Endocrine Emergencies.part2,adrenal,thyroid And Parathyroid Disorders

Vol. 19, No. 1 January 1997

V

HEINZ SYMPOSIUM 1996

Continuing Education Article

FOCAL POINT ★Endocrine disorders often cause life-threatening emergencies in small animals.

Endocrine Emergencies. Part II. Adrenal, Thyroid, and Parathyroid Disorders

KEY FACTS Colorado State University ■ Addisonian “tip-offs” include a normal or slow heart rate despite circulatory shock and the waxing and waning course before collapse. ■ Endogenous corticotropin must be measured before any corticosteroids are given. ■ Patients with myxedema or hypothyroid coma need intravenous replacement of thyroid hormone (5 µg/kg every 12 hours). ■ In-house testing can confirm the diagnosis of hypothyroidism before emergency treatment begins. ■ Calcitriol (0.25 µg orally every 48 hours) can be given for a short time after surgical thyroidectomy to prevent hypocalcemia.

Deborah S. Greco, DVM, PhD

D

isorders of the thyroid gland, adrenal glands, and parathyroid gland can cause life-threatening emergencies in small animals.

ADRENAL DISORDERS Addisonian Crisis One of the most well-recognized endocrine emergencies is classic addisonian crisis.1–4 Brought on by a deficiency of adrenocortical steroids, the classic hypoadrenal crisis is manifested as severe, profound shock. Although most affected dogs and cats are presented in severe cardiovascular collapse, they often have a recent history of vague, waxing and waning signs that presaged the onset of collapse.1–4 Hypoadrenocorticism is most commonly diagnosed in young female dogs and may be immune mediated. Historical findings compatible with hypoadrenocorticism include intermittent vomiting, diarrhea, weight loss, lethargy, anorexia, and weakness. These signs often resolve with fluid therapy and/or corticosteroid treatment. Physical examination of animals in an acute hypoadrenal crisis reveals weak pulses, bradycardia, prolonged capillary refill time, severe mental depression, and profound muscle weakness. Addisonian “tip-offs” include a normal or slow heart rate in the face of circulatory shock and the waxing and waning course of signs prior to collapse. Electrolyte abnormalities consisting of severe hyponatremia and hypochloremia associated with hyperkalemia are the hallmarks of hypoadrenocorticism. Although a sodium:potassium ratio below 1:27 suggests hypoadrenocorticism, it is not pathognomonic. Gastrointestinal disease, acute renal failure, and postrenal azotemia may also result in a low sodium:potassium ratio. Azotemia and hyperphosphatemia also attend primary hypoadrenocorticism, thus making it difficult to differentiate from acute renal failure. Hematologic abnormalities consist of eosinophilia and lymphocytosis or

