Wednesday, March 16, 2011

What's the Best Protocol for ACTH Stimulation Testing in Dogs and Cats?

Preparing for the ACTH stimulation test: Does the animal need to be fasted?

The dog or cat does not have to be fasted overnight, and lipemia does not appear to “clinically’ affect serum cortisol values. However, having a nonlipemic sample may be better in some situations, especially if serum cholesterol or triglycerides are being measuring on same sample.

Remember that the ACTH stimulation test is the most useful test for monitoring dogs being treated with trilostane (Vetoryl) or mitotane (Lysodren) see my blog entitled, Diagnosing Cushing's disease: Should the ACTH stimulation test ever be used? Both medications are fat-soluble drugs and must be given at time of meals, or the drugs will not be well absorbed.

With trilostane, it’s extremely important to give the morning medication with food, and then start the ACTH stimulation test 3 to 4 hours later.

Fasting these dogs on the morning in which the ACTH stimulation test is scheduled should be avoided since it invalidates the test results.

When a dog ‘s food is withheld, the absorption of trilostane from the gastrointestinal tract is decreased. This leads to low circulating levels of trilostane, resulting in little to no inhibition of adrenocortical synthesis. Therefore, serum cortisol values will higher when the drug is given in a fasted state than when it is given with food.

The higher basal or ACTH-stimulated cortisol results could prompt one to unnecessarily increase the daily trilostane dose. That misjudgment may lead to drug overdosage, with the sequelae of hypoadrenocorticism and adrenal necrosis in some dogs.

Recommended ACTH stimulation test protocol:

There are many different published protocols for how to perform the ACTH stimulation testing. Both ACTH gel or synthetic ACTH can be used, but over the last 2 decades, the use of cosyntropin (Cortrosyn) has become the “gold standard” preparation for ACTH stimulation testing.

In the USA, Cortrosyn is available through Henry Schein (800-872-4346; www.henryschein.comwhere it can be purchased as an individual vial ($68/vial) or a box of 10 ($720 per box or 68/vial). 

This is the protocol for the Cosyntropin (Cortrosyn) ACTH stimulation test that I recommend:

1. Collect baseline serum or plasma sample for cortisol determination.

Use of a serum separator tube should be acceptable for serum cortisol measurements, but check with your laboratory to ensure proper sample collection.

2. Prepare the ACTH preparation for administration (see below).

Cortrosyn is supplied by the manufacturer as a lyophilized cosyntropin powder in vials containing 0.25 mg (250 µg) of ACTH to be reconstituted with sterile saline solution.

In order to make this test more cost effective when using Cortrosyn and to make it easier to administer this dose to smaller dogs, I recommend diluting the Cortrosyn and dividing the solution into 25-μg to 50-μg aliquots in a tuberculin or insulin syringe, and then refrigerating or freezing the capped syringe.

For specific guideline on how to dilute the Cortrosyn and store it to extend it’s shelf-life, look for may next post entitled: How to extend your supply of Cortrosyn and lower the cost of ACTH stimulation testing.

3. Administer the cosyntropin at a dosage of a 5.0 μg/kg, up to a maximum dose of 250 μg; 1 entire vial).

This 5.0 μg/kg dosage will result in maximum stimulation of the adrenocortical reserve, the most important criteria for any ACTH stimulation protocol.

4. In dogs, the Cortrosyn can be administered either IV or IM, with equivalent cortisol results. Obviously, if the dog is dehydrated or in shock, the Cortrosyn must be administered intravenously.

In cats, its best to administer the Cortrosyn IV, because the adrenocortical response is more consistent and the peak is higher. Given subcutaneously, the Cortrosyn is not well absorbed in cats. In addition, giving Cortrosyn by the IM route is painful for cats and should be avoided.

5. Collect post-ACTH serum sample for cortisol determination 1 hour later.

6. After the clot has retracted, centrifuge both samples. 

If using plasma or a serum tube without a separator, aspirate the plasma or serum and transfer into a plastic or glass vial.

