5 Steps in the Workup of Dogs with Hypercalcemia

Hypercalcemia in the dog can result from many different causes, as I discussed in my last post on "Top 10 Differentials for Hypercalcemia in the Dog." These include malignancy (lymphosarcoma and apocrine gland carcinoma of the anal sac), hypoadrenocorticism, primary hyperparathyroidism, renal failure, vitamin D toxicosis, and spurious results due to laboratory error or hyperlipidemia (1-3).

In some dogs with hypercalcemia, the primary diagnosis will soon become obvious after analysis of history and findings from physical examination. In other dogs, the underlying cause of the hypercalcemia will still not be known.

Diagnosing the cause of hypercalcemia in dogs can be difficult. Therefore, I recommend a stepwise approach to diagnosis to help elucidate the underlying cause of each patient's hypercalcemia.

Important Initial Steps in Workup of All Hypercalemic Dogs

1. Verify that hypercalcemia exists
The first step in workup is to verify that true hypercalcemia is really present by repeating the total calcium concentration and by directly measuring an ionized calcium (iCa) concentration (4).  Both of these samples should be collected after an overnight fast. Measurement of serum iCa is important to determine whether increase in calcium is clinically significant since the total calcium can sometimes be mildly increased but the ionized calcium remains normal (e.g., renal disease).

2. Complete history and physical exam
Diagnosing the source of ionized hypercalcemia begins with a complete history to rule out vitamin D toxicosis caused by over-supplementation, rodenticide, certain plants, or antipsoriasis creams (1-3).  A complete physical examination may reveal the presence or absence of enlarged lymph nodes, hepatospenomegaly, rectal (anal sac) masses, or skeletal pain. Don't forget to do a thorough rectal examination since some of the anal sac tumors can not be easily visualized.

3. Routine laboratory data and imaging
Even though hypercalcemia associated with Addison's disease is third on my "Top 10 list," such hypercalcemia only develops in dogs with severe hyperkalemia, hyponatremia, and hypocortisolemia (5). Atypical hypoadrenocorticism does not generally lead to ionized hypercalcemia. If Addison's is suspected, basal serum cortisol or the cortisol response to ACTH stimulation should be monitored. The hypercalcemia resolves spontaneously with cortisosteroid therapy for the dog's Addison's disease and does not require specific treatment (5).

In most dogs, most of the differentials on this list can be quickly excluded (based on history, physical exam, and routine laboratory and imaging findings), leaving only primary hyperparathyroidism and occult lymphosarcoma (and other malignancies) to worry about.

4. Measure serum PTH and PTH-rp
Once we reach this point, the next step is to determine whether the hypercalcemia is parathyroid-dependent (parathyroid thyroid hormone (PTH)-secreting tumor causing hypercalcemia) or parathyroid-independent (normal parathyroid glands with appropriately suppressed PTH secretion in response to hypercalcemia).  This is easily done by measuring a serum PTH concentration. Dogs with primary hyperparathyroidism will have mid-normal to high concentrations of PTH, whereas dogs with most other forms of hypercalcemia have low to undetectable PTH concentrations (1-3).

Because hypercalcemia associated with nonparathyroid neoplasia is often caused by the secretion of parathyroid hormone-related protein (PTHrP), determination of serum PTH-rp can be helpful if malignancy is suspected (1,3,6). However, PTHrP concentrations are not always increased in malignancy, so hypercalcemia of malignancy always remains a differential diagnosis in a hypercalcemic dog found to have low serum concentrations of both PTH and PTHrP (1,3).

5. Perform cervical ultrasound
If serum PTH is mid-normal to high, cervical ultrasonography can be used to detect a parathyroid tumor (3,7). For definitive diagnosis primary hyperparathyroidism, histopathological examination of the excised parathyroid tumor is ideal.

Bottom Line

In some dogs with hypercalcemia, the primary diagnosis will soon become obvious after analysis of the patient's history and results of the physical examination. In other dogs, the cause will not be obvious. In these animals, one must look at the information from hematology, serum biochemistry, body cavity imaging, cytology, and histopathology, if necessary. Parathyroid ultrasound, as well as assays for measurement of PTH, and PTH-related protein, may necessary to confirm a diagnosis.

References:

1. Schenck PA, Chew DJ, Nagode LA, et al.  Disorders of calcium: hypercalcemia and hypocalcemia. In: Fluid, Electrolyte, and Acid-Base Disorders in Small Animal Practice, ed. DiBartola SP, 3rd ed., pp. 122–194. Saunders Elsevier, St. Louis, MO, 2006.
2. Schenck PA, Chew DJ. Hypercalcemia: a quick reference. Veterinary Clinics of North America Small Animal Practice 2008;38:449–453.
3. Schenck PA, Chew DJ. Investigation of hypercalcaemia and hypocalcaemia In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;221-233.
4. Schenck PA, Chew DJ. Prediction of serum ionized calcium concentration by use of serum total calcium concentration in dogs. American Journal of Veterinary Research 2005; 66:1330–1336.
5. Peterson ME, Fineman JM. Hypercalcemia associated with hypoadrenocorticism in sixteen dogs. Journal of the American Veterinary Medical Association 1982; 181:802-804.
6. Strewler GJ. The physiology of parathyroid hormone-related protein. New England Journal of Medicine 2000;342:177–185.
7. Wisner ER, Nyland TG. Ultrasonography of the thyroid and parathyroid glands. Veterinary Clinics of North America Small Animal Practice 1998;28:973–991.

Top 10 Differentials for Hypercalcemia in the Dog

Hypercalcemia in the dog can have many etiologies, including malignancy (e.g., humoral hypercalcemia of malignancy, primary hyperparathyroidism, multiple myeloma, and neoplasia in bone), increased vitamin D activity (e.g., rodenticides containing cholecalciferol, anti-psoriasis creams containing calcipotriene or calcipotriol, plants containing calcitriol glycosides, excess dietary supplementation), granulomatous inflammation, adrenal insufficiency, or renal disease (1-10).

