing (perhaps up to 20 years) disease. The older patient with severe osteopenia, and perhaps vertebral compression fractures, should prompt suspicion of hyperparathyroidism. Many patients with hyperparathyroidism can tolerate blood calcium levels of 12 mg/dL without many symptoms.[5] This situation, often found by multiphasic screening, presents the dilemma of whether to operate on asymptomatic patients. The risk-benefit ratio is not clear at this point, and advocates of no treatment but watchful waiting appear to have the outcome data to at least present a reasonable argument.[5] Although surgical removal of a parathyroid adenoma is usually curative in asymptomatic patients and can be done safely in the very elderly, patients with mild, uncomplicated primary hyperparathyroidism may be followed medically if the serum calcium levels are less than 11.5 mg/dL and bone density and renal function are normal. Such patients should have quarterly check-ups of blood pressure, bone density, and renal function. Complications may be prevented by avoiding dehydration, thiazide diuretics, and immobilization. Parathyroid hyperplasia, usually involving all four parathyroid glands, may be a major cause of the hyperparathyroid syndrome. Carcinoma of the parathyroid glands is extremely rare. It is conceivable that all adenomas begin as hyperplasia[7]; therefore, for any one patient, exactly where in the natural history of the disease an operation occurs may determine whether hyperplasia or an adenoma is found.

Patients with hyperparathyroidism have elevated calcium and low serum phosphate levels. Very mild hyperchloremic acidosis may be present. The PTH level is usually elevated but is certainly elevated for the level of calcium concentration, and PTH reduction is the hallmark of successful surgery. [5] [8] [9] The only two situations in which hypercalcemia would be associated with a high PTH level are hyperparathyroidism and the ectopic PTH syndrome (usually secondary to a tumor of the lung or kidney that produces a biologically active fragment of PTH).[1] All other causes of hypercalcemia are associated with either normal or, more appropriately, low levels of PTH. When a patient presents with an extremely high blood calcium level (above 14 mg/dL), more likely than not, the patient has a distant cancer rather than hyperparathyroidism. Overall, about 50% of all cases of hypercalcemia are due to cancer invading bone. In these cases, prognosis is poor: more than 50% of patients die within 6 months. Treating hypercalcemia does not prolong survival but usually improves quality of life. [10] [11] The technetium diphosphonate bone scan is positive in a large percentage of cancers that have metastasized to bone. Myeloma is another important cancer that is associated with hypercalcemia. The isotope bone scan is sometimes normal in this disease.

A number of other anomalies have to do with excessive absorption of calcium from the gastrointestinal tract. These abnormalities include (1) milk-alkali syndrome, which is usually due to excessive ingestion of calcium-containing antacids; (2) vitamin D intoxication; and (3) sarcoidosis, which is associated with hypersensitivity of the gastrointestinal tract to vitamin D. Hyperthyroidism is occasionally associated with increased bone resorption, and hypercalcemia may be present. Many patients with hyperthyroidism also have hyperparathyroidism. Some patients become hypercalcemic during treatment with thiazide diuretics. Thiazides increase renal tubular reabsorption of calcium and may even enhance the PTH effects on the renal tubule. Most patients who have significant hypercalcemia associated with thiazide diuretics have hyperparathyroidism. An important cause of increased bone reabsorption, and occasionally of mild hypercalcemia, is prolonged immobilization. Immobilization in any situation that is already associated with increased bone reabsorption, such as Paget's disease or ingestion of large quantities of vitamin D, can result in exaggerated hypercalcemia and excessive bone reabsorption. Cancer may produce hypercalcemia by at least three mechanisms: (1) metastasis to bone with increased bone reabsorption, (2) production by the cancer of a biologically active fragment of PTH, and (3) production of a prostaglandin that causes bone reabsorption. Table 13-1 lists the different causes of hypercalcemia and laboratory studies that differentiate them. In addition to obtaining the blood calcium and phosphate levels, determination of the bony fraction of the alkaline phosphatase, creatinine level, electrolyte values, and urinary calcium level is done, as well as obtaining the appropriate skeletal radiographs and isotope bone scan, by endocrinologists to aid diagnosis.

TABLE 13-1   -- Differential Diagnosis of Hypercalcemia

 

Serum Phosphorus

Serum Alkaline Phosphatase

Creatinine

Urinary Calcium

Blood Parathyroid Hormone

Comments

Cancer (metastatic)

N

N

N or ↑

Osteolytic lesion bone scan is +

Ectopic PTH production

N or ↑

N

↑ or N

Cancer of lung and kidney common

Myeloma

N

N or ↑

Plasma protein F

Hyperparathyroidism

N or ↑

N

N or ↑

Subperiosteal resorption, kidney stones

Milk-alkali syndrome

N

N

N

Alkalosis; history of calcium intake

Vitamin D intoxication

N or ↑

Vitamin D levels F

Hyperthyroidism

N

N or ↑

N

T4 or T3 levels ↑

Sarcoid

N

N or ↑

N

Plasma proteins ↑

Thiazides

N or ↓

N or ↑

N

N or ↓

N or ↑

Coexistent hyperparathyroidism often

Adrenal insufficiency

N

N

N or ↑

N

Hyponatremia, hyperkalemia

Immobilization

N

N

N

N

If fracture, alkaline phosphatase ↑

Paget's disease

N

↑↑

N

N

Bone scan is +

↑, elevated; ↑↑, markedly elevated; ↓, decreased; N, normal.

 

 

 

Severe hypercalcemia (especially above levels of 14 to 16 mg/dL) constitutes a medical emergency, and often treatment must be begun before the diagnosis is complete. There is no way to relate the signs and symptoms any one patient experiences to the level of blood calcium. In an extreme situation it is possible to have one patient who is almost asymptomatic, with a total blood calcium level of 14 mg/dL, whereas another who has an identical blood calcium level has severe polyuria, tachycardia, dehydration, and even psychosis. Age seems to be a factor; that is, for any given calcium level, the older patient is more likely to be symptomatic than a younger one. Tachydysrhythmias, including sinus tachycardia, are extremely common and usually out of proportion to the degree of volume depletion. Occasionally heart block results. Extreme care must be exercised in the use of digitalis derivatives for patients with hypercalcemia. Digitalis intoxication occurs quite readily in the presence of hypercalcemia. Digitalis toxicity dysrhythmias are extremely common in this setting.

Other measures decrease reabsorption of bone and include pamidronate sodium (90 mg intravenously), salmon calcitonin (100 to 400 units) or plicamycin hydration; and, in general, any patient with a calcium level of 16 mg/dL should be considered a medical emergency and treated with saline hydration (with careful attention to the risk of precipitating congestive heart failure [CHF]) and furosemide. Salmon mithramycin (or human, if a patient is allergic), corticosteroids, intravenous phosphates, or indomethacin can also be used.[11] A few patients with calcium levels of 14 mg/dL (especially older patients) also qualify for emergency treatment.

Preoperative Considerations for Patients with Hyperparathyroidism

Patients with moderate hypercalcemia who have normal renal and cardiovascular function present no special preoperative problems. Electrocardiographic (ECG) findings can be examined preoperatively and intraoperatively for shortened PR or QT interval.[12] Because severe hypercalcemia can result in hypovolemia, normal intravascular volume and electrolyte status should be restored before anesthesia and surgery are begun.

Management of hypercalcemia can include increasing urinary calcium excretion by means of hydration and diuresis.[11] Complications of these interventions include hypomagnesemia and hypokalemia.

Phosphate should be given to correct hypophosphatemia, because hypophosphatemia decreases calcium uptake into bone, increases calcium absorption from the intestine, stimulates breakdown of bone, and can result in CHF or pump failure.[13] Hydration and diuresis, accompanied by phosphate repletion, suffice as management for most hypercalcemic patients. If additional intervention is needed, glucocorticoids, pamidronate sodium (90 mg intravenously), plicamycin, or salmon calcitonin (100 to 400 units) may be given. Corticosteroids inhibit further gastrointestinal calcium absorption. Consultation with an endocrinologist or oncologist is advisable before mithramycin is given, because it has a narrow therapeutic-to-toxic ratio.

Calcitonin lowers serum calcium levels through direct inhibition of bone resorption. It can decrease serum calcium levels within minutes after intravenous administration. Calcitonin is less effective than phosphate or plicamycin, however, for patients with hypercalcemia caused by hyperparathyroidism. Side effects include urticaria and nausea.

It is especially important to know whether hypercalcemia has been chronic, because serious abnormalities in the cardiac, renal, or central nervous system may have resulted. Hypercalcemia associated with severe renal failure often can be treated successfully only by peritoneal dialysis or hemodialysis, with a low calcium concentration in the dialysis bath.

Finally, there are a few additional preanesthetic considerations. Aspiration precautions must be taken because the hypercalcemic patient with altered mental status may have a full stomach or be unable to protect the airway. The possibility of lytic or pathologic fractures warrants careful positioning. Radiographs of the cervical spine should be taken to rule out lytic lesions when hypercalcemia results from cancer.[14] Laryngoscopy in a patient with an unstable cervical spine may result in quadriplegia.

Intraoperative and Postoperative Considerations for Patients with Hyperparathyroidism

No controlled study has demonstrated clinical advantages of any one anesthetic drug over others. A review of cases at the University of California, San Francisco, and another at the University of Chicago from 1968 to 1982 revealed that virtually all anesthetic techniques and agents have been employed without adverse effects that could have been even remotely attributable to either the agent or the technique.

Maintenance of anesthesia usually presents little difficulty. No special intraoperative monitoring for patients with these conditions is required; a blood pressure cuff, lead II and/or MCL5 electrocardiogram, temperature probe, and esophageal stethoscope typically are used. Because of the proximity of surgical retraction to the face, meticulous care is taken to protect the eyes. Response to neuromuscular blocking agents may be unpredictable when calcium levels are elevated[15]; reversal of the effects may be difficult.[14]

Failure to remove all the lesions at the first operation at times necessitates a second or third or even additional operation. Sestamibi scanning and venous sampling of PTH levels in thyroidal venous beds at times provide useful information to the surgeon at reoperation.[16] Unusual sites of parathyroid adenoma include areas behind the esophagus, in the mediastinum, and within the thyroid.

Of the many possible postoperative complications (nerve injuries, bleeding, and metabolic abnormalities), bilateral recurrent nerve trauma and hypocalcemic tetany are feared most. Bilateral recurrent laryngeal nerve injury (by trauma or edema) causes stridor and laryngeal obstruction as a result of unopposed adduction of the vocal cords and closure of the glottic aperture. Immediate endotracheal intubation is required in such cases, usually followed by tracheostomy to ensure an adequate airway. This rare complication occurred only once in more than 30,000 operations at the Lahey Clinic. Unilateral recurrent nerve injury often goes unnoticed because of compensatory overadduction of the uninvolved cord. Because bilateral injury is rare and clinically obvious, laryngoscopy after thyroid or parathyroid surgery need not be performed routinely; however, one can easily test vocal cord function after surgery by asking the patient to say “e” or “moon.” Unilateral nerve injury is characterized by hoarseness, and bilateral nerve injury is characterized by aphonia. Selective injury of adductor fibers of both recurrent laryngeal nerves leaves the abductor muscles relatively unopposed, and pulmonary aspiration is a risk. Selective injury of abductor fibers, on the other hand, leaves the adductor muscles relatively unopposed, and airway obstruction can occur.

Bullous glottic edema is edema of the glottis and pharynx, which occasionally follows parathyroid surgery. This is an additional cause of postoperative respiratory compromise; it has no specific origin, and there is no known preventive measure.

Unintended hypocalcemia during surgery for parathyroid disease occurs in rare cases, usually from the lingering effect of vigorous preoperative treatment. This effect is especially important for patients with advanced osteitis because of the calcium affinity of their bones. After parathyroidectomy, magnesium or calcium ions may be redistributed internally (into “hungry bones”), thus causing hypomagnesemia, hypocalcemia, or both.

Management after parathyroid surgery should include serial determinations of serum calcium, inorganic phosphate, magnesium, and PTH levels. [13] [17] [21] Serum calcium levels should fall by several milligrams per deciliter in the first 24 hours. The lowest level usually is reached within 4 or 5 days. In some patients, hypocalcemia may be a postoperative problem. Causes include insufficient residual parathyroid tissue, operative trauma or ischemia, postoperative hypomagnesemia, and delayed recovery of function of normal parathyroid gland tissue. It is particularly important to correct hypomagnesemia in patients with hypocalcemia because PTH secretion is diminished in the presence of hypomagnesemia. [18] [19] Potentially lethal complications of severe hypocalcemia include laryngeal spasm and hypocalcemic seizures.

In addition to monitoring total serum calcium or ionized calcium postoperatively, one can test for Chvostek's and Trousseau's signs. Because Chvostek's sign is present in 10% to 20% of individuals who do not have hypocalcemia, an attempt should be made to elicit this sign preoperatively. Chvostek's sign is a contracture of the facial muscles produced by tapping the ipsilateral facial nerves at the angle of the jaw. Trousseau's sign is elicited by application of a blood pressure cuff at a level slightly above the systolic pressure for a few minutes. The resulting carpopedal spasm, with contractions of the fingers and inability to open the hand, stems from the increased muscle irritability in hypercalcemic states, which is aggravated by ischemia produced by the inflated blood pressure cuff. Because postoperative hematoma can compromise the airway, the neck and wound dressings should be examined for evidence of bleeding before a patient is discharged from the recovery room.

Hypophosphatemia may also occur postoperatively. It is particularly important to correct this deficiency in patients with congestive heart failure. In a group of patients with severe hypophosphatemia, correction of serum phosphate concentration from 1.0 to 2.9 mg/dL led to significant improvement in left ventricular contractility at the same preload.[13] Other complications of hypophosphatemia include hemolysis, platelet dysfunction, leukocyte dysfunction (depression of chemotaxis, of phagocytosis, and of bactericidal activity), paresthesias, muscular weakness, and rhabdomyolysis.[19] In patients with both hypocalcemia and hypomagnesemia, correction of the hypomagnesemia may cause markedly increased PTH secretion, resulting in dramatic hypophosphatemia. Serum phosphate levels should be monitored closely in such patients. [18] [19]

Hypomagnesemia may occur postoperatively. Clinical sequelae of magnesium deficiency include cardiac dysrhythmias (principally ventricular tachydysrhythmias), hypocalcemic tetany, and neuromuscular irritability that is independent of hypocalcemia (tremors, twitching, asterixis, and seizures).[17] Both hypomagnesemia and hypokalemia augment the neuromuscular effects of hypocalcemia. Often, just restoring the magnesium deficit corrects the hypocalcemia. It is preferable to use oral calcium (1 or 2 g four times daily of calcium gluconate) when the patient is able to take oral fluids.

During the first week or 10 days after surgery, vitamin D derivatives are avoided to allow the suppressed parathyroid tissue (if present) to function. Vitamin D derivatives are always started if the patient has significant hypocalcemia 2 weeks after surgery. The older vitamin D derivatives include vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Of these derivatives, 40,000 units is equal to approximately 1 mg. Therapy in the patient with permanent hypoparathyroidism is begun with 40,000 units daily of either vitamin D2 or D3. The dosage is increased by 20,000 units every 2 weeks until the desired calcium level is attained. Vitamin D is fat soluble, and the significant fat stores in adipose tissue, muscle, and liver must first be saturated before a therapeutic level is achieved.

Patients with surgical hypoparathyroidism sometimes require huge quantities of vitamin D derivatives (200,000 to 300,000 units or 5 to 7 mg daily) and thus appear to have an end organ resistance to its effects. In the hypoparathyroid patient it is best to aim for a calcium level of 8.5 to 9.0 mg/dL. While these patients have a urinary calcium leak because of the absence of PTH, in general it is best to keep the urinary calcium level below 300 mg/24 hr. If the urinary calcium level is above 300 mg/24 hr, the vitamin D dose should be dropped back by 25% of the patient's initial dose. Another vitamin D derivative is dihydrotachysterol (Dygratyl). Doses of 250 to 2000 μg of dihydrotachysterol are required to control the hypocalcemia in hypoparathyroidism. The compound 25-hydroxycholecalciferol is 15 times more potent than the parent vitamin D2, and 1,25(OH)2D3 is about 1500 times more potent.

The management of hypoparathyroidism is not easy, and careful follow-up of patients is mandatory. Blood calcium and urinary calcium should be checked every 6 months after surgery. Vitamin D intoxication is an ever-present danger.

Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Copyright © 2005 Saunders, An Imprint of Elsevier

Hypocalcemia

Probably the most common cause of hypocalcemia is hypoalbuminemia, followed by surgical removal of the parathyroids. However, the differential diagnosis of hypocalcemia should also include chronic renal insufficiency, malabsorption syndrome, pseudohypoparathyroidism, hypomagnesemia, osteoblastic metastasis to bone, pancreatitis, and the rare autoimmune abnormality of deficiency in multiple endocrine glands. A very rare cause of hypocalcemia is thymic hypoplasia associated with hypoparathyroidism (DiGeorge syndrome). In true hypocalcemia (i.e., when free calcium is low), myocardial contractility is often affected. Table 13-2 lists the differential diagnosis of hypocalcemia and some tests used to differentiate these cases. Measurement of PTH is not nearly as useful in differentiating the hypocalcemic states as it is in the hypercalcemic disorders. The vitamin D deficiency of the malabsorption syndrome, osteomalacia (in the adult) and rickets (in the child), is associated with a low serum phosphorus concentration. In all other causes of hypocalcemia the serum phosphorus value tends to be elevated. It is disproportionately elevated in chronic renal failure. Cataracts and basal ganglion calcification are seen in both hypoparathyroidism and pseudohypoparathyroidism. Subperiosteal resorption (the hallmark of excessive PTH secretion) is seen mainly in chronic renal failure associated with secondary hyperparathyroidism and in some forms of pseudohypoparathyroidism. Most of the clinical manifestations of hypoparathyroidism are attributable to hypocalcemia. Hypocalcemia occurs because of a fall in the equilibrium level of the blood-bone calcium relationship, in association with a reduction in renal tubular reabsorption and gastrointestinal absorption of calcium. PTH inhibits renal tubular reabsorption of phosphate and bicarbonate; hence, serum phosphate and bicarbonate levels are elevated in patients with hypoparathyroidism.

TABLE 13-2   -- Differential Diagnosis of Hypocalcemia

 

Serum Phosphorus

Serum Alkaline Phosphatase

Creatine

PTH

Comments

Hypoparathyroidism (usually surgical)

N

N

↓ or 0

Cataracts; basal ganglia calcification; other endocrine gland hypofunction

Chronic renal disease (secondary hyperparathyroidism)

↑↑

↑↑

↑↑

Impaired renal 1,25(OH)2D synthesis

Malabsorption syndrome (vitamin D deficiency)

↓↓

N

N or ↓

Vitamin D malabsorption or deficiency (osteomalacia or rickets)

Pseudo-hypoparathyroid variants

N

N

Metastatic calcification, cataracts, short stature

Hypomagnesemia

N

N

N or ↑

Malnutrition, alcoholism, and malabsorption

Osteoblastic metastasis

N

N or ↑

N

N or ↑

X-ray skeletal, seen in prostatic cancer

Acute pancreatitis

N

N or ↑

N

N or ↓

Mechanism unknown

Low plasma proteins

N

N

N or ↑

N

Ionized calcium may be normal; malnutrition nephrosis

↑, Elevated; ↑↑, markedly elevated; ↓, decreased; N, normal.

 

 

 

Pseudohypoparathyroidism is an unusual entity associated with short stature, round facies, and short metacarpals, as well as parathyroid hyperplasia. It represents in part as end organ resistance to the action of PTH. 1,25(OH)2D3 levels are low in pseudohypoparathyroidism, and replacement of this vitamin D derivative can partially reverse the end organ resistance. Hypomagnesemia impairs PTH release and thus can cause profound hypocalcemia. [17] [19] Hypomagnesemia is common in patients with alcoholism, malnutrition, or chronic severe malabsorption states. The calcium level may be restored by replacing magnesium. Relative parathyroid insufficiency may account for the persistent hypocalcemia observed in patients with acute pancreatitis.

The acute manifestations of acute hypoparathyroidism have already been discussed with postoperative management of hypercalcemia.

A nerve exposed to low calcium concentration has a reduced threshold of excitation, responds repetitively to a single stimulus, and has impaired accommodation and continuous activity. Tetany usually begins with paresthesias of the face and extremities, which increase in severity. Spasms of the muscles in the face and extremities follow. Pain in the contracting muscle may be severe. Patients often hyperventilate, and the resulting hypocapnia worsens the tetany. Spasm of laryngeal muscles can cause the vocal cords to be fixed at the midline, and this leads to stridor and cyanosis.

