STANDARDS of CARE. Calcium is a vital intracellular and extracellular ion involved in neuronal EMERGENCY AND CRITICAL CARE MEDICINE HYPERCALCEMIA

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1 Visit us at JUNE 2003 STANDARDS of CARE EMERGENCY AND CRITICAL CARE MEDICINE VOL 5.5 FROM THE PUBLISHER OF COMPENDIUM HYPERCALCEMIA Cassandra G. Brown, DVM Resident Rhonda L. Schulman, DVM, DACVIM Assistant Professor Thomas K. Graves, DVM, PhD, DACVIM Assistant Professor Small Animal Internal Medicine College of Veterinary Medicine University of Illinois Urbana, Illinois Calcium is a vital intracellular and extracellular ion involved in neuronal activation, muscle contraction, enzymatic reactions, hormone secretion, and bone matrix. Normal calcium homeostatic mechanisms maintain extracellular calcium concentrations within a narrow normal range. Hypercalcemia results from a variety of mechanistic imbalances and diagnoses, and treatment is based on the underlying pathophysiology of the disease. Extracellular calcium exists in three forms: ionized (the biologically active form), complexed (to plasma buffers), and protein-bound (mainly to albumin). Most commonly, total calcium is measured on serum biochemical analyses and represents the sum of all calcium fractions. Total calcium must be adjusted in dogs with hypoalbuminemia in the following manner: Adjusted Total Calcium = Serum Calcium (mg/dl) Serum Albumin (g/dl) This formula is only valid for dogs with hypoalbuminemia. Ionized calcium can be measured to more fully define calcium disorders. For example, high total calcium with normal or low ionized calcium suggests an etiology of renal disease or bone growth. Elevated ionized calcium suggests neoplasia, primary hyperparathyroidism, granulomatous disease, osteolysis, vitamin A or D toxicosis, acidosis, idiopathic hypercalcemia, or, rarely, hypothermia. Hypercalcemia is usually defined as a persistent elevation of fasted total calcium. Fasted samples are necessary because lipemia interferes with and falsely elevates calcium measurements on most biochemical analyzers. Consequences of persistent pathologic hypercalcemia include cell injury and death, disturbed nerve and muscle conduction abilities, metastatic Questions? Comments? soc.vls@medimedia.com, fax , or post on the Feedback page at calcification of tissues when calcium phosphorus product is >60, polyuria and polydipsia, secondary renal failure, gastrointestinal (GI) abnormalities, urolithiasis, and pancreatitis. The most common cause of pathologic hypercalcemia is neoplasia. Hypercalcemia also results from hypoadrenocorticism, acute or chronic renal disease, primary hyperparathyroidism, granulomatous disease, osteolytic lesions, vitamin A or D toxicosis, acidosis, and hypothermia. Young animals with normal bone growth will have mild to moderate hypercalcemia. Additionally, idiopathic hypercalcemia has been reported in cats. DIAGNOSTIC CRITERIA Historical Information Varies with underlying cause of the hypercalcemia. Gender Predisposition: Middleaged female dogs are overrepresented in patients with hypoadrenocorticism. Age Predisposition: Middle-aged to geriatric dogs and cats are more Inside this issue: Peer-Reviewed Articles on 1 Hypercalcemia 6 Hypothermia 11 Back Issue Index 1

2 likely to develop neoplasia and renal disease; young sporting breeds are prone to granulomatous disease, especially blastomycosis. Breed Predisposition: Keeshonds are predisposed to development of primary Owner Observations: Often mild and nonspecific. Renal signs predominate; polyuria and polydipsia can be profound; stranguria may be reported if urolithiasis or urinary tract infection has developed. GI signs are common, including inappetence, vomiting, and constipation. Weakness, mental depression, and other signs of central nervous system dysfunction have been reported. Signs of underlying disease resulting in hypercalcemia may cause the most significant abnormalities; cachexia, respiratory abnormalities, and cutaneous lesions may be present if neoplasia or disseminated mycotic disease is also present. Other Historical Considerations/ Predispositions: Dietary history (vitamin and mineral supplementation, especially vitamin A or D) or any history of toxin exposure (vitamin D analogues such as cholecalciferol rodenticides, calcipotriene [a vitamin D derivative used in the topical treatment of human psoriasis], or