Two Helpful Mnemonics to Remember the Differential Diagnosis of Hypercalcemia

HARD IONS

• H—Hyperparathyroidism, Humoral hypercalcemia of malignancy, Houseplants
• A—Addison’s disease; Aluminum or vitamin A toxicity
• R—Renal disease, Raisins (Grapes)
• D—Vitamin D toxicosis
• I—Idiopathic (particularly in cats; very rare in dogs)
• O—Osteolytic
• N—Neoplasia (humoral hypercalcemia of malignancy)
• S—Spurious

GOSH DARN IT

• G—Granulomatous disease, Grapes
• O—Osteolytic
• S—Spurious
• H—Hyperparathyroidism, Humoral hypercalcemia of malignancy, House plants
• D—Vitamin D toxicity, Dehydration
• A—Addison’s, Vitamin A, or Aluminum toxicity
• R—Renal disease
• N—Neoplasia (humoral hypercalcemia of malignancy)
• I—Idiopathic
• T—Temperature (hypothermia)

My Top 10 Differential List for Canine Hypercalcemia

Even though these mnemonics can be helpful in recalling all of the various causes of hypercalcemia, I find my list below to be more helpful.

This is my top-10 list for potential rule outs for hypercalcemia in dogs, in an approximate incidence order as seen in practice, starting with the most common to least common problem:

1. Spurious (lab error, lipemic sample causing false elevation of calcium)
2. Lymphosarcoma  
3. Hypoadrenocorticism (Addison's disease)
4. Primary hyperparathyroidism (parathyroid tumor)
5. Renal failure
6. Vitamin D toxicosis
7. Apocrine gland carcinoma of the anal sac  
8. Multiple myeloma of bone (10-15% of cases have high calcium)
9. Other carcinomas (e.g., lung, mammary, nasal, pancreatic, thymic, thyroid, testicular)
10. Granulomatous diseases (e.g., blastomycosis, histoplasmosis, schistosomiasis)

Steps in Workup for the Dog with Hypercalemia

In some dogs with hypercalcemia, the primary diagnosis becomes obvious after analysis of history and findings from physical examination. In most dogs, however, the underlying cause for the hypercalcemia is not all that clear and further testing must be done.

In these dogs, a stepwise approach to diagnosis of the underlying cause of the hypercalcemia is recommended. I'll discuss my approach to diagnosis of these difficult cases in my next post.

References:

1. Schenck PA, Chew DJ, Nagode LA, et al.  Disorders of calcium: hypercalcemia and hypocalcemia. In: Fluid, Electrolyte, and Acid-Base Disorders in Small Animal Practice, ed. DiBartola SP, 3rd ed., pp. 122–194. Saunders Elsevier, St. Louis, MO, 2006.
2. Schenck PA, Chew DJ. Hypercalcemia: a quick reference. Veterinary Clinics of North America Small Animal Practice 2008;38:449–453.
3. Schenck PA, Chew DJ. Investigation of hypercalcaemia and hypocalcaemia In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;221-233.
4. Schenck PA, Chew DJ. Prediction of serum ionized calcium concentration by use of serum total calcium concentration in dogs. American Journal of Veterinary Research 2005; 66:1330–1336.
5. Peterson ME, Fineman JM. Hypercalcemia associated with hypoadrenocorticism in sixteen dogs. Journal of the American Veterinary Medical Association 1982; 181:802-804.
6. Hare WR, Dobbs CE, Slayman KA, et al. Calcipotriene poisoning in dogs. Veterinary Medicine 2000; 95:770–778.
7. Gwaltney-Brant S, Holding JK, Donaldson CW, et al. Renal failure associated with ingestion of grapes or raisins in dogs. Journal of the American Veterinary Medical Association 2001; 218:1555–1556.
8. Feldman EC, Hoar B, Pollard R, et al. Pretreatment clinical and laboratory findings in dogs with primary hyperparathyroidism: 210 cases (1987-2004). Journal of the American Veterinary Medical Association  2005;227:756.
9. Gear RN, Neiger R, Skelly BJ, et al. Primary hyperparathyroidism in 29 dogs: diagnosis, treatment, outcome and associated renal failure. Journal of Small Animal Practice 2005;46:10-16.
10. Messinger JS, Windham WR, Ward CR. Ionized hypercalcemia in dogs: a retrospective study of 109 cases (1998–2003). Journal of Veterinary Internal Medicine 2009;23: 514–519.
    

Diagnosing Subclinical Hyperthyroidism in Cats

Evaluation of Predictors for the Diagnosis of Hyperthyroidism in Cats

By J. Wakeling, J. Elliott, and H. Syme

Journal of Veterinary Internal Medicine 2011; 25: 1057-1065.

In human patients, measurement of serum thyroid stimulating hormone (TSH) concentration is commonly used as a front-line test of thyroid function (1-3). The pituitary gland constantly monitors the circulating levels of T4 and T3, and if it senses the slightest increase in serum thyroid hormone concentrations, it stops producing TSH. Therefore, the finding of a suppressed to undetectable serum TSH value in a human patient is considered diagnostic hyperthyroidism, even if serum T4 concentrations remain normal (1-3).

In cats, TSH can be measured using the widely available canine TSH (cTSH) assay (4-7). However, a major problem with the canine TSH assay, being a first generation assay, is that its detection limit (assay sensitivity) is not very good. This can make it difficult to distinguish between low-normal TSH values (found in many normal cats) from suppressed TSH concentrations (expected in hyperthyroid cats).

Despite this limitation, there are two published retrospective studies that suggest that subclinical hyperthyroidism may develop in cats. In one study, TSH concentrations were found to be undetectable in 15 of 16 cats when tested 1 to 3 years before hyperthyroidism was definitively diagnosed (8). In the second study, euthyroid cats that had low serum TSH values (<0.03 ng/ml) had a higher prevalence of adenomatous changes in the thyroid gland than a group of euthyroid cats with higher serum TSH concentrations (9).

The purpose of this study by Wakeling et al (10) was to determine whether or not euthyroid geriatric cats with undetectable TSH concentrations (<0.03 ng/ml) actually have subclinical hyperthyroidism and are at increased risk for subsequently developing overt hyperthyroidism.

Hypothesis of study 
Euthyroid cats with undetectable TSH concentrations have subclinical hyperthyroidism and may subsequently develop overt signs of hyperthyroidism.

Animals studied
104 client-owned geriatric cats (median age, 12.1 years).

Methods
In this prospective cohort study, 104 euthyroid, geriatric (>9 years) cats were recruited during routine health checks. Plasma biochemistry was performed at baseline and every 6 months thereafter. Total T4 and TSH concentrations were determined annually.

Short-term follow-up data (within 14 months of recruitment) were used to detect variables at entry that were predictive of the diagnosis of hyperthyroidism, using univariable analysis followed by multi-variable logistic regression analysis. Log rank analysis was used to test the association of initial TSH concentration with diagnosis of hyperthyroidism during the total available follow-up.