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normal eosinophil Glucocorticoid and lymphocyte and mineraloScreening Tests for Hypoadrenocorticism counts in the face corticoid therapy of severe metamust be initiated Corticotropin (ACTH) Stimulation Test bolic stress. The only after diagProtocol: • 0.5 U/kg aqueous corticotropin intravenously, anemia of hyponostics for hyserum samples at 0 and 1 hour adrenocorticism poadrenocortihas classically been cism have been Protocol: • 2.2 U/kg corticotropin gel intramuscularly attributed to lack performed. Glu(maximum 20 U/dog), serum samples at 0 and 2 of glucocorticoid cocorticoid therhours effects on bone apy, using ultra– Normal levels: • Baseline 1–4 mg/dl (28–110 mmol/L); after marrow; however, short-acting corcorticotropin: < 20 mg/dl (550 mmol/L) recent studies sugticosteroid esters gest that hemor(e.g., dexamethEndogenous Corticotropin rhagic gastroenasone sodium teritis contributes phosphate and Protocol: • Single plasma sample (may be collected before significantly to prednisolone screening test and frozen for later analysis); collect the anemia.2 Hysodium succiin EDTA vacuum tube (with aprotinin), centrifuge poglycemia is nate) is indicatand store in plastic, ship at 4°C (or frozen if not more common ed. Dexamethacollected in aprotinin) with secondary or sone does not Normals: • 20–80 pg/ml (4.4–8.8 pmol/L) atypical hypoadinterfere with re n o c o r t i c i s m ; the cortisol assay however, hypoand may be preglycemia is an unusual manifestation of hypoadrenocortiferred if the animal requires immediate glucocorticoid adcism in dogs.2 ministration. Furthermore, a single dose of short-acting Diagnosis of primary hypoadrenocorticism is based corticosteroid will not suppress the hypothalamic– on appropriate clinical signs and classic electrolyte imhypophysial–adrenal axis and therefore will not interfere balances and is confirmed with a corticotropin with diagnostics.2 Recent studies have emphasized the importance of (ACTH) response test (see Screening Tests for Hypoadtreating the gastrointestinal complications of hypoadrenocorticism). Intramuscularly injected corticotropin renocorticism.2 Some dogs with addisonian crisis die of (gel or synthetic) may not be absorbed if the animal is gastrointestinal hemorrhage. The cause of the gastroinin circulatory shock. Intravenous administration of syntestinal hemorrhage is unknown but may be glucocortithetic corticotropin is preferred.2 Furthermore, the gel is no longer available in some parts of the country. Encoid deficiency or poor intestinal perfusion caused by dogenous corticotropin may be measured to determine shock. Treatment of anemia secondary to severe gasif the hypoadrenocorticism is primary (adrenal atrophy) trointestinal hemorrhage should include blood transfuor secondary (corticotropin deficiency); however, the sion coupled with gastrointestinal protectants (e.g., sutest sample must be collected before any corticosteroids cralfate, H2 antagonists, and misoprostol). are given. All dogs with hypoadrenocorticism should receive Treatment of the addisonian crisis (see the protocol) gastrointestinal protectants and immediate glucocorticonsists of fluid therapy, electrolyte stabilization, glucocoid therapy after adrenal testing has been performed. Mineralocorticoid supplementation, using oral fludrocorticoid replacement therapy, treatment of gastroincortisone acetate (0.2 mg per 10 kg orally every 24 testinal hemorrhage, and mineralocorticoid replacehours) or desoxycorticosterone pivalate (2 mg/kg intrament therapy. muscularly every 25 days), should be initiated only afNormal saline is the fluid of choice for hypoadrenal ter the results of dynamic adrenal testing have been recrises; in fact, shock doses of normal saline alone are viewed and hypoadrenocorticism confirmed. enough to reverse the circulatory shock caused by the renal loss of sodium and chloride resulting from aldosPulmonary Thromboembolism terone deficiency. Hyperkalemia often resolves with fluSecondary to Hyperadrenocorticism id therapy alone. The article on electrolyte imbalances Pulmonary thromboembolism is an uncommon rein this issue of Compendium describes treatment of lifethreatening hyperkalemia. sult of hyperadrenocorticism but is often fatal.5 Dogs FLUID THERAPY ■ GLUCOCORTICOID ■ MINERALOCORTICOID ■ GASTROINTESTINAL PROTECTANTS

The Compendium January 1997

Small Animal

PROTOCOL FOR TREATMENT OF HYPOADRENAL CRISIS Step

Drug or Fluid

Dosage

Side Effects

Caution

Step 1: Fluids

0.9% Saline

≤90 ml/kg/hr

Overhydration

Monitor central venous pressure

Step 2: Electrolytes if hyperkalemia is life-threatening

Calcium gluconate

5–15 mg/kg

Bradycardia

Monitor electrocardiogram

Insulin

0.5 U/kg

Dextrose

2 g/U of insulin

Hypoglycemia

Monitor electrocardiogram

Bicarbonate

1–2 mmol/kg intravenously over 5–15 min

Alkalosis

Monitor blood pH

Dexamethasone sodium phosphate

2–4 mg/kg intravenously

None

None

Prednisolone succinate

30 mg/kg intravenously

None

Do not use before corticotropin response test

Step 4: Restoration of acid–base balance

Sodium bicarbonate

See discussion of diabetic ketoacidosis in Part I

Alkalosis

Monitor pH, bicarbonate

Step 5: Treatment of gastrointestinal hemorrhage

Whole blood transfusion

Depends on packed cell volume, body weight

—

Monitor packed cell volume every 4 hours

Misoprostol

2–5 µg/kg orally three times a day

—

Ranitidine

2 mg/kg intravenously or orally twice a day

Step 3: Glucocorticoid

undergoing medical or surgical treatment for hyperadrenocorticism appear to be at increased risk for thromboembolic complications. Recent studies have shown that Cushing’s syndrome results in an increase in vitamin K–dependent coagulation factors and a decrease in antithrombin III concentrations.6,7 Clinical signs of acute respiratory distress, including orthopnea and jugular pulse, are common. Panting may occur secondary to hypoxia and/or pleuritic pain.8 Radiographic signs may include hypoperfusion, alveolar pulmonary infiltrates, pleural effusion, increased diameter and blunting of pulmonary arteries, lack of perfusion of the obstructed pulmonary vasculature, and overperfusion of the unobstructed pulmonary vasculature.5,9 However, many dogs with pulmonary throm-

