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ACTH Stimulation Testing: A Low-Dose Protocol

Information on the common testing procedure ACTH.

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Based on abstracts presented at the 23rd Annual ACVIM Forum in Baltimore (2005).

ACTH stimulation testing is a common procedure in small-animal practice used for diagnosing both hypoadrenocorticism and hyperadrenocorticism.

Pituitary versus Adrenal

When diagnosing hyperadrenocorticism, the most common screening tests are the ACTH stimulation test and the low-dose dexamethasone suppression test. Each has advantages and disadvantages.

It has been shown that the LDDS is more sensitive with fewer false negatives, but less specific with more false positives than the ACTH stimulation test in dogs with significant non-adrenal illness, especially liver disease.

The LDDS test has an advantage in that it is possible to differentiate between pituitary and adrenal tumor dependent disease in approximately 30 percent to 50 percent of cases.

Test results typical for hyperadrenocorticism would have a cortisol value greater than 1.4 µg/dL at eight hours.

It is the four-hour sample that helps to differentiate the cause of hyperadrenocorticism. If the four-hour sample is either below 1.4 µg/dL or 50 percent lower than the baseline or eight-hour value, it is consistent with PDH.

Synthetic ACTH

ACTH stimulation testing has become significantly more expensive since the cost of synthetic ACTH has increased. An ACTH gel is available, but the function of this product is questionable. The synthetic ACTH (cosyntropin; Cortrosyn) is preferred for consistency.

There are two ways to administer ACTH, either intravenously or intramuscularly. It has been shown that 5 mcg/kg achieves maximal adrenal stimulation when given intravenously. The typical 250 mcg vial would be adequate for a 50 kg dog.

In practice, this means that a vial of ACTH is reconstituted and frozen in aliquots. At the Western College of Veterinary Medicine in Saskatchewan we freeze five aliquots from each vial and then use as needed.

The product is stable at Ð200 C for up to six months when frozen in plastic syringes or vials (Frank LA, Oliver JW. Comparison of serum cortisol concentrations in clinically normal dogs after administration of freshly reconstituted versus reconstituted and stored frozen cosyntropin. JAVMA 212;1569-1571:1998).

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This translates into a substantial cost saving, especially when you are testing a smaller dog where previously we would have given a whole vial. To date, the only protocol for intramuscular administration is to give a 250 mcg vial IM and sample at one hour post injection.

IM versus IV Delivery

Researchers from Auburn University and VCA West Los Angeles Animal Hospital investigated if it was possible to reduce the dose of ACTH given intramuscularly (Behrend EN, Kemppainen RJ, et al. Administration of low dose ACTH intramuscularly for ACTH stimulation testing in dogs. JVIM 19:461-462:2005).

The research was carried out on five healthy dogs. The dogs received 5 mcg/kg ACTH either IV or IM initially. The next time they were tested the alternate route was used. Blood samples were collected before the injection (t=0), as well as 30, 60, 90 and 120 minutes after the injection.

The results showed that stimulation of the adrenal gland was maximal at t=60 to 90. Cortisol concentrations dropped off at 120 minutes. With IV use, cortisol was 297 nmol/L at 60 minutes whereas it was 289 nmol/L at 60 minutes when given IM.

The conclusions that can be drawn from this study is that synthetic ACTH given at a dose of 5 mcg/kg achieves equivalent maximal stimulation of the adrenal glands at both 60 and 90 minutes in healthy dogs.

Oral Corticosteroids

Use of oral corticosteroids is associated with a wide range of side effects. This is especially true in humans that are not nearly as resistant to the effects of the drugs as dogs and cats are. As a result, there are a variety of corticosteroids on the market with attractive properties that limit systemic side effects.

Budesonide is one of these products. It is used as an oral medication as well as in inhalers. The advantage to this medication is that after oral administration, rapid first pass metabolism in the liver results in breakdown products that have minimal glucocorticoid effect.

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Experimentally, budesonide has a much higher affinity for the glucocorticoid receptor than cortisol (1000 times) and a stronger topical effect (200 times), yet, is only 25 times as potent as cortisol when given orally.

In humans, this translates into good clinical response without as much suppression of the hypothalamic-pituitary-adrenal axis.

Experience with budesonide is limited in dogs. One study looked at six dogs with IBD. The dogs were given 3 mg/m2 once daily for one month and the extent of effect on the HPA axis was investigated (Tumulty JW, Broussard JD, et al. Clinical effects of short-term oral budesonide on the hypothalamic-pituitary-adrenal axis in dogs with inflammatory bowel disease. JAAHA 40;120-123:2004).

The dogs showed significant suppression of basal cortisol, cortisol response to ACTH administration and decreased endogenous ACTH concentrations. All are consistent with HPA axis suppression.

In this study ALP  did not increase and urine specific gravity remained unchanged, suggesting that typical corticosteroid side effects were not present.

Researchers from Auburn University presented results from a study on the effects of budesonide in healthy dogs (Stroup S, Behrend E, et al. Assessment of suppression of the hypothalamic-pituitary-adrenocortical (HPA) axis and systemic effects in normal dogs treated with oral controlled-release budesonide. JVIM 19;462:2005).

There had been concern in the dogs with IBD that intestinal inflammation might have increased drug absorption leading to the HPA suppression. In the Auburn study, 10 dogs were given either budesonide (3 mg/dog if they weighed more than 9 kg or 2 mg/dog if they weighed less than 9 kg) or placebo for 28 days. Similar tests were run to determine if HPA-axis suppression occurred.

In these healthy dogs, significant suppression was noted again, however clinical signs of glucocorticoid excess were not seen. It would appear that although this medication has effects on the HPA axis, it does not appear to cause the signs typically seen with aggressive glucocorticoid therapy.

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HPA axis in Cats

Corticosteroids are a mainstay for asthma treatment in cats.

Generally oral or injectable products are used. Recently, metered-dose inhalers have become popular, as well. Delivering the corticosteroid directly to the lung should minimize systemic side effects.

Researchers from the University of California, Davis compared the effects of placebo, oral prednisone (10 mg/day) and a 250 mcg puff of flunisolide given twice daily to six healthy cats using a randomized crossover design (Brownlee L, Sequin B, et al. Systemic endocrine effects of an inhalant glucocorticoid in healthy cats. JVIM 19;463:2005).

The use of inhaled corticosteroids was associated with a suppression of the HPA axis (decreased ACTH stimulation test response).

Surprisingly the relatively high dose of prednisone only suppressed the HPA axis in two of the six cats. Overall, it would appear that inhaled corticosteroids result in HPA axis effects. Whether this is clinically significant is difficult to know.

Anthony Carr, DVM, Dipl. ACVIM, is an associate professor at the Western College of Veterinary Medicine in Saskatoon, Saskatchewan, Canada.

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