Results and Conclusions
In total, 17 of the 104 cats entered into this study were diagnosed with hyperthyroidism —11 cats diagnosed within 14 months that were included in the short-term follow-up data analysis and an additional 6 cats that were diagnosed during the subsequent period of longer follow-up. Median time for follow-up was 26 months (range, 0–54) and the annual incidence of hyperthyroidism developing during the study was 7.4%.

Cats that became hyperthyroid within 14 months had higher serum alkaline phosphatase activity (P = 0.02) and higher prevalence of goiter (P = 0.03) at baseline than the cats that remained euthyroid.

Cats with undetectable TSH at baseline (29/104; 28%) were significantly (P < 0.001) more likely to be diagnosed with hyperthyroidism. However, not all cats with undetectable TSH became hyperthyroid during the study.

My Bottom Line: 

Using cTSH Values as a Diagnostic Test for Feline Hyperthyroidism

This prospective study provides evidence that an undetectable TSH concentration (< 0.03 ng/ml) in euthyroid cats is associated with an increased risk for the subsequent diagnosis of hyperthyroidism. However, it is important to point out that not all cats with low TSH values went on to develop hyperthyroidism.

Of course, the poor detection limit of the current cTSH assay represents a major issue in cats with hyperthyroidism, where low suppressed values are expected. In one of the best studies of cTSH concentrations in cats (4), all of the hyperthyroid cats tested had cTSH concentrations at or below the limit of detection of the assay (0.03 ng/ml). However, of the 40 cats without hyperthyroidism tested in that same study, 5 cats also had undetectable levels of TSH, indistinguishable from the values in the hyperthyroid cats (4).

It is important to remember that the current canine TSH assay only detects approximately 35% of the circulating feline TSH (5,6). In other words, the current cTSH assay does not completely cross-react with feline TSH; therefore, the assay is not measuring the total amount of TSH present in the cat's serum. This poor cross-reactivity of feline TSH in the canine assay explains why the upper limit of the reference range for TSH is so much lower in cats (0.15-0.3 ng/ml) than it is in dogs (0.5-0.6 ng/ml).

All human TSH assays currently used are second- or even third-generation assays (1-3). Like the cTSH assays, the first-generation human TSH assays were also unable to distinguish low-normal from low TSH concentrations. The major advantages of the second to third generation TSH assays is their 10- to 100-fold improvement in assay sensitivity (1-3); this much lower detection limit greatly improves their ability to accurately distinguish between normal and even partially suppressed TSH results.

Obviously, a better TSH assay for feline hyperthyroidism is needed— particularly, a feline-specific TSH assay that has adequate sensitivity to reliably distinguish a normal value from a low one. However until better TSH assays for cats are available, caution is advised in over interpreting values in cats since it can be so difficult to distinguish normal values from the suppressed values expected in cats with hyperthyroidism (11,12). Perhaps the only use for TSH measurements using the cTSH assay would be to exclude hyperthyroidism, i.e., finding a mid- to high-normal value rather than a suppressed value (7).

References:

1. Dunlap DB. Thyroid Function Tests. In: Walker HK, Hall WD, Hurst JW (eds). Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Boston, 1990.
2. Ross DS. Serum thyroid-stimulating hormone measurement for assessment of thyroid function and disease. Endocrinology and Metabolic Clinics of North America 2001; 30:245–264.
3. Kasagi K, Kousaka T, Misaki T, et al. Comparison of serum thyrotrophin concentrations determined by a third generation assay in patients with various types of overt and subclinical thyrotoxicosis. Clinical Endocrinology 1999; 50:185–189.
4. Wakeling J, Moore K, Elliott J, et al. Diagnosis of hyperthyroidism in cats with mild chronic kidney disease. Journal of Small Animal Practice 2008;49:287-294.
5. Rayalam S, Eizenstat LD, Davis RR, et al. Expression and purification of feline thyrotropin (fTSH): Immunological detection and bioactivity of heterodimeric and yoked glycoproteins. Domestic Animal Endocrinology 2006; 30:185–202.
6. Ferguson DC, Caaffall Z, Hoenig M. Obesity increases free thyroxine proportionally to nonesterified fatty acid concentrations in adult neutered female cats. Journal of Endocrinology 2007;194:267-273.
7. Wakeling J. Use of thyroid stimulating hormone (TSH) in cats. Canadian Veterinary Journal 2010;51:33-34.
8. Wakeling J, Elliott J, Syme HS. Does subclinical hyperthyroidism exist in cats? Journal of Veterinary Internal Medicine 2006;20:726 (abstract).
9. Kirkby R, Scase T, Wakeling J, et al. Adenomatous hyperplasia of the thyroid gland is related to TSH concentration in cats. Journal of Veterinary Internal Medicine 2007;20:1522 (abstract).
10. Wakeling J, Elliott J, Syme H. Evaluation of predictors for the diagnosis of hyperthyroidism in cats. Journal of Veterinary Internal Medicine 2011;25:1057-1065.
11. Mooney CT, Peterson ME. Feline hyperthyroidism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;92-110.
12. Baral RM, Peterson ME. Thyroid gland disorders In: Little SE, ed. The Cat: Clinical Medicine and Management. St. Louis: Elsevier Saunders, 2012;571-592.

Why Precise Dose Calculation is Critical for Low Dose Dexamethasone Suppression Testing

I just read your latest blog post on the low dose dexamethasone suppression test (LDDST) and have a couple of questions. I think many veterinarians are aware that the active dexamethasone portion of dexamethasone sodium phosphate (Dex SP) is less than what the labeled concentration states. However, I also know that some colleagues do not take the "active" dose of dexamethasone vs the total Dex SP into account. when calculating the dose administered for LDDST testing.

So, from your experience, if a veterinarian fails to take into account the fact that 1-ml of Dex SP (4 mg/ml) is really only delivering 3 mg of active dexamethasone, will the actual test results be effected or altered to a significant degree? Would it really make a clinical difference?

And you mentioned diluting the Dex SP. How do you do the dilution? Do I have to make a fresh dexamethasone dilution for every LDDST I do or can I store the diluted dexamethasone? If so, how long would this dilution be stable?

My Response:

Let me address your second question about diluting the Dex SP first, because I believe that dilution is key to giving an accurate dose. This is true in all dogs, but is mandatory in small breed dogs.

How to dilute and store dexamethasone sodium phosphate preparation for the LDDST
I routinely dilute the dexamethasone sodium phosphate (Dex SP) used for the LDDST. This is my protocol for diluting the steroid, but actually it probably can be diluted more or less as needed based upon the size of the dog.