—

boembolism have normal radiographs. Normal radiographs despite severe dyspnea suggest pulmonary thromboembolism. Blood gas analysis reveals hypoxemia (50 to 60 mm Hg) and hypocapnia (17 to 30 mm Hg), which result from panting. Blood gas analysis following oxygen administration often reveals a moderate to marked increase in arterial blood oxygen content except in those animals with severe pulmonary thrombosis or concurrent pulmonary disease.9 Treatment of pulmonary thromboembolism secondary to hyperadrenocorticism consists of oxygen therapy and medical treatment to prevent the formation of more blood clots. Medical therapy for pulmonary thromboembolism is best achieved via the use

COAGULATION FACTORS ■ RADIOGRAPHIC SIGNS ■ BLOOD GAS ■ PREVENTING CLOTS

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TABLE I Drugs Used in the Treatment of Thyrotoxicosis Drug

Dose

Route and Frequency

Mechanism

Propylthiouracil

11 mg/kg

Orally three times a day

Impairs peripheral deiodination of T4 to T3

Dexamethasone sodium phosphate

2–4 mg/kg

Intravenously, subcutaneously, or orally

Impairs peripheral deiodination of T4 to T3

Propranolol

2.5–7.5 mg

Orally twice or three times a day

Impairs peripheral deiodination of T4 to T3

1–2 mg

Intramuscularly every 24 hours

Reverses thiamine deficiency

One drop in gelatin capsule

Orally every 24 hours

Blocks release of T4 from thyroid

Thiamine hydrochloride Saturated solution of potassium iodide

of heparin initially, followed by anticoagulant vitamin K antagonists. The prognosis is very poor—most of the dogs die or are euthanatized within a week of a thromboembolic episode.9

THYROID DISORDERS Thyrotoxicosis Thyrotoxic crisis (“thyroid storm”) occasionally occurs in human patients with hyperthyroidism secondary to Grave’s disease or toxic multinodular goiter.10 Hyperthyroid cats probably also suffer from thyrotoxic crises. In fact, feline apathetic hyperthyroidism has many of the same clinical features (e.g., anorexia and congestive heart failure).11–13 Thyrotoxic crisis is manifested as severe hypermetabolism characterized by fever, tachycardia, pulmonary edema, or congestive heart failure. Early in the crisis, tremulousness and restlessness may be accompanied by frank delirium or psychosis.10 Nausea, anorexia, vomiting, and pain may accompany the syndrome. As the disorder progresses, apathy and stupor may occur as blood pressure falls to hypotensive levels because of circulatory failure.10 Clinicians should suspect thyrotoxic crisis if a cat with a history of thyrotoxicosis or evidence of previously undiagnosed thyroid disease (goiter) is presented with pyrexia, tachycardia, or signs of congestive heart failure. Therapy for the crisis consists of efforts to inhibit hormone synthesis and release and to antagonize adrenergically mediated aspects of peripheral thyroid hormone action11,14 (Table I). In human medicine, propyl-

thiouracil is preferable to methimazole as initial therapy for thyroid storm because it prevents peripheral conversion of T4 to the active form (triiodothyronine [T3]).14 The use of propylthiouracil in cats, however, may be limited because of serious side effects.15 Large doses of dexamethasone may be given to inhibit T4 release from the thyroid and peripheral generation of T3.10 A saturated solution of potassium iodide can be used to acutely retard the release of hormone from the thyroid. However, cats dislike the taste of inorganic iodine, so it must be enclosed in a capsule for oral administration.11 Cardiac manifestations should be treated using β-blockers, such as propranolol.11 Pyrexia, if present, should be addressed supportively by evaporative cooling. Thiamine deficiency has been observed in apathetic hyperthyroid cats; humans with thyroid storm also improve after treatment with B vitamins.10,11 Both thiamine deficiency and hypokalemia are manifested as ventroflexion of the neck.

Myxedema Coma Myxedema coma in dogs is a rare complication of canine hypothyroidism and is observed in young to middle-aged dogs in breeds with a high incidence of thyroid disease (e.g., Doberman pinschers). 16,17 In myxedema coma, the dog becomes hypothermic, profoundly weak, and exhibits a diminished level of consciousness.17 Secondary signs include nonpitting edema, mental dullness, depression, unresponsiveness, inappetence, anorexia, and bradycardia.

