CA se R ep OR t Rat bait is not always an anticoagulant!

Cholecalciferol rat bait poisoning in a dog.

NeI l s tuttle, BVsc

Introduction t his report describes diagnosis and treatment of a dog that ingested an unknown amount of rat bait containing cholecalciferol.

In New Zealand pest control baits containing cholecalciferol (vitamin D3) are commonly used for control of possums. However it is also available for use as a rodenticide as Selontra soft gel blocks. Cholecalciferol is as a pest bait used due to its properties of breaking down in contact with soil, light and heat, insolubility in water, low toxicity in birds and a low risk of secondary poisoning. once ingested cholecalciferol is absorbed completely and rapidly from the jejunum. It is metabolised by the liver and kidney and excreted mainly in the faeces. Cholecalciferol acts as a positive regulator of calcium homeostasis. Excessive amounts of cholecalciferol lead to hypercalcaemia by increasing calcium and phosphorus absorption from the intestinal tract, mobilising of calcium and phosphorus from bone and decreasing renal excretion of calcium. It generally takes 12–24 hours for hypercalcaemia and hyperphosphatemia to develop (Parton et al. 2018) with hyperphosphatemia preceding the hypercalcemia by up to 12 hours. t he effects of hypercalcaemia are caused by calcium being deposited (metastatic calcification) in the heart, blood vessels, kidneys, liver and lungs. t he most common clinical signs associated with hypercalcaemia are polydipsia, polyuria and anorexia. Weakness vomiting and constipation can also occur (Chew 2001).

Contact: neil.stuttle@vshb.co.nz

Case history

“Herbie” a 2-year-old, male, Jack Russell/ Shih tzu cross was presented to the clinic with anorexia and vomiting. t he owners reported that Herbie had ingested some rat poison blocks 2 days earlier, but were unsure the total amount Herbie had eaten. t he rat bait Herbie had ingested was Selontra Soft Bait (BASF New Zealand Ltd., Auckland, NZ) blocks containing 0.75 g/kg cholecalciferol.

Further questioning revealed Herbie was also drinking and urinating significantly more than normal.

Clinical examination

on clinical examination Herbie was quiet and responsive. t he oral mucous membranes were pink with a capillary refill time of < 2 seconds. mild drooling was present. Skin turgor was within normal limits. on chest auscultation lungs sounds were clear and the heart rate was 120 beats per minute, with a regular rhythm and no murmur. t he abdomen was soft and comfortable on palpation. Herbie’s rectal temperature was 38.6°C and he weighed 8.7 kg.

Diagnostic findings

A jugular blood sample was taken and a comprehensive diagnostic serum biochemistry profile (see table 1) was run on a Vetscan VS2 Chemistry Analyser (Zoetis New Zealand, Auckland, NZ) to determine the severity of metabolic effects. It was decided not to obtain a complete blood count or urinalysis as easurements in red and blue text are greater or less than the reference range respectively the results were unlikely to change the treatment approach.

Based on the clinical exam and serum biochemistry data Herbie’s problem list was as follows: l Anorexia l Vomiting/nausea l Polyuria/polydipsia l Hypercalcaemia l Hyperphosphataemia l Increased BuN l Hypokalaemia t he biochemical changes were all supportive of a diagnosis of vitamin D toxicity. If a urine sample had been obtained this would be expected to show hyposthenuria, proteinuria and glucosuria ( t illey et al. 2004). treatment and outcome to correct dehydration, Herbie was started on IV fluids (compound sodium lactate; Baxter Healthcare Ltd, Auckland, NZ) with 20 mmol/L potassium chloride to manage the existing hypokalaemia. IV fluids were administered at a rate of 100 mL/kg/day (Chew 2001). maropitant (Cerenia; Zoetis) was administered slow IV at 1 mg/kg once daily to treat nausea/ vomiting. Herbie was also started on furosemide (Baxter Healthcare Ltd.) 2.5 mg/kg IV once daily to decrease serum calcium concentration through diuresis. o ver the following 48 hours Herbie was stable but remained quiet, anorexic, polydipsic and polyuric. A repeat blood sample was taken to assess serum analytes ( table 1, 2 days). Concentrations of total calcium and creatinine in serum had increased while the concentration of urea level decreased but was still elevated above the normal range. Concentrations of phosphate and potassium in serum were now in the normal range.

