Case Report
Journal of Veterinary Emergency and Critical Care 12(3) 2002, pp 177±181
Calcipotriene toxicosis in a dog successfully treated with pamidronate disodium S. Anna Pesillo, VMD, Safdar A. Khan, DVM, MS, PhD, DABVT, Elizabeth A. Rozanski, DVM, DACVECC, DACVIM and John E. Rush, DVM, MS, DACVIM (Cardiology), DACVECC
Abstract Objective: To describe a case report of hypercalcemia following ingestion of calcipotriene, and successful treatment of hypercalcemia with pamidronate disodium as an adjuvant therapeutic agent. Case summary: A 3-year-old spayed female Boxer dog presented with polyuria, polydipsia, vomiting, lethargy and anorexia 4 days after ingesting 100 g of a topical antipsoriatic (0.005% calcipotriene). Severe hypercalcemia and moderate hyperphosphatemia were present on a serum biochemical profile. Treatment was initiated with salinea diuresis, furosemideb, dexamethasone sodium phosphatec, and cimetidined. A single dose of pamidronate disodiume was administered on the first day of hospitalization. Ionized and total calcium levels normalized within 24 hours and there was immediate clinical improvement. Serum calcium concentration and renal values were monitored for 3 weeks and remained within normal limits. Unique information provided: Pamidronate disodium, used in combination with other calciuretic agents, was a safe and effective adjuvant therapeutic agent in the management of hypercalcemia due to calcipotriene toxicosis. (J Vet Emerg Crit Care 2002; 12(3): 177±181) Keywords: bisphosphanates, hypercalcemia, vitamin D3 analog
Introduction Accidental ingestion of cholecalciferol and vitamin D3 analogs is becoming more common in dogs.1±5 The introduction of cholecalciferol-containing rodenticides in the mid-1980s resulted in an increased number of cases of dogs and cats with hypercalcemia secondary to vitamin D3 intoxication. More recently, antipsoriatic ointments that contain vitamin D3 analogs have been developed for topical use in humans. Dovonextf is a product that contains 0.005% calcipotriene (50 mg/g), which is a novel synthetic structural analog of calcitriol (1,25dihydroxycholecalciferol), the most active metabolite of From the Department of Clinical Sciences, Tufts University School of Veterinary Medicine, 200 Westboro Road, North Grafton, MA 01536, (S. Anna Pesillo, Elizabeth Rozanski, John Rush), and ASPCA Animal Poison Control Center, 1717 S. Philo Road, Suite 36, Urbana, IL 61802 (Safdar Khan). Address correspondence and reprint requests to: Dr Elizabeth Rozanski, Tufts University School of Veterinary Medicine, 200 Westboro Road, North Grafton, MA 01536. E-mail: elizabeth.rozanski@tufts.edu ß Veterinary Emergency and Critical Care Society 2002
cholecalciferol. Dovonext is available as an ointment or a cream in 30, 60, and 100 g aluminium tubes. It works as an antipsoriatic, by promoting differentiation of epithelial cells while inhibiting the proliferation of keratinocytes.6 Studies in rats found calcipotriene to be 100±200 times less potent than calcitriol on calcium metabolism and was therefore thought to have a low toxic potential for causing hypercalcemia.1,7 Reports of accidental ingestion of calcipotriene in dogs have indicated that 40±60 mg calcipotriene per kilogram of body weight could cause severe hypercalcemia and a significant risk of mortalityg. To date, the American Society for the Prevention of Cruelty to Animals (ASPCA) Animal Poison Control Center (APCC) has reported data on several cases of calcipotriene toxicosis in dogs. Aside from 2 abstractsg,h and 2 letters,i,j there are few reports of this novel toxicity in veterinary literature. A recent case series of 3 dogs with calcipotriene toxicity described the use of pamidronate disodiume in one dog as an alternative therapeutic to salmon calcitonin to control hypercalcemia. Although the dog treated with pamidronate did 177