HYPERTHYROIDISM ■ THIAMINE DEFICIENCY ■ HYPOTHYROIDISM

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TABLE II Treatment of Hypocalcemia Drug

Dose

Administration

1.0–1.5 ml/kg

Slow intravenous bolus to effect

Monitor electrocardiogram; if bradycardia, ventricular premature contractions or short Q-T interval, discontinue briefly. Do not add to bicarbonate solution.

5–15 mg/kg

Intravenously to effect

Never give subcutaneously (causes perivasculitis); monitor as above

Constant-rate infusion

Monitor electrocardiogram; if bradycardia, ventricular premature contractions or short Q-T interval, discontinue briefly. Do not add to bicarbonate solution.

1.0–1.5 ml/kg

Subcutaneously every 6–8 hours

Used to maintain serum calcium >8 mg/dl

Vitamin D Therapy Calcitriol

0.03–0.06 µg/kg

Orally every 24 hours

Avoid hypercalcemia

Dihydrotachysterol

0.02–0.03 mg/kg

Orally every 24 hours

Initial dose; switch to every 48 hours after several days

Emergency Treatment Calcium gluconate 10% solution

or Calcium chloride

To Maintain Serum Calcium Calcium gluconate 60 mg/kg/day 10% solution

or

In humans and dogs, myxedema coma results from myxedematous accumulations in the brain and severe hyponatremia.10,16,17 Hyponatremia results from an increase in total body water because of impaired renal excretion of water and retention of water by hydrophilic deposits in tissue. The hyponatremia occurs despite a concurrent decrease in plasma volume.10 Early recognition and aggressive therapy are crucial to survival. Diagnostic differentials include metabolic abnormalities (e.g., hypoglycemia, electrolyte imbalances, hypoadrenocorticism, and hepatoencephalopathy) and neuromuscular diseases (e.g., myasthenia gravis and polyradiculoneuritis). Presumptive diagnosis should be based on signalment (predisposed breed, age), clinical signs (weakness, hypothermia, coma, bradycardia), and supporting clinicopathologic features (i.e., hypercholesterolemia and hyponatremia). Therapy should be initiated immediately—without waiting for results of serum total thyroxine (T4) analysis. With the advent of in-house thyroid testing units, however, emergency total T4 analysis may be possible

Comments

and is recommended to differentiate myxedema coma from other, more common causes of coma. Levothyroxine should be administered intravenously at a dosage of 5 µg/kg every 12 hours.11,16 Supportive care, in the form of assisted ventilation and judicious fluid therapy with 0.9% saline, may be indicated. Slow, passive rewarming should be considered—but only after thyroid hormone supplementation because increased oxygen requirements and decreased peripheral vascular tone may exacerbate circulatory failure.17

PARATHYROID DISORDERS Hypocalcemic Seizures Prompt treatment of hypocalcemia is necessary to prevent secondary complications, such as cerebral edema and hyperthermia. Hypocalcemia may be iatrogenic (after thyroidectomy) or may result from chronic or acute renal failure, acute pancreatitis, hypoalbuminemia, hypoparathyroidism, puerperal tetany, ethylene glycol intoxication, intestinal malabsorption, and nutritional secondary hyperparathyroidism.18–21 Early signs