• Draw up 1-ml of Dex SP (4 mg/ml), containing 3 mg (3,000 μg) of active dexamethasone,
• Add this 1-ml volume of Dex Sp into a sterile glass vial.
• Add 5-ml of bacteriostatic 0.9% saline to the sterile glass vial containing the 1-ml of Dex SP. 
• The concentration of the diluted Dex SP salt in the glass vial is now 0.67 mg/ml (667 μg/ml). 
• More importantly, the concentration of the diluted "active" dexamethasone is now 0.5 mg/ml (500 μg/ml).
• Store the diluted Dex SP for up to 1 month in the refrigerator (1). It's likely that this diluted Dex SP is stable for much longer than 1 month, but we just don't know how long.
• Remember to protect the diluted Dex SP from light (i.e., keep in dark refrigerator).

Diluting the Dex SP is recommended to ensure administration of the correct dose

Calculating the correct dexamethasone dose for the LDDST 
Now let me address your question: does it really matter if we calculate the dose for the LDDST based on the weight of the Dex SP salt or the actual dexamethasone contained with the salt? Again, as I discussed in my last blog post, the Dex SP label states a concentration of 4 mg/ml for the dexamethasone salt, but that is equivalent to only 3 mg/ml of active dexamethasone (2).

For an example, let's take a dog weighting 20 kg that we need to test for Cushing's syndrome with the LDDST. Let's do the dose calculations both ways — based on the weight of the dexamethasone salt and then based on the active dexamethasone:

• Remember that the dose of the LDDST test is 0.01 mg/kg (or 10 μg/kg); I find working with micrograms easier since it avoids all the tiny numbers and decimal points!
• So first, take 20 kg times 0.01 mg/kg (or 10 μg/kg) = 0.2 mg or 200 μg (the dose to inject).
• If we use the 3 mg/ml of active dexamethasone for the calculation, that means we would administer 200 μg of active dexamethasone to the patient.
• In contrast, if we use the 4 mg/ml of Dex SP salt for the calculation, that means we would administer 200 μg of Dex SP salt, but only 150 μg of active dexamethasone! This calculates out to an administered dose that contains 25% less active dexamethasone than what we should be giving.

So could it really make a difference if we calculated the dose based on the weight of the dexamethasone salt or based on the active dexamethasone contained in the Dex SP? Of course it could, and that's why it is important to carefully calculate and draw up an accurate Dex SP dose to administer when doing a LDDST.

Bottom Line: 

If we miscalculate the dose for the LDDST using the concentration of the total Dex SP salt rather than the concentration of active dexamethasone, we will administer a dose that is 25% less than is needed to ensure complete suppression of the hypothalamic-pituitary-adrenal axis (3-5). In other words, by giving a lower dexamethasone dose, it would certainly be possible to see a normal dog fail to completely suppress the serum cortisol concentrations or show "escape" from suppression at 8 hours.

In other words, if we make the calculation incorrectly, this may lead to false positive test results for Cushing's disease. And that's the last thing we want to do.

References:

1. Plumb DC. Plumb's Veterinary Drug Handbook. Seventh Edition. Wiley-Blackwell; 2011.
2. Lugo RA, Nahata MC. Stability of diluted dexamethasone sodium phosphate injection at two temperatures. The Annals of Pharmacotherapy 1994;28:1018-1019.
3. Melián C, M. Pérez-Alenza, D, Peterson ME. Hyperadrenocorticism in dogs, In: Ettinger SJ (ed): Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat (Seventh Edition). Philadelphia, Saunders Elsevier, 2010;1816-1840.
4. Peterson ME. Diagnosis of hyperadrenocorticism in dogs. Clinical Techniques in Small Animal Practice 2007;22:2-11.
5. Herrtage ME, Ramsey IK. Canine hyperadrenocorticism. In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association; 2012:167-189.

Canine Hyperthyroidism and the Heart

Cardiovascular Manifestations of Iatrogenic Hyperthyroidism
in Two Dogs

by D.M. Fine, A. H. Tobias, and J.D. Bonagura

Journal of Veterinary 2010; 12: 141-146.

Background
While hypothyroidism is a common endocrine disorder in dogs, canine hyperthyroidism is rare. Like hyperthyroid cats, most dogs with naturally occurring hyperthyroidism have a functional thyroid tumor (1-3). However, unlike the situation in hyperthyroid cats, where most thyroid tumors are benign, almost all of these hyperthyroid dogs will have thyroid carcinoma. Therefore, the prognosis is generally guarded to poor.

The most common cause of hyperthyroidism in dogs is iatrogenic hyperthyroidism, which results from excessive intake of exogenous thyroid hormones. This is most commonly caused by the chronic administration of too-high a dose of L-thyroxine (L-T4) for treatment of hypothyroidism (1,3-5), but dietary hyperthyroidism secondary to consumption of meat contaminated with thyroid tissue may also rarely occur (6).

In general, most veterinarians consider thyroid hormone replacement to be a very safe and benign treatment. Iatrogenic hyperthyroidism, when it develops, is generally thought to have minimal undue effects. However, some dogs, especially those with underlying cardiac disease, are sensitive to even moderate L-T4 overdosage and will develop clinical complications of thyrotoxicosis (4).

This report by Fine et al (7) illustrates how chronic iatrogenic hyperthyroidism can lead to severe and life-threatening cardiovascular complications (e.g., tachycardia, arrhythmia, syncope) in dogs.

Case reports
Two dogs were diagnosed with iatrogenic thyrotoxicosis as a result of L-T4 overdosage. Both showed clinical signs of agitation, tachypnea, panting, and tachycardia.

One of the dogs (9-year-old, male Golden Retriever) also showed evidence of hyperthermia, polyuria, polydipsia, and polyphagia. The other dog (6-year-old, male castrated Great Pyrenees) also showed signs of severe weakness, syncope, and collapse.

Both dogs had been previously diagnosed with hypothyroidism and had been treated chronically with high doses of L-T4 (i.e., 40 μg/kg, BID, and 25 μg/kg, BID, respectively). On post-pill serum T4 testing, both dogs were confirmed as having severe hyperthyroidism.

Sinus tachycardia with supraventricular ectopy was diagnosed in one dog, whereas and syncope and atrial flutter was diagnosed in the other. Clinical signs and cardiac rhythm abnormalities resolved in both dogs with resolution of the thyrotoxicosis.

Conclusions of report
In both dogs of this report, iatrogenic hyperthyroidism resulted in clinical features and cardiovascular conduction disturbances of sinus tachycardia, supraventricular tachycardia, atrial fibrillation, and atrial flutter. Both dogs also had concurrent cardiac disease (degenerative atrioventricular valve disease) that might have contributed to the severity of their clinical signs. However, clinical signs and rhythm abnormalities resolved in both dogs with resolution of the thyrotoxicosis.

