increases osteoclastic resorption, and in- creases renal reabsorption of Ca
2. All lead to persistent hypercalcemia and hy- perphosphatemia, which leads to calcifi cation of tissues
D. Clinical signs
1. Develop within 3 to 5 days post-ingestion of cholecalciferol (may see as early as 6 hours post-ingestion of calcipotriene). Time delay also depends on degree of metabolic activation and overcoming homeostatic mechanisms 2. Initially will see GI and neurologic signs (hyper-
calcemia → depressed muscular excitability); progressively gets more severe. As the disease progresses, will see cardiac (PVCs, hyperten- sion, conduction disturbances, dyspnea, lung sounds, weakness) and renal involvement or signs (PU, polydipsia [PD], depression, an- orexia, vomiting) compatible with mineraliza- tion of multiple tissues
3. GI and neurologic signs: Anorexia, depression, lethargy, vomiting, generalized muscle weak- ness or twitching, constipation or diarrhea (with or without blood), seizures (rare), PU or PD (calciuria)
4. Cardiac signs: Ventricular fi brillation, PR inter- val prolongation, shortening of QT interval, hy- pertension, PVCs
5. Renal signs: PU or PD, acute or progressive re- nal failure. May see medullary washout or nephrogenic diabetes insipidus
6. As disease progresses, calcifi cation occurs and death is usually a result of multiple organ failure (mostly renal, GI, cardiac, respiratory, vascular)
E. Clinical pathology
1. Persistent total hypercalcemia (i.e., more than 12 mg/dL) $ calciuria (earliest change). Ion- ized Ca concentration is also elevated. 2. Persistent hyperphosphatemia: Early and reli-
able sign in affected horses
3. Other fi ndings: Azotemia (prerenal or renal), hyposthenuria, proteinuria, glucosuria F. Lesions
1. Gross: Mineralization (raised white or red plaques): Buccal cavity, thorax, lungs, heart, stomach, kidney, aorta, almost any tissue may be involved. Diffuse hemorrhages, ulcerations in GI mucosa
2. Microscopic: Degeneration of renal tubular epi- thelium or mild glomerular degeneration with mineralization; calcifi cation or necrosis of cor- onary arteries, atria, gastric mucosa, intestinal wall, parietal pleura, pancreas, bladder, etc.; hypertrophy and hyperplasia of parafollicular cells (C cells)
G. Diagnosis
1. History of potential exposure
2. Compatible clinical signs get worse; multisys- temic; or postmortem lesions
3. Persistent hypercalcemia and hyperphosphatemia
4. Rule out other major differentials: Serum lev- els, screen. Parathyroid hormone (PTH) should be low; 25-(OH)D (will not be elevated with overdose of calcitriol or synthetic forms), se- rum ionized Ca, parathormone related protein (positive in some malignancies). The 25-(OH)D assay measures both chole- and ergo-calcifer- ols but does not measure calcipotriene, or other analogues of calcitriol
5. Bile, renal cortex: 25-hydroxycholecalciferol H. Treatment
1. Aim is to normalize serum Ca and P, prevent dehydration and renal insuffi ciencies, control cardiac arrhythmias, and correct electrolyte imbalances. Length of treatment is dependent on response, and that form of vitamin D is in- gested. Hypercalcemia from overdose of cal- citriol therapy will resolve fairly quickly after discontinuation of calcitriol because of the short half-life of the compound. Overdoses with cholecalciferol or ergocalciferol may need to be treated for a month or longer due to the long half-life (T1/2: 29 days)
2. Decontamination: Emesis, repeated doses of AC, cathartic, gastric lavage, depending on time of exposure
3. Calcitonin or pamidronate disodium 4. Fluid therapy (0.9% saline) at least 2 to 3*
maintenance. Monitor renal output 5. Furosemide
6. Prednisone or prednisolone: Primary effect on bone (K, GI tract). Usually for 2-4 weeks 7. Low calcium, phosphorus diet (chicken and
rice, Hill’s Prescription k/d or s/d) 8. Phosphate binders: Aluminum hydroxide 9. Periodic monitoring: Ca, phosphorus, K, BUN,
Cr, ECG
III. Ethylene glycol (EG) and propylene glycol A. Source
1. Antifreeze (94.6%), heat-exchange fl uid in solar collectors and ice rink freezing equipment, brake and transmission fl uid, color fi lm pro- cessing fl uid, electrolytic condensers, skin lo- tions, taxidermist’s preservation solutions, paint, some snow globes
2. Colorless, odorless, water-soluble, sweet tast- ing; some have bittering agents added (denato- nium benzoate, bitrex)
B. Toxicity
1. Typical solutions from the radiator: 50:50; 1 tbsp lethal to a 10-pound cat
2. Occurs all year round. Dogs and cats most commonly affected
3. Mortality can be very high because of diffi culty in diagnosing and a narrow timeframe in which to work
C. Pharmacodynamics
1. Absorption: Rapid from GI tract. Peak blood lev- els: 1 to 4 hours in dog. Half-life: 2 to 10 hours. By 16-24 hours, almost all ethylene glycol is me- tabolized or excreted (#50% excreted un- changed in urine)