IN-HOUSE THYROID TESTING ■ INTRAVENOUS LEVOTHYROXINE ■ FLUID THERAPY ■ REWARMING

The Compendium January 1997

Small Animal

of hypocalcetial signs of hyTABLE III mia are nonspepercalcemia are Emergency Treatment of Hypercalcemia cific and include polydipsia and anorexia (espe- Fluid/Drug polyuria resultDosage Comments cially in cats); ing from imfacial rubbing; 0.9% saline paired response 120–180 ml/kg/day Increases renal calcium excretion ner v o u s n e s s ; of distal renal intravenously and a stiff, stilttubules to vasoed gait.18 Later, Furosemide pressin.23 List5 mg/kg/hr Volume expansion must precede signs progress to lessness, depresintravenously furosemide administration paresthesias, hysion, and muscle perventilation, Etridonate weakness result 7.5 mg/kg For 3–7 days or until serum calcium and finally genfrom depressed intravenously over normalizes; based on human dose eralized tetexcitability of 4 hours any and/or seizneuromuscular ures.18,19 tissue. Mild gasEDTA 25–75 mg/kg hourly Chelator, nephrotoxic Treatment of trointestinal hypocalcemia Calcitonin signs of hyper4 U/kg intramuscularly Until serum calcium normalizes (Table II) rapidcalcemia inevery 12 hours (cats) ly resolves cliniclude inappecal signs. Intratence, vomiting, 8 U/kg subcutaneously Until serum calcium normalizes venous calcium and constipaevery 24 hours (dogs) chloride or caltion.23 Pe r s i s t e n t cium gluconate Bicarbonate 1–4 mEq/kg intravenously Decreases ionized fraction of mild elevations is required imevery 4 hours calcium, may cause alkalosis in serum calcimediately to um (12 to 14 treat tetany and mg/dl) can cause uroliths and signs of urinary tract seizures. The protocol outlines treatment of hypocaldisease, such as hematuria and strangury. On the other cemia. Perivascular injection of calcium chloride can rehand, severe hypercalcemia (>14 mg/dl) can progress sult in calcinosis cutis and severe tissue trauma.18,20 Calcium gluconate is less irritating to tissue, but a larger rapidly to acute renal failure when the calcium-phosvolume must be given to achieve the same effect.18 phorus product (Ca2+ [mg/dl] × PO43- [mg/dl]) exceeds The most convenient form of supplemental vitamin 60 to 80 because of mineralization of renal tissue. D is vitamin D3 or calcitriol. If hypercalcemia results These patients require emergency therapy for hypercalfrom calcitriol administration, it will resolve within 48 cemia. Rapid treatment of hypercalcemia is essential to hours after the drug is discontinued. A short-term preserve normal renal function and prevent the onset course of calcitriol at a dose of 0.25 µg can be given of renal failure in a patient with treatable underlying orally every 48 hours after surgical thyroidectomy to disease. prevent hypocalcemia caused by inadvertent damage to Initial treatment of hypercalcemia includes fluid dithe parathyroid gland.22 Similarly, dogs and cats underuresis using sodium-containing fluids23–25 (Table III). going parathyroidectomy for hyperparathyroidism may Once the animal has been rehydrated and extracellular be started on an appropriate dose of vitamin D before fluid volume has been expanded by 3% to 5% using surgery to prevent severe hypocalcemia after the procefluid therapy, pharmacologic diuresis may be induced dure. with furosemide.25 Thiazide diuretics enhance calcium resorption in distal tubules and are therefore contraOther emergency measures include monitoring body indicated.25 Once the cause of the hypercalcemia is temperature and cooling the animal if hyperthermia is identified, corticosteroids (2 mg/kg twice a day) may be severe. Short-acting glucocorticoids can be given if used to increase renal excretion of calcium. cerebral edema is suspected. Although hypercalcemia of malignancy responds Hypercalcemic Nephropathy to corticosteroid therapy, other causes of hypercalceHypercalcemic nephropathy has numerous possible mia (e.g., hyperparathyroidism) do not.23 Furthermore, causes, including hypercalcemia of malignancy, hyperuse of corticosteroids before a definitive diagnosis is parathyroidism, and hypervitaminosis D.23–25 The iniestablished may obscure the cause of hypercalcemia. THYROIDECTOMY ■ VITAMIN D ■ UROLITHS ■ FLUID DIURESIS ■ CORTICOSTEROIDS

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Phosphonates (etridonate, pamidronate), calcitonin, plicamycin, EDTA, and bicarbonate may also be used in refractory cases as emergency treatment of hypercalcemia.26–30

About the Author Dr. Greco is affiliated with the Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado, and is a Diplomate of the American College of Veterinary Internal Medicine.

REFERENCES 1. Hardy RM: Hypoadrenal gland disease, in Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine, ed 4. Philadelphia, WB Saunders Co, 1995, pp 1579–1593. 2. Peterson ME, Kintzer P: Pretreatment clinical and laboratory findings in 225 dogs with hypoadrenocorticism. JAVMA 208:85–91, 1996. 3. Willard MD, Schall WD, McCaw DE, Nachreiner RF: Canine hypoadrenocorticism: Report of 37 cases and review of 39 previously reported cases. JAVMA 180:59–62, 637–640, 1982. 4. Peterson ME, Greco DS, Orth DN: Primary hypoadreno-