Test protocol for tetracosactide (Synacthen):

If you live in a part of the World other than the USA, it’s likely that you will be using tetracosactide (Synacthen) rather than Cortrosyn as the synthetic ACTH preparation. The chemical structure of tetracosactide and cosyntropin are identical, and the test protocol outlined above will work. However, because the cost of Synacthen is much less than Cortrosyn, it is common practice to administer Synacthen at the dose of a half vial (125 μg) to a cat or small dog and an entire vial (250 μg) to a larger dog, rather use the 5-ug/kg dosage.


Pia Pet said...

(this may be a re-resubmit. Not sure if first comment went through).

Dr Peterson,

My dog's trilostane dosage was recently reduced (25%, to 15 mg, twice daily) after 3 years. The recent re-check ACTH stim test indicated his original dose was a bit too much. The dog will be 15 years in a couple months. I need to run another stim to see if this reduced dose is adequate. The vet practice I was considering using says 1) it will use the entire reconstituted vial of Cortrosyn, even though my dog is only 22 kg (therefore 108 mcg Cortrosyn). An entire vial is 2x the recommended stimulation dose. Is there harm to my dog if he were to be stimulated with so much? 2) The vet also says to fast him for 12 hours but to give the trilostane with a little food 4 hours before bringing for test. None of my prior ACTH stim tests were conducted with fasting, and I see your posted protocol gives the good reasons why the blood samples shouldn't be from a fasted pet. I am thinking, not to use this practice for the stim test. Your recommendation would be appreciated. Thank you, Susan

Dr. Mark E. Peterson said...

Giving a larger dose of ACTH (cosyntropin) to your dog will not produce any harm. However, it will be more expensive cost you more money.

Trilostane is a fat-soluble drug and must be given with food in order to be absorbed. If you fast your dog overnight and do the ACTH stimulation test the next morning after you give the medicine without food, the test will be meaningless.

Jan Mullaly said...

Our 12 year old Min-Pin has diabetes/Cushing's Disease. In the past when he has ACTH tests, we have always been told to fast him for 12 hours, give half a dose of insulin (1.5 units) and 10mg of trilostane before he goes for the test. After first result we were told test was too LOW and to change the dosage from 10 mg. daily to 10 mg. once every other day. This last test his readings were 12.1, so now we are instructed to order compounded medicine of 5 mg. to be given once daily. I am just wondering how accurate the tests have been with the fasting, and if the once daily dose is a good idea. I see that twice a day is recommended in some places. I thank you for your help. Jan

Dr. Mark E. Peterson said...

First of all, trilostane is a fat-soluble drug and should always be given with food to ensure that it get absorbed. The same is certainly true the morning that you are going to do ACTH stimulation testing to monitor your dog. You do NOT want to fast in that situation, because it's not going to mimic what is going on all the other days of the month(s) between monitoring periods.

Secondly, a note on the frequency of administration: Once a day trilostane works well in most dogs with Cushing's disease, and that's actually the protocol we use to treat most of the dogs.

However, in diabetic dogs, we need to give the trilostane twice a day to keep the diabetes better regulated. It sounds like your dog may only need 2.5 mg twice a day, but you could have a pharmacy prepare that for you.

Alison556 said...

Dear Dr Peterson,

My staffordshire bull terrier was diagnosed with Cushing's in August 2013.

He has been on trilostane since diagnosis, with regular ACTH stim tests.

There is now a European shortage of synacthen and we've been told that any supplies left are only for emergencies and he is no longer to get the ACTH Stim test. The vet has said that baseline cortisol and electrolytes is more than adequate to monitor his dose.

This is causing me huge amounts of concern as his dose had been changed from the starting dose and we now don't know how he's doing when stimmed.

I'm sure the vet could apply to import an alternative (I assume cortrosyn) but they've told me there is no alternative.

In your opinion, is baseline cortisol and electrolytes adequate for monitoring?

We've been told to also monitor clinical signs but that's not a good guideline for us, as we got a phonecall from the vet to tell us his cortisol levels had dropped to 17 and to stop the trilostane - yet at that precise moment, he was a happy boy, running around at the park and having a ball - he wasnt showing any signs of low cortisol. Thank you for your time, Alison

Dr. Mark E. Peterson said...