Chvostek's and Trousseau's signs (see earlier) are two classic signs of latent tetany. Manifestations of spasm distal to the inflated blood pressure cuff should occur within 2 minutes (see earlier).

Hypocalcemia delays ventricular repolarization, thus increasing the QTc interval (normal, 0.35 to 0.44). With electrical systole thus prolonged, the ventricles may fail to respond to the next electrical impulse from the SA node, causing 2:1 heart block. Prolongation of the QT interval is a moderately reliable ECG sign of hypocalcemia, not for the population as a whole but for individual patients. [20] [22] Thus, following the QT interval as corrected for heartrate ( Fig. 13-1 ) is a useful but not always accurate means of monitoring hypocalcemia. CHF may also occur with hypocalcemia, but this is rare. Because CHF in patients with coexisting heart disease is reduced in severity when calcium and magnesium ion levels are restored to normal, these levels should be normal before surgery. Sudden decreases in blood levels of ionized calcium (as with chelation therapy) can result in severe hypotension.[18]

 
 

FIGURE 13-1  The QTC interval (properly termed QETC, to indicate that it begins with the start of the Q wave, lasts for the entire QT interval, ends with the end of the T wave, and is corrected for heart rate) is measured as illustrated. RR, RR interval in seconds.  (From Hensel P, Roizen MF: Patients with disorders of parathyroid function. Anesthesiol Clin North Am 1987;5:294.)

 

 

 

Patients with hypocalcemia may have seizures. These may be focal, jacksonian, petit mal, or grand mal in appearance, indistinguishable from such seizures in the absence of hypocalcemia. Patients may also have a type of seizure called cerebral tetany, which consists of generalized tetany followed by tonic spasms. Therapy with standard anticonvulsants is ineffective and may even exacerbate these seizures (by an anti–vitamin D effect). In long-standing hypoparathyroidism, calcifications may appear above the sella, representing deposits of calcium in and around small blood vessels of the basal ganglia. These may be associated with a variety of extrapyramidal syndromes.

Other common clinical signs of hypocalcemia are clumsiness, depression, muscle stiffness, paresthesias, dry scaly skin, brittle nails and coarse hair, and soft tissue calcifications. Patients with long-standing hypoparathyroidism sometimes adapt to the condition well enough to be asymptomatic.

The symptoms related to tetany seem to correlate best with the level of the ionized calcium. If alkalosis is present, it is possible for the total calcium level to be normal but the ionized calcium low, and symptoms of neuromuscular irritability may result (i.e., hyperventilation syndrome). With slowly developing chronic hypocalcemia the symptoms may be very mild despite severe hypocalcemia, and this may in part be due to adaptive changes in the level of the ionized calcium. Even with calcium levels of 6 to 7 mg/dL, minor muscle cramps, fatigue, and mild depression may be the only symptoms. Many patients with a calcium level of 6 to 6.5 mg/dL are totally asymptomatic aside from some mild depression of intellectual function.

Vitamin D derivatives are used in the management of hypoparathyroidism (see preceding section), chronic renal insufficiency with secondary hyperparathyroidism, pseudohypoparathyroidism, the malabsorption syndromes, and other vitamin D deficiency states. Malabsorption syndrome associated with fat malabsorption may require an intramuscular preparation of vitamin D (2000 to 4000 units/day) if adequate oral therapy fails. A high-calcium diet (2 g elemental calcium) is indicated whenever a vitamin D preparation is used for this purpose. A low-phosphorus diet (including use of aluminum hydroxide) is useful in chronic renal failure, but a high-phosphate diet (calcium phosphate preparation may be used) is useful in patients with malabsorption syndrome and other vitamin D deficiency states (rickets and osteomalacia). In chronic renal disease the bone abnormalities due to excessive PTH levels (subperiosteal reabsorption) are essentially reversed by 1 or 2 μg of 1,25(OH)2D3 (Rocaltrol); however, the osteomalacic changes in chronic renal disease may not be totally reversed by this potent vitamin D derivative. Pseudohypoparathyroidism and hypoparathyroidism are managed essentially in the same fashion (see earlier). Phenothiazines should be used with caution in patients with hypocalcemia (especially hypoparathyroidism), because they may precipitate dystonic reactions or dysrhythmias. Furosemide may decrease calcium levels more in patients with hypoparathyroidism.

Perioperative Considerations for Patients with Hypoparathyroidism

Because treatment of hypoparathyroidism is not surgical, hypoparathyroid patients who come to the operating room are those who require surgery for an unrelated condition. Their calcium, phosphate, and magnesium levels should be measured both preoperatively and postoperatively. Patients with symptomatic hypocalcemia should be treated with intravenous calcium gluconate before surgery. Initially, 10 to 20 mL of 10% calcium gluconate may be given at a rate of 10 mL/min. The effect on serum calcium levels is of short duration, but a continuous infusion with 10 mL of 10% calcium gluconate in 500 mL of solution over 6 hours may help to maintain adequate serum calcium levels.

The objective of therapy is to have symptoms under control before surgery and anesthesia. In patients with chronic hypoparathyroidism, the objective is to maintain the serum calcium level in at least the lower half of the normal range. A preoperative electrocardiogram can be obtained and the QTC interval calculated. The QTC value may be used as a guide to the serum calcium level if a rapid laboratory assessment is not possible. No special choice of anesthetic agents or techniques is indicated, with the exception of avoidance of respiratory alkalosis, because this tends to further decrease levels of ionized calcium.

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Summary

Physiologic derangements in patients with disorders of parathyroid function are caused principally by inappropriate serum calcium levels. Preoperative evaluation of these patients commonly includes determination of calcium, phosphate, and magnesium levels. An electrocardiogram with calculation of the QTC interval can be obtained preoperatively and can be followed intraoperatively. The patient's volume status may be affected, because both hypercalcemia and its treatment may lead to hypovolemia. Other measures to decrease calcium such as with other anticancer agents and with calcitonin may need other measures of side effects.

There is no evidence supporting any particular anesthetic technique. In addition to the QTC interval, the free calcium level can be checked intraoperatively, if possible. Muscle relaxant dose and timing may be a special concern.[21] Calcium, phosphate, and magnesium levels often vary postoperatively. The patient should be observed closely for evidence of nerve injury, hematoma, or hypocalcemic tetany.

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THYROID GLAND

Perhaps no endocrine organ has contributed as much to the development of surgery as a specialty as has the thyroid gland. The Cleveland Clinic and the clinics of such prominent surgeons as Lahey, Crile, and the Mayo brothers had their beginnings as centers for the traditional “steal” of the hyperthyroid patient and for the safe removal of enlarged thyroid glands. These clinics were located in regions where the soil was deficient in iodine. As a result, both water and food contained less than optimal amounts of iodine, thus contributing to the development of endemic goiter.

As with many other endocrinopathies, two themes emerge when anesthesia for patients with thyroid disease is discussed: (1) The organ system that most affects the anesthetic management of patients having any endocrinopathy is the cardiovascular system. (2) In almost all emergency situations, and certainly in all elective situations, any endocrine abnormality affecting the patient's preoperative state that can be stabilized may improve outcome. It is the task of the anesthesiologist to educate the primary care physician and surgeon about the hazards of not optimizing endocrine function preoperatively. [22] [23] [24]

Physiology

Thyroid hormone biosynthesis involves five steps. [25] [26] They are as follows: (1) iodide trapping, (2) oxidation of iodide and iodination of tyrosine residues, (3) hormone storage in the colloid of the thyroid gland as part of the large thyroglobulin molecule, (4) proteolysis and release of hormones, and (5) conversion of less active prohormone thyroxine to more potent hormone 3,5,3-triiodothyronine. The first four steps are regulated by pituitary thyroid-stimulating hormone (TSH). Proteolysis of stored hormone in the colloid is inhibited by iodide.

The major thyroid products are the prohormone thyroxine (T4, a product of the thyroid gland) and the more potent hormone 3,5,3-triiodothyronine (T3, a product of both the thyroid and the extrathyroidal enzymatic deiodination of thyroxine). Approximately 85% of T3 is produced outside the thyroid gland. Production of thyroid hormones is maintained by secretion of TSH by the pituitary gland, which in turn is regulated by secretion of thyrotropin-releasing hormone (TRH) in the hypothalamus. The production of thyroid hormone is initiated by absorption of iodine from the gastrointestinal tract, where the iodine is reduced to an iodide and released into plasma. It is then concentrated up to 500-fold by the thyroid gland.

Once in the gland, the iodide is oxidized by a peroxidase to iodine (organification) and then bound to tyrosine, forming either monoiodotyrosine or diiodotyrosine. Both of these are then coupled enzymatically to form T4 or T3. The T3 and T4 are bound to the protein thyroglobulin and stored as colloid in the gland. A proteolytic enzyme releases T3 and T4 from the thyroglobulin as the prohormones pass from the cell to the plasma. T3 and T4 are transported through the bloodstream on thyroxine-binding globulin and thyroxine-binding prealbumin. The plasma normally contains 4 to 11 μg of T4 and 0.1 to 0.2 μg of T3 per 100 mL. Secretion of TSH and TRH appears to be regulated by T3 in a negative-feedback loop. Most of the effects of thyroid hormones are mediated by T3; T4 is both less potent and more protein bound, thus having lesser biologic effect, and is now considered a prohormone.[26]

In peripheral tissues there exists a ubiquitous deiodinase that converts T4 to T3. Thus, T4 appears to be a prohormone for T3. Monodeiodinations can remove either the iodine at the 5 position to yield T3 or the iodine at the 5 position to yield reverse T3 (rT3). Reverse T3 is totally inactive biologically. In general, when T3 levels are depressed, rT3 levels are elevated. In a number of circumstances, rT3 levels are increased, such as during gestation, malnutrition, chronic disease, and surgical stress ( Fig. 13-2 ).[27] A feedback circuit exists between the pituitary gland and the circulating thyroid hormones. High levels of thyroid hormones reduce release of pituitary TSH, whereas low levels result in more TSH release ( Fig. 13-3 ).

 
 

FIGURE 13-2  Peripheral deiodination of T4.

 

 

 
 

FIGURE 13-3  Hypothalamic pituitary thyroid axis. TRF, thyrotropin-releasing factor; TSH, thyroid-stimulating hormone; T3, triiodothyronine; T4, 1-tetraiodothyronine; +, stimulation; –, inhibition.

 

 

Energy-dependent transport systems move T3 across the target cell membrane into the cytoplasm. It then diffuses to receptors in the cell nucleus, where its binding to high-affinity nuclear receptors (TR α and TR β) alters the production of specific messenger-RNA sequences that result in physiologic effects. Thyroid hormone has anabolic effects, promotes growth, and advances normal brain and organ development. Thyroid hormone also increases the concentration of adrenergic receptors,[28] which may account for many of its cardiovascular effects.

The diagnosis of thyroid disease is confirmed by one of several biochemical measurements: levels of free T4, total serum concentration of T4, or estimate of free T4. The estimate is obtained by multiplying total T4 (T4-RIA) by the thyroid-binding ratio (formerly called the resin T3 uptake). [26] [29]

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Thyroid Function Tests

Total Thyroxine

Serum Thyroxine by Radioimmunoassay (T4-RIA).

The normal plasma range of the total T4 is 4.5 to 10 μg/dL. The T4 is high in hyperthyroidism and low in hypothyroidism. Most of the T4 is bound to a plasma protein known as thyroid-binding globulin (TBG). Changes in TBG can affect the total T4 level. Estrogens, infectious hepatitis, and genetic factors can elevate the level of the TBG and thus secondarily raise total T4. Androgens, nephrosis, hypoproteinemia, and genetic factors can lower the TBG and thus secondarily lower the total T4.

Thyroid-Binding Ratio

Resin Triiodothyronine Uptake (RT3U).

This important in-vitro test depends on the binding of a tracer amount of radioactive T3 to an artificial resin. The amount of binding to resin is inversely proportional to the unoccupied binding sites of TBG. If the T4 level is high because there is an excess of TBG (i.e., after estrogen administration), there will be an increase in the number of unoccupied binding sites and the thyroid-binding ratio will be low. The thyroid-binding ratio varies in different laboratories but the average is 20% to 25%. If the ratio is multiplied by total T4, an index is achieved. This index is usually called the “free T4 estimate.” The free T4estimate corrects the total T4 level for any changes in TBG concentration or in unoccupied binding sites on the TBG molecule. It is very difficult to assay the free T4 level directly, because it amounts to only about 0.5% of the total T4 (approximately 1 to 2 ng/dL). The free T4 estimate correlates directly with the metabolic status of the patient.

Free Serum Triiodothyronine by Radioimmunoassay (T3-RIA).

This extremely potent hormone normally is present in a concentration range of 75 to 200 ng/dL. It is important to note that the upper limit of normal tends to drop with each decade of life. Thus, a 20-year-old patient with a level of 190 ng/dL may be euthyroid whereas an 80-year-old patient with the same level may be hyperthyroid.

Serum Thyroid-Stimulating Hormone.

In patients with primary hypothyroidism, the TSH level is high for the level of T4 or T3 in blood. Often serum concentrations of thyroid hormone are in the normal range, and only serum TSH levels are elevated.[29]

Radioactive Iodine Uptake.

The radioactive iodine uptake (RAIU) is measured as the percentage of a tracer that is taken up by the thyroid in 24 hours. The normal range is 10% to 25%. Patients with hyperthyroidism have values above 25%. The major use of this test is to confirm the diagnosis of hyperthyroidism; however, patients with subacute thyroiditis can be hyperthyroid but have essentially no uptake. If a patient has used inorganic iodides or dyes (e.g., for gallbladder scans or intravenous pyelography) the RAIU may be low.

Ultrasound Radioactive, MRI and Thin-Slice CT Thyroid Scan

These scans all have uses in diagnosis and treatment. Functioning thyroid nodules are rarely malignant, whereas “cold” or hypofunctioning nodules have a greater probability of malignancy.

Other Tests

The diagnosis of pituitary or hypothalamic disease can be quite complicated. The procedure is often aided by the use of TRH. This tripeptide is the hypothalamic factor that brings about release of TSH from the pituitary. It may also be used to confirm the diagnosis of hyperthyroidism. Thyroid antibodies (antithyroglobulin and antimicrosomal) are useful in arriving at the diagnosis of Hashimoto's thyroiditis. Serum thyroglobulin levels tend to be elevated in patients with thyrotoxicosis. Painless thyroiditis is associated with transient hyperthyroidism. This latter entity is a lymphocytic thyroiditis associated with low RAIU.

Measurement of the α subunit of TSH has been helpful in identifying the rare patients who have a pituitary neoplasm and who usually have increased α-subunit concentrations. Some patients are clinically euthyroid in the presence of elevated levels of total T4 in serum. Certain drugs, notably gallbladder dyes, corticosteroids, and amiodarone, block the conversion to T3 to T4, thus elevating T4 levels. Severe illness also slows the conversion of T4 to T3. Levels of TSH are often high when the rate of this conversion is decreased. In hyperthyroidism, cardiac function and responses to stress are abnormal; return of normal cardiac function parallels the return of TSH levels to normal values.

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Pathophysiology of Thyroid Disease

Hyperthyroidism

Hyperthyroidism is usually caused by multinodular diffuse enlargement of the gland in Graves' disease that is also associated with disorders of the skin and eyes.[30] Hyperthyroidism can be associated with pregnancy,[31] thyroiditis (with or without neck pain), thyroid adenoma, choriocarcinoma, or TSH-secreting pituitary adenoma. Five percent of women have been reported to suffer thyrotoxic effects 3 to 6 months post partum, and they tend to have recurrences with subsequent pregnancies.[31]

Major manifestations of hyperthyroidism are weight loss, diarrhea, warm moist skin, weakness of large muscle groups, menstrual abnormalities, nervousness, intolerance of heat, tachycardia, cardiac dysrhythmias, mitral valve prolapse,[32] and heart failure. When the thyroid is functioning abnormally, the system threatened most is the cardiovascular system. Severe diarrhea can lead to dehydration, which can be corrected before a surgical procedure is undertaken. Mild anemia, thrombocytopenia, increased serum alkaline phosphatase, hypercalcemia, muscle wasting, and bone loss frequently occur in patients with hyperthyroidism. Muscle disease usually involves proximal muscle groups; it has not been reported to cause respiratory paralysis. In the apathetic form of hyperthyroidism (seen most commonly in persons over 60 years of age), cardiac effects dominate the clinical picture. [33] [34] The signs and symptoms include tachycardia, irregular heartbeat, atrial fibrillation, heart failure, and occasionally papillary muscle dysfunction. [33] [34] [35] [36] In fact, the presence of atrial fibrillation of unknown origin indicates the need to be concerned about apathetic hyperthyroidism. This concern is more than academic because “thyroid storm” can occur in such patients when they undergo operations for other diseases.

Although β-adrenergic receptor blockade can control heart rate, its use is fraught with hazards in a patient who is already experiencing CHF. However, decreasing the heart rate may improve the cardiac pump function. Thus, hyperthyroid patients who have high ventricular rates, who have CHF, and who require emergency surgery are given propranolol in doses guided by changes in pulmonary artery wedge pressure and the overall clinical condition. If slowing the heart rate with a small dose of esmolol (50 μg/kg) does not aggravate heart failure, more esmolol (50 to 500 μg/kg) is administered. The aim is to avoid imposing surgery on any patient whose thyroid function is clinically abnormal. Therefore, only “life-or-death” emergency surgery should preclude making the patient pharmacologically euthyroid, a process that can take 2 to 6 weeks.

Preparation of the Hyperthyroid Patient for Surgery.

Nevertheless, 200,000 thyroid and parathyroid operations are performed annually in the United States. In general, the patients still considered appropriate for surgery are children, adolescents, women whose pregnancy is associated with Graves' disease, women of child-bearing age, and patients who have extremely large thyroid glands. A number of patients refuse radioactive iodine treatment, thereby becoming candidates for surgery. The traditional method for making the patient euthyroid involves giving one of the antithyroid drugs for 2 to 3 months before surgery to inhibit thyroid hormone synthesis. The drug that is still (after 30 years) most used is propylthiouracil, because it inhibits both thyroid hormone synthesis and the peripheral conversion of T4 to T3. The usual dosage is 300 mg daily in divided doses. Most patients will be euthyroid in 2 to 3 months on this dosage. If the patient is severely hyperthyroid or has an unusually large gland, larger doses may be used (up to 1 g daily). In general, the smaller the gland, the shorter the interval necessary to achieve euthyroidism. An alternative drug is methimazole (Tapazole). Doses of 30 to 60 mg daily are comparable to the above doses of propylthiouracil. About 10 days before surgery it is common to give the patient a potassium iodide solution (10 drops daily of a saturated solution) to decrease gland vascularity and block release of stored hormone. Lithium carbonate (300 mg four times daily) may be given in lieu of iodide, especially if there is a known allergy to iodine. Lithium carbonate, like iodide, blocks the proteolysis and release of stored thyroid hormone.

