Introduction

Vitamin D₃ toxicosis is uncommonly reported among dogs and rarely reported in cats.^1–7 Few isolated veterinary case reports describe both experimental and clinical exposure to cholecalciferol with associated hypercalcemia. Similar cases of accidental overdose exist in humans because of errors in formulation or fortification, inappropriate prescribing or dispensing, and errors in administration.⁸ With regulation changes in 2011 dictating transition from first-generation anticoagulant-based rodenticide to bromethalin and vitamin D analogs, a rising risk of exposure to cholecalciferol can be expected.^9–12

Cholecalciferol rodenticides confer their effects following conversion to the metabolically active metabolite calcitriol (1,25-dihydroxyvitamin D). Calcitriol subsequently causes increases in serum calcium and phosphorous concentrations through enhanced calcium absorption in the intestinal tract, bone mobilization, and renal tubular reabsorption.^9–14 The most common clinical signs seen following cholecalciferol toxicosis are lethargy, vomiting, anorexia, muscular weakness, weight loss, and polyuria/polydipsia.^9–12

To the authors’ knowledge, this is the first case report to describe an outpatient therapy approach to hypercalcemia due to acute cholecalciferol toxicosis. This report details a successful clinical outcome with normalization of serum calcium concentration following outpatient management in a puppy.

Case Report

A 4 mo old female intact boxer was presented for lethargy and increased thirst and urination following cholecalciferol rodenticide ingestion roughly 3 days prior. The owners noted that she had access to D-Con^a in the yard but were unable to estimate a volume ingested. The owners described that she was lethargic with polyuria and polydipsia over approximately 48 hr. She vomited the day of presentation. Her initial examination showed her to be thin (Body Condition Score 3/9), but she was otherwise within normal limits. She weighed 8.6 kg. Her temperature was 38.1^°C, her heart rate was 140 beats per minute, and her respiratory rate was 40 breaths per minute. Initial blood work showed a marked ionized hypercalcemia 2.23 mmol/L (reference range 1.04–1.33 mmol/L; Table 1). The patient was nonazotemic at presentation with blood urea nitrogen (BUN) 18 mg/dL (reference range 8–23 mg/dL) and creatinine 0.8 mg/dL (reference range 0.5–1.1 mg/dL). Complete blood work was submitted, which showed a mildly elevated alkaline phosphatase 192 U/L (reference range 5–150 U/L) and a total hypercalcemia 17.3 mg/dL (reference range 9–11.4 mg/dL) with a mild hyperphosphatemia 7.3 mg/dL (reference range 2.1–6.3 mg/dL). The mild elevations in ALP and phosphorous were considered acceptably elevated secondary to enhanced osteoblastic activity and bone growth in a patient of this age.¹⁴ Furthermore, elevations in serum phosphorous could be expected from enhanced renal tubular reabsorption in the face of circulating growth hormone.¹⁵ A urinalysis showed isosthenuria (specific gravity of 1.017) but was otherwise unremarkable.

TABLE 1 Serial Blood Work Parameters over 21-Day Follow-Up Period

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Because of the severe ionized hypercalcemia, hospitalization for aggressive inpatient management and parenteral care was recommended. However, given significant financial limitations, outpatient care was elected. She was treated with a single dose of pamidronate^b at 1.5mg/kg over 4hr diluted into 250 mL of 0.9% NaCl^c.Oralmedications dispensed included maropitant^d (2.7 mg/kg per os [PO] q 24 hr), prednisone^e (0.87 mg/kg PO q 12 hr), furosemide^f (1.45 mg/kg PO q 12 hr), famotidine^g (1 mg/kg PO q 12 hr), and 350 mL subcutaneous fluids of 0.9% NaCl (115 mL/kg/day) administered every 8 hr until recheck. It was also recommended she be fed a calcium-restricted diet (Hill’sk/d^h) to limit further calcium and phosphorous intake.

The patient was rechecked 3 days later. Her energy level had normalized, and she was perceived as clinically improved at home. She continued to be polyuric and polydipsic. Recheck blood work showed a persistent but improved ionized hypercalcemia (1.68 mmol/L). Her serum phosphorous had normalized (4.5 mg/dL). Given her good appetite and absence of additional vomiting, the maropitant was discontinued. At this time, she was transitioned back to her previous diet formulated for puppies. All other treatments remained unchanged.

The patient was again rechecked 7 days following initial presentation. She weighed 9.1 kg and was clinically well. Recheck blood work showed normal ionized calcium (1.33 mmol/L) and renal values (BUN 21 mg/dL and creatinine 0.8 mg/dL). At this point, the prednisone was reduced (0.5 mg/kg PO q 12 hr) and the frequency of subcutaneous fluids was decreased to once daily (350 mL 0.9% NaCl). The furosemide dose remained unchanged.