2. Metabolism occurs in liver: Series of oxidation reactions; important to know where you are in the cycle. Diagnostic criteria will vary depend- ing on stage of disease animal is in; helpful to diagnose accurately
D. Mechanism of action
1. Ethylene glycol, glycoaldehyde, glycolic acid cause CNS depression; may lead to coma and death if dose is high enough
2. Metabolites, particularly glycolic acid, induce severe metabolic acidosis
3. Metabolites are cytotoxic to renal tubular cells 4. Renal edema compromises renal blood fl ow
and further promotes renal failure
5. Metabolites interfere with TCA cycle and oxi- dative phosphorylation
6. Calcium oxalate crystal precipitation in renal tubules lead to mechanical disruption E. Clinical signs
1. Varies: Time and dose dependent; many over- lapping signs
2. Stage 1: Mimics acute ethanol, methanol, other glycol intoxications: 2 to 4 hours post-ingestion. See CNS depression. Signs include nausea, vom- iting, depression, ataxia, peripheral neuropathy, PD (rise in serum osmolality stimulates thirst), PU, seizure, stupor, coma, death (if large amount consumed). Less common signs include muscle fasciculations, head tremors, nystag- mus. Animals may appear to recover near end of stage 1 due to metabolism of ethylene glycol and glycoaldehyde
3. Stage 2: Metabolic acidosis; 2 to 24 hours post- ingestion. Clinical signs worsen; tachypnea, tachycardia, bradycardia occur
4. Stage 3: Oliguric renal failure 24 to 72 hours (dog), 12 to 24 hours (cat) after ingestion. Signs include depression, vomiting, diarrhea, oliguria or anuria, seizures. Retinal lesions in- clude retinal detachment and edema, anterior uveitis
F. Clinical pathology
1. Abnormalities observed are time dependent. Not specifi c but consistent for just ethylene glycol. Look for the preponderance of evidence 2. Hyperosmolality: Early in disease process (4 to 12 hours post-ingestion). Elevated osmolal gap (difference between measured and calculated). Other fi ndings include elevated anion gap, and metabolic acidosis
3. Hypocalcemia may appear within 4 to 6 hours. Not always present. Patients can be hypocalce- mic, normocalcemia, and hypercalcemic. Aci- dosis will impact the ionized calcium fraction, causing an increase in ionized calcium
4. Calcium monohydrate oxalate crystalluria: 6 hours (dog), 3 hours (cat) post-ingestion. Sometimes dihydrates are observed. Not al- ways present! (in kidney, but may not see in urine)
5. Renal failure changes: Hyperphosphatemia (may be elevated earlier owing to phosphate
rust preventatives added), azotemia, hypergly- cemia, hyperkalemia. Proteinuria, glucosuria, isosthenuria, casts observed 12 to 72 hours af- ter ingestion
6. Neutrophilic leukocytosis and lymphopenia: Corticosteroid release secondary to vomiting, CNS depresssion, and metabolic acidosis 7. Hyperglycemia: Inhibition of glucose
metabolism and release of epinephrine and corticosteroids
G. Gross lesions: Dehydration, hyperemia of GI tract; swollen or shrunken kidneys (depending on stage of disease), pulmonary edema, ulcers
H. Microscopic lesions: Calcium oxalate crystals (bi- refringent) within renal tubules; degeneration or necrosis of tubular epithelium (glomerular changes and signifi cant infl ammatory changes ab- sent); necrotizing vasculitis, several organs I. Diagnosis
1. Diffi cult: Early diagnosis is imperative for a fa- vorable prognosis. Clinicians must have a high index of suspicion
2. History of potential exposure
3. Appropriate clinical signs and clinical pathol- ogy (multiple diagnostics): Interpret in light of stage of disease
4. Chemical analysis
a. Blood-urine-serum-plasma for ethylene gly- col; high-performance liquid chromatography (HPLC)
b. In-house ethylene glycol kits; positive test confi rms possible exposure only! Be aware of false-positives and false-negatives
c. Serum or urine: Glycolic acid (up to 60 hours post-ingestion) or ethylene glycol
5. Renal ultrasound: Halo sign
6. Postmortem or biopsy examination: Renal changes (impression smears, squashed preps); histopathology is diagnostic
7. Fluorescein is usually added to detect radiator leaks; may see in urine, skin, or stomach con- tents using Wood’s light
J. Treatment
1. All treatments require periodic monitoring and adjustments
2. Decontaminate: Emesis (almost always occur- ring in clinically affected patient), gastric la- vage with AC (will bind some)
3. IV isotonic fl uid therapy for maintenance and diuresis
4. Ethanol: Competitive inhibitor of alcohol dehy- drogenase; OR 4-methylpyrazole (fomepizole- Antizol-Vet); alcohol dehydrogenase inhibitor 5. Sodium bicarbonate: Correct metabolic acido-
sis if necessary
6. Calcium borogluconate: If hypocalcemic 7. Bland, low-protein, high-carbohydrate diet,
oral phosphate binders
8. Peritoneal dialysis, hemodialysis 9. Kidney transplant
K. Note: Propylene glycol is safer (less toxic) and is generally regarded as safe (GRAS). Estimated