Published reports indicate a trend toward preoperative preparation with propranolol and iodides alone. [37] [38] [39] This approach is less time consuming (i.e., 7 to 14 days vs. 2 to 6 weeks); it causes the thyroid gland to shrink, as does the more traditional approach; and it treats symptoms, but abnormalities in left ventricular function may not be corrected. [34] [36] [38] [39] Regardless of the approach used, antithyroid drugs should be administered both chronically and on the morning of surgery. If emergency surgery is necessary before the euthyroid state is achieved or if the hyperthyroidism gets out of control during surgery, intravenous administration of 50 to 500 μg/kg of esmolol can be titrated for restoration of a normal heart rate (assuming that CHF is absent; see previous discussion). Larger doses may be required, and in the absence of better data, the return of a normal heart rate and the absence of CHF serve as guides to therapy. In addition, intravascular fluid volume and electrolyte balance should be restored. It should be kept in mind that administering propranolol does not invariably prevent “thyroid storm.” [38] [39] [40] [41]

Management of Thyrotoxicosis During Pregnancy

The management of the thyrotoxicosis of Graves' disease during pregnancy presents some special problems. Radioactive iodine therapy is usually considered contraindicated because it crosses the placenta. The physician has a choice between antithyroid drugs and surgery. Antithyroid drugs also cross the placental barrier and can cause fetal hypothyroidism. This problem may theoretically be obviated by the simultaneous administration of L-thyroxine or T3. However, most of the evidence indicates that neither T4 nor T3 crosses the placental barrier. The occurrence of fetal hypothyroidism when small doses of antithyroid drugs alone are used is quite unusual as long as the mother remains euthyroid. It is usually better to err on the side of undertreatment than overtreatment with antithyroid drugs. Small amounts of propylthiouracil (50 to 100 mg/day or even every other day) are often sufficient. Chronic use of iodide in the mother is usually contraindicated because fetal goiter and hypothyroidism may result. The use of propranolol during pregnancy is controversial. There have been case reports that infants whose mothers had received propranolol experienced intrauterine growth retardation and low Apgar ratings. Bradycardia and hypoglycemia also have been described in these infants. The thyrotoxicosis of pregnancy tends to be quite mild and often improves in the second and third trimester. Surgery is an acceptable alternative to treatment (this surgery is usually postponed until neural development and organogenesis of the first trimester are complete).[42]

After pregnancy, it is impossible to predict the thyroid status of the mother. Whereas some patients remain hyperthyroid, some become hypothyroid after delivery. Approximately 5% of women suffer transient thyrotoxic effects 3 to 6 months post partum, and these mothers tend to have recurrences with subsequent pregnancies.[31]

The status of the neonate after delivery needs attention. Either hypothyroidism or hyperthyroidism may be present. Neonatal hypothyroidism is characterized by a low total T4 (below 7 μg/dL) and an elevated TSH. At times the T4 may be perfectly normal and only the TSH elevated. Amniotic fluid reverse T3 levels tend to be low in the hypothyroid fetus in the third trimester, and likewise the blood reverse T3 concentration is low after birth if hypothyroidism exists.

Management of neonatal hypothyroidism consists of the immediate replacement with L-thyroxine in the dose range of 9 μg/kg/day. This dose is relatively large, but it is often required to normalize the TSH level and T4 concentration. Normally the total T4 level (8 to 15 μg/dL) tends to be high in the first year of life and slowly but progressively drops until after puberty. Likewise, thyroid hormone replacement doses tend to be higher than in the average adult until puberty is complete.

Neonatal hyperthyroidism is most unusual and is always associated with high levels of thyroid-stimulating immunoglobulins. These immunoglobulins cross the placental barrier and are probably the cause of fetal hyperthyroidism. Consequently, it is common to measure these immunoglobulins in thyrotoxic women in the third trimester. Controlling maternal hyperthyroidism seems to prevent the development of hyperthyroidism in infants.

Thyroid storm refers to the clinical diagnosis of a life-threatening illness in a patient whose hyperthyroidism has been severely exacerbated by illness or operation. It is manifested by hyperpyrexia, tachycardia, and striking alterations in consciousness. [40] [41] No laboratory tests are diagnostic of thyroid storm, and the precipitating (nonthyroidal) cause is the major determinant of survival. Therapy usually includes blocking the synthesis of thyroid hormones by administration of antithyroid drugs, blocking release of preformed hormone with iodine, meticulous attention to hydration and supportive therapy, and correction of the precipitating cause. In fact, survival is directly related to the success of treatment of the underlying cause. Blocking of the sympathetic nervous system with α- and β-receptor antagonists may be exceedingly hazardous and requires skillful management and constant monitoring of the critically ill patient. More than 10% of patients treated with the antiarrhythmic agent amiodarone develop thyroid dysfunction, either hyperthyroidism or hypothyroidism.[24] Approximately 35% of the drug's weight is iodine, and a 200-mg tablet releases about 20 times the optimal daily dose of iodine. This iodine can lead to reduced synthesis of thyroxine or to increased synthesis. In addition, amiodarone inhibits the conversion of T4 into the more potent T3.

Patients receiving amiodarone might be considered in need of special attention preoperatively, and even may require special attention to anesthesia, not just due to the arrhythmia that led to such therapy but also to ensure no perioperative dysfunction or surprises due to unsuspected thyroid hyperfunction or hypofunction.[24] Many patients with amiodarone thyrotoxicosis receive corticosteroids for a period of time, another area of questioning that might be triggered by the use of amiodarone by a preoperative patient.

Hypothyroidism

Hypothyroidism is a common disease, occurring in 5% of a large adult population in Great Britain, in 3% to 6% of a population of healthy elderly individuals in Massachusetts, and in 4.5% of a medical clinic population in Switzerland. [43] [44] The apathy and lethargy that often accompany hypothyroidism often delay its diagnosis, so that the perioperative period may be the first place to spot many such hypothyroid patients. However, usually hypothyroidism is subclinical, serum concentrations of thyroid hormones are in the normal range, and only serum TSH levels are elevated. [25] [45] The normal range of TSH being 0.03 to 4.5 mU/L, TSH values of 5 to 15 mU/L are characteristic of this entity.[35] In such cases, hypothyroidism may have little or no perioperative significance. However, a retrospective study of 59 mildly hypothyroid patients found that more hypothyroid patients than control subjects required prolonged postoperative intubation (9 of 59 vs. 4 of 59) and had significant electrolyte imbalances (3 of 59 vs. 1 of 59) and bleeding complications (4 of 59 vs. 0 of 59).[46] Because only a small number of charts were examined, these differences did not reach statistical significance. In another study, a high percentage of patients with a history of subclinical hypothyroidism later developed overt hypothyroidism. Many women with postpartum thyroiditis develop hypothyroidism, which is often mistaken for postpartum depression.

Hypofunction of the thyroid gland can be caused by surgical ablation, radioactive iodine administration, irradiation to the neck (e.g., for Hodgkin's disease), iodine deficiency or toxicity, genetic biosynthetic defects in thyroid hormone production, antithyroid drugs such as propylthiouracil, amiodarone pituitary tumors, or hypothalamic disease. Perhaps the most common cause of primary thyroid hypofunction is a form of thyroiditis, often chronic lymphocytic thyroiditis or Hashimoto's thyroiditis. The gland is usually enlarged, nontender, and extremely firm and indurated. A variety of antithyroid antibodies are found in the serum, including antithyroglobulin and antimicrosomal antibodies in high titer. Hypothyroidism seems to be the most common consequence of Hashimoto's thyroiditis and, indeed, is the most common cause of hypothyroidism in adults.[45] Patients with Hashimoto's thyroiditis are extremely susceptible to iodides and to antithyroid drugs, and overt severe hypothyroidism can be exacerbated by these maneuvers. Usually, symptoms of hypothyroidism are subclinical, serum concentrations of thyroid hormones are in the normal range, and only serum TSH levels are elevated. [25] [45] [46]

In the less frequent cases of overt hypothyroidism, the deficiency of thyroid hormone results in slow mental functioning, slow movement, dry skin, intolerance to cold, depression of the ventilatory responses to hypoxia and hypercarbia,[47] impaired clearance of free water, slow gastric emptying, and bradycardia. In extreme cases, cardiomegaly, heart failure, and pericardial and pleural effusions are manifested as fatigue, dyspnea, and orthopnea.[48] Hypothyroidism is often associated with amyloidosis, which may cause enlargement of the tongue, abnormalities of the cardiac conduction system, and renal disease. The tongue may be enlarged in the hypothyroid patient even in the absence of amyloidosis, and this may hamper intubation.[49] Full-blown myxedema presents as a variety of symptoms, including cold intolerance, apathy, hoarseness, constipation, retarded movement, anemia, hearing loss, and bradycardia.

Preparation of the Hypothyroid Patient for Surgery.

Hypothyroidism decreases anesthetic requirements slightly.[50] Ideal preoperative management of hypothyroidism consists of restoring normal thyroid status: the normal dose of T3 or T4 should be administered routinely on the morning of surgery, even though these drugs have long half-lives (1.4 to 10 days). The usual daily replacement dose in adults is 0.1 to 0.2 mg of L-thyroxine (Synthroid). The T4 level itself can be used as a guide to therapy. Both the T4 and TSH serum levels are usually in the normal range in adequately treated patients.

Myxedema coma is a rare complication that is associated with profound hypothyroidism. It is associated with extreme lethargy, severe hypothermia, bradycardia, and alveolar hypoventilation with hypoxia and is occasionally accompanied by pericardial effusion and CHF. Hyponatremia associated with marked decrease in free water clearance by the kidney is also often part of the syndrome. This is the one single indication for intravenous T4 therapy. For patients in myxedema coma who require emergency surgery, T3 or T4 can be given intravenously (with the risk of precipitating myocardial ischemia, however) while supportive therapy is undertaken to restore normal intravascular fluid volume, body temperature, cardiac function, respiratory function, and electrolyte balance. L-Thyroxine is given in a single intravenous dose of 300 to 500 μg. Intravenous T3 (Cytomel) may also be given in the dose range of 25 to 50 μg every 8 hours until the blood level of T3 is normal. Intravenous T3 probably is superior to intravenous T4, because T3 is the most physiologically active form of thyroid hormone therapy and because it bypasses the normal T4 to T3 peripheral conversion pathway, which tends to be markedly depressed in patients with serious systemic illnesses. The intravenous preparations should always be prepared fresh before use.

Hypothyroid Patients with Coronary Artery Disease

Treating hypothyroid patients who have symptomatic coronary artery disease poses special problems and may require compromises in the general practice of preoperatively restoring euthyroidism with drugs. [24] [51] [52] Although both T4 and esmolol may be given, adequate amelioration of both ischemic heart disease and hypothyroidism may be difficult to achieve. The need for thyroid therapy must be balanced against the risk of aggravating anginal symptoms. One review suggests early consideration of coronary artery revascularization.[51] It advocates initiating thyroid replacement therapy in the intensive care unit soon after the patient's arrival from the operating room after myocardial revascularization surgery. However, several deaths resulting from dysrhythmias and CHF as well as cardiogenic shock with infarction have occurred while patients who were not given thyroid therapy were awaiting surgery. Thus, there is a need to consider “truly” emergency coronary artery revascularization in patients who have both severe coronary artery disease and significant hypothyroidism. In fact, several large medical centers consider the presence of both disease to be as important an indicator for immediate surgery as is left main coronary artery disease with unstable angina for immediate coronary revascularization.

In the presence of hypothyroidism, respiratory control mechanisms do not function normally.[48] However, the response to hypoxia and hypercarbia and the clearance of free water become normal with thyroid replacement therapy. Drug metabolism has been reported anecdotally to be slowed, and awakening times after administration of sedatives were found to be prolonged during hypothyroidism. However, no formal study of the pharmacokinetics and pharmacodynamics of sedatives or anesthetic agents in patients with hypothyroidism has been published. These concerns disappear when thyroid function is normalized preoperatively.

Addison's disease (with its relative steroid deficiency) is more common in hypothyroid than in euthyroid individuals, and some endocrinologists routinely treat patients who have noniatrogenic hypothyroidism by giving stress doses of corticosteroids perioperatively. The possibility that this steroid deficiency exists should be considered if the patient becomes hypotensive perioperatively.

Thyroid Nodules and Carcinoma

Identifying malignancy in a solitary thyroid nodule is a difficult and important procedure. Fine-needle aspiration biopsy has become a standard tool.[53] Males and patients with previous radiation to the head and neck have an increased likelihood of malignant disease in their nodules.[54] Twenty-seven percent of all irradiated patients develop nodules. Often, needle biopsy and scanning are sufficient for the diagnosis, but occasionally an excisional biopsy is needed. If a cancer is found at surgery it is usually routine to do total thyroidectomy. Instead of starting these patients on exogenous thyroid immediately after surgery, this decision should be temporarily postponed until a decision is made as to whether massive amounts of radioactive [131]I therapy are indicated. A week after 50 to 100 mCi of [131]I is given, exogenous replacement thyroid therapy can be instituted. Some internists prefer to start exogenous thyroid immediately after surgery, because it may have a cancer-suppressing effect.[55] However, before a radioactive iodine scan or definitive therapy with radioactive iodine can be accomplished, exogenous thyroid hormone must be stopped for at least 6 weeks. Papillary carcinoma accounts for more than 60% of all carcinomas. Simple excision of lymph node metastases appears to be as efficacious for patient survival as are radical neck procedures.[56]

Medullary carcinoma is the most aggressive form of thyroid carcinoma. It is associated with familial incidence of pheochromocytoma, as are parathyroid adenomas. For this reason, a history should be obtained for patients who have a surgical scar in the thyroid and parathyroid region, so that the possibility of occult pheochromocytoma can be ruled out.

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Intraoperative Anesthetic Considerations and Postoperative Problems in Patients with Thyroid Disease

The major considerations regarding anesthesia for patients with disorders of the thyroid are (1) attainment of a euthyroid state preoperatively, (2) preoperative preparation and attention to the characteristics of the diseases mentioned previously, and (3) normalization of cardiovascular function and temperature perioperatively.

No controlled study has demonstrated clinical advantages of any one anesthetic drug over another for surgical patients who are hyperthyroid. Thus, there are no data on human subjects to imply that the choice of anesthetic affects patient outcome in the presence of thyroid disease. Furthermore, although some authors have recommended that anticholinergic drugs (especially atropine) be avoided because they interfere with the sweating mechanism and cause tachycardia, atropine has been given as a test for adequacy of antithyroid treatment. Because patients are now subjected to operative procedures only when they are euthyroid, the traditional “steal” of the heavily premedicated hyperthyroid patient to the operating room has vanished.

A patient who has a large goiter and an obstructed airway can be treated like any other patient whose airway management is problematic. Preoperative medication need not include “deep” sedation, and an airway can be established, often with the patient awake. A firm armored endotracheal tube is preferable and should be passed beyond the point of extrinsic compression. It is most useful to examine computed tomographic (CT), magnetic resonance imaging (MRI), or ultrasound scans of the neck preoperatively to determine the extent of compression. Maintenance of anesthesia usually presents little difficulty. Body heat mechanisms are inadequate in hypothyroid patients, and temperature can be monitored and maintained, especially in patients who require emergency surgery before the euthyroid state is attained.[44] Because there is an increased incidence of myasthenia gravis in hyperthyroid patients, it may be advisable to use a twitch monitor to guide muscle relaxant administration.

Postoperatively, extubation should be performed under optimal circumstances for reintubation, in case the tracheal rings have been weakened and the trachea collapses. Possible postoperative complications are those for hyperparathyroidism (see earlier).

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Summary

Preoperative normalization of thyroid function helps ensure that the patient with thyroid disease is at little additional risk of experiencing perioperative complications. The organ system most threatened by thyroid disease is the cardiovascular system. In apathetic hyperthyroidism, a rapid heart rate or idiopathic atrial fibrillation may be the only clue to such a diagnosis. Patients with hypothyroidism and myocardial ischemia also pose problems for perioperative management. No particular anesthetic techniques or agents have proved more beneficial or successful than others. Securing the airway and checking for nerve palsies, hematoma formation, hypothermia, and hypocalcemia must not be overlooked perioperatively. If a patient has a neck scar, the medical history should probably be reviewed because of the possibility of associated pheochromocytoma.

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PITUITARY GLAND

Physiology

The pituitary gland is divided into an anterior and a posterior portion that have substantially different organizations. The anterior pituitary is connected to the hypothalamus via a complex portal vascular system. Hypothalamic releasing or inhibitory factors are synthesized in the hypothalamus, are secreted into the portal system, and reach the anterior pituitary gland in very high concentrations. Functional activity in the posterior pituitary has a different organization: specialized neurons in the hypothalamus synthesize vasopressin and oxytocin. These two hormones are then secreted through specialized axons down the stalk of the pituitary gland and are stored in the posterior pituitary gland.

Each pituitary hormone has a specific releasing factor associated with it—and in some cases a specific inhibitory factor. Except for the positive effect of TRH on both TSH and prolactin secretion and for disease states, generally there is no overlap in function of the hypothalamic hormones. For instance, in acromegaly, both somatotropin-releasing factor and thyrotropin-releasing factor can bring about release of growth hormone (GH). In the normal state this would not occur. Specific hypothalamic-releasing hormones have been defined for TSH, adrenocorticotropic hormone (ACTH), and the gonadotropins (both luteinizing hormone [LH] and follicle-stimulating hormone [FSH]). Both a releasing and an inhibitory hypothalamic factor have been discovered for GH. Prolactin is primarily associated with an inhibitory hypothalamic factor (probably the neurotransmitter dopamine). An additional factor involving hypothalamic control of the pituitary is the pulsatile periodic operation of the hypothalamus. Probably the most important biologic rhythm is the sleep or light-dark pattern. For instance, GH and ACTH show specific nocturnal bursts in males. Prolactin also tends to increase in concentration in the blood immediately after sleep begins. LH shows a sleep pattern especially during puberty.

The three monoamine neurotransmitters—dopamine, norepinephrine, and serotonin—can profoundly affect hypothalamic function and are found in high concentration in major hypothalamic centers. There is essentially no blood-brain barrier in either the pituitary or the hypothalamus, and target organ products such as estrogen, testosterone, thyroid, and adrenal hormones can exert feedback at either the hypothalamic or pituitary level ( Fig. 13-4 ).

 
 

FIGURE 13-4  Basic feedback mechanisms in the neuroendocrine system.  (From Hosp Pract 1975;10:60.)

 

 

 

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Diseases of the Anterior Pituitary Gland

Hypofunction of the Pituitary Gland

All or several of the trophic hormones may be involved in hypopituitary states. The causes of hypopituitarism include chromophobe adenoma, Rathke's pouch cysts or craniopharyngioma in children, necrosis following circulatory collapse due to hemorrhage after delivery (Sheehan's syndrome), surgical hypophysectomy, irradiation to the skull or brain, granulomatous diseases, other infectious diseases, surgical or other trauma, and hemochromatosis. [56] [57] [58] Metastatic disease (especially from breast cancer) is only rarely seen. Destruction of the gland by tumor (i.e., chromophobe adenoma) is probably the most common cause of hypopituitarism. One third to one half of all patients with chromophobe adenoma secrete excessive quantities of the hormone prolactin. Excessive secretion of prolactin may be associated with galactorrhea and amenorrhea (gonadotropin deficiency).[57] GH deficiency in a child results in severe growth failure. Loss of TSH or ACTH function usually occurs later in life, when variable features related to thyroid deficiency or cortisol lack inevitably manifest themselves. If a tumor exists, it may grow above the sella (suprasellar extension), and headaches and visual field defects, notably bitemporal hemianopsia, will occur. Single isolated deficiencies of specific pituitary hormones have been described. The most common is gonadotropin deficiency. A well-known syndrome is gonadotropin deficiency associated with loss of the sense of smell (Kallmann's syndrome). This interesting hypothalamic entity is caused by failure of gonadotropin-releasing factor to function appropriately. Although depression might be expected to decrease ACTH response, it did not do so in a recent controlled study.[59]

It is possible to measure by radioimmunoassay virtually all of the hormones of the anterior pituitary gland. This includes measurements of GH, TSH, LH, FSH, prolactin, and ACTH. Low LH and FSH associated with estrogen deficiency in a female or low testosterone in a male points to a hypothalamic or pituitary deficiency even of ACTH.[60] Likewise low TSH with a low T4 by radioimmunoassay also indicates either hypothalamic or pituitary deficiency. An elevated prolactin level is commonly associated with chromophobe adenomas.

An evaluation of the hypothalamic-pituitary-adrenal axis, however, can be quite difficult. The metapyrone test has long been a standard test for determination of the pituitary-adrenal axis. Metapyrone blocks the conversion of 11-deoxycortisol to cortisol. Normally, 11-deoxycortisol is not measurable. The metapyrone test consists of giving a single oral dose of metapyrone (3 g) at midnight and measuring plasma cortisol and 11-deoxycortisol concentrations the following morning. If the 11-deoxycortisol level is greater than 10 μg/mL, ACTH stimulation must have occurred and the patient has a normal pituitary-adrenal axis. If both 11-deoxycortisol and cortisol are low, this means that ACTH was not stimulated and the patient has little or no ACTH pituitary reserve. The test can also be performed using the measurement of urinary 17-hydroxycorticoids while 750 mg of metapyrone is given every 4 hours for six doses.

Hypoglycemia induced by giving 0.1 unit of insulin per kilogram of body weight intravenously can also be used to test not only ACTH reserve but also GH reserve. Hypoglycemia (blood glucose concentration less than 50 mg/dL) should result in significant rises in both plasma cortisol and GH if the pituitary gland is functioning normally. Failure of the plasma cortisol level to rise after intravenous insulin is an indication that ACTH reserve is low.