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corticism in ten cats. J Vet Intern Med 3(2):55–58, 1989. 5. LaRue MJ, Murtaugh RJ: Pulmonary thromboembolism in dogs: 47 cases (1986–1987). JAVMA 197:1368–1373, 1990. 6. Feldman BF: Hemostatic abnormalities in canine Cushing’s syndrome. Res Vet Sci 41:228, 1986. 7. Ortega TM, Feldman EC, Ownings JT, et al: Hypercoagulopathy in dogs with hyperadrenocorticism. J Vet Intern Med 10(3):185, 1996. 8. Burns MG, Kelly AB, Hornof WJ, Howerth EW: Pulmonary artery thrombosis in three dogs with hyperadrenocorticism. JAVMA 178:388–392, 1981. 9. Johnson LR, Lappin MR: Clinical features of fatal pulmonary thromboembolism: 1985–1995. J Vet Intern Med 10(3):162, 1996. 10. Ingbar SH: The thyroid gland, in Wilson JD, Foster DW (eds): Textbook of Endocrinology. Philadelphia, WB Saunders Co, 1985, pp 682–815. 11. Feldman EC, Nelson RW: Canine and Feline Endocrinology and Reproduction. Philadelphia, WB Saunders Co, 1996, pp 163–165. 12. Peterson ME: Hyperthyroidism, in Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine, ed 4. Philadelphia, WB Saunders Co, 1995, p 1466. 13. Peterson ME, Kintzer PP, Cavanagh PG, et al: Feline hyperthyroidism: Pretreatment clinical and laboratory evaluation of 131 cases. JAVMA 183:103–110, 1983. 14. Davis LE: Propylthiouracil in the treatment of feline hyperthyroidism. JAVMA 179:485–487, 1981. 15. Meric SM: Diagnosis and management of feline hyperthyroidism. Compend Contin Educ Pract Vet 11(9):1053–1062, 1989. 16. Kelly MJ, Hill JR: Canine myxedema stupor and coma. Compend Contin Educ Pract Vet 6(12):1049–1057, 1984. 17. Bichsel P, Jacobs G, Oliver JE: Neurologic manifestations associated with hypothyroidism in four dogs. JAVMA 192:1745–1747, 1988. 18. Feldman EC, Nelson RW: Hypocalcemia and primary hypoparathyroidism, in Feldman EC, Nelson RW (eds): Canine and Feline Endocrinology and Reproduction. Philadelphia, WB Saunders Co, 1996, pp 497–516. 19. Kornegay JN: Hypocalcemia in dogs. Compend Contin Educ Pract Vet 4(2):103–110, 1982. 20. Schick MP: Calcinosis cutis secondary to percutaneous penetration of calcium chloride in dogs. JAVMA 191:207, 1987. 21. Peterson ME: Hypoparathyroidism and other causes of hypocalcemia in cats, in Kirk RW, Bonagura JA (eds): Current Veterinary Therapy. XI. Philadelphia, WB Saunders Co, 1992, p 376. 22. Graves T: Complications of treatment and concurrent illness associated with hyperthyroidism in cats, in Kirk RW, Bonagura JA (eds): Current Veterinary Therapy. XII. Philadelphia, WB Saunders Co, 1994, pp 369–372. 23. Feldman EC, Nelson RW: Hypercalcemia and primary hyperparathyroidism, in Feldman EC, Nelson RW (eds): Canine and Feline Endocrinology and Reproduction. Philadelphia, WB Saunders Co, 1996, pp 455–493. 24. Chew DJ, Capen CC: Hypercalcemic nephropathy and associated disorders, in Kirk RW (ed): Current Veterinary Therapy. VII. Philadelphia, WB Saunders Co, 1980, pp 1067. 25. Chew DJ, Meuten DJ: Disorders of calcium and phosphorus metabolism. Vet Clin North Am Small Anim Pract 12:411, 1982. 26. Fleisch H: Bisphosphonates: A new class of drug in disease of bone and calcium metabolism. Recent Results Cancer Res

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116:1, 1989. 27. Percival RC, et al: Role of glucocorticoids in the management of malignant hypercalcemia. Br Med J 289:287, 1984. 28. Bilezikian JP: Management of acute hypercalcemia. N Engl J Med 326:1196, 1992. 29. Parfitt AM, Kleerkoper M: Clinical disorders of calcium,

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phosphorus, and magnesium metabolism, in Maxwell MH, Kellman CR (eds): Clinical Disorders of Fluid and Electrolyte Metabolism. New York, McGraw-Hill, 1980, p 947. 30. Kruger JM, Osborne CA: Canine and feline hypercalcemic nephropathy. Part I. Causes and consequences. Compend Contin Educ Pract Vet 16(10):1299–1315, 1994.