In order to further reduce serum calcium concentrations, it was decided to start Herbie on dexamethasone (Dexa 0.2 injection; PHENIX NZ) IV 0.15 mg/kg twice daily along with an infusion of 1.3 mg/kg pamidronate disodium (Pamisol; Pfizer NZ Ltd., Auckland, NZ) in 150 mL 0.9% saline given as an IV infusion over 2 hours. Following the infusion Herbie was maintained on IV fluids (0.9% saline) at 100mL/kg/day. o ver the next 24 hours Herbie continued to eat well and was much brighter. t he IV fluids were discontinued and Herbie was discharged home on oral furosemide, prednisone and oral potassium at the doses described above.

A day later Herbie was eating and appeared brighter. A repeat blood sample was taken for serum biochemistry analysis ( table 1, 4 days) which revealed a reduction in serum calcium concentration, though Herbie was still hypercalcaemic. t he concentration of creatinine was now within normal limits but the BuN was mildly increased. Hypokalaemia was present along with hypophosphataemia.

Herbie was switched onto 2.5 mg/kg furosemide and 1.5 mg/kg prednisone both given orally twice daily. oral potassium supplementation (1000 mg) was also started (Kaminox, Vetplus), given twice daily. Herbie’s diet was changed to a kibble with a low calcium concentration (Hill’s K/D; 0.57% calcium Dm).

Herbie was seen again 1 week later. t he owners reported he was bright and eating well. He was still drinking and urinating substantially more than usual. t he clinical exam was unremarkable.

Herbie had lost 100 g in body weight. A blood sample was taken for serum biochemistry ( table 1, 11 days). t he total calcium concentration was still marginally elevated. t he serum concentration of phosphate, urea and potassium were now within the normal reference ranges.

Herbie was weaned off the prednisone, kaminox and furosemide over the following 2 weeks and continued on Hill’s K/D diet. Herbie was seen 1 month later. t he owners reported his rate of drinking and urinating had returned to normal. He was bright, alert and responsive. Herbie had gained 1 kg in weight. A blood sample was taken to assess serum biochemistry ( table 1, 41 days). t he total calcium concentration was now within the reference range. Herbie was re-introduced onto a standard commercial diet. No further follow-up examinations were scheduled.

Discussion

t his report describes diagnosis and treatment of a dog that ingested an unknown amount of a rat bait containing cholecalciferol. toxicity of cholecalciferol has been reported with a dose as low as 3 mg/kg but is more likely with doses >10 mg/kg (Parton et al. 2018). It was uncertain the exact amount Herbie had ingested but given his clinical signs it was presumed to be at least 10 mg/kg. In Herbie’s case his owners were aware of the ingestion of cholecalciferol and so the reason for the subsequent hypercalcaemia was apparent. t his however is not always the case and the cause of hypercalcaemia is often not initially known. Hypercalcaemia can be transient and inconsequential (common), persistent and inconsequential or persistent and pathological (Chew 2001). Inconsequential hypercalcaemia can be caused by haemoconcentration, post-feeding, lipaemia and EDtA/citrate contamination. Puppies and kittens

< 12 weeks old have significantly higher normal concentrations of calcium in serum than adult dogs/cats (mackay 2022). t he most common pathological causes of hypercalcaemia in dogs are neoplasia (e.g. lymphoma, anal gland adenocarcinoma) and vitamin D toxicity. In cats the most common causes are renal failure and idiopathic (mackay 2022).