Hyperfunction of the Pituitary Gland

There are three major hyperfunctioning pituitary gland tumors: (1) prolactin-secreting chromophobe adenoma, (2) an ACTH-secreting tumor associated with Cushing's disease (see section on adrenal disease), and (3) acromegaly associated with excessive GH secretion. Gonadotropin- and thyrotropin-secreting pituitary tumors are extraordinarily rare.

Acromegaly is a syndrome that presents as characteristic facies, weakness, enlargement of the hands (often to the point of rendering the usual oximeter probes difficult to use) and feet, thickening of the tongue (often to the point of making endotracheal intubation difficult), and enlargement of the nose and mandible with spreading of the teeth (often to the point of requiring larger than normal laryngoscope blades). [60] [61] [62] [63] The patient may even appear myxedematous. Other findings include abnormal glucose tolerance, carpal tunnel syndrome, and osteoporosis. The most specific test for acromegaly is measurement of GH before and after glucose administration. The typical acromegalic has very elevated fasting levels of GH (usually above 10 mg/mL), and the levels do not change appreciably after oral glucose is administered. In the normal state, glucose markedly suppresses the GH level. A few patients with active acromegaly have normal levels of fasting GH that are not suppressed after glucose is given. The drug L-dopa, which normally causes an elevation of GH in healthy subjects, in the acromegalic either has no effect or lowers GH levels. Therapy for acromegaly includes the options of pituitary irradiation (heavy particle or implants) and transsphenoidal hypophysectomy. [64] [65] [66] If suprasellar extension exists, conventional transfrontal hypophysectomy is often employed. The dopaminergic agonist bromocriptine can lower GH levels, but long-term follow-up has not shown that this therapy is definitive.

Prolactin has been one of the most interesting markers for identifying patients with pituitary tumors.[57] Elevated prolactin levels are often (but not invariably) associated with galactorrhea. Females commonly have amenorrhea, and males have impotence. Optimal therapy for prolactin-secreting tumors is still being evaluated: the dopamine agonist bromocriptine can be extremely effective in controlling the prolactin level and restoring gonadotropin function; however, in females who wish to get pregnant, the concern that pregnancy will cause rapid growth of these tumors may make a surgical procedure more desirable. Pituitary irradiation has not been uniformly successful.

Multiple Endocrine Adenomatosis Syndrome

Pituitary tumors are sometimes associated with multiple endocrine adenomatosis syndrome (MEA). Pituitary tumors are found more commonly in the MEA I syndrome where adenomas of the parathyroid glands and islets of the pancreas along with the Zollinger-Ellison syndrome may be associated.

Anesthetic Considerations for Patients with Abnormal Anterior Pituitary Function

The basic approach of rendering normal all abnormal endocrine functions before surgery holds for endocrine abnormalities originating in the pituitary as well as in the end organ. These considerations are dealt with in the individual sections in this chapter on thyroid and adrenal disorders and on conditions with abnormal glucose metabolism or control, and, as noted earlier, acromegalic patients can be difficult to intubate. [60] [61] [62] One special area—that of operations on the pituitary itself—deserves note here, however. The most common approach is now transsphenoidal hypophysectomy, performed on more than 30,000 patients in the United States each year. [63] [66]For the patient undergoing craniotomy, the concerns common to any craniotomy, such as provision of patent airway, adequate pulmonary ventilation, control of circulating blood volume, inhibition of increase in brain size, and effective constant monitoring for adverse complications associated with posture, anesthesia, and operation are appropriate. Premedication, use of anesthetic agents and techniques, and monitoring indicated for operations on the pituitary gland are essentially measures that the individual anesthesiologist prefers for operations on other parts of the brain. The effects of anesthetic agents on secretion of pituitary hormones do not constitute an important factor in the selection of agents for use during operation on the pituitary gland. [64] [65] Disorders arising from this surgery include temperature deregulation and abnormalities of endocrine function, including the need for immediate treatment of steroid deficiency, hypoglycemia, and excessive or deficient secretion of vasopressin (also called antidiuretic hormone [ADH]). Even for operations done under local anesthesia, the risk of carotid artery injury may necessitate the participation of an anesthesiologist[67]; placement of a nasal endotracheal tube can be hazardous in the patient who has had prior transsphenoidal surgery.[68] An exaggerated response on extubation to epinephrine infiltration for transsphenoidal hypophysectomy has been reported, [69] [70] even without the drugs that sensitize the myocardium to epinephrine.

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Disorders of the Posterior Pituitary Gland

Deficiency of vasopressin synthesis results in the disease known as diabetes insipidus. Clinically, it is characterized by the excretion of a large volume of hypotonic urine, which in turn necessitates the intake of equally large amounts of fluid or prevention of hyperosmolarity of body fluids and dehydration.[71] Other causes of diabetes insipidus include compulsive water drinking and nephrogenic resistance to the action of vasopressin ( Table 13-3 ).

TABLE 13-3   -- Causes of Diabetes Insipidus

  

 

Vasopressin Deficiency (Neurogenic Diabetes Insipidus)

  

 

Acquired

  

 

Idiopathic

  

 

Trauma (accidental, surgical)

  

 

Tumor (craniopharyngioma, metastasis, lymphoma)

  

 

Granuloma (sarcoid, histiocytosis)

  

 

Infections (meningitis, encephalitis)

  

 

Vascular (Sheehan's syndrome, aneurysm, aortocoronary bypass)

  

 

Familial (autosomal dominant)

  

 

Excessive Water Intake (Primary Polydipsia)

  

 

Acquired

  

 

Idiopathic (resetting of the osmostat)

  

 

Psychogenic

  

 

Familial (?)

  

 

Vasopressin Insensitivity (Nephrogenic Diabetes Insipidus)

  

 

Acquired

  

 

Infectious (pyelonephritis)

  

 

Postobstructive (prostatic, ureteral)

  

 

Vascular (sickle cell disease, trait)

  

 

Infiltrative (amyloid)

  

 

Cystic (polycystic disease)

  

 

Metabolic (hypokalemia, hypercalcemia)

  

 

Granuloma (sarcoid)

  

 

Toxic (lithium, demeclocycline, methoxyflurane)

  

 

Solute overload (glucosuria, postobstructive)

  

 

Familial (X-linked recessive)

 

 

The classic test to distinguish patients with diabetes insipidus from compulsive water drinkers and patients with nephrogenic diabetes insipidus is the water deprivation test.[71] Following dehydration, patients with diabetes insipidus can only minimally concentrate their urine. When the serum osmolarity rises to 295 mOsm/L (osmotic threshold), all normal patients release vasopressin into the blood and concentrate their urine to conserve water. Simultaneous measurements of urine and plasma osmolarity are made as water deprivation continues. Once the urine and plasma osmolarity have stabilized (usually with a 3% to 5% loss in body weight), the patient is given an injection of vasopressin. If vasopressin is being maximally secreted by the posterior pituitary, then exogenous pitressin or vasopressin will have no effect. The patient with vasopressin deficiency never quite reaches stable plasma osmolarity, and the urine osmolarity rarely gets much above 500 mOsm/L. Moreover, even after severe dehydration, exogenous pitressin or vasopressin causes a significant increase in urine osmolarity only in patients with true diabetes insipidus. Thus, this sensitive test even distinguishes patients who have partial diabetes insipidus.

Compulsive water drinkers may at times present a diagnostic problem, because they often cannot concentrate their urine well, and the water deprivation test must be carried out until the osmotic threshold is reached. Tests employing hypertonic saline as a physiologic stimulus to ADH are cumbersome and difficult to interpret. Adrenocortical insufficiency can mask the polyuria of partial diabetes insipidus, because it lowers the osmotic threshold for vasopressin release. Institution of corticosteroid therapy in such patients unmasks the diabetes insipidus, and severe polyuria may result.

A number of drugs have been shown to alter the release and action of ADH. The sulfonylurea agents, notably chlorpropamide, have been shown to augment release of ADH and are used in the treatment of patients with partial nephrogenic diabetes insipidus. Likewise, clofibrate, carbamazepine (Tegretol), vincristine, and cyclophosphamide all either release ADH or potentiate its action on the renal tubule. Ethanol as well as phenytoin (Dilantin) and chlorpromazine inhibit the action of ADH and its release. Lithium, a drug widely used to treat manic-depressive disorders, can inhibit the formation of cyclic adenosine monophosphate (AMP) in the renal tubule and probably even inhibit its synthesis of ADH directly and thus can result in a diabetes insipidus–like picture.

The treatment of diabetes insipidus usually consists of replacement of ADH. The preparation of ADH for intramuscular use is pitressin tannate in oil, 5 units/mL, given intramuscularly every 48 hours. A synthetic lysine vasopressin, Diodid (50 units/mL in isotonic saline), is also used as a nasal spray. This agent is short acting and is given as an adjunct to pitressin tannate. A longer-acting nasal preparation, desmopressin (1-deamino-8-D-arginine vasopressin [DDAVP]), is most commonly used.

For patients with incomplete diabetes insipidus, a trial of thiazide diuretics or chlorpropamide can increase the renal adenyl cyclase response to low levels of ADH, and this can be used for control of urinary flow. Other agents used for incomplete diabetes insipidus are carbamazepine (Tegretol) and clofibrate.

Management of the patient with complete diabetes insipidus during surgery usually does not present difficult problems. A very small amount of aqueous vasopressin (10 to 20 units per ampule) can be given as a continuous intravenous infusion. Just before surgery, the patient is given an intravenous bolus of 100 mU aqueous vasopressin and then a constant intravenous infusion of 100 to 200 mU of vasopressin per hour. In this situation isotonic fluids such as normal saline may be given safely, and there is little danger of water depletion or hypernatremia. The plasma osmolarity can be monitored during surgery and in the immediate postoperative period. The normal range for plasma osmolarity is 283 to 285 mOsm/L. Serum osmolarity can be calculated from the following formula:

When blood glucose and blood urea nitrogen are normal, the plasma osmolarity may be calculated by multiplying the serum sodium concentration by 2. If the plasma osmolarity comes up much above 290 mOsm/L, then hypotonic fluids should be considered and the amount of aqueous vasopressin given intravenously should be increased above 200 mU/hr. In patients who have only partial vasopressin or ADH insufficiency, nonosmotic stimuli such as volume depletion or the stress of surgery may stimulate large quantities of ADH, and it probably is not necessary to use aqueous vasopressin unless there is a demonstrated rise in plasma osmolarity above 290 mOsm/L during surgery or immediately postoperatively. Pitressin tannate in oil (5 to 10 units daily) may be given intramuscularly or desmopressin given intranasally in the immediate postoperative period until the long-acting intranasal preparations can be used.

Hypersecretion of Vasopressin

As first described by Bartter and Schwartz in 1967, excessive secretion of ADH (syndrome of inappropriate secretion of ADH [SIADH]) is a disorder characterized by hyponatremia that results from water retention, which in turn is due to ADH release that is inappropriately high for the plasma osmolality or serum sodium concentration.[71] Because patients with this syndrome are unable to excrete dilute urine, ingested fluids are retained and expansion of extracellular fluid volume without edema occurs. The hallmark of SIADH is hyponatremia in the presence of urinary osmolality that is higher than plasma osmolality.

The most common cause of SIADH is production of ADH by neoplasms. The ADH produced by neoplasms is identical to the arginine vasopressin secreted by the normal neurohypophysis. The most common of the neoplasms producing ADH are small cell and oat cell carcinomas of the lungs. SIADH is also associated with various nonmalignant and inflammatory conditions of the lungs and central nervous system (CNS). Any patient suspected of having SIADH should be screened for possible adrenal insufficiency or hypothyroidism.[71] The diagnosis is essentially one of exclusion. A wide variety of drugs can bring about hypersecretion or augmentation of ADH and result in the syndrome of inappropriate secretion. The most common drugs that cause inappropriate secretion of ADH are chlorpropamide, clofibrate, psychotropics, thiazides, and the antineoplastic agents vincristine, vinblastine, and cyclophosphamide.

Most of the clinical features associated with SIADH are related to hyponatremia and the resulting brain edema; these features include weight gain, weakness, lethargy, mental confusion, obtundation, and disordered reflexes and may progress, finally, to convulsions and coma. This form of edema rarely leads to hypertension.

SIADH should be suspected when any patient with hyponatremia excretes urine that is hypertonic relative to plasma. The following laboratory findings further support the diagnosis:

  

   

Urinary sodium greater than 20 mEq/L

  

   

Low blood urea nitrogen and serum levels of creatinine, uric acid, and albumin

  

   

Serum sodium less than 130 mEq/L

  

   

Plasma osmolality less than 270 mOsm/L

  

   

Hypertonic urine relative to plasma

The response to water loading is a useful means of evaluating the patient with hyponatremia. Patients with SIADH are unable to excrete dilute urine, even after water loading. Assay of ADH in blood can confirm the diagnosis.

Patients with mild to moderate symptoms of water intoxication can be treated with restriction of fluid intake to 500 to 1000 mL/day. Patients with severe water intoxication and CNS symptoms may need vigorous treatment, with intravenous administration of 200 to 300 mL of 5% saline solution over several hours, followed by fluid restriction.

Treatment should be directed at the underlying problem. If SIADH is drug induced, the drug should be withdrawn. Inflammation should be treated with appropriate measures, and neoplasms should be managed with surgical resection, irradiation, or chemotherapy, whichever is indicated.

At present, no drugs are available that can suppress release of ADH from the neurohypophysis or from a tumor. Phenytoin (Dilantin) and narcotic antagonists such as naloxone and butorphanol have some inhibiting effect on physiologic ADH release but are clinically ineffective in SIADH. Drugs that block the effect of ADH on renal tubules include lithium, which is rarely used because its toxicity often outweighs its benefits, and demethylchlortetracycline in doses of 900 to 1200 mg/day. The last drug interferes with the ability of the renal tubules to concentrate urine, causing excretion of isotonic or hypotonic urine and thus lessening hyponatremia. Demethylchlortetracycline can be used for ambulatory patients with SIADH in whom it is difficult to accomplish fluid restriction.

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Anesthetic Considerations for Patients with ADH Abnormalities

The abnormalities of ADH function that affect perioperative management are those of either a relative or an absolute lack of ADH or an excess of ADH. No matter what the cause of the ADH disorder, the perioperative management problems can be grouped into situations with inadequate ADH and situations with excess ADH.[71] This categorization or emphasis is not meant to minimize the importance of the diverse causes of perioperative management. Moreover, the cause of the ADH disorder should be sought and the potential perioperative problems evaluated; however, the focus in the remainder of this chapter is on “how to” and “why to” manage the ADH disorder perioperatively.

Inadequate ADH

Diabetes insipidus, and thus an inadequate ADH level, is a significant problem in children undergoing posterior fossa craniotomy[72] and is the most significant complication after hypophysectomy. The severity and duration of diabetes insipidus depend on the degree of injury to the adjacent hypothalamus. The majority of patients who develop diabetes insipidus after hypophysectomy recover within a few days to 6 months. Patients with diabetes insipidus secondary to head trauma or surgery usually recover after a short period. Those who continue to have symptoms, and patients with a long history of diabetes insipidus who require surgery, present a challenge for the anesthesiologist with regard to perioperative management.

Perioperative management of patients with diabetes insipidus is based on the extent of the ADH deficiency. Management of a patient with complete diabetes insipidus and a total lack of ADH usually does not present any major problems as long as side effects of the drug are avoided and as long as that status is known before surgery. Just before surgery, such a patient is given the usual dose of desmopressin intranasally or an intravenous bolus of 100 mU of aqueous vasopressin, followed by constant infusion of 100 to 200 mU/hr. All of the intravenous fluids given intraoperatively should be isotonic, so that the risk of water depletion and hypernatremia is reduced. Plasma osmolality should be measured every hour, both intraoperatively and in the immediate postoperative period. If the plasma osmolality goes well above 290 mOsm/L, hypotonic fluids should be administered; the rate of the intraoperative vasopressin infusion should be increased to more than 200 mU/hr.

In patients who have a partial deficiency of ADH, it is not necessary to use aqueous vasopressin perioperatively unless the plasma osmolality rises above 290 mOsm/L. Nonosmotic stimuli (e.g., volume depletion, stress of surgery) usually cause release of large quantities of ADH in the perioperative period. Consequently, these patients require only frequent monitoring of plasma osmolality during this period.

Because of the side effects, the dose of vasopressin should be limited to that necessary for control of diuresis. [72] [73] This limit is applicable especially to patients who are pregnant or who have coronary artery disease, because of the oxytocic and coronary artery–constricting properties of vasopressin.[72] Another problem for anesthesiologists is the care for patients who come to the operating room with a pitressin drip for treatment of bleeding from esophageal varices. Although this situation is rare, the vasoconstrictive effect of vasopressin on the splanchnic vasculature is being used to decrease bleeding. Such patients are often volume depleted and may have concomitant coronary artery disease. Because vasopressin has been shown to markedly decrease oxygen availability, primarily because of a decreased stroke volume and heart rate, monitoring of tissue oxygen delivery may be useful. In 1982, Nikolic and Singh[74] reported on a patient with a history of angina pectoris who received a combination of cimetidine and vasopressin for esophageal varices and who developed bradyarrhythmias and atrioventricular block, requiring a pacemaker. Cessation of either of these drugs alleviated the symptoms on two occasions. This indicates that the combination of cimetidine and vasopressin could be deleterious to patients because of the combined negative inotropic and dysrhythmogenic effects of the two drugs.

Excessive ADH

Patients with SIADH resulting from malignancy have the usual problems present in malignancy, such as anemia and malnutrition, and often they have an imbalance of fluids and electrolytes. [71] [72] [73] [74] [75] Perioperatively, they usually have low urine output, high urine osmolality, low serum osmolality, and delayed awakening from anesthesia or awakening with mental confusion.

When a patient with SIADH comes to the operating room for any surgical procedure, fluids are managed by measuring the central volume status by central venous pressure or pulmonary artery lines, by transesophageal echocardiography, and by frequent assays of urine osmolarity, plasma osmolarity, and serum sodium, often into the immediate postoperative period. Despite the common impression that SIADH is frequently seen in elderly patients in the postoperative period, studies have shown that the patient's age and the type of anesthetic have no bearing on the postoperative development of SIADH. It is not unusual to see many patients in the neurosurgical intensive care unit suffering from this syndrome. The diagnosis is usually one of exclusion. Patients with SIADH usually require only fluid restriction; very rarely is hypertonic saline needed.

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Summary

There have been no controlled studies on the risks and benefits of various types of perioperative management for patients with either inadequate or excessive ADH.[75] Nevertheless, increasing knowledge of the pathophysiology of these endocrine aberrations and the use of pharmacologic treatment probably have led to improved clinical results. Inadequate levels of ADH secretion lead to a diabetes insipidus state, with production of large amounts of hypotonic urine, hypernatremia, and a resulting intravascular volume deficit (dehydration). Perioperative treatment consists of replacement of vasopressin by infusion or nasal spray. Because vasopressin causes vasoconstriction of arteriolar beds, monitoring of tissue oxygen delivery and of myocardial ischemia is commonly used. Excess levels of ADH lead to SIADH, which is manifested by low urine output, high urine osmolality, low serum osmolality, hyponatremia, and disordered nervous system functioning (ranging from confusion and delayed awakening from anesthesia to seizures). The perioperative procedures used for SIADH consist of fluid management with a central volume monitor (I tend to restrict fluids and administer normal saline) and frequent assays for serum sodium level and osmolality and for urine volume and osmolality.

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ADRENAL CORTEX

Physiology

Cholesterol in the adrenal gland is converted to Δ[5] pregnenolone. This compound is changed either to progesterone or to 17-hydroxypregnenolone. Progesterone can be converted to aldosterone, the principal mineralocorticoid, only in the zona glomerulosa of the adrenal cortex. In the zona fasciculata and zona reticularis, progesterone is made into 11-deoxycortisol and finally to cortisol, the principal glucocorticoid. Sex hormones are also synthesized in the adrenal cortex. Testosterone is the most potent sex hormone synthesized; dehydroisoandrosterone and [4] Δ-androstenedione are weaker androgens but at times can contribute significantly to the androgen pool. Under certain circumstances, even estradiol, the female sex hormone, can be synthesized from its precursor hormone testosterone. Thus, three major classes of hormones—glucocorticoids, mineralocorticoids, and androgens—are secreted by the adrenal cortex. An excess or a deficiency of each of these is associated with a characteristic clinical syndrome. [76] [77] [78] [79] [80] Medical use of corticosteroids, now widespread, may render the adrenal cortex incapable of responding normally to the demands placed on it by surgical trauma and subsequent healing.