I know this is a big problem, which I don't have an answer for in these cases.

Monitoring basal cortisol values is fine to look for overdosage. So in your dog, stopping the trilostane and then retesting in 2-4 weeks is a good idea. Once the cortisol value goes up again (generally to >1.5-2 ug/dl or >30-40 nmol/L), the the drug can be started once again.

The problem with basal cortisol valeus that that we really have no idea when we can raise the dose of the drug. Certainly, dogs that remain polydipsic and polyuric on a standard daily trilostane dosage should be changed from once daily dosing to twice daily, divided dosing.

In other words, if a dog is on 60 mg once daily and remains symptomatic, this dose should always be divided and given as 30 mg twice daily before we go up on the total daily dose.

Claudia Rodrigues said...

Dear Dr. Peterson,
I found this site information very useful... I just realize that there is no agreement among vets on treatment and how this very expensive test is done. I've been treating my little Nina with the very expensive drug Vetoryl for almost a year. I don't see any improvement in "symptoms" other than normalization of her cortisol levels. I have to mention that based on symptoms I read on line she is a very mild case. Her only issue is extreme appetite and large tummy. Nothing else. The medication didn't help reduce her increased appetite, and since starting it she has diarrhea everyday. It's been getting worse with time. She also takes Vetmedin and I read that both medications can cause diarrhea. In addition, she takes enalapril and lasix. Nobody mentioned to be the danger of mixing these medications and I found that it can be dangerous when taken together. I feel like Nina is intoxicated. Her bowel is crashing. I may even consider stopping her Cushing treatment as I sincerely don't see benefits. Her triglycerides are reaching the roof and I also believe it can be a side effect. She's been on H/D diet since diagnosed with heart problems. Any recommendation is greatly appreciated. I heard some dogs do better with lysodren.

Dr. Mark E. Peterson said...

I agree with you that your dog maybe should not be on the Vetoryl, especially if there are so many other problems going on and you haven't noticed any improvmement.

Talk to your vet about your concerns and about what to do.

Monalisa Jales said...

Dr. Peterson, you have experience with use of Synacthen Depot for monitoring treatment of hyperadrenocorticism in dogs? The dose may be the same or intravenous larger? Collection with two hours of application, right? Thank you.

Dr. Mark E. Peterson said...

We don't have Synacthen depot in the USA. But I do know that most use a dose of 1 vial per dog (half a vial may be enough in very small dogs).

A 2-hour post-Synacthen depot cortisol concentration is thought to correlate well with a 1-hour post-Cortrosyn cortisol value (the product I use).

Bette Wetherspoon said...

Dr Peterson,
My 4 year old english bulldog was ACTH tested today with Cortrosyn given IV at 8 40 am. She has since developed high sensitivity to low and high lights and appears to loose her vision. But these episodes are short. I am an RVT and have monitored and conducted may of these test through out my career but have never seen such a reaction. Thank you for your insight. Bette

Dr. Mark E. Peterson said...

I have not ever seen or heard of such a side effect. The timing, however, would certainly indicate that the Cortrosyn (or saline used to dilute it) is responsible. Talk to your vet about possible short term steroid treatment for an allergic reaction. Also have them do a good eye exam. But I honestly do not know what the pathogenesis of your dog's signs could be.

Marcia M said...

My vet always asks to fast the night before the acth stim test... so you advise against it?

Dr. Mark E. Peterson said...

Only if you are monitoring trilostane therapy. If you fast and give the drug the morning of the test, the trilostane might not be absorbed on an empty stomach.

Therefore, the ACTH test results you get when you give trilostane without food cannot be used to accurately gauge what the drug is doing when you do feed your dog.

Marcia M said...

Sorry, I should have explained better. My min dachshund is on Trilostane, my vet always requests a complete fast (no food, meds, or water).

Dr. Mark E. Peterson said...