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respond to therapy and showed no ill effects from the drug, it was concluded that the routine use of pamidronate could not be supported due to lack of safety and efficacy of pamidronate in dogs.1 The purpose of this report is to present a case of hypercalcemia from calcipotriene toxicosis that responded well to pamidronate disodium administration. Case Report A 3-year-old, 28 kg, spayed female Boxer dog was referred to the veterinary emergency service at Tufts University for the evaluation and treatment of hypercalcemia following Dovonext ointment (0.005% calcipotriene) ingestion. The dog had ingested a 100-g tube 4 days previously at an estimated dose of 178 mg of calcipotriene per kilogram of body weight. The owner noted vomiting, decreased appetite, and increased thirst within 24 hours of eating the ointment. The dog was evaluated by the referring veterinarian 36 hours after ingestion of the toxicant. A physical examination was normal and blood was drawn for a serum biochemical profile. Three hundred ml of 0.9% sodium chloride (10 ml/kg) was administered subcutaneously and the dog was discharged to the owner with instructions to feed a bland diet. A total serum calcium concentration of 16.3 mg/dl (reference range 8.8±11.0 mg/dl) was present on the serum biochemical profile. Serum phosphorus was moderately elevated (7.2 mg/dl; reference range 3.0±6.0 mg/dl). All other values on the biochemistry profile were within normal limits. The dog continued to vomit and remained polydipsic and polyuric at home. Lethargy and complete anorexia ensued. The referring veterinarian contacted the ASPCA Animal Poison Control Center. Aggressive treatment was recommended including intravenous fluids, furosemideb, and dexamethasone. The bisphosphanate pamidronate disodium was suggested as an additional therapeutic agent. The dog was referred to Tufts University for pamidronate disodium administration and continued supportive care. Physical examination upon presentation was normal with the exception of tacky mucous membranes and a quiet mentation. The dog exhibited intermittent hypersalivation. Blood and urine samples were submitted for a complete blood count (CBC), serum biochemistry profile, and urinalysis. Point-of-care biochemical testingk providing blood gas analysis, lactate, and electrolytes, including ionized calcium, was performed in the emergency room. Survey abdominal radiographs were obtained. The complete blood count was within normal limits, however, the spun hematocrit was slightly elevated at 178
55% and the total solids (TS) were moderately elevated (8.8 g/dl), supporting moderate dehydration. Serum biochemical abnormalities included hypercalcemia (15.3 mg/dl; reference range 9.4±11.6 mg/dl) and an elevated creatinine (1.4 mg/dl; reference range 0.6±1.2 mg/ dl). The phosphorus was normal (5.1 mg/dl; reference range 2.6±7.2 mg/dl). The ionized calcium was markedly elevated (1.77 mmol/l; reference range 1.29±1.33 mmol/l) and the ionized magnesium was elevated (0.44 mmol/l; reference range 0.26±0.32 mmol/l). The urine specific gravity was 1.017; the remainder of the urinalysis was normal. Survey abdominal radiographs were within normal limits. A diagnosis of vitamin-D3-analog toxicosis was suspected given the ingestion of calcipotriene 4 days earlier, the clinical signs of polyuria, polydipsia, vomiting, anorexia and lethargy, and the serum biochemical abnormality of hypercalcemia. Therapy was aimed at decreasing serum calcium levels and supporting renal function. Intravenous fluids (0.9% sodium chloride) were administered at 100 ml/kg/d and furosemide at a continuous rate infusion at 2.5 mg/kg/hr to promote diuresis and renal calcium excretion. Dexamethasone sodium phosphatec (0.25 mg/kg q 12 hr) was given subcutaneously to further lower serum calcium concentrations. Cimetidined (5.0 mg/kg IV q 8 hr) was administered to treat and prevent gastrointestinal irritation and esophagitis due to vomiting. A single dose of pamidronate disodium (Arediat) was administered within 4 hours of admission. A 1.5 mg/kg dose was diluted into 250 ml of 0.9% sodium chloride and was administered intravenously over 2 hours. No adverse effects were seen during administration of the drug. An ionized calcium level obtained 6 hours after completion of pamidronate administration was markedly lower at 1.45 mmol/l. The furosemide infusion rate was lowered to 1.0 mg/kg/hr. The dog was brighter and had not vomited. She was offered food later in the day but was not interested. On day 2 of hospitalization, the dog was more active and had a good appetite. An ionized calcium concentration was slightly above