More than 100 years ago, Brown-Séquard first demonstrated that bilateral adrenalectomy caused premature death. Over the past century, the central role of adrenal hormones in the maintenance of hemodynamic and metabolic homeostasis by regulation of volume and electrolytes has been defined.

Glucocorticoids

The principal glucocorticoid cortisol is an essential regulator of carbohydrate, protein, lipid, and nucleic acid metabolism.[78] Cortisol exerts its biologic effects by a sequence of steps initiated by its binding to stereospecific, intracellular cytoplasmic receptors. This bound complex stimulates nuclear transcription of specific messenger RNAs. These messenger RNAs are then translated to give rise to proteins that mediate the ultimate effects of these hormones.[78]

Most cortisol is bound to corticosteroid-binding globulin (CBG, transcortin). It is the relatively small amounts of unbound cortisol that enter cells to induce actions or to be metabolized.[78] Conditions that induce changes in the amount of CBG include liver disease and nephrotic syndrome, both of which result in decreased circulating levels of CBG, and estrogen administration and pregnancy, which result in increased CBG production. Total serum cortisol levels may become elevated or depressed under these conditions that alter the amount of bound cortisol and yet the unbound, active form of cortisol is present in normal amounts. The most accurate measure of cortisol activity is the level of urinary cortisol, that is, the amount of unbound, active cortisol filtered by the kidney.[78]

The serum half-life of cortisol is 80 to 110 minutes; however, because cortisol acts through intracellular receptors, pharmacokinetics based on serum levels is not a good indicator of cortisol activity. After a single dose of glucocorticoid, the serum glucose level is elevated for 12 to 24 hours; improvements in pulmonary function in patients with bronchial asthma can still be measured 24 hours after glucocorticoid administration. [79] [80] Treatment schedules for glucocorticoid replacement are based, therefore, not on the measured serum half-life but on the well-documented, prolonged end-organ effect of these steroids. In the past, hospitalized patients who required chronic glucocorticoid replacement therapy were usually treated twice daily, with a slightly higher dose in the morning than in the evening to simulate the normal diurnal variations in cortisol levels. [81] [82] For patients who require parenteral “steroid coverage” during and after surgery (see later), administration of glucocorticoid every 8 to 12 hours seems appropriate. [83] [84] [85] Relative potencies of glucocorticoids are listed in Table 13-4 . Cortisol is inactivated primarily in the liver and is excreted as 17-hydroxycorticosteroid. Cortisol is also filtered and excreted unchanged into the urine.

TABLE 13-4   -- Relative Potencies and Biologic Half-Lives of Cortisol and Its Synthetic Analogues

Common Name

Other Name

Estimated Potency

Biologic

 

 

Glucorticoid

Mineralocorticoid

Half-Life (hr)

Cortisol

Compound F, hydrocortisone

1

1

8–12

Cortisone

Cortone

0.8

0.8

8–12

Prednisone

 

4

0.25

12–36

Methylprednisolone

Medrol

5

0.25

12–36

Triamcinolone

Aristocort, Kenacort

5

0.25

12–36

Dexamethasone

Decadron

20–30

±

26–54

Fluorohydrocortisone

Florinef

5

200

Desoxycorticosterone

Percorten

0

15

 

 

The synthetic glucocorticoids vary in their binding specificity in a dose-related manner. When given in supraphysiologic doses (more than 30 mg/day), cortisol and cortisone bind to mineralocorticoid receptor sites and cause salt and water retention and loss of potassium and hydrogen ions. [86] [87] When these steroids are administered in maintenance doses of 30 mg/day or less, patients require a specific mineralocorticoid for electrolyte and volume homeostasis. Many other steroids do not bind to mineralocorticoid receptors, even in large doses, and have minimal mineralocorticoid effect (see Table 13-4 ).[87]

Control of Glucocorticoid Secretion.

The hypothalamic-pituitary-adrenal axis is shown in Figure 13-4 . Secretion of glucocorticoids is regulated exclusively by pituitary ACTH. [76] [88] ACTH is synthesized from a precursor molecule (preopiomelanocortin) that breaks down to form an endorphin (β-lipoprotropin) and ACTH. ACTH secretion has a diurnal rhythm; it is normally greatest during the early morning hours in men (afternoon in women) and is regulated at least in part by sleep-wake cycles.[78] Its secretion is stimulated by release of corticotropin-releasing factor (CRF) from the hypothalamus.[76] Cortisol and other glucocorticoids exert negative feedback at both pituitary and hypothalamic levels to inhibit secretion of ACTH and CRF.

Overproduction of glucocorticoids can be caused by adrenal tumors (primary Cushing's disease)[89] or by overstimulation of normal adrenal glands by elevated levels of ACTH from pituitary microadenomas (secondary Cushing's disease). Inappropriately low levels of glucocorticoids may result from destruction or atrophy of the adrenal gland itself (primary adrenal insufficiency) or from diminished levels of ACTH in pituitary dysfunction (secondary adrenal insufficiency).[90]

Mineralocorticoids

Aldosterone, the major mineralocorticoid secreted in humans, comes from the zona glomerulosa of the adrenal cortex, causes reabsorption of sodium and secretion of potassium and hydrogen ions, and thus contributes to electrolyte and volume homeostasis. This action is most prominent in the distal renal tubules, but it also occurs in salivary and sweat glands. The main regulator of aldosterone secretion is the renin-angiotensin system.[91] Juxtaglomerular cells in the cuff of the renal arterioles are sensitive to decreased renal perfusion pressure or volume and consequently secrete renin. Renin splits the precursor angiotensinogen (from the liver) into angiotensin I, which is further converted by converting enzyme, primarily in the lung, to angiotensin II. Mineralocorticoid secretion is increased by increased levels of angiotensin.

Androgens

Androstenedione and dehydroepiandrosterone, which are weak androgens arising from the adrenal cortex, constitute major sources of androgens in women[75] (and have gained prominence for their use or abuse by baseball players seeking to hit more home runs). These androgens are converted outside the adrenal glands to testosterone, a potent virilizing hormone. [75] [92] Excess secretion of androgen in women causes masculinization, pseudopuberty, or female pseudohermaphroditism. Some tumors convert this androgen to an estrogenic substance, in which case feminization results. Some congenital enzyme defects that cause abnormal levels of androgens in blood also result in glucocorticoid and mineralocorticoid abnormalities. The altered sexual differentiation in the presence of such defects requires no specific modification of anesthetic technique. All syndromes related to abnormal androgen levels are associated with cortisol deficiency. In patients who have associated alterations in glucocorticoid or mineralocorticoid activity, anesthetic plans should be modified as outlined in the following sections.

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Excessive Adrenocortical Hormones: Hyperplasia, Adenoma, Carcinoma

Sex Hormone–Secreting Tumors of the Adrenal Glands

Hirsutism in females may be due to either adrenal or ovarian tumor. Adrenal virilizing tumors are almost always associated with markedly elevated 17-ketosteroid urinary excretion, whereas functioning ovarian tumors tend to produce very potent androgens such as testosterone or dihydrotestosterone, which are not measured as part of the 17-ketosteroids. Rarely, adrenal tumors produce only testosterone and are stimulated by human chorionic gonadotropin. Similarly, some androgen-producing ovarian tumors have been shown to respond to dexamethasone suppression. A common cause of hirsutism in females is polycystic ovarian disease, which is associated with bilaterally enlarged ovaries.[77] Extreme feminization in males can occasionally be due to an estrogen-producing tumor of the adrenal gland. Functioning sex hormone– producing tumors of the adrenal gland almost always tend to be unilateral. Pelvic B-mode ultrasonography, CT, and MRI are very useful modalities for localizing lesions. Most patients do not have to be managed with glucocorticoids during or after surgery. The only exception is the patient who has associated Cushing's syndrome with cortisol excess; in this instance management should be as outlined later for tumors of the adrenal gland.

Adrenal genital syndrome should be ruled out as a possible cause of hirsutism. These patients are not surgical candidates. Generally, in addition to high 17-ketosteroid levels in the urine, these patients have very high urinary pregnanetriol levels and elevated 17-OH progesterone blood levels. They are usually managed with mildly suppressive doses of corticosteroids.

Excessive Glucocorticoids

Glucocorticoid excess (Cushing's syndrome), resulting from either endogenous oversecretion or long-term treatment with large doses of glucocorticoids, produces a characteristic appearance and a predictable complex of disease states ( Table 13-5 ). The individual appears moon faced and plethoric, having a centripetal distribution of fat and thin extremities because of muscle wasting. The heart and diaphragm apparently are spared the effects of muscle wasting.[78] The skin is thin and easily bruised, and striae are often present. Hypertension (because of increases in renin substrate and vascular reactivity caused by glucocorticoids) and fluid retention are present in 85% of patients. [78] [91] Nearly two of every three patients also have hyperglycemia resulting from inhibition of peripheral glucose use with concomitant stimulation of gluconeogenesis. These patients often have osteopenia as a result of decreased bone matrix formation and impaired calcium absorption. One third of the patients have pathologic fractures.

TABLE 13-5   -- Clinical Features of Hyperadrenalism (Cushing's Syndrome) and Hypoadrenalism

Cushing's Syndrome

Hypoadrenalism

Central obesity

Weight loss

Proximal muscle weakness

Weakness, fatigue, lethargy

Osteopenia at a young age and back pain

Muscle and joint pain

Hypertension

Postural hypotension and dizziness

Headache

Headache

Psychiatric disorders

Anorexia, nausea, abdominal pain, constipation, diarrhea

Purple stria

 

Spontaneous ecchymoses

Hyperpigmentation

Plethoric facies

Hyperkalemia, hyponatremia

Hyperpigmentation

Occasional hypoglycemia

Hirsutism

Hypercalcemia

Acne

Prerenal azotemia

Hypokalemic alkalosis

 

Glucose intolerance

 

Kidney stones

 

Polyuria

 

Menstrual disorders

 

Increased leukocyte count

 

From Miller RD (ed): Miller's Anesthesia, 6th ed. Philadelphia, Churchill Livingstone, 2005, with permission.

 

 

 

Special preoperative considerations for patients with Cushing's syndrome include regulating diabetes and hypertension and ensuring that intravascular fluid volume and electrolyte concentrations are normal. [92] [93] Ectopic ACTH production from sites other than the pituitary may cause marked hypokalemic alkalosis.[78] Treatment with the aldosterone antagonist spironolactone arrests the potassium loss and helps mobilize excess fluid. Because of the high incidence of severe osteopenia and the risk of fractures, meticulous attention to patient positioning is necessary.[76] In addition, glucocorticoids are lympholytic and immunosuppressive, perhaps increasing the patient's susceptibility to infection. [94] [95] [96] The tensile strength of healing wounds decreases in the presence of glucocorticoids, an effect at least partially reversed by topical administration of vitamin A.[97]

Specific considerations pertain to the surgical approach for each cause of Cushing's syndrome. For example, nearly three fourths of the cases of spontaneous Cushing's disease result from a pituitary adenoma that secretes ACTH.[78] Perioperative treatment for patients who have Cushing's disease and a pituitary microadenoma differs from that for patients who have a pituitary adenoma associated with amenorrhea and galactorrhea. The Cushing's syndrome patient tends to bleed more easily and (based on anecdotal evidence) tends to have a higher central venous pressure. Thus, during transsphenoidal tumor resection in such patients, we routinely monitor central venous pressure or end-diastolic left ventricular volume on transesophageal echocardiography and maintain pressure and/or volume in the low end of the normal range. Such monitoring is needed only infrequently in other cases of transsphenoidal resection of microadenoma.[78]

Ten to 15 percent of patients with Cushing's syndrome have adrenal overproduction of glucocorticoids (adrenal adenoma or carcinoma). If either unilateral or bilateral adrenal resection is planned, I normally begin administering glucocorticoids at the start of the tumor resection, normally giving 100 mg of hydrocortisone phosphate intravenously every 24 hours.[93] This amount is reduced over the next 3 to 6 days until a maintenance dose of 20 to 30 mg/day in divided doses is reached. Beginning on about day 3, 9α-fluorocortisone (a mineralocorticoid) is also given, 0.05 to 0.1 mg/day. Both steroids may require several adjustments in some patients. This therapy is continued for patients who have undergone bilateral adrenal resection. For patients who have had unilateral resection, therapy is individualized, based on the status of the remaining adrenal gland.

Patients with Cushing's syndrome who require bilateral adrenalectomy have a high incidence of postoperative complications. The incidence of pneumothorax approaches 20% with adrenal carcinoma resection, and it is sought and treatment begun before the wound is closed. Ten percent of patients with Cushing's syndrome who undergo adrenalectomy are found to have an undiagnosed pituitary tumor. After reduction of high levels of cortisol by adrenalectomy, the pituitary tumor enlarges (Nelson's syndrome).[98] These pituitary tumors are potentially invasive and may produce large amounts of ACTH and melanocyte-stimulating hormone, thus increasing pigmentation.

Adrenal tumors are at least 85% incidentomas, that is, discovered incidentally during screening (and largely unindicated) CT scans. Nonfunctioning adrenal adenomas are found in as many as 10% of autopsies. [99] [100] [101]

Adrenal adenomas are usually treated surgically, and often the contralateral gland will resume functioning after several months. Frequently, however, the effects of carcinomas are not cured by surgery. In such cases, administration of inhibitors of steroid synthesis such as metyrapone or o, p′-DDD[2,2-bis-(2-chlorophenyl-4-chlorophenyl)-1,1-dichloroethane] may ameliorate some symptoms but may not improve survival. These drugs and the aldosterone antagonist spironolactone may alleviate symptoms in the case of ectopic ACTH secretion if the primary tumor proves unresectable. Patients given these adrenal suppressants are also given chronic glucocorticoid replacement therapy (with the goal of complete adrenal suppression). These patients should be considered to have suppressed adrenal function, and glucocorticoid replacement should be increased perioperatively as discussed earlier.

Excessive Mineralocorticoids

Excess mineralocorticoid activity leads to sodium retention, potassium depletion, hypertension, and hypokalemic alkalosis. [102] [103] [104] [105] [106] [107] [108] These symptoms constitute primary hyperaldosteronism, or Conn's syndrome (a cause of low-renin hypertension, because renin secretion is inhibited by the effects of the high aldosterone levels).

Primary hyperaldosteronism is present in 0.5% to 1% of hypertensive patients who have no other known cause of hypertension. Primary hyperaldosteronism is most often the result of a unilateral adenoma, although 25% to 40% of patients may have bilateral adrenal hyperplasia. Intravascular fluid volume, electrolyte concentrations, and renal function should be restored to within normal limits preoperatively by treatment with spironolactone. The effects of spironolactone are slow to appear and increase for 1 to 2 weeks. In addition, patients with Conn's syndrome have a high incidence of ischemic heart disease and hemodynamic monitoring appropriate for their degree of cardiovascular impairment should be undertaken. A retrospective anecdotal study indicated that intraoperative stability, with preoperative control of blood pressure and electrolytes, was better with spironolactone than with other antihypertensive agents.[103] The efficacy for patient outcome of optimizing the preoperative status of patients with disorders of glucocorticoid or mineralocorticoid secretion, however, has not been clearly established.

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Adrenocortical Hormone Deficiency

Glucocorticoid Deficiency

Withdrawal of steroids or suppression of their adrenal synthesis by steroid therapy is the leading cause of underproduction of corticosteroids.[76] The management of this type of glucocorticoid deficiency is discussed below (see Patients Taking Corticosteroids for Medical Conditions). Fewer cases of this potential problem are expected, in part because of a change from systemic corticosteroids to inhaled ones for treatment of asthma.[79] Other causes of adrenocortical insufficiency include destruction of the adrenal gland by cancer (including AIDS), tuberculosis, hemorrhage, or an autoimmune mechanism; some forms of congenital adrenal hyperplasia (see previous discussion); and administration of cytotoxic drugs.

Primary adrenal insufficiency (Addison's disease) is caused by a local process within the adrenal gland that leads to destruction of all zones of the cortex and causes both glucocorticoid and mineralocorticoid deficiency if the insufficiency is bilateral. Autoimmune disease is the most common cause of primary (nonendogenous) bilateral ACTH deficiency. [76] [90] Autoimmune destruction of the adrenals may be associated with other autoimmune disorders, such as Hashimoto's thyroiditis. Enzymatic defects in cortisol synthesis also cause glucocorticoid insufficiency, compensatory elevations of ACTH, and congenital adrenal hyperplasia.

Adrenal insufficiency usually develops slowly. Patients with Addison's disease can develop marked pigmentation (because excess ACTH is present to drive an unproductive adrenal gland) and cardiopenia (apparently secondary to chronic hypotension).

Secondary adrenal insufficiency occurs when ACTH secretion is deficient, often because of a pituitary or hypothalamic tumor. Treatment of pituitary tumors by surgery or radiation may result in hypopituitarism and consequent adrenal failure.

If glucocorticoid-deficient patients are not stressed, they usually have no perioperative problems.[93] However, acute adrenal (addisonian) crisis can occur when even a minor stress (e.g., upper respiratory tract infection) is present.[104] In the preparation of such a patient for anesthesia and surgery, hypovolemia, hyperkalemia, and hyponatremia can be treated. Because these patients cannot respond to stressful situations, it was traditionally recommended that they be given a maximum stress dose of glucocorticoids (i.e., hydrocortisone, 300 mg/70 kg/day) perioperatively. Symreng and colleagues[105]gave 25 mg of hydrocortisone phosphate intravenously to adults at the start of the operative procedure, followed by 100 mg intravenously over the next 24 hours. Because using the minimal drug dose that will cause an appropriate effect is desirable, this latter regimen seems attractive. Evidence is accumulating that less steroid supplementation does not cause problems, and I recommend giving hydrocortisone phosphate intravenously in a dose of 100 mg/70 kg/24 hr. [104] [105]

Udelsman and colleagues[104] studied glucocorticoid replacement in primates. In that study, adrenalectomized primates and sham-operated controls were maintained on physiologic doses of steroids for 4 months. The animals were then randomized to receive subphysiologic (one tenth the normal cortisol production), physiologic, and supraphysiologic (10 times the normal cortisol production) doses of cortisol for 4 days before abdominal surgery (cholecystectomy). Hemodynamic variables were measured with arterial and pulmonary artery catheters. The animals were maintained on their randomized dosing schedules during and after surgery. The group receiving subphysiologic doses of steroid perioperatively had a significant increase in postoperative mortality. The death rates in the physiologic and supraphysiologic replacement groups were the same and did not differ from that for sham-operated controls. Death in the subphysiologic replacement group was related to severe hypotension associated with a significant decrease in systemic vascular resistance and a reduced left ventricular stroke work index. The filling pressures of the heart were unchanged, as compared with those in control animals. There was, therefore, no evidence of hypovolemia or severe CHF. Despite the low systemic vascular resistance, the animals did not become tachycardic. All of these responses are compatible with the previously documented interaction of glucocorticoids and catecholamines, suggesting that glucocorticoids mediate catecholamine-induced increases in cardiac contractility and maintenance of vascular tone.

The investigators used a sensitive measure of wound healing by studying hydroxyproline accumulation. All treatment groups, including that which received supraphysiologic doses of glucocorticoids, had the same capacity for wound healing. Furthermore, there were no adverse metabolic consequences of supraphysiologic corticosteroid doses given perioperatively.[104]

This well-conducted study confirms several “old wives' tales” about patients who have inadequate adrenal function, either from underlying disease or secondary to exogenous steroids. Inadequate replacement of corticosteroids perioperatively can lead to addisonian crisis and death. Administration of supraphysiologic doses of corticosteroids for a short time perioperatively caused no discernible complications. It is clear that inadequate corticosteroid coverage can cause death. What is not so clear is what dose of corticosteroid for replacement therapy should be recommended.

Mineralocorticoid Deficiency

Hypoaldosteronism, a condition less common than glucocorticoid deficiency, can be congenital or can occur after unilateral adrenalectomy or prolonged administration of heparin.[106] It may also be a consequence of long-standing diabetes and renal failure. Nonsteroidal inhibitors of prostaglandin synthesis may also inhibit renin release and exacerbate this condition in patients with renal insufficiency.[107] Levels of plasma renin activity are below normal and fail to rise appropriately in response to sodium restriction or diuretics. Most of the patients have low blood pressure; rarely, however, a patient may be normotensive or even hypertensive. Most symptoms are due to hyperkalemic acidosis rather than hypovolemia. Patients with hypoaldosteronism can have severe hyperkalemia, hyponatremia, and myocardial conduction defects. These defects can be treated successfully with mineralocorticoids (9α-fluorocortisone, 0.05 to 0.1 mg/day) preoperatively. Doses must be carefully titrated and monitored so that increasing hypertension can be avoided.