Well, you cannot monitor the effects of trilostane therapy if you don't give the drug the morning of the text. The drug has a very short half life and will be totally gone from the circulation in 12-18 hours.

Ji Park said...

Dr. Peterson,

My dog needs to have ACTH test done again to monitor his trilostane therapy. I give his daily trilostane around 6-7 pm with food, after I get home from work.
My question is, will it be ok to give him trilostane again with food in the morning before the test? That would be like giving him recommended dosage every 12 hr instead of every 24 hr, although it would be just for that day for the test. What would be the best way to get a correct result from the test?

Dr. Mark E. Peterson said...

If you are going to use once daily trilostane, it must be given in the morning if you are going to check the peak effect of the drug (3-6 hrs after administration). It makes no sense to give an extra dose on the day of testing -- then you have effectively raised the dose given for that day.

If you must give the once daily trilostane at night, then test the next morning but your vet should realize that the cortisol values will be higher because the peak effect of the trilostane will be worn off.

Carmen Cortes said...

Dr. Peterson,

My dog was diagnosed with Cushing's one year ago. He has been on trilostane since diagnosis, with regular ACTH stim tests.

When my dog started to take Trilostane, I was pregnant and I lost the baby. Since then, I´m trying to be pregnant again but it is not possible. I never touch the capsules, but I Touch the dog. could be the trilostane responsible for infertility? What can I do? and What is the effect of trilostane in person in contact with dogs that they are taking??


Dr. Mark E. Peterson said...

Bottom line is that I do not know the answer.However, I highly doubt that touching, holding or petting a dog that received trilostane could result in enough absorption of the drug to result in infertility. The worry is that this drug will inhibit progesterone secretion if you take or absorb the drug by handling it (see reference). Again, this doesn't seem possible after ingestion by a dog, but I'm not a pharmacologist!

le Roux PA, Tregoning SK, Zinn PM, van der Spuy ZM (June 2002). "Inhibition of progesterone secretion with trilostane for mid-trimester termination of pregnancy: randomized controlled trials". Human reproduction (Oxford, England) 17 (6): 1483–9.

Carmen Cortes said...

Thank for your quick answer.

Kind regards

Laurie said...

Hello. We have a dog with Cushings and am wondering if there is a way to lower the cost of the ACTH Stim test...such as any assistance programs. The Vet bills are overwhelming for our family but we want to help our dog as much as we can. Any suggestions? The test just recently went up and is now $400.00.

Thanks for any help you may have.

Best regards,
Laurie Cordeniz

Dr. Mark E. Peterson said...

Sorry, I do not know of any assistance programs.

janice craumer said...

,my pom has had cushing for over a year. when my vet confrimed he needed treated, he wanted to give him lysodren. I read on line about side effects of both drugs (trilostane) I did not want lysodren, tried to talk my vet out of it.But had his mind made up. I changed vets and feel so bad,he had taken care of my dog for 7 years. Is trilostane better than lysodren?

Dr. Mark E. Peterson said...

No best drug for all dogs. Both drugs nave pros and cons.

n Pomerantz said...

I am fostering a shelter dog who is so very fearful that she cannot be groomed or handled by a vet without sedation. She becomes beyond stressed, combatant and bites. I have had cushingoid dogs of my own as well as fostered two rescues with cushing's so when I saw her, the symptoms and her physical appearance were very familar to me. Her symptoms are defintely not mild either. She was constantly hungry, panting, excessive dilute urine, excessive drinking, very thin coat, and very bad skin. Her behavioral problem is not conducive to doing all of the usual screening test but this is a shelter dog whose alternative was euthanasia so we're doing what we can with the information we have. A UC:CR was done with a specimen collected first thing in the morning at home. Results were greater than 100, suggestive of cushing's. She weighs 20 lbs and was started on 10 mg Vetoryl twice a day. The dog was sedated and an acth stimulation test was done at day 16. Results were pre 3.4 ug/dl and post 10.9 ug/dl. I have definitely noted improvement in symptoms so I don't feel an adjustment to dosing should be made at this time. I spoke with a representative at Dechra and asked her if sedation can skew the results of an acth stimulation test and she said she didn't think so. That wasn't very reassuring so I was hoping that you may have a more definitive answer for me. If sedation does skew results, is cortisol normally lower or higher when the dog is sedated. Any guidance you can provide in this very special case would be most appreciated. Thank you for your time.