These cases illustrate that thyroid hormone supplementation is not always benign and that appropriate diagnostic studies, proper dosing, and regular post-treatment monitoring are essential to prevent adverse cardiovascular effects. Based on the 2 cases that we report here, this seems especially true for dogs with preexisting cardiac disease.

My Bottom Line:

Over the years, numerous therapeutic strategies have been recommended for the treatment of hypothyroid dogs. Today there is almost general agreement among endocrinologists that a dose of approximately 20–22 μg/kg once daily suffices in most cases, at least for long-term maintenance treatment (7,8).

The clinical response of hypothyroid dogs to once-daily therapy with this dosage is usually excellent. Although the use of divided BID dosing certainly results in less fluctuation of circulating T4 concentrations compared to once-daily administration, the biological action of thyroid hormones far exceeds that of their serum half-life. This presumably explains the clinical success of once-daily therapy. This once-daily dosage approach is also safer, since the total daily dosage administered is almost always less than when BID administration is used (8,9).

Both dogs of this report (7) had been treated chronically for years with high doses of L-T4, administered twice daily, which were at 2-to 4-fold higher than this recommended dose range of approximately 20 μg/kg/day (8,9).

While most dogs are relatively resistant to the thyrotoxic effects of excessive T4 supplementation, some dogs are sensitive to even moderate L-T4 over-dosage (4). If iatrogenic hyperthyroidism does develop in dogs undergoing treatment for hypothyroidism, the most common clinical signs include marked polydipsia and polyuria, followed by polyphagia, panting, weight loss, hyperactivity, tachycardia and pyrexia (1-5).

If any signs suggestive of hyperthyroidism develop in dogs on L-T4 replacement, a post-pill T4 concentration should be measured to document thyrotoxicosis, and the daily L-T4 dose should be decreased as needed. If present, all clinical signs of hyperthyroidism should resolve within a few days after the daily L-T4 dosage has been lowered.

References:

1. Peterson ME, Ferguson DC: Thyroid diseases, In: Ettinger SJ (ed): Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat, Third Edition. Philadelphia, WB Saunders Co., 1989;1632-1675.
2. Peterson ME: Hyperthyroidism and thyroid tumor in dogs. In: Melian C, Perez Alenza MD, Peterson ME, Diaz M, Kooistra H (eds): Manual de Endocrinología en Pequeños Animales (Manual of Small Animal Endocrinology). Multimedica, Barcelona, Spain, 2008;113-125.
3. Mooney CT. Canine hyperthyroidism. In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology, Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association; 2012:86-91.
4. Refsal K, Nachreiner R. Monitoring thyroid hormone replacement therapy. In: Bonagura JD, Ed. Kirk’s Current Veterinary Therapy XII. Philadelphia: WB Saunders Co. 1995:364-368.
5. Mooney CT, Shiel RE. Canine hypothyroidism. In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology, Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association; 2012:63-85.
6. Köhler B, C. Stengel C, Neiger R. Dietary hyperthyroidism in dogs. Journal of Small Animal Practice 2012; 53, 182–184.
7. Fine DM, Tobias AH, Bonagura JD. Cardiovascular manifestations of iatrogenic hyperthyroidism in two dogs. Journal of Veterinary Cardiology 201012:141-146. 
8. Dixon RM, Reid SW, Mooney CT. Treatment and therapeutic monitoring of canine hypothyroidism. Journal of Small Animal Practice 2002; 43, 334–340. 
9. Le Traon G, Brennan SF, Burgaud S, et al. Clinical evaluation of a novel liquid formulation of L-thyroxine for once daily treatment of dogs with hypothyroidism. Journal of Veterinary Internal Medicine 2009;23:43-49. 

Helpful Tips to Improve the Accuracy of the Low Dose Dexamethasone Suppression Test

Of the 3 major screening tests for Cushing's syndrome, the low-dose dexamethasone suppression test (LDDST) is considered by many to be the test of choice for the diagnosis of hyperadrenocorticism in dogs (1-3).

In this post, I want to address some of the common mistakes I see veterinarians make when performing this test. Addressing a few small but important issues in dosing and timing of sampling can greatly improve the diagnostic accuracy of this test.

Advantages of the LDDST as a diagnostic test
Compared with the ACTH stimulation test, the LDDST is much more sensitive in confirming Cushing's syndrome in dogs. The sensitivity of the LDDST is excellent, approximately 90% to 95% in dogs with pituitary-dependent hyperadrenocorticism (PDH) and virtually 100% in dogs with a cortisol-secreting adrenal tumor (1-3).

Thus, this test will fail to confirm hyperadrenocorticism in only about 5% of dogs with the disease. That's not too bad.

Disadvantages of the LDDST as a diagnostic test
In contrast to the ACTH stimulation test, the LDDST is not helpful in the detection of iatrogenic hyperadrenocorticism. The test is also affected by more variables than the ACTH stimulation test, takes 8 hours to complete, and does not provide pre-treatment information that may be used in monitoring the effects of mitotane or trilostane therapy (1-3). For more information about when to use the ACTH stimulation test, see my previous post entitled, Diagnosing Canine Cushing's Disease: Should the ACTH Stimulation Test Ever Be Used?

The specificity of the LDDST can be low (40% to 50%), especially when measured in a population of sick dogs (4).  Because of the low specificity of this test, diagnosis of Cushing's syndrome should never be based on results of an LDDST alone, especially in a dog with nonadrenal disease. It is best to delay testing for hyperadrenocorticism until the dog has recovered from the concurrent illness (4).

Published protocols for the LDDST
Two similar protocols have been described for the LDDST in dogs, both of which yield similar patterns of cortisol suppression (1-3,5). One of these protocols used the veterinary-labeled preparation, dexamethasone in polyethylene glycol (Azium® Solution; 2 mg/ml; Schering-Plough).  Unfortunately, after merger with Merck in 2009, this Azium preparation has been discontinued and is no longer available (6).

The other test protocol for the LDDST —which I currently recommend— uses dexamethasone sodium phosphate (4 mg/ml) as the form of glucocorticoid administered.