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Patients Taking Corticosteroids for Medical Conditions

Perioperative Stress and the Need for Corticoid Supplementation[77]

Many reports (mostly anecdotal) concerning normal adrenal responses during the perioperative period and responses of patients taking steroids for other diseases indicate the following:

  

1.   

Perioperative stress is related to the degree of trauma and the depth of anesthesia. Deep general or regional anesthesia causes the usual intraoperative glucocorticoid surge to be postponed to the postoperative period.

  

2.   

Few patients who have suppressed adrenal function have perioperative cardiovascular problems if they do not receive supplemental steroids perioperatively.[108]

  

3.   

Occasionally, a patient who habitually takes steroids will become hypotensive perioperatively, but this event has only rarely been documented sufficiently to implicate glucocorticoid or mineralocorticoid deficiency as the cause.

  

4.   

Although it occurs rarely, acute adrenal insufficiency can be life threatening.

  

5.   

There is little risk in giving these patients high-dose corticosteroid coverage perioperatively.

What dose of corticosteroids should one give and to whom? A definitive answer is not available; however, the recommendation of 100 mg/70 kg/24 hr stands until a prospective, randomized, double-blind trial in patients receiving physiologic doses of corticosteroids is performed. A smaller dose probably can be used. In any case, I never supplement perioperatively with a dose lower than that the patient has already been receiving.

If in doubt, how can one determine a patient's need for perioperative supplementation with glucocorticoids? Because the risk is low, I normally provide supplementation for every patient who has received corticosteroids, including inhaled corticosteroids, at any time during the previous year. It has been shown that topical application of corticosteroids (even without the use of occlusive dressings) can suppress normal adrenal responses for as long as 9 months or a year.[109]

How can one determine whether the patient's adrenal responsiveness has returned to normal? The morning plasma cortisol level does not reveal whether the adrenal cortex has recovered sufficiently to ensure that cortisol secretion increases enough to meet the demands under stress. Insulin-induced hypoglycemia has been advocated as a sensitive test of pituitary-adrenal competence (see Anterior Pituitary Disease), but its use is impractical and probably more dangerous than simply administering glucocorticoids. If plasma cortisol is measured during acute stress, a value greater than 25 μg/dL assuredly indicates, and more than 15 μg/dL probably indicates, normal pituitary-adrenal responsiveness.

The most sensitive test of adrenal reserve is the ACTH stimulation test. To test pituitary-adrenal sufficiency, one determines the baseline plasma cortisol level. Then 250 μg of synthetic ACTH (cosyntropin) is given, and the plasma cortisol is measured 30 to 60 minutes later. An increment in plasma cortisol of 7 to 20 μg/dL or more is normal. A normal response indicates a recovery of pituitary-adrenal axis function. A lesser response usually indicates pituitary-adrenal insufficiency, possibly requiring perioperative supplementation with corticosteroids.

Usually, laboratory data defining pituitary-adrenal adequacy are not available before surgery. However, rather than delay surgery or test most patients, it is assumed that any patient who has taken corticosteroids at any time in the preceding year has pituitary-adrenal suppression and will require perioperative supplementation.

Under perioperative conditions, the adrenal glands secrete 116 to 185 mg of cortisol daily. Under maximum stress, they may secrete 200 to 500 mg daily. A good correlation between the severity and duration of the operation and the response of the adrenal gland was shown during major surgery that included procedures such as colectomy and minor surgery procedures such as herniorrhaphy. In one study, the mean maximal plasma cortisol level during major surgery in 20 patients was 47 μg/dL (range, 22 to 75 μg/dL). Values remained above 26 μg/dL for a maximum of 72 hours after operation. The mean maximal plasma cortisol level during minor surgery was 28 μg/dL (range, 10 to 44 μg/dL).[84]

Although the precise amount of glucocorticoid required has not been established, I usually administer one third of the maximal amount that the body manufactures in response to maximal stress; that is, about 200 mg/70 kg/day of intravenous hydrocortisone phosphate. For minor procedures, I usually give hydrocortisone phosphate, 25 to 50 mg/70 kg/day intravenously. Unless infection or some other perioperative complication develops, this is decreased by approximately 25% per day until oral intake can be resumed. At this point, the usual maintenance dose of glucocorticoids can be employed.

Risks of Supplementation

Rare potential risks of perioperative supplementation with steroids include aggravation of hypertension, hyperglycemia, fluid retention, the induction of stress ulcers, and psychiatric disturbances. Two risk factors associated with glucocorticoid administration to surgical patients have been described and reviewed[94]: abnormal wound healing and an increased rate of infection. However, the evidence is inconclusive because it relates to acute glucocorticoid administration and not to chronic administration of glucocorticoids with increased doses at times of stress. For example, in rats wounded before and after topical application of cortisone, delayed wound closure was found secondary to inhibition of granulation tissue and decreased proliferation of fibroblasts and of new blood vessels. Ehrlich and Hunt[97]found that moderate to large doses of steroids exerted their morphologic effects maximally within 3 days after injury, and they postulated that the inhibition of the early inflammatory process by steroids after wounding was responsible for delayed healing. Vitamin A protected somewhat against delayed healing, presumably because of its effect in stabilizing lysosomes. In contrast to these studies that suggest a deleterious effect of perioperative glucocorticoid administration on wound healing in rats, a study on primates suggests that large doses of glucocorticoids, administered perioperatively, did not impair sensitive measures of wound healing.[104] An overall assessment of these results suggests that short-term perioperative steroid treatment has a small but definite deleterious effect on wound healing that is perhaps partially reversed by topical administration of vitamin A.

Information on the risk of infection as a result of perioperative supplement with glucocorticoids is also unclear. Winstone and Brook[96] reported four cases of septicemia among 18 surgical patients given perioperative supplementation with glucocorticoids but no similar complications in 17 others who also took glucocorticoids but were not given perioperative supplementation. In a controlled study of 100 patients who received perioperative supplementation with glucocorticoids, there were 11 wound infections in the steroid-treated group and only one in the control group.[94] Test subjects and controls were not matched for underlying disease, however. In contrast, Jensen and Elb[110] found no change in the incidence of wound infections or other infections in an uncontrolled series of 419 patients subjected to surgery and perioperative supplementation with glucocorticoids. Oh and Patterson[111] found only one minor suture abscess among a group of 17 corticosteroid-dependent asthmatic patients undergoing 21 surgical procedures. Thus, these data are inadequate to show that perioperative supplementation with corticosteroids increases the risk of infection.

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Summary

Abnormalities in adrenal cortical function can be manifested as deficiencies or excesses of androgens, mineralocorticoids, or glucocorticoids. Deficiency of androgens is often accompanied by deficiency of the other hormones. Excess androgens result in no unusual perioperative problems for the anesthetist. Mineralocorticoid abnormalities can be associated with blood volume, electrolyte, and cardiac disturbances. I routinely seek and treat these abnormalities preoperatively as well as intraoperatively and postoperatively.

Abnormal levels of glucocorticoids often cause mineralocorticoid disturbances, as well as suppressing healing and the capacity to combat infection. It is probably better to give supplemental corticosteroids to any patient who has received exogenous steroids in the previous year. The dose that provides the greatest benefit-risk ratio for supplementation appears to be declining (I now use 100 mg/70 kg/day of hydrocortisone phosphate intravenously). Etomidate suppresses adrenal cortical steroid synthesis, and its use probably should be accompanied by steroid supplementation.[112] No controlled studies indicate that any one anesthetic practice or choice of drugs is better than any other for patients with adrenal disease. As with most other endocrinopathies, the focus of complications resides in the cardiovascular system.

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ADRENAL MEDULLA: PHEOCHROMOCYTOMA

Cells of neural crest origin are capable of developing into catecholamine-secreting tumors. Indeed, pheochromocytomas, or catecholamine tumors, have been reported in neural-crest sites ranging from the neck to the inguinal ligament. Pheochromocytomas have been reported as part of the multiple endocrine adenomatosis syndrome and in association with neuroectodermal dysplasias, including neurofibromatosis, tuberous sclerosis, Sturge-Weber syndrome, and von Hippel-Lindau disease. Although pheochromocytomas cause fewer than 0.1% of all cases of hypertension, they are important to the anesthesiologist. Twenty-five to 50 percent of hospital deaths of patients with pheochromocytoma occur during induction of anesthesia or during operative procedures for other disorders.[113]

Three issues are important in considering pheochromocytoma [24] [114] [115] [116] [117] [118] [119] [120] [121]: (1) the organ system that most influences the anesthetic management of patients with pheochromocytoma is the cardiovascular system; (2) major reductions in morbidity associated with resection of pheochromocytoma occurred when the anesthetist was adequately informed about this disorder and when the patient had received adequate α-adrenergic blockade; and (3) no controlled studies have been done on almost any aspect of the diagnosis or treatment of pheochromocytoma; thus this summary is based on conclusions derived from the many published anecdotal studies.

Physiology and Diagnosis

The physiologic transmitters (catecholamines) are released from the terminals of the postganglionic sympathetic nervous system. Synthesis of catecholamines begins in the postganglionic nerve cell bodies when tyrosine is hydroxylated in the rate-limiting step to dopa; dopa is decarboxylated to dopamine; and, in most cells, dopamine is hydroxylated to norepinephrine. In the adrenal, in rare parts of the CNS, and at some ganglia, this norepinephrine can be converted by phenyl-ethanolamine-N-transferase to epinephrine. The release of dopamine, norepinephrine, and epinephrine occurs both basally and in response to physiologic and pharmacologic stressors such as hypotension (through baroreceptors), low tissue perfusion, hypoxia, hypoglycemia, anger, determination, fear, and anxiety. Such release from the sympathetic nervous system can be generalized or localized. Most pheochromocytomas are independent of these physiologic stressors, however.

Some pheochromocytomas are under neurogenic control, with increased release of catecholamines stimulated by physiologic and pharmacologic stressors. However, much of the release of catecholamines from pheochromocytomas is not controlled by neurogenic influence. This lack of neurologic control is utilized in the clonidine suppression test for pheochromocytoma (see later).[122]

Painful or stressful events such as intubation often cause an exaggerated catecholamine response in a less than perfectly anesthetized patient with pheochromocytoma. This response is caused by release of catecholamines from nerve endings that are “loaded” by the reuptake process. Stresses may cause catecholamine levels of 200 to 2000 pg/mL in normal patients. For the patient with pheochromocytoma, even simple stresses can lead to blood catecholamine levels of 2000 to 20,000 pg/mL. Squeezing the tumor, however gently, or infarction of the tumor with release of products onto peritoneal surfaces can result in blood levels of 200,000 to 1 million pg/mL, a potentially disastrous situation that should be anticipated and avoided. The physician should ask for a temporary stay of surgery, if at all possible, during which the rate of nitroprusside infusion will be increased.

It has been found in several studies that the triad of paroxysmal sweating, hypertension, and headache is more sensitive and specific than any laboratory test for the diagnosis of pheochromocytoma. These are the symptoms that one experiences when given an infusion of epinephrine.[123]Physical examination of a patient with pheochromocytoma is usually unrewarding unless the patient is observed during an attack. Occasionally, palpation of the abdomen causes the bladder or rectum to rub against the tumor and stimulates release of catecholamines; however, the laboratory measurement of catecholamines or their metabolites has been the standard method of diagnosis.

Half of all patients with pheochromocytoma have continuous hypertension with occasional paroxysms, and another 40% have paroxysmal hypertension. Labile hypertension or the triad of hypertension, headache, and sweating usually is an indication for urine testing.

In more than 85% of cases, pheochromocytomas are sporadic tumors of unknown cause that are localized in the medulla of one adrenal gland; however, these vascular tumors can occur anywhere. They are found in the right atrium, the spleen, the broad ligament of the ovary, or the organs of Zuckerkandl at the bifurcation of the aorta. Malignant spread, which occurs in fewer than 15% of cases of pheochromocytoma, usually proceeds via venous and lymphatic channels, with a predilection for the liver. Occasionally, this tumor is a familial autosomal-dominant trait. It may be a part of the pluriglandular-neoplastic syndrome known as multiple endocrine adenoma type IIa or type IIb. Type IIa consists of medullary carcinoma of the thyroid, parathyroid adenoma or hyperplasia, and pheochromocytoma. Type IIb consists of medullary carcinoma of the thyroid, a marfanoid appearance, mucosal neuromas, and pheochromocytoma. Often, bilateral tumors are present in the familial form.

Urine tests have become a mainstay of diagnosis. The usual urine tests used measure 3-methoxy-4-hydroxymandelic acid, or metanephrines, or native catecholamines per milligram of creatine secreted. If the results of three 24-hour collections of urine are normal, the patient is considered not to have a pheochromocytoma. [114] [115] [121]

Although urine testing has been the standard for diagnosis, many more patients are found at autopsy to have had pheochromocytoma and to have died of its complications (often during operations for other problems) than have pheochromocytoma diagnosed while they are alive. If urine test results are normal, but the suspicion is strong enough, provocative tests with glucagon to promote catecholamine release by the tumor can be used, and the diagnosis is based on the blood pressure response and plasma catecholamine elevation. Catecholamine levels in urine and plasma are diagnostic when elevated to three times the normal median value. If plasma catecholamine levels are above normal, but below three times the normal median, a clonidine suppression test is recommended. Clonidine, by its α2-adrenergic agonist activity in the brainstem, suppresses neurogenically controlled peripheral catecholamine release. Because most pheochromocytomas are not under neurogenic control, catecholamine release in patients with pheochromocytoma will not be suppressed and the plasma level will remain elevated.[122]

Once the diagnosis of pheochromocytoma is made, the tumor must be localized and pretreated before surgical resection. The protocol for localizing these often small tumors has undergone radical revision. Plain radiographs or intravenous pyelograms that show lateral displacement of a kidney are a first approach. MRI has replaced CT, which itself replaced urography and venous sampling. When such techniques do not yield definitive results, scanning with [129]I-metaiodobenzylguanidine (a guanethidine analog) can be tried.

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Anesthetic Considerations for Patients With Pheochromocytoma

There are many published reports on perioperative morbidity and mortality associated with pheochromocytoma, but little is known about the factors that affect the rates of morbidity and mortality. [116] [124] [125] [126] [127] Although no controlled, randomized, prospective clinical study has been done on the value of adrenergic blocking drugs, the preoperative use of these drugs for patients with pheochromocytoma is recommended because these α blockers are likely to reduce the incidence of the perioperative complications of hypertensive crisis, wide fluctuations in blood pressure during intraoperative manipulation of the tumor (especially until the venous drainage is obliterated), and perioperative myocardial dysfunction. [118] [122] [127] Perioperative mortality associated with the excision of pheochromocytoma was reduced from 13% to 45% to 0% to 3% when α-adrenergic blockade was introduced as preoperative therapy and when it was recognized that these patients often had hypovolemia preoperatively ( Table 13-6 ). [127] [128]

TABLE 13-6   -- Perioperative Mortality for Pheochromocytoma Resection

Year

Investigator(s)

Mortality (%)

No. of Patients in Study

1951

Apgar (review)

45

91

1951

Apgar

33

12

1963

Stackpole, et al.

13

100

Before 1960

Mayo Clinic

0–26?

101?

After 1960

Mayo Clinic

2.9?

44?

 

Modlin, et al.

 

 

Before 1967

No alpha blockade

18

17

After 1967

Alpha blockade

2

41

1976

Scott, et al.

3

33

1976–1985

Roizen, et al.

0

38

Data abstracted from Roizen MF: Anesthetic implications of concurrent diseases. In Miller RD (ed): Anesthesia. New York, Churchill Livingstone, 1994, vol 1, pp 903-1014.

 

 

 

The presence of hyperglycemia preoperatively reflects the metabolic effects of catecholamines, resolves with tumor resection, and usually does not require insulin therapy preoperatively or perioperatively. Persistently elevated catecholamine levels may result in catecholamine myocarditis. This cardiomyopathy appears to pose an extra risk for patients,[129] but it can be treated successfully by α-adrenergic blockade preoperatively (see later). Mortality for patients with pheochromocytoma is usually the result of myocardial failure, myocardial infarction, or hemorrhage (hypertensive) into the myocardium or brain. The incidence of all of these catastrophic situations appears to be reduced with α-adrenergic blockade.

Preoperative therapy consisting of α-adrenergic blockade with phenoxybenzamine, prazosin, or labetalol alleviates the patient's symptoms, favors a successful fetal outcome (i.e., in patients whose pheochromocytoma is discovered during pregnancy), [119] [120] [124] and allows reexpansion of intravascular plasma volume by eradicating the vasoconstrictive effects of high levels of catecholamines. This reexpansion of fluid volume is often accompanied by a decreased hematocrit. Because some patients are sensitive to phenoxybenzamine, it should initially be administered in doses of 10 to 20 mg orally two or three times a day. Most patients require 60 to 250 mg/day. The efficacy of the therapy is judged by the reduction of symptoms (especially sweating) and by stabilization of blood pressure. For patients with catecholamine myocarditis as evidenced by often localized ST and T wave ECG changes, preoperative, long-term administration of α-adrenergic blockade (for 15 days to 6 months) has been shown to be effective in resolving the clinical and ECG alterations.[124]

β-Adrenergic receptor blockade with concomitant administration of phenoxybenzamine is suggested for patients who have persistent dysrhythmias or tachycardia. It is recommended that β-adrenergic receptor blockade not be used without α-adrenergic blockade, however, lest the vasoconstrictive effects of the latter go unopposed and produce dangerous hypertension. The latter complication has been reported only rarely, however, and perhaps no firm rules are necessary.

To date, no one has investigated the optimal duration of preoperative phenoxybenzamine therapy. Most patients require treatment for 10 to 14 days, as determined by the time needed for stabilization of blood pressure and amelioration of symptoms. If the patient does not complain of nasal stuffiness, he or she is not ready for surgery. Because pheochromocytomas spread slowly, little is lost by waiting until the patient's preoperative condition has been optimized by means of medical therapy. The following criteria for an optimal preoperative condition are recommended:

  

1.   

No “in-hospital” blood pressure reading higher than 160/90 mm Hg should be evident for 24 hours before surgery. I normally measure the blood pressure in each patient (as an outpatient) every minute for an hour in a recovery room setting during preoperative visits. This setting is most stressful to the medically naive and thus a good test of inhibition of responses to sympathetic stimulation. If no blood pressure reading higher than 160/90 mm Hg is recorded, the patient is scheduled for surgery, assuming the following three criteria are also met.

  

2.   

Orthostatic hypotension, with readings above 80/45 mm Hg, should be present.

  

3.   

The electrocardiogram should be free of ST-T abnormalities for at least a week; if abnormalities are persistent, two-dimensional echocardiography should reveal no evidence of global or regional dysfunction that cannot be attributed to a permanent deficit.

  

4.   

The patient should have no more than one premature ventricular contraction every 5 minutes.

Although specific anesthetic drugs have been recommended for patients with pheochromocytoma, optimal preoperative preparation, careful and gradual induction of anesthesia, and good communication between surgeon and anesthesiologist are most important. I usually give phenoxybenzamine in one half to two thirds of its normal dose immediately preceding surgery. Virtually all anesthetic agents, muscle relaxants, and techniques have been used successfully for patients with pheochromocytoma, and all are associated with a high rate of transient intraoperative dysrhythmias.[125] Although some agents may have advantages or disadvantages in theory, they have not been demonstrated clinically. For example, one might wish to avoid histamine release, because it can stimulate catecholamine release. Yet neither curare nor morphine has been associated with poor patient outcome. Case reports of hypertension after small doses of droperidol have appeared, but no study comparing variation in blood pressure after droperidol and after saline has been published. And it is very evident, on placement of an arterial line, that patients with pheochromocytoma have wide variations in blood pressure. In our randomized studies, use of Innovar (which contains droperidol) was not associated with greater blood pressure fluctuations than the other three agents tested.[125] (Patients with pheochromocytoma tend to be particularly sensitive to pain; we often have much more difficulty than in normal cases placing arterial and venous lines in such patients.)