Dr. Mark E. Peterson said...

Stress will increase the basal cortisol concentration but should now affect the post-ACTH cortisol value.

n Pomerantz said...

I apologize if I was unclear in my question. The dog had to be sedated in order to even do the stimulation test so she was knocked out completely before starting the acth stimulation test. I apologize but I don't know which sedation was used. My question is are pre and post stimulated results affected by sedation and if so, would you expect them to be lower or higher? Thank you.

Dr. Mark E. Peterson said...

Basal cortisol will be increased. Post cortisol should not be affected.

Unknown said...

Dr. Peterson,
Trilostane being fat soluble, does the fat content of the meal given with the trilostane administration matter to its absorption? My 15-17 y/o beagle is on 40mg q.d., but he eats Purina OM (Overweight Management) Rx kibbles, which are (from what I understand) higher protein, higher fiber, and more medium-to-low in fat than most dog foods. Would it benefit the absorption of trilostane to add something to his breakfast (like, say, 1/2 tsp. of olive oil), or is "fat solubility" more of an internal process of digestion that wouldn't be effected by the lipids in the actual meal?

Thank you for this great website!

Dr. Mark E. Peterson said...

If your dog is well controlled, I wouldn't worry about it. If not, then added a bit a fat to the food at time of drug administration wouldn't be a bad idea.

Cocker Owner said...

I am in an awkward situation and need advise. I am in Florida for the winter and seeing a covering vet until our return home to my regular vet. I have a 7 yr old cocker diagnosed last October. We caught Cushings early and dog's only symptoms was overeating, hair and skin is normal, no overdrinking, etc. He is 32 lbs and taking 30 mg Vetoryl daily and doing great. First ACTH tests were good, pre 2.5, post 10; pre 3.3, post 8.3. Normal ranges are pre 1-5 and post 8-17. But the most recent ACTH was pre <1, post 3.4 which are both low and I am very afraid he will go Addisons and think he should be decreased to 20 mg daily, but vet wants to continue 30 mg. Covering vet told me over the phone that the pre was 1, but when I got the actual written lab report it showed <1. I spoke with my regular vet at home and told him it was 1 and he said to continue with the 30 mg, but he did not know it was lower and is on vacation this week. What do you suggest I do?

A few other notes, when I got the written lab report and vet notes they were not accurate, documented notes about a discussion with me about watching for Addisons signs with the owner which never took place-I spoke with a woman there, not the owner which is a man. I do not think this practice deals with Cushings much as when I need the Vetoryl they have to order it, they do not have any in stock.

Thank you.

Dr. Mark E. Peterson said...

If you lower the dose this week and talk to your vet when he or she returns from vacation, that isn't going to hurt anything.

Your dog will have a decreased appetite or other signs of illness before Addison's develops.

Rie Rie said...

Dr. Peterson,

My vet's office (and their lab) are stating that a sample could be too lipemic for their machine to get a successful reading if not taken fasted. The fat refractiles off and the results are - not wrong - just not available. If that's true, then why doesn't every other lab provide the same recommendation? And if it's not true, then what gives?

They recommend a fasted test or in lieu of that, giving the Vetoryl with a small amount of highly fatty food (like a piece of cheese).

Do you have any suggestions or insight to help me understand the dilemma here? What would you do in my situation?

Thank you.

Dr. Mark E. Peterson said...

You can't evaluate trilostane treatment if given without food. I have never fasted a dog when retested on this drug. I don't find that feeding produces significant lipidemia to influence cortisol measurement.

Honestly, this is not my problem and I'm not here to get in the middle of this. If this were my own dog, I'd find another vet.

Rie Rie said...

Thank you. I hope I didn't offend. I was only looking for more opinions and yours seems highly respected. I do appreciate your taking the time to respond.