Test Protocol & Sampling times
The protocol and steps that I take when performing a LDDST on a dog suspected of suffering from hyperadrenocorticism is as follows:

1. Hospitalize the dog at least 1 hour before the start of test
2. Carefully measure dog's body weight
3. Calculate the dog's dexamethasone sodium phosphate dose to be administered (0.010 mg/kg)
4. Collect a basal sample for serum or plasma cortisol concentration
5. Inject the dexamethasone, IV or IM
6. Collect additional serum or plasma cortisol samples at 4 and 8 hours

Calculating the dose: Remember that only 75% is active dexamethasone
Again, with this LDDST protocol, the dose of dexamethasone to inject is 0.010 mg/kg, IV or IM (1-3,5). A common mistake made by many veterinarians is to miscalculate the dose of dexamethasone to inject for the test.  When using dexamethasone sodium phosphate, one must remember that the label states a concentration of 4 mg/ml of the dexamethasone salt, but that is equivalent to only 3 mg/ml of active dexamethasone (7).

In other words, if you use dexamethasone sodium phosphate, we must use 3 mg/ml for the calculation of how much to inject. Even though it says 4 mg/ml on the label, only 3 mg/ml of it is actually dexamethasone (7).

Best to dilute in dexamethasone in small breed dogs
In smaller breed dogs, it is very important to dilute the dexamethasone (with saline solution) in order to administer an accurate dosage to the dog. Otherwise, too-much or too-little dexamethasone might be administered, which could result in false-negative or false-positive test results.

Stress and other factors to avoid when performing the LDDST
It is important to remember that "stress"activates the hypothalamic-pituitary-adrenal axis, leading to increased secretion of both ACTH and cortisol. In some normal dogs, the stress response may override the suppressive effects of the LDDST to produce a false-positive test result.

Each dog's threshold to stress is different, and it is sometimes difficult to judge the severity of stress in some dogs.  To minimize the effect of stress on this test, remember the following guidelines:

• Allow the dog at least 1 hour to relax and acclimate to the hospital environment before collecting any blood or starting the test.
• Avoid performing other diagnostic procedures on the day of the test, such as radiographs or an abdominal ultrasound. If one must do one of these procedures on the same day that the LDDST is run, the radiography or ultrasonography should be performed a minimum of 2 hours before the start of the LDDST to allow the cortisol concentrations to return to baseline values (8).
• Even more importantly, anesthesia for even minor procedures (e.g., dental, biopsies) must not be done on the day of the LDDST (9-11).
• In dogs that become highly stressed while in the hospital, tranquilizers and sedatives can not be administered before or during the LDDST. Any of the commonly used tranquilizers may skew the cortisol results and make the LDDST invalid.
• In highly stressed or agitated dogs, one option is to have the owner stay with the hospitalized dog in a quiet area of the hospital during the testing day. Alternatively, a house call veterinarian can perform the LDDST on the dog in the home environment.  If neither of those options are feasible, the owner can take the dog out of the hospital after one collects the basal cortisol sample and injects the dexamethasone, then returns at 4 hours and again at 8 hours for the post-dexamethasone cortisol samples.

Interpreting the results of the LDDST
If the LDDST fails to adequately suppress circulating cortisol concentrations in a dog with compatible clinical signs, this is consistent with a diagnosis of Cushing's syndrome (see Figure below).  Although each laboratory should establish their own diagnostic "cut-off" limits, most labs have the suppression set at 1.4-1.5 μg/dl (40 nmol/L).

Although basal and 8-hour post-dexamethasone samples are most important for test interpretation, one or more samples taken at intermediate times (e.g., 4 hours) during the test period may also be very helpful. Approximately 30% of dogs with PDH exhibit serum cortisol suppression at 4 hours (<1.4 μg/dl or <40 nmol/L), with a rise in cortisol concentration 8 hours after dexamethasone administration. This escape from suppression is diagnostic for PDH, and further tests to determine the cause of hyperadrenocorticism are not necessary (1-3,5).

Figure 3: Patterns of serum cortisol suppression seen with the LDDST in normal dogs and dogs with hyperadrenocorticism.  
PDH = pituitary-dependent hyperadrenocorticisim
ADH = adrenal-dependent hyperadrenocorticism (i.e., adrenal tumor).
Figure from reference (3).

Failure to show suppression (serum cortisol remaining above 1.4 μg/dl with less than 50% of basal cortisol concentration at both 4 and 8 hours) is diagnostic for Cushing's syndrome. However, these results do not aid in determining the cause of the disorder. Further tests, such as use of abdominal ultrasound, high-dose dexamethasone suppression testing, or determination of plasma ACTH concentration, must be used to determine the cause of the Cushing's syndrome in those cases (1-3).

References:

1. Melián C, M. Pérez-Alenza, D, Peterson ME. Hyperadrenocorticism in dogs, In: Ettinger SJ (ed): Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat (Seventh Edition). Philadelphia, Saunders Elsevier, 2010;1816-1840.
2. Peterson ME. Diagnosis of hyperadrenocorticism in dogs. Clinical Techiques in Small Animal Practice 2007;22:2-11.
3. Herrtage ME, Ramsey IK. Canine hyperadrenocorticism. In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association; 2012:167-189.
4. Kaplan AJ, Peterson ME, Kemppainen RJ. Effects of disease on the results of diagnostic tests for use in detecting hyperadrenocorticism in dogs. Journal of the American Veterinary Medical Association 1995; 207:444-451. 
5. Mack RE, Feldman EC. Comparison of two low-dose dexamethasone suppression protocols as screening and discrimination tests in dogs with hyperadrenocorticism. Journal of the American Veterinary Medical Association 1990;15;197:1603-1606.
6. Merck/Schering-Plough Merger. Merckpr.com website. 
7. Plumb DC. Plumb's Veterinary Drug Handbook. Seventh Edition. Wiley-Blackwell; 2011.
8. May ER, Frank LA, Hnilica KA, et al. Effects of a mock ultrasonographic procedure on cortisol concentrations during low-dose dexamethasone suppression testing in clinically normal adult dogs. American Journal of Veterinary Research 2004;65:267-270. 
9. Fox SM, Mellor DJ, Firth EC, et al. Changes in plasma cortisol concentrations before, during and after analgesia, anaesthesia and anaesthesia plus ovariohysterectomy in bitches. Research in Veterinary Science 1994;57:110-118. 
10. Church DB, Nicholson AI, Ilkiw JE, et al. Effect of non-adrenal illness, anaesthesia and surgery on plasma cortisol concentrations in dogs. Research in Veterinary Science 1994;56:129-131. 
11. Fox SM, Mellor DJ, Lawoko CR, et al. Changes in plasma cortisol concentrations in bitches in response to different combinations of halothane and butorphanol, with or without ovariohysterectomy. Research in Veterinary Science 1998;65:125-133. 