houseplants [day-blooming jasmine]) may aid in diagnosis. Physical Examination Findings Generalized lymphadenopathy is possible if lymphoma or disseminated fungal disease is present. Hepatosplenomegaly with lymphoma, multiple myeloma. Anal sac mass or sublumbar lymphadenopathy with anal sac adenocarcinoma. Evidence of other neoplastic processes (mammary masses, prostatomegaly, many others). Uremic odor and abnormally sized or painful kidneys may be present in animals with significant renal insufficiency. Pain may be present on palpation of long bones or vertebrae if osteolytic lesions are present (neoplasia, fungal disease, osteomyelitis). Hypothermia. Uveitis and retinal changes may be noted in fungal disease and some neoplastic processes. Cutaneous lesions of fungal disease or neoplasia. Cardiac arrhythmias may be present due to myocardial mineralization; calcium s effect on excitatory cardiac tissue may also play a minor role. Dehydration may be noted in animals with renal insufficiency, hypoadrenocortical crisis, or prominent GI abnormalities. Physical examination may be normal in dogs and cats with primary hyperparathyroidism and hypoadrenocorticism. Laboratory Findings Persistent fasting hypercalcemia: Total calcium >12 mg/dl in dogs and 11 mg/dl in cats. Low to normal serum phosphorus: Present in cases of primary hyperparathyroidism or hypercalcemia of malignancy when secondary renal insufficiency has not occurred. Normal to high serum phosphorus: Present in cases of primary or secondary renal failure, vitamin D toxicity, Addison s disease, granulomatous disease, or osteolytic lesions. Isosthenuria or hyposthenuria: Often present due to hypercalcemia-induced renal tubular dysfunction. Minimum database (complete blood count [CBC], chemistry panel, urinalysis, urine culture): May reflect primary or secondary organ dysfunction or inflammation. JUNE 2003 VOL 5.5 STANDARDS of CARE EMERGENCY AND CRITICAL CARE MEDICINE Editorial Mission: To provide busy practitioners with concise, peer-reviewed recommendations on current treatment standards drawn from published veterinary medical literature. This publication acknowledges that standards may vary according to individual experience and practices or regional differences. The publisher is not responsible for author errors. Compendium s Standards of Care: Emergency and Critical Care Medicine is published 11 times yearly (January/February is a combined issue) by Veterinary Learning Systems, 780 Township Line Road, Yardley, PA The annual subscription rate is $69. For subscription information, call , fax , soc.vls@medimedia.com, or visit Copyright 2003, Veterinary Learning Systems. Executive Series Editor Richard B. Ford, DVM, MS Editor in Chief Beth Thompson, VMD Editorial Staff Lilliane Anstee, Editorial Director Perri Stark, VMD, Editorial Consultant Cynthia Laufenberg, Managing Editor Chris Reilly, Editorial Assistant Creative Director Sue Wiedorn Art Studio Manager Bethany L. Wakeley Editorial Review Board Nishi Dhupa, DVM, DACVECC Cornell University Cynthia Otto, DVM, DACVECC University of Pennsylvania Mark Rubash, DVM, DACVECC Houston, Texas Gregory Grauer, DVM, MS, DACVIM (Internal Medicine) Kansas State University Thomas Schermerhorn, VMD, DACVIM (Internal Medicine) Kansas State University 2 J U N E V O L U M E 5. 5

3 Significant elevations in BUN and creatinine: May indicate renal secondary hyperparathyroidism or hypercalcemic renal calcification and subsequent insufficiency (i.e., it may be difficult to distinguish primary hypercalcemia resulting in renal failure from renal secondary hyperparathyroidism). Azotemia with isosthenuria or hyposthenuria: May be present as a result of prerenal dehydration and calcium-mediated renal tubular dysfunction. Ionized hypercalcemia: Present in most cases of pathologic hypercalcemia except some instances of renal secondary Parathyroid hormone (PTH): Elevated in the face of ionized hypercalcemia in primary Parathyroid hormone-related protein (PTHrp): Elevated in some cases of hypercalcemia of malignancy. 