The patient was rechecked 7 days later, 2 wk after her initial evaluation. She weighed 8.8 kg, and the owners had no clinical concerns. Recheck blood work showed normal ionized calcium (1.33 mmol/L). The renal values were noted to have increased compared with previous measurements but remained within reference range (BUN 24 mg/dL and creatinine 1.1 mg/dL). At this visit, no changes were made to the prednisone and furosemide schedules and the subcutaneous fluids were discontinued.

The patient was rechecked the following week. She weighed 8.6 kg. She had been doing well, and the owners observed a normal frequency of urination. Recheck blood work showed normal ionized calcium (1.3 mmol/L). Her renal values (BUN 33 mg/dL and creatinine 1.1 mg/dL) were at the upper limit of normal. At this time, the furosemide was discontinued. The prednisone frequency was decreased (0.58 mg/kg PO q 48 hr) and given for five additional doses before being discontinued. After this visit, the patient was released to normal activity and without scheduled recheck.

Discussion

Cholecalciferol (vitamin D₃) in mammals is required through diet or dermal exposure to ultraviolet light.^9–14 Cholecalciferol is metabolized to calcifediol (25-hydroxycholecalciferol) in the liver.^9–14 There is limited negative regulatory feedback of this cycle. Calcifediol is then metabolized to the active metabolite, calcitriol, within the kidney.^9–14 A rising serum calcitriol concentration will initiate a negative feedback loop, halting further conversion. However, calcifediol has a functional half-life of 29 days; therefore, patients with cholecalciferol exposure may still require treatment and demonstrate adverse effects for extended periods of time.^9,10,12,16

Cholecalciferol metabolites cause effects by increasing serum calcium and phosphorous concentrations. This occurs because of increased intestinal absorption of calcium, calcium and phosphorus mobilization to plasma from bones, and enhanced renal tubular reabsorption of calcium.^1,4 Pathologic tissue mineralization can result from increased calcium and phosphorous concentrations, with the rising likelihood of mineralization as the product of these concentrations exceeds 60 mg/dL.^{9,10,12,14,15} Unlike adult animals, growing puppies may demonstrate total calcium concentrations greater than 12.0–15 mg/dL and be considered normal.¹⁴ In puppies less than 8 wk of age, phosphorous concentrations can reach 10.8 mg/dL and are aligned with normal skeletal development.¹⁵ Phosphorous then remains elevated above adult reference interval with a gradual decline for months to follow.¹⁵ Because these serum values are physiologically higher in healthy puppies, the [Ca] × [Phos] product may subsequently be unreliable in predicting pathologic tissue mineralization in scenarios of toxicosis.

With new commercial availability and rising prevalence of non-anticoagulant rodenticide baits following the EPA’s 2011 policy change, cholecalciferol exposure and subsequent toxicosis is likely to become a more frequently encountered emergency in dogs. Clinical signs following ingestion of 0.5 mg/kg cholecalciferol can develop in as little as 12–36 hr, with peak serum calcitriol concentrations at 48–96 hr following exposure.^9–12 Common clinical signs include lethargy, vomiting, anorexia, depression, and polyuria/polydipsia coinciding with acute renal failure often within 24–72 hr of ingestion.^9–12,14,16

If owners are aware of cholecalciferol rodenticide ingestion, prompt and time-sensitive emergency medical care should be sought. For asymptomatic patients within 6 hr of exposure, standard of care should first include induction of emesis, followed by administration of activated charcoal to reduce the enterohepatic recirculation of cholecalciferol. Additional treatment includes the oral administration of cholestyramine every 8 hr for 4 days, allowing an 8 hr interim from the last activated charcoal dose.^9,10,12 Monitoring recommendations for asymptomatic patients may reasonably include baseline urine specific gravity, ionized calcium, BUN, creatinine, and phosphorous concentrations. Subsequent daily blood work rechecks of ionized calcium, BUN, creatinine, and phosphorous concentrations for 72–96 hr after exposure is reasonable, after which biological changes are considered unlikely. Those who develop biochemical abnormalities consistent with toxicosis should then pursue further care.^9,10,12

For symptomatic patients, treatment is aimed at correcting hypercalcemia and managing associated signs.^9–12,14,16 Previously recommended gold standard treatment includes aggressive IV fluid diuresis and medications to induce calciuresis. In hypercalcemic patients, 0.9% sodium chloride is used to restore and maintain euvolemia and to promote calciuresis as a calcium-free isotonic crystalloid.^9–12,14,16 Loop diuretics and glucocorticoids are used to further promote calciuresis. Sodium ions within the renal filtrate will result in reduced tubular calcium reabsorption.^9–12,14,16 Loop diuretics further enhance calciuresis by decreasing sodium and chloride reabsorption across the loop of Henle.^9–12,14,16 Glucocorticoids lessen bone resorption through suppression of osteoclastic activity.^9–12,14,16 They also reduce gastrointestinal calcium absorption and further promote urinary excretion of calcium.^9–12,14,16 Depending on the level of hyperphosphatemia, a phosphate binder may be beneficial.^9–12,14,16 Pamidronate, a bisphosphonate, has also been used to successfully to treat hypercalcemia by inhibiting bone resorption.^{4,9–12,14,16–18} Bisphosphonates inhibit osteoclastic action and suppress calcium release from bone. Their utility in treating hypercalcemia due to cholecalciferol toxicosis has been previously demonstrated.^4,5,17,18