Transient Hyperthyroidism in Cats

My patient is a 13-year-old, F/S, DSH who I first examined because of vomiting and weight loss 3 months ago. I was suspicious of intestinal disease and did a full blood work panel, including a CBC, serum chemistry profile, urinalysis, and serum T4 concentration.

The serum T4 concentration was 4.0 μg/dl, which was right at the upper reference range limit (0.8-4.0 μg/dl). So I recommended that we measure free T4 by dialysis, which came back high at 75 pmol/L (reference range, 15-55 pmol/L). Based on this high free T4 value, I diagnosed hyperthyroidism and started the cat on methimazole (1.25 mg, BID).

After 2 weeks of treatment with methimazole, a recheck T4 value was normal at 2.5 μg/dl, and her vomiting had also stopped completely. I then rechecked her 4 weeks later and her T4 remained normal at 2.9 μg/dl.

The owners then decided that they wanted to treat their cat with I-131 so they stopped the methimazole for 10 days and we repeated the serum total and free T4 values to confirm the diagnosis. Results revealed normal serum concentration of both T4 (2.8 μg/dl) as well as free T4 (15 pmol/L). So based on those thyroid results, she is not currently hyperthyroid.

My questions: 

• So did she have a transient hyperthyroid episode or was she not hyperthyroid in the first place? 
• If her free T4s were elevated due to non-thyroidal illness, I wouldn't have expected the vomiting to stop so coincidentally with the start of the methimazole. 
• And I would have thought that her T4s would have gone a good bit lower when she was started on the methimazole if she were not truly hyperthyroid.

My Response:

To make the diagnosis of hyperthyroidism, we need more evidence than just a high free T4 value, or even a high T4. We see false-positive elevations in free T4 in up to 10-15% of euthyroid cats (1,2), so the finding of a high free T4 alone really isn't that helpful unless other historical and physical exam findings also support hyperthyroidism.

In addition, I've also seen a few euthyroid cats (and dogs) that have slightly high total T4 and free T4 concentrations (3,4). This is probably due to the fact that all of the labs are going away from the use of radioimmunoassay (RIA) and chemiluminescence to more automated techniques that just aren't as accurate so we are seeing more false-positive test results.

Normal cats do not necessarily fall into the hypothyroid range when treated with relatively low doses of methimazole, as you used in this cat. So that cannot be used to rel ably diagnose  or exclude occult hyperthyroidism in cats.

So what do I look for in these cats with suspected hyperthyroidism? 

1. Well, it's not always so easy to confirm the diagnosis of early or "occult" hyperthyroidism, but the finding of a thyroid nodule is key (5-11). If we cannot palpate a thyroid nodule but hyperthyroidism is still suspected, use of thyroid scintigraphy can be extremely help in ruling out the diagnosis (12).
2. Other findings I look for on my physical examination, include tachycardia, pounding heart on palpation of the thoracic wall, heart murmur, muscle wasting over the back, and increased nervousness (5-11).
3. Historically, we would want to know if the appetite was increased or just normal or even decreased. Almost all hyperthyroid cats vomit because they eat too much too fast —if this cat's vomiting is not related to eating, it's less likely that the vomiting was related to hyperthyroidism.
4. On your routine blood work, I look at the serum alanine aminotransference activity (ALT) because over 70% of hyperthyroid cats will have a high value (5-11). On the CBC, a low normal or low RBC count, hemoglobin or PCV goes against hyperthyroidism. Excess T4 stimulates the bone marrow so these cats are never anemic unless something else is going on.
5. I know that this cat responded to methimazole, but that doesn't mean very much unless we stop the drug (and vomiting returns) and retrial the cat on the methimazole again to determine if a cause-and effect relationship really exists (in other words, the vomiting stops again on the drug).

References:

1. Peterson ME, Melian C, Nichols R. Measurement of serum concentrations of free thyroxine, total thyroxine, and total triiodothyronine in cats with hyperthyroidism and cats with nonthyroidal disease. Journal of the American Veterinary Medical Association 2001;218:529-536.
2. Mooney CT, Little CJ, Macrae AW. Effect of illness not associated with the thyroid gland on serum total and free thyroxine concentrations in cats. Journal of the American Veterinary Medical Association 1996;208:2004-2008.
3.  Peterson ME: Diagnostic testing for feline hyper- and hypothyroidism. Proceedings of the 2011 American College of Veterinary Internal Medicine (ACVIM) Forum. 2011; 95-97.
4. Peterson ME. Diagnostic tests for hyperthyroidism in cats. Clinical Techniques in Small Animal Practice 2006;21:2-9.
5. Peterson ME, Kintzer PP, Cavanagh PG, et al. Feline hyperthyroidism: pretreatment clinical and laboratory evaluation of 131 cases. Journal of the American Veterinary Medical Association 1981;183:103-110. 
6. Broussard JD, Peterson ME, Fox PR. Changes in clinical and laboratory findings in cats with hyperthyroidism from 1983 to 1993. Journal of the American Veterinary Medical Association 1995;206:302-305. 
7. Baral R, Peterson ME. Thyroid gland disorders. In: Little, S.E. (ed), The Cat: Clinical Medicine and Management. Philadelphia, Elsevier Saunders 2012; 571-592. 
8. Peterson ME: Hyperthyroidism, In: Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat (Fifth Edition). Philadelphia, WB Saunders Co. 2000; pp 1400-1419.
9. Peterson ME: Hyperthyroidism in cats. In: Melian C (ed): Manual de Endocrinología en Pequeños Animales (Manual of Small Animal Endocrinology). Multimedica, Barcelona, Spain, 2008, pp 127-168.
10. Mooney CT, Peterson ME: Feline hyperthyroidism, In: Mooney C.T., Peterson M.E. (eds), Manual of Canine and Feline Endocrinology (Fourth Ed), Quedgeley, Gloucester, British Small Animal Veterinary Association, 2012:92-110.
11. Peterson ME: Hyperthyroidism in cats, In: Rand, J (ed), Clinical Endocrinology of Companion Animals. New York, Wiley-Blackwell, 2012; in press.
12. Peterson ME, Broome MR. Thyroid scintigraphic findings in 917 cats with hyperthryoidism. Journal of Veterinary Internal Medicine 2012; in press.

Treating Diabetic Dogs with Insulin Glargine

PAPER REVIEW

Use of Insulin Glargine in Dogs with Diabetes Mellitus

by F. Fracassi, F.S. Boretti, N.S. Sieber-Ruckstuhl, and C.E. Reusch

Veterinary Record 2012; 170, 52.