normal (1.36 mmol/l) and the serum potassium was slightly low (3.5 mmol/l). An estimation of blood urea nitrogen (BUN) with a dipstickl was elevated (30±40 mg/dl) and there was a slight rise in the packed cell volume and TS from the previous day (56% and 8.8 mg/dl, respectively). The changes in these indices were interpreted as insufficient fluid replacement given ongoing losses due to a urine-concentrating defect secondary to calcipotriene toxicosis and furosemide administration. The rate of intravenous 0.9% saline was increased to 135 ml/kg/d, and was supplemented with 40 mEq/l of potassium chloride. The intravenous furosemide was discontinued, and oral furosemide was ß Veterinary Emergency and Critical Care Society 2002
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started (2 mg/kg PO q 6 hr). The dexamethasone sodium phosphate and the cimetidine were continued. On day 3 of hospitalization, the ionized calcium was normal (1.26 mmol/l). All treatments and medications remained the same as on day 2, and the dog continued to appear clinically well, although there was some loose stool produced. The dog had a good appetite and was drinking large amounts of water. On the fourth day, the ionized calcium concentration was below the reference range (1.18 mmol/l). The loose stool persisted, but the dog's appetite and activity level remained normal. All medications were continued except that the furosemide dose was decreased (1 mg/kg PO q 8 hr). On the fifth day, the serum creatinine was normal (0.7 mg/dl) and the total calcium and phosphorus were both slightly below the reference range (8.1 mg/dl and 1.9 mg/dl, respectively). Serum potassium had normalized. The rate of intravenous fluid administration was decreased to 50 ml/kg/d and the furosemide was discontinued. The dog was discharged later that day on a tapering dose of prednisonem. Serum creatinine, BUN, calcium, phosphorus, and potassium concentrations were measured 3 and 11 days after discharge, and were within normal limits. The diarrhea had resolved after the dog returned to her regular diet at home. A follow-up phone call to the owner 10 months following discharge found the dog to be in good health. Discussion Hypercalcemia is an important electrolyte abnormality in veterinary medicine that may be associated with several different disease states including chronic renal failure, hypoadrenocorticism, primary hyperparathyroidism, granulomatous disease, and malignancy.8±10 Calcium ions, the physiologically active form of calcium, are important in maintaining cell membrane stability and excitability, and act as second messengers in a variety of cellular responses. Increases in the serum calcium ion concentration, normally under strict homeostatic control, can lead to a wide array of clinical signs involving primarily the neuromuscular, gastrointestinal, cardiovascular and renal systems.3,5,8,11,12 Vitamin D3 (cholecalciferol) ingestion may also lead to clinically significant hypercalcemia.3,4,11,12 Cholecalciferol is the active ingredient in several commercial rodenticides. Ingestion of this toxicant by dogs can lead to life-threatening hypercalcemia. Cholecalciferol, a fat-soluble vitamin, is rapidly converted to 25-hydroxycholecalciferol (calcidiol) in the liver and then to 1, 25dihydroxycholecalciferol (calcitriol) in the kidney.8,12 Calcitriol is the most active metabolite of cholecalciferol, acting to increase intestinal absorption of calcium, liberate calcium stores from bone through resorption, and ß Veterinary Emergency and Critical Care Society 2002
facilitate calcium re-absorption in the kidney.8 In the healthy animal, calcitriol serves an important role in calcium homeostasis; however, if toxic amounts are ingested, calcitriol can lead to hypercalcemia, and even death. The introduction of synthetic vitamin D3 analogs such as calcipotriene for the treatment of psoriasis in people has led to numerous reports of toxicity in dogs. The onset of clinical signs of calcipotriene toxicosis usually occurs within 24±72 hours of ingestion and include anorexia, vomiting, diarrhea, polyuria, polydipsia, depression, and weakness.1,3,5 Serum calcium concentrations are elevated by 12±24 hours and this may persist for weeks.1,5 Serum phosphorus concentrations also increase