25-OH vitamin D levels: Increased in vitamin D toxicosis. PTH, PTHrp, and vitamin D levels: Low to normal in some malignancies, granulomatous disease, hypoadrenocorticism, acidosis, and osteolysis. dence of primary or secondary Summary of Diagnostic Criteria True, persistent, fasting total calcium >12 mg/dl in dogs and 11 mg/dl in cats. Ionized calcium, PTH, PTHrp, and vitamin D levels may define underlying etiology if other screening tests above do not yield diagnosis. Cytology or biopsy consistent with neoplasia or fungal disease. Differential Diagnoses Spurious hypercalcemia (not persistent on fasted sample). Neoplasia (rectal examination, minimum database, lymph node palpation and aspirates, thoracic radiographs, abdominal ultrasound, cytology, elevated PTHrp, bone marrow aspirate). Hypoadrenocorticism (ACTH stimulation test). Chronic renal failure (azotemia with isosthenuria, low to normal ionized calcium, normal to elevated serum phosphorus, elevated PTH). Granulomatous disease (cytology demonstrating fungal organism in lungs, globe, cutaneous or bony lesions). Primary hyperparathyroidism (elevated total and ionized calcium, normal to minimally elevated BUN and creatinine, low to normal serum phosphorus, elevated PTH, enlarged parathyroid gland[s] on palpation or ultrasound). Acidosis (venous ph <7.25). Hypervitaminosis D (history of toxin exposure, elevated serum vitamin D levels). Osteolytic lesions (radiographic changes, nuclear scintigraphy bone scan). Idiopathic hypercalcemia of cats (elevated total and ionized calcium, normal phosphorus, no evidence of neoplasia or fungal CHECKPOINT Use of plicamycin, an antitumor antibiotic, inhibits osteoclastic bone resorption and can be effective in lowering serum calcium concentrations. However, side effects are numerous and include thrombocytopenia, hepatotoxicity, GI upset, and nephrotoxicity. Use of plicamycin is controversial, as other treatments are associated with much fewer side effects and appear to be as effective. Other Diagnostic Findings Thoracic radiographs may reveal a mediastinal mass (lymphoma, thymoma), metastatic neoplasia, fungal pneumonia, osteopenia, or lytic bone lesions. Abdominal radiographs may have evidence of mass effect, hepatosplenomegaly, bony changes, uroliths, or renal mineralization. Skeletal radiographs may indicate lytic lesions or osteopenia. Abdominal ultrasound may reveal evidence of neoplasia, renal disease, or uroliths. Parathyroid ultrasound is indicated to evaluate size and shape of the parathyroid glands for evidisease, normal PTH, PTHrp, and vitamin D levels). TREATMENT RECOMMENDATIONS Initial Treatment Initial treatment is guided by severity of hypercalcemia, rate of its development, clinical condition of the patient, and other metabolic abnormalities. In general, total serum calcium >16 mg/dl, calcium phosphorous product >70, or neurologic, cardiac, or renal dysfunction should be treated more aggressively than asymptomatic patients. Rehydration and calciuresis can be achieved with 0.9% NaCl IV fluid therapy (120 to 180 ml/kg/day in patients with normal cardiac and renal function). After rehydration and fluid diuresis, furosemide (2 to 4 mg/kg IV bid to tid) may be necessary to promote calciuresis. An oral phosphate binder such as aluminum hydroxide (30 to 90 mg/kg/day in food) reduces phosphorus absorption and may ameliorate renal secondary Definitive therapy for the underlying cause is necessary and will correct hypercalcemia. STANDARDS of CARE: EMERGENCY AND CRITICAL CARE MEDICINE 3

4 Chemotherapy for lymphoma or multiple myeloma. Surgical resection or radiation therapy for other neoplasms with paraneoplastic hypercalcemia. Antifungal therapy for disseminated mycoses. Surgical parathyroidectomy, ethanol ablation, or radiofrequency ablation for primary Mineralocorticoid and glucocorticoid replacement for hypoadrenocorticism. Alternative/Optional Treatments/Therapy If acidosis is present, sodium bicarbonate promotes increased calcium-albumin binding (lowers ionized calcium) per the following dose: Bicarb (meq) needed = 0.3 base deficit (meq/l) body weight (kg) One-third this amount should be given over 1 2 hour and the remainder administered over the following 8 hours. Calcitonin (4 to 6 IU/kg SQ bid to tid) inhibits bone resorption and increases calciuresis. Bisphosphonates: Pamidronate (1 mg/kg IV over 2 hours in 100 ml 0.9% NaCl every 21 days). Bisphosphonates inhibit osteoclastic activity and formation of calcium-phosphate crystals. Pamidronate is approved for use in treatment of hypercalcemia of malignancy in humans. Life-threatening cardiac arrhythmias should be treated with a calcium channel blocker such as diltiazem (0.5 to 1.5 mg/kg PO tid or 0.25 mg/kg IV bolus every 15 minutes up to