Background

Diabetes mellitus is a common disease in dogs requiring insulin  therapy in order to maintain glycemic control. Insulin glargine (Lantus) is a synthetic, long-acting analogue of human insulin that has been designed for once-daily use in human beings (1).

Insulin glargine has been shown to provide effective glycemic control in cats with diabetes (2-4), and in one report, the remission rate of the disease was higher with insulin glargine than with other types of insulin (3). 

Information on the use of insulin glargine for the treatment of diabetes in dogs is scarce and, except for one study that investigated its pharmacokinetics and pharmacodynamics in experimental animals (5), no clinical studies on its use have been published. Therefore, the objective of the study by Fracassi et al (6) was to prospectively evaluate the safety and efficacy of insulin glargine therapy in dogs with naturally occurring diabetes mellitus.

Objectives
The objective of this study was to evaluate the safety and efficacy of insulin glargine in dogs with diabetes mellitus.


Methods
Twelve client-owned dogs with diabetes mellitus were studied (8 females and 4 males). All dogs received insulin glargine every 12 hours for at least six months.The starting dose was 0.25-0.5 U/kg, SC, every 12 hours. Re-evaluations were performed after 1, 2, 4, 8, 12 and 24 weeks and included clinical signs, blood glucose curves, and measurement of serum fructosamine concentrations.

Results
The median starting insulin dose was 0.27 U/kg, BID (range, 0.18-0.53) and increased significantly to a median of 0.60 U/kg (range, 0.11-1.07) after 24 weeks of therapy. Mean blood glucose concentrations were significantly lower after 2 weeks of glargine treatment and remained significantly lower for the duration of the study. Serum fructosamine concentrations were found to be significantly lower after 8 and 24 weeks of insulin glargine therapy compared with the concentrations before treatment.

The number of hours after insulin injection at which the glucose nadir occurred varied between the blood glucose curve, ranging from zero to 12 hours. Taking into consideration all of the blood glucose curves, the nadirs were most commonly observed after 6, 8, and 10 hours.

By week 24, polyuria/polydipsia had improved in 91% of the dogs. No clinical signs that could have been caused by hypoglycaemia were observed. Based on serial blood glucose curves and remission of the clinical signs for judging the success of the treatment, 58%, 33%, and 8% of the dogs attained good, moderate and poor glycemic control by week 24 of the study, respectively.

Conclusions
Insulin glargine administered subcutaneously twice daily is a possible and safe method of treatment for dogs with naturally occurring diabetes mellitus. Although only a few studies are available on the use of other types of insulin in dogs, their success rate is somewhat greater than that with insulin glargine.

My Bottom Line:

These results of this study suggest that insulin glargine administered subcutaneously twice daily is a valid method of treatment for naturally occurring diabetes in dogs, and that it is an alternative to other insulin preparations that have been shown to be effective in the treatment of canine diabetes (4,5,7-10).

In human patients, glargine is generally considered to be a peakless insulin (1). However, in the dogs of this study, a clear glucose nadir was identified in almost all of the blood glucose curves, indicating that the pharmacokinetics and pharmacodynamics of insulin glargine are not the same in dogs as they are in human beings.

In terms of the resolution of clinical signs achieved with insulin glargine, the results of this study were similar to those of other investigators using NPH insulin (7) or a lente insulin (8). The median insulin glargine dose at the end of the study (0.60 U/kg every 12 hours) was comparable with doses in other studies of NPH and lente insulins where insulin was administered every 12 hours (7,8).

It should be noted, however, that the median dose of glargine (0.6 U/kg) was much less than the median dose of PZI insulin (0.9 U/KG, BID) required for glycemic control in these diabetic dogs in a recent study (9).

Unfortunately, insulin glargine was not compared directly with other insulin preparations in this study. However, based on mean blood glucose concentration during 12-hour blood glucose curves, 58% of dogs in the present study obtained good control of hyperglycemia, which is less than the reported 75% of dogs with good control in a similar study where a porcine insulin zinc suspension (lente insulin) was used (8).

Therefore, although insulin glargine may be an acceptable insulin choice for some dogs with diabetes mellitus, the disease control success rate appears to be lower with glargine than with NPH or lente insulins (7,8). Certainly, if a more potent insulin preparation is needed (i.e., in a dog with insulin resistance), detemir insulin would be the insulin of choice, since determir appears to be at least  4-times more potent than the other insulin preparations which have been evaluated in the dog (10).

References:

1. Owens DR, Bolli GB. Beyond the era of NPH insulin--long-acting insulin analogs: chemistry, comparative pharmacology, and clinical application. Diabetes Technology and Therapuetics 2008;10:333-349.
2. Weaver KE, Rozanski EA, Mahony OM, et al. Use of glargine and lente insulins in cats with diabetes mellitus. Journal of Veterinary Internal Medicine 2006; 20:234-238.
3. Marshall RD, Rand JS, Morton JM.  Treatment of newly diagnosed diabetic cats with glargine insulin improves glycaemic control and results in higher probability of remission than protamine zinc and lente insulins. Journal of Feline Medicine and Surgery 2009; 11: 683-391.
4. Gilor C, Graves TK.  Synthetic insulin analogs and their use in dogs and cats. Veterinary Clinics of North America: Small Animal Practice 2010; 40:297-307.
5. Mori A, Sako T, Lee P, et al.  Comparison of time-action profiles of insulin glargine and NPH insulin in normal and diabetic dogs. Veterinary Research Communications 2008; 32:563-573.
6. Fracassi F, Boretti FS, Sieber-Ruckstuhl NS, et al. Use of insulin glargine in dogs with diabetes mellitus.  Veterinary Record 2012;170(2):52. 
7. Palm CA, Boston RC, Refsal KR, et al. An investigation of the action of neutral protamine Hagedorn human analogue insulin in dogs with naturally occurring diabetes mellitus. Journal of Veterinary Internal Medicine 2009;23:50–55.
8. Monroe WE, Laxton D, Fallin EA, et al. Efficacy and safety of a purified porcine insulin zinc suspension for managing diabetes mellitus in dogs. Journal of Veterinary Internal Medicine 2005;19:675-82.
9. Maggiore AD, Nelson RW, Dennis J, et al. Efficacy of protamine zinc recombinant human insulin for controlling hyperglycemia in dogs with diabetes mellitus. Journal of Veterinary Internal Medicine 2012;26: 109-115.
10. Sako T, Mori A, Lee P, et al.  Time-action profiles of insulin detemir in normal and diabetic dogs.  Research in Veterinary Science 2011; 90:396-103.