secondary to vitamin D3 intoxication through increased resorption from bone, increased renal tubular re-absorption, and increased intestinal absorption.1,13 As the calcium phosphorus product rises, soft tissue mineralization can occur. Urine concentrating ability is impaired secondary to mineralization of tubular basement membrane and tubular degeneration.5 Acute renal failure (from renal vasoconstriction and ischemia as well as metastatic calcification), coma, and death can occur in severe or untreated cases.1,2,5 Treatment of calcipotriene toxicosis in dogs is aimed at decreasing further intestinal absorption of the toxicant and reducing serum calcium concentrations. Standard gastrointestinal decontamination techniques (emesis induction, administration of activated charcoal and cathartics) should be employed if the ingestion occurs within 4 hours. Traditional methods of decreasing serum calcium concentrations include saline diuresis, furosemide, and corticosteroid administration, with or without salmon calcitonin administration.5,14 Corticosteroids lower serum calcium concentrations through inhibition of bone resorption, decreased intestinal calcium absorption, and increased calcium excretion in renal tubular cells leading to calciuria.5,8,15 Calcitonin primarily functions to inhibit bone resorption but also enhances renal excretion of calcium.1,5,8 Calcitonin is usually effective at rapidly lowering serum calcium levels, however, its use is not without side-effects. Calcitonin has been associated with anorexia and vomiting in humans16 and these gastrointestinal effects are also suspected to occur in dogs.1 Calcitonin has a relatively short half-life, and injections need to be administered several times a day.14 Resistance to the drug may also develop; this effect (tachyphylaxis) is observed in humans but it is unclear if this occurs in dogs.1,16±18 Multiple daily injections and a potential to develop resistance to calcitonin make it less than ideal for treating hypercalcemia due to calcipotriene toxicosis where serum calcium concentrations may remain elevated for weeks. 179
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Bisphosphonates are a relatively new class of drugs that act as potent inhibitors of bone resorption to lower serum calcium concentrations. Although their precise mechanisms of action are not fully understood, they have been shown to act directly and indirectly on osteoclasts to decrease activity and induce apoptosis.19 They may also decrease intestinal absorption of calcium and influence vitamin D3 metabolism.17,18 Bisphosphanates have been used successfully in humans to treat tumorinduced hypercalcemia and are currently being evaluated as potential inhibitors of bone metastases in human cancer patients.19 Bisphosphanates have recently been investigated as a potential treatment for the hypercalcemia of vitamin D3 toxicosis in dogs. Two studies have been performed in Beagles to evaluate the efficacy of pamidronate disodium, a bisphosphanate compound, on an experimental model of vitamin D3 toxicosis. These studies concluded that pamidronate effectively reduced the hypercalcemia induced by vitamin D3 toxicosis in a dose-related manner. Pamidronate treatment alone was found to be more effective and resulted in the fewest clinical signs, even when compared to combined treatment with pamidronate and calcitonin.17,18 Pamidronate has not been associated with significant side-effects in dogs, and although its safety has not been fully evaluated in this species, information from the manufacturer indicates a potential for nephrotoxicity in dogs receiving doses of 10 mg/kg or greater (Arediat package insert). The effective doses of pamidronate studied in dogs (between 1.3 and 2 mg/kg) were not associated with changes in renal histopathology.15 In usual doses, pamidronate has not been associated with renal impairment in humans and has even been used safely in dialysis patients.20 A major advantage of the use of pamidronate in cases of vitamin D3 toxicosis is its long duration of action. Although it requires an intravenous injection, normocalcemia is usually maintained for up to 2 weeks in humans20 and this appears to be similar in dogs.17,18 One dose of pamidronate is usually enough to treat most cases of