three times to achieve cardioversion) or verapamil (0.05 mg/kg IV every 10 to 30 minutes up to three times). Prednisone (1 to 2 mg/kg PO bid) or dexamethasone (0.1 to 0.2 mg/kg PO or IV bid) will reduce hypercalcemia in most patients; however, glucocorticoids will rapidly promote lympholysis and make diagnosis of lymphoma very difficult. The use of prednisone or dexamethasone should be withheld until definitive diagnosis is obtained. Supportive Treatment IV fluid therapy should be administered as above to maintain hydration and promote calciuresis and diuresis. Adequate nutrition should be ensured by offering palatable food and considering enteral feeding tubes or parenteral nutrition. Low-calcium diets should be fed, such as Hill s k/d, u/d, or s/d. Supplemental oxygen administration may be necessary for patients with fungal or neoplastic pulmonary involvement (based upon patient s condition and arterial blood gas analysis). Other therapies related to primary disease may be indicated. Patient Monitoring Primary diseases causing hypercalcemia should be monitored as deemed appropriate. Electrocardiographic monitoring in patients with severe hypercalcemia. Once to twice monthly rechecks of thoracic radiographs in patients with pulmonary disease. Once to twice monthly rechecks of electrolytes in patients with hypoadrenocorticism. Serial rechecks in patients with lymphoma dependent upon chemotherapeutic regimen (generally once every 1 to 3 weeks). Renal profiles, CBCs, blood pressure analyses, and intermittent urine cultures in patients with chronic renal disease. Following parathyroidectomy, calcium levels must be monitored closely because hypercalcemia may occur. Home Management Ensure adequate water intake. Monitor for appropriate urination. Milestones/Recovery Time Frames Patients with hypercalcemia of malignancy should exhibit normalization of total serum calcium within 1 week of appropriate surgical intervention or chemotherapy. Patients with vitamin D toxicosis (without permanent renal damage) will vary in response to treatment depending on the half-life of the ingested toxin. Hypercalcemia of hypoadrenocorticism will improve with 72 hours of treatment. Surgical or ethanol ablation therapy of parathyroid adenomas will resolve hypercalcemia within 1 week. Renal secondary hyperparathyroidism may be permanent or may resolve over weeks to RESOURCE LIST Aluminum hydroxide (Amphogel, Wyeth): mg/kg/day in food indefinitely Pamidronate (Aredia, Novartis): mg/kg IV over 2 hours in 0.9% NaCl every 21 to 28 days Calcitonin (Calcimar, Aventis): 4 6 IU/kg SQ bid to tid until calcium normalizes Dexamethasone (Azium, Schering-Plough Animal Health): mg/kg PO or IV bid for 2 weeks, then tapered Diltiazem (Cardizem, Aventis): mg/kg PO tid Furosemide (Lasix, Intervet): 2 4 mg/kg IV bid to tid as needed Prednisone (many formulations): 1 2 mg/kg PO bid for 2 weeks, then tapered Verapamil (Calan, Pharmacia): 0.05 mg/kg IV every minutes up to three times 4 J U N E V O L U M E 5. 5

5 months with SC fluid and phosphate-binding therapy. Hypercalcemia associated with acidosis will resolve with resolution of the acidosis. Hypercalcemia associated with granulomatous disease should resolve within 1 month of appropriate antifungal therapy. Treatment Contraindications Calcium-containing IV or SC fluid therapy Corticosteroid therapy without definitive diagnosis Calcium-containing antacids Furosemide administration prior to volume expansion PROGNOSIS Favorable Criteria Hypercalcemia due to acidosis alone Normal renal parameters on presentation Asymptomatic patient Unfavorable Criteria Severe respiratory compromise in patients with fungal disease Presence of metastatic tissue mineralization Presence of renal azotemia RECOMMENDED READING Feldman EC: Disorders of the parathyroid glands, in Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine. Philadelphia, WB Saunders, 2000, pp Feldman EC, Nelson RW: Hypercalcemia and primary hyperparathyroidism, in Canine and Feline Endocrinology and Reproduction. Philadelphia, WB Saunders, 1996, pp Martin LG: Hypercalcemia and hypermagnesemia. Vet Clin North Am 28(3): , Pfeilschifter J: Cytokines as mediators of hypercalcemia of malignancy. Recent Results Cancer Res 137:1 19, Sharma OP: Hypercalcemia in granulomatous disorders: A clinical review. Curr Opinions Pulmonary Med 6: , STANDARDS of CARE: EMERGENCY AND CRITICAL CARE MEDICINE 5