Recently, IV lipid emulsion therapy was used as an adjunctive treatment in a case of cholecalciferol toxicosis.⁶ Because cholecalciferol is lipophilic in nature, the use of intralipid emulsion would be of theoretical benefit in decreasing circulating cholecalciferol load in cases of acute overdose. However, in cases in which hypercalcemia or azotemia have developed, intralipid therapy would no longer infer a therapeutic benefit. Overall, intralipid therapy could be instituted in patients with acute exposure to vitamin D analogs but likely offers little to no treatment benefit after the onset of hypercalcemia.^6,19 A previously published case described the use of lipid emulsion therapy 12 hr after ingestion of cholecalciferol in a patient who remained normocalcemic throughout treatment. Pre- and posttreatment samples were analyzed for cholecalciferol and showed an immediate plasma concentration reduction following intralipid therapy.⁶ In the current case report, we did not employ intralipid therapy given the delay between ingestion and treatment, presumed complete metabolism of cholecalciferol by the time of evaluation, and the established presence of hypercalcemia. Similarly, cholecalciferol concentration testing was not pursued; however, both intralipid therapy and concentration testing could be advocated for in future cases of acute exposure.

We often recognize logistical and financial limitations in veterinary medicine that force adaptation and flexibility in the development of individual treatment plans. This case describes an outpatient protocol to treat life-threatening hypercalcemia secondary to cholecalciferol toxicosis in a puppy. This patient had established clinical signs during the time period between exposure and presentation that precluded other means for gastrointestinal decontamination and treatment. In the described treatment course, normocalcemia was achieved within 7 days of presentation. This patient demonstrated marked improvement in her ionized calcium over just 72 hr and showed no indication of acute kidney injury or soft tissue mineralization. At the conclusion of treatment, her BUN had mildly increased in comparison with baseline. When evaluated with her clinical wellness and re-established normocalcemia, this rise could reasonably be the result of being fed a commercial puppy diet high in protein and concurrent use of diuretics with mild dehydration. This puppy’s rapid improvement and apparent recovery are largely attributed to multiagent treatments, including bisphosphonate inhibitor, subcutaneous fluid support, and medications aimed at calciuresis. However, we can consider the absence of age-related degenerative renal disease and the general resilience of juvenile animals as unmeasurable factors in this excellent outcome. We are uncertain if this protocol would be successful in patients of other ages or with underlying renal dysfunction. Similarly, the presence of kidney failure secondary to mineralization of hypercalcemia would undoubtedly lend to a more guarded prognosis; therefore, this treatment protocol and outcome should not be extrapolated to animals who present with azotemia.

For this case, there remain a number of unanswered questions and limitations. The most obvious limitation includes the inability to approximate a dose of exposure, recognizing that the value in describing a successful outpatient care approach is reduced in the scenario that a sublethal cholecalciferol dose was ingested. Other limitations in this case include multiple days’ time period during which toxin ingestion, onset of signs, and presentation for care occurs. As is the case for all acute toxic ingestions, knowledge of accurate timeline, subclinical phase, and onset of illness in temporal relation to the exposure are of significant value in assessing toxin-induced risk, therapeutic options, and prognosis. Additional limitations include the absence of measured serum cholecalciferol or other metabolites, which may have been useful to guide treatment duration and have allowed a more rapid taper of treatments. The potential utility of intralipid therapy in this case is thought to be poor given the delay between exposure and pursuit of emergency care but should be considered for other cases with more recent ingestions. Finally, repeat blood work after discontinued treatments would have been ideal to confirm that the patient’s BUN, creatinine, and calcium concentrations remained normal. This patient was lost to follow-up after 21-day recheck but was clinically doing well and without concerns at that time.

This case report suggests that outpatient therapy for hypercalcemia due to cholecalciferol toxicosis may be considered, although it should not be a surrogate for in-hospital care when permitted. The role that this patient’s young age played in her recovery is unknown. The successful outcome of this patient should not be extrapolated to those patients with azotemia at diagnosis or who subsequently develop renal failure while undergoing treatment. Further investigation into optimal treatment protocols remains a priority for the future, because we can expect to see rising patient exposures to cholecalciferol rodenticide.

Conclusion

Cholecalciferol-based rodenticides can cause clinically relevant and potentially life-threatening hypercalcemia when ingested. This case details the clinical course and treatment of severe hypercalcemia in a young boxer dog with cholecalciferol toxicosis. Because of significant financial constraints, this patient could not be hospitalized for standard of care. As an alternative, the patient was treated on an outpatient basis over a 3 wk period during which the hypercalcemia completely resolved. Additionally, a review of vitamin D metabolism is provided.