Because both are easy to administer, phenylephrine or dopamine is used for treatment of hypotension, whereas nitroprusside is preferable when hypertension occurs.[24] Phentolamine, previously a mainstay of intraoperative therapy, has too long a period of onset and duration of action. After the venous supply has been secured, and if the intravascular volume is normal (as measured by pulmonary artery wedge pressure), the blood pressure usually becomes normal. I usually do not treat abnormal blood pressure in α-adrenergically blocked patients unless it is below 75/40 mm Hg; however, some patients become hypotensive after tumor removal and occasionally require a relatively large infusion of catecholamines. On rare occasions, patients remain hypertensive intraoperatively. Postoperatively, about 50% of patients have hypertension for 1 to 3 days and have markedly elevated but declining plasma catecholamine levels. After 3 to 10 days, all but 25% become normotensive. Catecholamine levels do not return to normal for 10 days; therefore, early measurement of urine concentrations of catecholamines is usually not helpful in ensuring that all catecholamine has been removed from tissue.

Because pheochromocytomas may be hereditary, it is important to screen other family members and advise them that, should they require surgery in the future, they should inform the anesthesiologist about the potential for such disease.

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Summary

A lack of controlled studies precludes definitive statements about anesthetic management of patients with pheochromocytoma. It is known that the symptoms of paroxysmal hypertension, sweating, and headache are highly suggestive of the diagnosis. It appears that mortality can be reduced by preoperative α-adrenergic receptor blockade with progressively increasing doses of a blocking agent for 10 days to 2 months for treatment of symptoms, by treatment of myocarditis, and by restoration of intravascular volume. In fact, the largest decrease in mortality of patients after pheochromocytoma resection occurred with the introduction of preoperative α-adrenergic receptor blockade. I believe that knowledge on the part of the anesthetist about the pathophysiology of pheochromocytoma, preoperative patient preparation, and communication between surgeon and anesthetist are more important to patient outcome than is the choice of the anesthetic or muscle-relaxing agent.

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PANCREAS

Physiology

Pancreatic islets are composed of at least three cell types: alpha cells that secrete glucagon, beta cells that secrete insulin, and delta cells that contain secretory granules. Insulin is first synthesized as proinsulin, converted to insulin by proteolytic cleavage, and then packaged into granules within the beta cells. A large quantity of insulin, normally about 200 units, is stored in the pancreas, and continued synthesis is stimulated by glucose. There is basal, steady-state release of insulin from the beta granules and additional release that is controlled by stimuli external to the beta cell. Basal insulin secretion continues in the fasted state and is of key importance in the inhibition of catabolism and ketoacidosis. Glucose and fructose are the primary and most important regulators of insulin release. Other stimulators of insulin release include amino acids, glucagon, gastrointestinal hormones (gastrin, secretin, cholecystokinin-pancreozymin, and enteroglucagon), and acetylcholine. Epinephrine and norepinephrine inhibit insulin release by stimulating α-adrenergic receptors, and they stimulate its release at β-adrenergic receptors.

A normal plasma glucose level requires adequate endogenous substrate for glucose production, normal enzymatic mechanisms capable of converting glycogen and other substrates to glucose, and normal hormonal modulation of gluconeogenesis.[130] The rise in glucose levels after a meal causes release of insulin from beta cells in the pancreas. The magnitude of the insulin response is governed in part by the action of other gastrointestinal hormones that are secreted after food intake. The action of these other hormones accounts for the greater rise in insulin levels after oral than after parenteral administration of glucose. Release of insulin can also be triggered by β-adrenergic stimuli that are believed to act by increasing cyclic AMP levels. Insulin release is inhibited by α-adrenergic stimuli. The action of insulin tends to return the levels of plasma glucose to normal within 1 to 2 hours after completion of a meal.

When endogenous nutrients are not available, plasma glucose levels are maintained by hepatic glycogenolysis and then gluconeogenesis.[130] In these situations, insulin levels are low and glucagon, GH, cortisol, and catecholamines play important roles in gluconeogenesis. Insulin is normally secreted from the pancreas in response to elevated levels of blood glucose as a prohormone (proinsulin). This hormone is rapidly cleaved into C-peptide and insulin in the portal vein. Patients with insulinoma tend to have high levels of proinsulin (more than 20% of total insulin) in plasma and levels of C-peptide that parallel insulin levels.

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Hypoglycemia and Hyperinsulinism (Islet Cell Tumors of the Pancreas)

Almost all of the signs and symptoms in patients with insulinomas are directly related to prolonged hypoglycemic states. The word “hypoglycemia” means different things to different people. Hypoglycemia is a clinical syndrome that may have a variety of causes and that results in plasma glucose levels sufficiently low to promote secretion of catecholamines and to impair the function of the CNS.[131] The diagnosis of hypoglycemia requires the presence of three findings: (1) symptomatic hypoglycemia (confusion, abnormal behavior, amnesia for the episode of hypoglycemia), (2) a plasma glucose level in the hypoglycemic range (less than 40 mg/dL for females and less than 45 mg/dL for males), and (3) amelioration of symptoms when plasma glucose is restored to normal levels.

The two major classifications of hypoglycemia can be distinguished by the relationship of symptoms to meals: (1) reactive, that is, if the hypoglycemia occurs within 2 to 4 hours after ingestion of food and is associated primarily with adrenergic symptoms, and (2) fasting, that is, if the hypoglycemia occurs more than 6 hours after a meal, is precipitated by exercise, and is often associated with CNS symptoms. Insulinomas usually cause fasting hypoglycemia. [130] [132]

Reactive hypoglycemia can be caused by alimentation, impaired glucose tolerance, or functional causes. Alimentary hypoglycemia is associated with low levels of plasma glucose 2 to 3 hours after ingestion of food by patients who have rapid gastric emptying, for example, after subtotal gastrectomy, vagotomy, or pyloroplasty. It is postulated that rapid gastric emptying and rapid absorption of glucose may result in excessive release of insulin, falling glucose levels, and reactive hypoglycemia. Impaired glucose tolerance resulting in hypoglycemia, an early symptom of diabetes, usually occurs 4 to 5 hours after ingestion of food. Functional hypoglycemia, on the other hand, usually occurs 3 to 4 hours after ingestion of food and is associated with adrenergic symptoms.

Because the brain is extremely sensitive to glucose utilization, CNS effects are often manifest. Most patients show CNS symptoms that included visual disturbances, dizziness, confusion, epilepsy, lethargy, transient loss of consciousness, and coma. Perhaps because of these many CNS manifestations of insulinomas, many patients with these tumors have been misdiagnosed as suffering from psychiatric illness.

Less frequent but nevertheless important manifestations of insulinomas involve the cardiovascular system. More than 10% of insulinoma patients have palpitations, tachycardia, or hypertension, or all three. These symptoms are probably related to catecholamine release secondary to hypoglycemia, and about 9% of the patients have either severe hunger or gastrointestinal upset, including cramping, nausea, and vomiting. Other investigators have noted obesity or weight gain as a symptom. The symptoms of hypoglycemia due to insulinoma may occur at a particular time of day that is associated with a low blood glucose level, especially 6 hours or more after eating, after fasting for a time, or in the early morning.

Fasting hypoglycemia results from inadequate hepatic glucose production or from overutilization of glucose in the peripheral tissues. The causes of inadequate production of glucose during the fasting state may be hormone deficiencies, enzyme defects, inadequate substrate delivery, acquired liver disease, or drugs. Overutilization of glucose may occur in the presence of either elevated or appropriate insulin levels.

To define the diagnosis of insulinomas, Whipple introduced a triad of diagnostic criteria, which have been modified to include (1) symptoms of hypoglycemia brought on by fasting and exercise; (2) blood glucose levels, while symptoms are present, of less than 40 mg/dL in females and less than 45 mg/dL in males; and (3) relief of these symptoms by administration of glucose, either orally or intravenously. If an insulinoma is suspected and Whipple's triad is confirmed, several tests may be done with which one can differentiate insulinoma from other causes of hypoglycemia.

In recent years, because it has been possible to determine insulin levels as well as glucose levels, the diagnosis has been made with even more certainty.[131] During a prolonged fast, in patients with insulinoma, hypoglycemia develops because of a relative underproduction of glucose by the liver rather than because of increased glucose utilization.[131] High levels of C-peptide and proinsulin levels greater than 20% of total insulin measured in blood are also helpful.

Selective celiac CT angiography or MRI of the pancreatic region is often used for localization of tumors before surgical exploration.

Medical management of insulin-secreting tumors is often difficult but has been simplified before and during surgery and in cases in which surgery fails to remove all of the tumor(s), by somatostatin.

Surgical treatment of insulin-secreting islet cell tumors involves their removal, usually from the pancreas, where they are most often located. In 13% of cases more than one adenoma has been present. Most insulinomas are benign; approximately one third of those that are malignant are found at laparotomy to have metastasized to the liver.

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Anesthetic Considerations for Patients with Hypoglycemia

Most patients who come to surgery with the diagnosis of reactive or fasting hypoglycemia do not require special intraoperative care other than frequent assays of blood glucose levels and adequate infusion of dextrose. The variations in plasma glucose levels are exaggerated in patients with functional islet cell adenoma, and the frequency of procedures to remove insulinomas has increased. [132] [133] [134]

A rise in blood glucose during operation, which is sometimes quite striking, is thought to be evidence of tumor removal. [133] [134] Therefore, two other methods of intraoperative glucose management have been designed not to mask this hyperglycemic rebound. In the first of these, glucose infusion is stopped approximately 2 hours before surgery. Blood glucose is monitored frequently, but no glucose is administered unless the level drops below a certain value, usually below 40 to 50 mg/dL. A bolus of glucose is then given that is calculated to return the level in blood to more than 50 mg/dL, and constant glucose infusion is also started so that the blood glucose level is maintained at more than 50 mg/dL.

The second method makes use of the “artificial beta cell,” or feedback-controlled dextrose infusion, during surgery. The artificial beta cell can be used either solely for monitoring of glucose or for monitoring and administering both glucose and insulin. A printout of the blood glucose level, amount of glucose infused, and amount of insulin infused can be obtained. This allows for frequent (every 60 seconds) determinations of the glucose level, so that any decrease in glucose requirement (the hyperglycemia response) can be observed.

Administration of insulin to hyperglycemic patients during and after surgery is aimed at short-term control of glucose levels. Intraoperatively, I treat blood glucose levels above 300 to 400 mg/dL by administering regular insulin intravenously. Frequent monitoring of glucose is continued, and more insulin is given every 60 to 90 minutes if the hyperglycemia persists. Postoperatively, hyperglycemia, especially ketosis, is also treated with insulin. Blood glucose levels of 250 to 400 mg/dL may be treated by subcutaneous administration of insulin while blood glucose is monitored at fairly frequent intervals. Blood glucose levels higher than this are treated more aggressively, not with additional insulin (10 units/70 kg/hr) but with more frequent glucose monitoring, intravenous administration of insulin (either as a bolus or as a continuous infusion), and repletion of fluid, potassium, and phosphate.

Blood glucose also is monitored in the postoperative period because hyperglycemia and its complications can occur. Hyperglycemic rebound has been used as a diagnostic tool by several authors but may not be as effective as was once thought. Muir and coworkers[132] reviewed 39 patients who underwent surgery for insulinoma. After tumor removal, all patients but one had an increase in plasma glucose concentration. That patient subsequently proved to be cured, whereas a patient who had a hyperglycemic response was later shown not to be cured. Furthermore, in 6 patients whose blood glucose concentration increased after tumor resection, the rise was less sharp than that before tumor removal.

Whether the perioperative control of glucose levels is aimed at euglycemia, with either glucose infusion or an artificial beta cell, or at slight hypoglycemia, one should try to keep the blood glucose level higher than the level at which the patient becomes symptomatic while awake. This aim is achieved more easily with euglycemic methods. Furthermore, although a hyperglycemic response is useful diagnostically when it occurs, it is not a substitute for careful exploration of the pancreas. Also, citrate-phosphate-dextrose (CPD) preservative or acid-citrate-dextrose (ACD) blood contains dextrose, which may create a rise in blood glucose that could be confused with a hyperglycemic response.

Summary

The signs and symptoms of insulinomas are the signs and symptoms of hypoglycemia, which have predominantly CNS manifestations. The symptoms of hyperglycemia and hypoglycemia are masked by general anesthesia, but their deleterious systemic effects are not prevented. It is important to monitor blood glucose levels frequently in the perioperative period because either hyperglycemia or hypoglycemia may develop. Hypoglycemia is more dangerous, particularly because of its effects on the CNS. Hyperglycemia is deleterious because hyperosmolar coma and ketoacidosis may occur. A hyperglycemic response does not invariably occur after successful tumor resection, nor is it always diagnostic of cure. When hyperglycemia does occur postoperatively, it is treated with insulin until euglycemic levels are restored.

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Diabetes Mellitus

Clinicians primarily think about diabetes in relation to glucose and the importance of its level chronically and in patients requiring intensive care. [135] [136] [137] [138] [139] [140] [141] Recent data indicate that the end organ disease that diabetes creates or with which it is associated should also be considered. This accent on problems other than hyperglycemia may seem strange at a time when lifelong tight control of blood glucose is being debated. The concern for the end organ manifestations of diabetes originates in recent epidemiologic studies of surgical mortality.

Surgical mortality rates for the diabetic population are on average five times higher than those for the nondiabetic population. [142] [143] [144] However, in epidemiologic studies in which diabetes itself was segregated from the complications of diabetes (including cardiac and vascular disease) and old age, this finding was questioned. [143] [144] [145] [146] [147] Similarly, if diabetics undergoing major vascular surgery are compared with nondiabetics matched for type of surgery, age, sex, weight, and complicating diseases, there is no difference in the mortality rate or the number of postoperative complications,[145] as long as the diabetic does not need to be cared for in an intensive care unit for longer than 24 hours.

Diabetes mellitus is a heterogeneous group of disorders (present in more than 5% of the population of developed countries) that have the common feature of a relative or absolute deficiency of insulin. Diabetes can be divided into two very different diseases, which share end organ abnormalities. [148] [149] Type I diabetes is associated with autoimmune diseases and has a concordance rate of 40% to 50% (i.e., if one of a pair of monozygotic twins has diabetes, the likelihood that the other twin also will have it is 40% to 50%). In type I the patient is insulin deficient, has inadequate basal and stimulated insulin secretion, and is prone to ketoacidosis if exogenous insulin is withheld. Treatment with immunolytic agents once a viral infection has occurred appears to decrease the rate of development of type I diabetes.[149] For type II (non-insulin-dependent) diabetes, the concordance rate is 100% (i.e., the genetic material is both necessary and sufficient for the development of type II diabetes). Type II patients are not prone to develop ketoacidosis in the absence of insulin, and they have peripheral insulin resistance.

Type I and type II diabetes differ in other ways as well. Type I formerly was termed “juvenile-onset diabetes.” The term may be a misnomer, because many older patients also fall into the same category. Most children and adolescents who are diabetic have type I diabetes; that is, they require insulin to prevent ketoacidosis. The maturity-onset diabetic is usually older and tends to be overweight; however, a younger person can develop type II and an older person can develop type I diabetes.

Type II diabetics tend to be elderly, overweight, relatively resistant to ketoacidosis, and prone to the development of a hyperglycemic, hyperosmolar, nonketotic state. Plasma insulin levels are normal or elevated but are low relative to the level of blood glucose.

Currently, therapy for type II diabetes usually begins with exercise and dietary management. A diet rich in fiber and less saturated fat, and daily physical activity of 30 minutes, is often associated with normalization of fasting blood glucose and delay of glucose intolerance by more than 50% of subjects. The next stage of therapy is use of oral hypoglycemic medications that act by stimulating release of insulin by pancreatic beta cells and by improving the tissue responsiveness to insulin by reversing the postbinding abnormality. The common orally administered drugs are tolazamide (Tolinase), tolbutamine (Orinase), and the newer sulfonylureas glyburide (Micronase), glipizide (Glucotrol), and glimperide. These last drugs have a longer blood glucose-lowering effect, which persists for 24 hours or more, and fewer drug-drug interactions. Oral hypoglycemic drugs may produce hypoglycemia for as long as 50 hours after intake (chlorpropamide [Diabinese] has the longest half-life). Other drugs include metformin, which decreases hepatic glucose output and may increase peripheral responsiveness to glucose (and is associated with lactic acidosis if the patient becomes dehydrated); acarbose, which decreases glucose absorption; and the thiaolidinediones (rosiglitazone and pioglitizone), which increases peripheral responsiveness to insulin. Troglitazone, another drug of this latter class, has been taken off the market because of 61 cases of acute renal failure after its use. Progressively, physicians advocating tight control of blood sugar levels give insulin to “maturity onset” insulin-dependent diabetic patients twice a day, or even more frequently.

Acute complications for the diabetic patient include hypoglycemia, diabetic ketoacidosis, and hyperglycemic, hyperosmolar, nonketotic coma. Diabetic patients also are subject to a series of long-term complications from cataracts, retinopathy, neuropathy, nephropathy, and angiopathy that lead to considerable morbidity and premature mortality. Many of these complications bring the diabetic patient to surgery. In fact, over 50% of all diabetics come to surgery at some time in their disease.

Hyperglycemic, hyperosmolar, nonketotic diabetic coma[150] is characterized by elevated serum osmolality (over 330 mOsm/L) and an elevated blood glucose level (over 600 mg/dL) without acidosis. Blood glucose level, in milligrams per deciliter, divided by 18 yields the contribution of glucose to osmolality. Trauma or infection in type II diabetes patients usually leads to this state rather than to ketoacidosis.[150] Hyperglycemia induces marked osmotic diuresis and dehydration, enhancing the hyperosmolar state; this can result in failure to emerge from anesthesia and persistent coma. Serum electrolyte values are often normal, although a widened anion gap (Na+[HCO3] - [Cl-] = 16) may point to lactic acidosis or a uremic state.

The evidence that hyperglycemia itself accelerates complications or that tight control of blood sugar levels decreases the rate of progression of microangiopathic disease is now definitive. [135] [136] [137] [138] [139] [140] Glucose itself may be toxic because high levels can promote nonenzymatic glycosylation reactions, leading to formation of abnormal proteins that may decrease elastance—responsible for the stiff joint syndrome (and fixation of the atlantooccipital joint, making intubation difficult)—and wound-healing tensile strength. Glucose elevations may increase production of macroglobulins by the liver, increasing blood viscosity, and may promote intracellular swelling by favoring production of nondiffusable, large molecules (like sorbitol). Newer drug therapies aim to decrease intracellular swelling by inhibiting formation of such large molecules, and surgical nerve compartment splitting is aimed at reducing the effect of such swelling. Glucose can also inhibit the phagocytic function.

Glycemia disrupts autoregulation. [151] [152] [153] [154] [155] [156] [157] [158] [159] [160] [161] Glucose-induced vasodilatation prevents target organs from protecting against increases in systemic blood pressure. Glycosylated hemoglobin of 8.1% is the threshold above which risk of microalbuminuria increases logarithmically. A person with type I diabetes with greater than 29 mg/day of microalbuminuria has an 80% chance of developing renal insufficiency. The threshold for glycemic toxicity is different for different vascular beds. The threshold for retinopathy is a glycosylated hemoglobin value of 8.5% to 9.0% (12.5 mmol/L or 225 mg/dl); for cardiovascular disease it is an average blood glucose value of 5.4 mmol/L (96 mg/dL). Thus, different degrees of hyperglycemia may be required before different vascular beds are damaged or certain degrees of glycemia are associated with other risk factors for vascular disease. Another view is that perhaps severe hyperglycemia and microalbuminuria are simply concomitant effects of a common underlying cause. Diabetics who develop microalbuminuria are more resistant to insulin; insulin resistance is associated with microalbuminuria in first-degree relatives of patients withtype II diabetes; and persons with normoglycemia who subsequently develop clinical diabetes have atherogenic risks before onset of disease.

Because of the known glucotoxicities, how tightly blood sugar levels should routinely be controlled was once controversial. It is now known that chronic tight control is a benefit. The controversy centers on whether attempts to attain normal blood sugar levels or levels that result in glycosylated hemoglobin values of less than 8.1% in diabetic patients are of greater benefit than risk.

Perioperative management of the diabetic patient may affect surgical outcome. Physicians who advocate tight control of blood glucose levels point to the evidence of increased wound healing tensile strength and decreased wound infections in animal models of (type I) diabetes under tight control. Insulin is necessary in the early stages of the inflammatory response but seems to have no effect on collagen formation after the first 10 days. Healing epithelial wounds exhibit minimal leukocyte infiltration and, unlike deep wounds, are not dependent on collagen synthesis for the integrity of the tissue. Thus, simple epithelial repair is not inhibited in the diabetes patient whereas the repair of deeper wounds is impaired with respect to collagen formation and defense against bacterial growth.

