Thursday, May 17, 2012

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.

  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.


Dr H Gittelman said...

Is there any reason that you using dexamethasone sp rather than conventional dexamethasone at 2.0mg/ml?

Dr. Mark E. Peterson said...

Using the dexamethasone solution (2 mg/ml) is fine. As you probably know, Azium is no longer made but a couple generic brands of dex solution are available.

With the dex solution, we don't have to worry about calculating the active dex fraction of the preparation because it's all active dexamethasone.