hypercalcemia secondary to vitamin D3 intoxication, although 2 doses are sometimes required if hypercalcemia returns. Pamidronate is expensive; however, the cost of a single IV dose may be less expensive than the cost of prolonged hospitalization or multiple calcitonin injections. The case presented here demonstrates a clinical case of calcipotriene toxicosis treated successfully with pamidronate disodium in combination with intravenous fluids, dexamethasone, and furosemide. Despite 3 days of clinical signs and over 36 hours of hypercalcemia, aggressive treatment returned total and ionized calcium concentrations to normal within 24 hours following 180
pamidronate use. Ionized calcium levels dropped within 6 hours after the infusion was complete. Furthermore, serum calcium levels remained at or below normal levels for 3 weeks following the ingestion of calcipotriene. No adverse effects of pamidronate were seen in this case. Pamidronate was administered concurrently with other treatments and therefore its actions cannot be evaluated as a sole therapy for hypercalcemia secondary to calipotriene toxicity. There can be no conclusion from this report that this patient would not have done equally as well without pamidronate as a part of therapy. Concurrent supportive measures (IV fluids, furosemide, steroids) are still warranted in cases of vitamin D3 toxicosis and serum calcium concentrations need to be monitored serially for several weeks; but the course of hospitalization and therapy may be shortened with a single longacting injection of pamidronate. Further clinical studies on the safety and efficacy of pamidronate are necessary. The use of pamidronate disodium appears to be a useful adjunct for treating hypercalcemia following calcipotriene ingestion in dogs. Footnotes a
b c
d e
f
g
h
i
j
k l m
Sodium chloride 0.9%, Abbott Laboratories, North Chicago, IL Lasix, Taylor Pharmaceuticals, Decatur, IL Dexamethasone sodium phosphate, American Reagent Laboratories, Shirley, NY Cimetidine HCl, Abbott Laboratories, North Chicago, IL Aredia, Novartis Pharmaceuticals Corporation, East Hanover, NJ Dovonex (calcipotriene), Bristol Myers Squibb Co., New York, NY Volmer PA, Gwaltney-Brant SM, Albretson JC, Khan SA, Costello SM. Severe hypercalcemia in dogs due to ingestion of Dovonext (calcipotriene) ointment. Abstract. J Vet Intern Medical 1999; 13(5):243. Gwaltney-Brant SM, Albretsen JC, Khan SA, Volmer PA. Use of pamidronate disodium in the treatment of hypercalcemia secondary to ingestion of calcipotriene in dogs. Abstract. J Vet Intern Medical 1999; 13(5):243. Calcipotriene poisoning in dogs. Letter. Vet Rec 1997; 141 (1):27±28. Durtnell RE. Canine vitamin D toxicosis. Letter. J Small Anim Prac 1999; 40(11):550. NOVA Biomedical Corporation, Waltham, MA Azostik, Bayer Corporation, Elkhart, IN Prednisone, Schein Pharmaceuticals, Florham Park, NJ
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12. Dorman DC, Beasley VR. Diagnosis and therapy for cholecalciferol toxicosis. In: Kirk, RW, ed. Current Veterinary Therapy X. Philadelphia: W.B. Saunders 1989, pp. 148±152. 13. Willard MD, DiBartola SP. Disorders of Phosphorus. In: DiBartola SP, ed. Fluid Therapy in Small Animal Practice, 2nd edn. Philadelphia: W.B. Saunders Co 2000, pp. 163±174. 14. Doughertry SA, Center SA, Dzanis DA. Salmon calcitonin as adjunct treatment for vitamin D toxicosis in a dog. J Am Vet Med Assoc 1990; 196(8):1269±1272. 15. Boothe DM, Mealey KA. Glucocorticoid therapy in the dog and cat. In: Boothe DM, ed. Small Animal Clinical Pharmacology and Therapeutics. Philadelphia: W.B. Saunders 2001, p. 316. 16. Deftos LJ, First BP. Calcitonin as a drug. Ann Intern Med 1981; 95(1):192±197. 17. Rumbeiha WK, Fitzgerald SD, Kruger JM, et al. Use of pamidronate disodium to reduce cholecalciferol-induced toxicosis in dogs. Am J Vet Res 2000; 61(1):9±13. 18. Rumbeiha WK, Kruger JM, Fitzgerald SF, et al. Use of pamidronate to reverse vitamin D3-induced toxicosis in dogs. Am J Vet Res 1999; 60(9):1092±1097. 19. Body JJ, Bartl R, Delmas PD, et al. Current use of bisphosphonates in Oncology. J Clin Oncol 1998; 16(12):3890±3899. 20. Flombaum CD. Metabolic emergencies in the cancer patient. Semin Oncol 2000; 27(3):322±334.
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