Infections account for two thirds of postoperative complications and about 20% of perioperative deaths in diabetic patients. Experimental data suggest many factors that may make diabetics vulnerable to infection. Many alterations in leukocyte function have been demonstrated in hyperglycemic diabetics, including decreased chemotaxis and impaired phagocytic activity of granulocytes, as well as reduced intracellular killing of pneumococci and staphylococci. When diabetic patients are treated aggressively and blood glucose levels are maintained below 250 mg/dL (13.7 mmol/L), the phagocytic function of granulocytes is improved and intracellular killing of bacteria is restored to nearly normal levels. It has been thought that diabetic patients experience more infections in clean wounds than do nondiabetics. In a review of 23,649 surgical patients, the rate of wound infection in clean incisions was found to be 10.7% for diabetics, as compared with 1.8% for nondiabetics; however, when age is accounted for, the difference in the incidence of wound infection in diabetic and nondiabetic surgical patients is not statistically significant.

Recent information on the relationship between blood glucose and neurologic recovery after a global ischemic event may have important implications for perioperative diabetes management. In a study of 430 consecutive patients resuscitated after out-of-hospital cardiac arrest, mean blood glucose levels were found to be higher in patients who never awakened (341 ± 13 mg/dL) than in those who did (262 ± 7 mg/dL). Among patients who awakened, those with persistent neurologic deficits had higher mean glucose levels (286 ± 15 mg/dL) than did those without deficits (251 ± 7 mg/dL). These results are consistent with the finding that hyperglycemia during a stroke is associated with poorer short- and long-term neurologic outcomes. The possibility that blood glucose is a determinant of brain damage after global ischemia is supported by studies of global and focal CNS ischemia. Data are accumulating that suggest that a major effect of glycemia is to disrupt autoregulation, making arteries and arterioles (macrovessels and microvessels) vulnerable to the force disruption caused by increased blood pressure. [155] [156] [157] [158] [159] [160] [161] Glycemia appears to disrupt autoregulation by enhancing activation of protein kinase C. [151] [161] This activation may occur in anyone whose glucose level exceeds 96 mg/dL (5.7 mmol/L) and is a major factor in arterial degeneration (aging). Before long, we may all want to tightly control our glucose levels, not only perioperatively but throughout our lives. Until better data are available, most recommend that the diabetic patient about to undergo surgery in which hypotension or reduced cerebral flow may occur should have a blood glucose level below 225 mg/dL during the period of cerebral ischemia. Two other special situations can also affect how tightly one should manage the patient's glucose level: (1) surgery requiring cardiopulmonary bypass and (2) surgery in pregnant patients or in patients already suffering from diabetic ketoacidosis.

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Perioperative Considerations for Patients with Diabetes

Before surgery, assessment and optimization of treatment of the potential end organ effects of diabetes are at least as important as an assessment of the diabetic's current overall metabolic status. Special emphasis should be placed on history; autonomic, cardiovascular, renal, and drug therapy; and the status of skin care. [135] [136] [137] [138] [139] [140] [141] [142] [143] [144] [145] [146] [147] [162] [163] [164] [165] Basic laboratory examinations might include determination of fasting blood sugar and blood urea nitrogen or creatinine levels and an electrocardiogram.

Patients with severe diabetic autonomic neuropathy are at increased risk for gastroparesis and consequent aspiration and for intraoperative and postoperative cardiorespiratory arrest. Recent data indicate that diabetics who exhibit signs of autonomic neuropathy, such as early satiety, lack of sweating, lack of pulse rate change with inspiration or orthostatic maneuvers, and impotence, have a very high incidence both of painless myocardial ischemia and gastroparesis. [144] [163] [164] [165]

Measuring the degree of sinus arrhythmia or beat-to-beat variability provides a simple, accurate test for significant autonomic neuropathy. The difference between maximal and minimal heart rate on deep inspiration, normally 15 beats per minute, was found to be five or less in all diabetic patients who previously sustained cardiorespiratory arrest. [163] [164]

Other characteristics of patients with autonomic neuropathy include postural hypotension with a drop of more than 30 mm Hg, resting tachycardia, nocturnal diarrhea, and dense peripheral neuropathy. Diabetics with significant autonomic neuropathy may have impaired respiratory responses to hypoxia and are particularly susceptible to the action of drugs that have depressant effects. Such patients may warrant very close, continuous cardiac and respiratory monitoring for 12 to 24 hours postoperatively, although such logical treatment has not yet been tested in a rigorous, controlled trial.

Approach to Perioperative Management

There may be a relationship between blood glucose and neurologic recovery after a global ischemic nervous system event that has important implications for perioperative diabetic management. [152] [166] In a study of 430 consecutive patients resuscitated after out-of-hospital cardiac arrest, mean blood glucose levels were found to be higher in patients who never awakened (341 ± 13 mg/dL) than in those who did (262 ± 7 mg/dL).[166] Among patients who awakened, those with persistent neurologic deficits had higher mean glucose levels (286 ± 15 mg/dL) than those without deficits (251 ± 7 mg/dL). These results are consistent with the finding in experimental models that hyperglycemia is associated with poorer short- and long-term neurologic outcomes.[152] If high glucose levels predispose to poor outcomes, the mechanism for the association of hyperglycemia with ischemic brain damage is not known. Until better data are available, there will be those who argue that the diabetic patient about to undergo surgery in which hypotension or reduced cerebral flow may occur should have a blood glucose level below 225 mg/dL during a period of cerebral ischemia; however, the risk of undetected hypoglycemia is much greater during surgery than while the patient is awake, because the normal physiologic responses are impaired and masked. Only frequent intraoperative monitoring of glucose levels can protect the patient. A popular approach, continuous insulin infusion for strict control of blood sugar during major surgery, has been highly recommended in some publications and is demonstrated to result in better outcome in those requiring intensive care for more than 24 hours. [135] [136] [137] [138] [139] [140] [141] [167] [168] This method does result in lower blood glucose levels but carries the risk of significant hypoglycemia in patients receiving 2 or more units of insulin per hour.

There are various methods of managing diabetes during surgery. The key to success includes individualized decision making for each patient, with the frequency of intraoperative monitoring appropriate to the tightness of control desired and with tailoring of insulin therapy to periodically measured blood glucose levels. The basic objectives of the perioperative management of diabetics include:

  

1.   

Achieving good control of blood glucose level with correction of any acid/base, fluid, or electrolyte abnormalities before surgery

  

2.   

Providing an adequate amount of carbohydrate to inhibit catabolic proteolysis, lipolysis, and ketosis (this requires an average of 100 to 150 g of glucose per day for a 70-kg person during the operative period)

  

3.   

Providing insulin adequate to prevent hyperglycemia, glycosuria, and ketoacidosis while also avoiding hypoglycemia

  

4.   

Keeping in mind problems associated with diabetes that require special perioperative attention or predispose to iatrogenic complications

  

5.   

Remembering that the tighter the desired control of blood glucose, the more frequently blood glucose must be measured

Non–Insulin-Dependent Diabetes.

Insulin is usually not required for minor surgery on patients whose diabetes is controlled by diet or small doses of oral agents. Short-acting oral hypoglycemic agents are omitted on the day of surgery, and long-acting agents are discontinued 2 days before surgery. Insulin may be required during and after surgery for major thoracic or abdominal operations or during prolonged parenteral alimentation. Given the potential of developing insulin allergy with intermittent insulin exposure, some physicians advocate the use of human insulin in this perioperative setting.

Insulin-Dependent Diabetes and Minor Surgery.

There are many methods for managing insulin-dependent diabetics during surgery, but few comparisons of efficacy and safety have been published. Regular insulin given subcutaneously begins to act within 30 minutes, reaches peak effect in 2 to 4 hours, and has a duration of action of 6 to 8 hours. Intermediate-acting insulin (NPH or Lente) given subcutaneously begins to act within 100 to 120 minutes, reaches a peak effect in 6 to 12 hours, and has an 18- to 24-hour duration of action. The conventional preoperative therapy for the well-controlled, fasting diabetic consists of administration of half of the dose of insulin the patient usually takes. This insulin is given subcutaneously on the morning of surgery with a 5% dextrose infusion at 100 to 150 mL/hr. Regular insulin is then given as a supplement to the intermediate-acting insulin when the need is indicated by blood glucose levels. The recommendations on whether a diabetic patient should be a morning admittance patient versus an outpatient for minor surgery are listed in Table 13-7 .

TABLE 13-7   -- Should a Diabetic be an Outpatient or a Morning-Admittance Patient?

Outpatient If:

Morning Admittance Patient If:

Can evaluate history in advance

Cannot evaluate history

End organ disease does not require monitoring

End organ disease requires invasive monitoring

Prehydration is available or is unnecessary

Needs careful prehydration

No central nervous system ischemia or planned cardiopulmonary bypass

Central nervous system ischemia is present or cardiopulmonary bypass is planned

Not pregnant

Pregnant

Patient or vested caregiver can determine blood glucose level

Patient cannot determine blood glucose level

Has vested individual to provide care

No vested individual to provide care

Can take temperature or look for “red” wound

Cannot take temperature or look for “red” wound

Plan higher admit rate (no data)

Social care network is unsuitable

From Miller RD (ed): Miller's Anesthesia, 6th ed. Philadelphia, Churchill Livingstone, 2005, with permission.

 

 

 

Insulin-Dependent Diabetes and Major Surgery.

Continuous intravenous insulin therapy similar to that used in the treatment of ketoacidosis is often administered to “brittle diabetics” during major surgery. Several methods of intravenous insulin therapy have been studied. Taitelman and coworkers compared constant intravenous insulin infusion with conventional subcutaneous administration of insulin in patients before orthopedic procedures.[168] They used 500 mL/hr of 5% dextrose for the first hour, followed by 125 mL/hr plus 1 or 2 units per hour of regular insulin (0.16 or 0.32 unit of insulin per gram of infused glucose) in one group of patients. They compared the outcome with that for a group of patients who were given two thirds of their daily maintenance dose of insulin subcutaneously immediately before surgery. The two methods resulted in equivalent diabetic control. At 2 units/hr, or 0.32 unit of insulin per gram of infused glucose, euglycemic levels were more readily achieved, but hypoglycemia requiring treatment occurred in several patients.

Guidelines for Continuous Intravenous Insulin Administration

The amounts of insulin and glucose that are administered need to be correlated. There is some argument about whether 5% or 10% dextrose should be used. Infusion of 10% dextrose provides more calories, thus favoring anabolism, but may lead to venous irritation and thrombosis. Concentrations of infused insulin vary from 0.2 to 0.4 unit per gram of glucose (equal to 1 to 2 units/100 mL of 5% dextrose in water) under normal conditions. Higher levels of insulin may be required under certain circumstances, for example, in patients with liver disease, marked obesity, or severe infection, and in patients undergoing corticosteroid therapy or coronary artery bypass surgery. Cessation of intravenous insulin may rapidly cause hyperglycemia, because insulin has a serum half-life of only 4 minutes and a biologic half-life of 20 minutes. Because it may be necessary to adjust the amount of insulin or glucose independently, these solutions should be kept in separate bottles, with one line “piggybacked” into the other. Separation of the intravenous line that contains the insulin and dextrose from all other intravenous fluids (these other fluids should contain no dextrose or lactate) reduces the risk of hypoglycemia or excessive hyperglycemia ( Table 13-8 ).


TABLE 13-8   -- Intravenous Insulin Regimen for “Brittle” Diabetic Undergoing Major Surgery

  

1.   

Obtain plasma glucose and potassium STAT on morning of surgery.

  

2.   

Begin intravenous infusion of 5% dextrose in water at 100 to 150 mL/hr and maintain dextrose infusion until the patient is taking oral nutrition.

  

3.   

“Piggyback” to above an IV infusion of 50 units of regular insulin in 500 mL of 0.9% normal saline by using infusion pump; flush 60 mL to saturate insulin-binding sites of tubing.

  

4.   

Set infusion rate at: Insulin (U/hr) = Last plasma glucose (mg/dL) ÷ 150. (Divide by 100 instead of 150 if patient is on corticosteroids, is markedly obese, or has infection.)

  

5.   

Determine glucose level every 2 o 3 hours; make appropriate insulin adjustments to obtain plasma glucose level of 80 to 150 mg/dL.

 

 

Renal Transplant Surgery.

The effectiveness of continuous intravenous administration of insulin has been compared with that of subcutaneous insulin in diabetics undergoing renal transplant surgery.[167] In this comparison, patients on intravenous insulin received 5% dextrose in water, with the hourly dose of insulin controlled by an infusion pump according to the following equation:

(divided by 150 instead of 100 if the patient is thin or is not taking corticosteroids). Low-dose continuous insulin infusion maintained blood glucose levels at between 100 and 200 mg/dL and was more effective than endogenous control, on the average, in nondiabetics. Conventional subcutaneous insulin therapy was found to be grossly inadequate for maintenance of acceptable glucose levels in diabetic patients undergoing renal transplantation.

Cardiopulmonary Bypass Operations.

For diabetics undergoing cardiopulmonary bypass surgery, the closed-loop “artificial pancreas” has been used in some studies for aggressive control of blood glucose level. Elliott and colleagues compared the use of Biostator, a closed-loop glucose-controlled system for infusion of insulin during open-heart surgery, with simpler, open-loop, constant intravenous administration of insulin.[169] A closed loop is characterized by automatic sensing and feedback control of insulin and glucose infusion. One intravenous line samples blood glucose levels by withdrawing blood at a rate of 1 mL/min, while insulin or glucose is infused through the other intravenous line as dictated by this measurement. An open-loop requires physician-directed regulation of insulin and glucose infusion. With both methods, no glucose infusion was given during the procedure, and blood glucose concentration was maintained at between 100 and 180 mg/mL throughout surgery. Insulin requirements increased during some phases of the operation, including cardiopulmonary bypass, transfusion of ACD stored blood, the rewarming phase, and injection of inotropic agents. A peak infusion rate of 20 units/hr was required during rewarming.

Mechanical problems were encountered postoperatively with the use of the Biostator. These included difficulties caused by peripheral vasoconstriction, movement of the patient, and nursing procedures that resulted in interruptions in feedback and led to elevations in blood glucose. Open-loop systems currently remain superior to closed-loop techniques because of cost and mechanical problems. [170] [171]

Emergency Surgery and Ketoacidosis

Many diabetics who need emergency surgery for trauma or infection have significant metabolic decompensation, including ketoacidosis.[172] Often little time is available for stabilization of the patient, but even a few hours may be sufficient for correction of fluid and electrolyte disturbances that are potentially life threatening. It is futile to delay surgery in an attempt to eliminate ketoacidosis completely if the underlying surgical condition will lead to further metabolic deterioration. The likelihood of intraoperative cardiac dysrhythmias and hypotension resulting from ketoacidosis will be reduced if volume depletion and hypokalemia are at least partially treated.

Insulin therapy is initiated with a 10-unit intravenous bolus of regular insulin, which is followed by continuous insulin infusion. The actual amount of insulin administered is less important than regular monitoring of glucose, potassium, and pH. Because the number of insulin-binding sites is limited, the maximum rate of glucose decline is fairly constant, averaging 75 to 100 mg/dL per hour, regardless of the insulin dose. [150] [173] During the first 1 to 2 hours of fluid resuscitation, the glucose level may fall more precipitously. When the serum glucose concentration reaches 250 mg/dL, I usually add 5% dextrose to the intravenous fluid.

The volume of fluid required for therapy varies with overall deficits; it ranges from 3 to 5 L, but it can be as high as 10 L. Despite losses of water in excess of losses of solute, sodium levels are generally normal or reduced. Factitious hyponatremia caused by hyperglycemia or hypertriglyceridemia may result in this seeming contradiction. The plasma sodium concentration decreases by about 1.6 mEq/L for every 100 mg/dL increase in plasma glucose concentration above normal. Initially, normal saline is infused at the rate of 250 to 1000 mL/hr, depending on the degree of volume depletion and on the cardiac status. Some measure of left ventricular volume should be monitored in diabetics who have a history of myocardial dysfunction. About one third of the estimated fluid deficit is corrected in the first 6 to 8 hours, and the remaining two thirds is corrected over the next 24 hours.

The degree of acidosis is determined by measurement of arterial blood gases and an increased anion gap [Na+ - (Cl- + HCO3-)]. Acidosis with an increased anion gap (at least 16 mEq/L) in an acutely ill diabetic may be caused by ketones in ketoacidosis, lactic acid in lactic acidosis, increased organic acids from renal insufficiency, or all three. In ketoacidosis, the plasma levels of acetoacetate, β-hydroxybutyrate, and acetone are increased. Plasma and urinary ketones are measured semiquantitatively with the Ketostix and Acetest tablets. The role of bicarbonate therapy in diabetic ketoacidosis is controversial. Myocardial function and respiration are known to be depressed at a blood pH below 7.0 to 7.10; yet rapid correction of acidosis with bicarbonate therapy may result in alterations in CNS function and structure. The alterations may be caused by (1) paradoxical development of cerebrospinal fluid and CNS acidosis resulting from rapid conversion of bicarbonate to carbon dioxide and diffusion of the acid across the blood-brain barrier, (2) altered CNS oxygenation with decreased cerebral blood flow, and (3) development of unfavorable osmotic gradients. After treatment with fluids and insulin, β-hydroxybutyrate levels decrease rapidly, whereas acetoacetate levels may remain stable or even increase before declining. Plasma acetone levels remain elevated for 24 to 42 hours, long after blood glucose, β-hydroxybutyrate, and acetoacetate levels have returned to normal; the result is continuing ketonuria.[150] Persistent ketosis, with a serum bicarbonate level of less than 20 mEq/L in the presence of a normal glucose level, represents a continued need for intracellular glucose and insulin for reversal of lipolysis.

The most important electrolyte disturbance in diabetic ketoacidosis is depletion of total body potassium. The deficits range from 3 mEq/kg up to 10 mEq/kg. Rapid declines in serum potassium level occur, reaching a nadir within 2 to 4 hours after the start of intravenous insulin administration. Aggressive replacement therapy may be required. The potassium administered moves into the intracellular space with insulin as the acidosis is corrected. Potassium is also excreted in the urine with the increased delivery of sodium to the distal renal tubules that accompanies volume expansion. Phosphorus deficiency in ketoacidosis caused by tissue catabolism, impaired cellular uptake, and increased urinary losses may result in significant muscular weakness and organ dysfunction. The average phosphorus deficit is approximately 1 mmol/kg. Replacement may be needed if the plasma concentration falls below 1.0 mg/dL.[150]

Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Copyright © 2005 Saunders, An Imprint of Elsevier

Summary

Management of the diabetic surgical patient includes careful preoperative assessment, prevention of infection,[173] frequent glucose and electrolyte monitoring, and, above all, administration of adequate amounts of insulin and glucose based on that monitoring. The sine qua non of tight control is frequent determination of blood glucose levels. With good control of glucose levels, many of the metabolic problems associated with surgery in diabetics can be prevented or alleviated. However, such tight control may not be worth the risk incurred. Epidemiologic evidence indicates that the major risk factor for the diabetic is not the blood glucose level but the end organ effects of diabetes. Autonomic neuropathy often is associated with painless myocardial ischemia and gastroparesis. These problems, as well as myocardial and renal dysfunction, may need special perioperative treatment or monitoring. Whether tight control of blood glucose levels is warranted remains to be determined in future studies. As with most of the other endocrinopathies dealt with in this chapter, it is not the endocrinopathy per se that is associated with morbidity but its cardiovascular and/or autonomic end organ effects that appear crucial to patient outcome. Little is known about how the choice of anesthetic or anesthetic adjuvant drug(s) affects outcome; consequently, attention might be directed to the cardiovascular and/or autonomic end organ effects to optimize outcome.

Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Copyright © 2005 Saunders, An Imprint of Elsevier

Acknowledgements

Parts of this chapter have been revised from Pender JW, Basso LV: Diseases of the endocrine system. In Katz J, Benumof J, Kadis L (eds): Anesthesia and Uncommon Diseases, 2nd ed. Philadelphia, WB Saunders, 1981, p 155. Other parts have been adapted from Roizen MF (ed): Anesthesia for Patients with Endocrine Disease. Anesthesiol Clin North Am 1987;5:245.

Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Copyright © 2005 Saunders, An Imprint of Elsevier

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