Calcium exists in three fractions in plasma: 35% is in the ionised (biologically active) form, 10% is chelated and 55% bound to albumin (mackay 2022). most in -house biochemistry analysers measure the concentration of total serum calcium. In clinically normal animals serum ionised calcium is typically proportional to the level of serum total calcium. Ideally serum concentration of ionized calcium is measured when there is a disease state resulting in hypercalcemia. t he concentration of ionised calcium is reduced in patients with renal failure and hypoalbuminaemia, and increased in patients with moderate to severe metabolic acidosis (Chew 2001). Serum samples for measurement of ionised calcium need to be stored anaerobically before analysis as concentrations are affected by exposure to oxygen and changes in pH. If pH decreases calcium is displaced from binding sites and the ionised serum levels increase. If pH increases more calcium is bound and the ionised serum levels decrease. If stored anaerobically at 4°C samples are stable for up to 72 hours (Chew 2001). In this case ionised calcium concentration was not measured due to logistics of storage and transport to an external laboratory. treatment of hypercalcaemia is best targeted towards the underlying cause, e.g. removal of parathyroid adenoma or chemotherapy for lymphoma. In Herbie’s case, the cause was vitamin D toxicosis so the management was supportive and aimed to reduce the degree of hypercalcaemia until the concentration of absorbed cholecalciferol reduced to below clinically significant levels. o nce the patient is hydrated, 2–4 mg/ kg IV furosemide, given SC or orally every 12 to 8 hours is used to decrease serum calcium concentration through diuresis.

If Herbie was presented within 4–6 hours of ingestion then emesis would have been induced and activated charcoal administered orally every 8 hours for 48 hours (Romine 2022). t his is due to vitamin D being fat soluble and the likelihood of enterohepatic recirculation. Herbie was presented 48 after ingestion so decontamination in this case was not possible. In Herbie’s case supportive therapy was undertaken to reduce serum concentration of calcium to less toxic levels.

Parental fluids were administered to correct dehydration. Haemoconcentration contributes to increased serum ionised calcium concentration. t he ideal parental fluid type is 0.9% saline at 100–125 mL/kg/day (Chew 2001). In Herbie’s case lactated Ringers solution (LRS) was initially chosen due to concurrent hypokalaemia. After 48 hours the fluids were changed to 0.9% saline based on increasing calcium concentration and normal potassium concentration in serum. on reflection, 0.9% saline could have been used initially with increased potassium supplementation to reduce calcium concentrations. one litre of LRS contains 2.7 mEq of calcium which would be adding to the already high concentration of calcium in the blood.

After 48 hours, despite this treatment, the concentration of calcium in Herbie’s serum had increased (from 3.83 to >4.00 mmol/L) so he was started on glucocorticoids and pamidronate. Corticosteroids exert their effect by reducing bone resorption, decreasing intestinal calcium absorption and increasing renal calcium excretion (Chew 2001). However they should be withheld if a definite diagnosis has not been established. t he administration of glucocorticoids in this case resulted in the steroid-induced elevation of the ALP isoenzyme and AS t in the day 5 and 11 blood results. Initial serum biochemistry results showed no evidence of liver disease and after treatment activities returned to within normal limits by day 42. Pamidronate is a diphosphonate that works by inhibiting osteoclastic bone resorption (mackay 2022). Pamidronate was sourced from a local pharmacy by external prescription and is relatively inexpensive (~ $40). Biphosphates are the standard of care in human oncology for treating hypercalcaemia of malignancy and prevention of pathological fractures associated with metastatic bone disease.

Herbie’s serum calcium concentration began to drop 24 hours after treatment with pamidronate and dexamethasone. Herbie also clinically improved in his demeanour and appetite. once he began eating, Herbie’s calcium concentrations were further managed with a restricted calcium diet. Low calcium diets are only helpful in substantially lowering serum calcium concentrations where hypercalcaemia is caused by the action of excess vitamin D metabolites (Chew 2001). Hill’s Canine K/D was chosen as it contains 0.57% calcium on a dry matter (Dm) basis. Standard dog food generally contains 1.0–1.7% calcium Dm o ther possible treatment options in this case included calcitonin treatment to treat hypercalcaemia and haemodialysis and lipid infusion therapy to help clear the toxin. Calcitonin acts to reduce osteoclast activity and inhibits the formation of new osteoclasts. Calcitonin can be used as an alternative to bisphosphonate (e.g. pamidronate) treatment or following bisphosphonate treatment if there has not been a sufficient response ( t illey et al. 2004). t he dose of calcitonin is 4u/kg SC once or twice daily (Nelson et al. 1998). many patients have a limited response and may become refractory to treatment so it needs to be combined with other treatments as discussed above ( t illey et al. 2004). Give the good response to the pamidronate infusion in this case, calcitonin treatment was not considered. t his case also highlights the need for client education in early presentation following a toxin ingestion. Presentation to the clinic immediately after ingestion in this case for induction of emesis and activated charcoal would have likely to have been sufficient in preventing the toxic dose being absorbed. on reflection on the management of this case, fluid therapy with 0.9% saline supplemented with potassium would have been started instead of LRS to minimise administration of exogenous calcium. In hindsight corticosteroid treatment could have been started earlier in the clinical management of the case, and indeed was considered at the time of initial treatment. It was decided to hold off administering this treatment until the response to IV fluids and furosemide could be assessed. If in this case, a large toxic dose of cholecalciferol was known to be ingested, then treatment corticosteroids and pamidronate would have been started earlier.

Haemodialysis is the process of exchanging water, solutes and toxins across a semi permeable membrane. toxins that are not tightly protein bound and are small enough to fit through the artificial membrane pores can effectively and quickly be removed. However, as it is generally a specialist procedure, haemodialysis is unavailable to most patients.

Intravenous lipid emulsion (ILE) therapy is another potential treatment of cases of vitamin D toxicosis given the lipophilic nature of cholecalciferol. Lipid emulsions are sterile mini-emulsions of oil and water. t he oil component consists of neutral long chain triglycerides or a mixture of medium and long chain triglycerides. ILE was first used in the early 2000s to treat local anaesthetic toxicities in humans. t here are growing case reports that ILE is useful in treating veterinary patients with lipid soluble toxins (Epstein et al. 2013). t he mechanism of action is still being investigated and is currently thought to be due to a “shuttle” effect. t his is where the liposomes scavenge toxins from lipid-rich tissues and carry them to other organs where metabolism and elimination can occur. Case reports have shown benefits in cats with permethrin toxicity (Di Pietro et al. 2022) and in dogs with avermectin/milbemycin toxicities (Epstein et al. 2013). t here are no reports to the author’s knowledge treating cholecalciferol toxicity with ILE.

Herbie made a complete clinical recovery and continues to do well at the time of writing.

References

Chew D. Hypercalcaemia in dogs: approach to diagnosis and treatment. https://www. vin.com/doc/?id=3843801 (accessed 7 may 2023). Proceedings World Small Animal Veterinary Association Congress, 2001

Di Pietro S, Falcone A, Arfuso F, Pennisi M, Piccione G, Giudice E. treatment of permethrin toxicosis in cats by intravenous lipid emulsion. Toxics 10, 165, 2022

Epstein SE, Hollingsworth SR. Ivermectin induced blindness treated with intravenous lipid therapy in a dog, Journal of Veterinary Emergency and Critical Care 23, 58–62, 2013 Mackay Bruce. Calcium disorders - highs and lows in small animal patients. Online Veterinary Conference 2022, Vet e ducation, James Cook university, Ql D, 2022

Nelson RW, Couto CG. (e ds) Small Animal Internal Medicine, 2nd e dtn, pp 826–9, mosby Inc., st l ouis. mO, usA, 1998

Parton K, Bruere AN, Chambers JP. (e ds) Veterinary Clinical Toxicology, 3rd e dtn. pp 131–4, massey university press, palmerston North, NZ. 2018

Romine J. Calcium and vitamin D disorders. Proceedings New Zealand Veterinary Association Conference, Companion Animal Branch, pp 15–6, 2022

Tilley LP, Smith FWK. (e ds) The 5-Minute Veterinary Consult, Canine and Feline, 3rd e dtn. pp 1356 –7. lippincott Williams & Wilkins, philadelphia, pA, usA, 2004 l