Decision Making in Veterinary Anesthesia: A Case Study

By Dr. Elana Rybak, CVMA

The patient:

One-year-old female spade German Shepherd mix with a history of seizures starting in August of last year and is on Phenobarbital, KBromide and Zonisamide. She presented for a brain MRI to try to identify a cause for her seizures.

The patient was a nervous girl so she was given Trazodone and Gabapentin on admission. This was sufficient to then allow IV catheter placement without further sedation.

Anesthesia plan and outcome:

For pre-medication, the patient received 0.2mg/kg Butorphanol and 3ug/kg Dexmedetomidine IV.  Anesthesia was then induced with Midazolam (0.2mg/kg) IV and just 0.5ml of Propofol.  The patient was then maintained with Isoflurane.

Her anesthesia was very smooth and no interventions were needed.  

The patient appeared to be taking a little bit longer than expected to wake up and so was given Antisedan to reverse the dexmedetomidine, which is often our culprit for prolonged recoveries.  She then started to wake up a bit (blink reflex, twitching ears when blown on, breathing well on her own) and so she was taken to her run to finish waking up and to be extubated because she was a larger, nervous dog and this was considered likely safer for all involved.

After getting to her run, the patient was still quite sleepy and was still taking longer than expected to wake up.  She had a blink reflex and would slightly shake her head when blowing in her ear, but otherwise was not really rousable.

At this time it was decided to give the patient some Naloxone to see if that would help wake her up further, and within 30-60 seconds after Naloxone administration, the patient was awake enough for extubation.

So…why did this patient take so long to wake up? Why did we choose to administer Naloxone?  Why not reverse the Midazolam?  What is going on here?!

Let’s discuss!

Why not reverse midazolam with Flumazenil?

The patient is a known seizure patient.  In humans, there is a box warning that Flumazenil administration may be associated with the occurrence of seizures.  This is more likely if the patient is taking benzodiazepines for seizures or if they have taken a pro-convulsant (ex: certain anti-depressants).  

While Flumazenil may/may not lower the seizure threshold in pets, it certainly could interfere with future midazolam dosing if the patient has a seizure after waking up from anesthesia. (The half-life of Flumazenil - the reversal drug for midazolam - is 1 hour).

Why give Naloxone (this drug is an opioid reversing medication, also known as Narcan)?

One thing that we noticed with this patient, is that she had white-haired spotted feet.  Remember that she was described as a 'German Shepherd Mix'.  White spotted feet is not a normal characteristic of German Shepherds, so what other breed could she be mixed with?  A suspicion was that she may be mixed with some sort of Australian shepherd type breed because of her hair coloring.  So what does that mean in regards to the drugs that were chosen for her anesthesia protocol?

MDR1/ABCB1 gene mutation:

Australian shepherds are one of the breeds that are more likely to have the MDR1 (Multidrug resistance) gene mutation (also known as ABCB1 gene mutation).  The MDR1 drug mutation demonstrates its most significant effects at the level of the blood-brain barrier. The term ‘blood-brain barrier’ is used to describe a filtering mechanism that keeps certain blood-borne substances from entering the brain tissue. In dogs who possess the MDR1 mutation, defective p-glycoproteins allow higher levels of drugs to enter the brain, increasing neurologic effects of some medications.  

This means that at normal/standard drug dosing, certain drugs can have much more profound effects in these dogs, and clinical signs can vary from excessive sedation, weakness, ataxia, and tremors, to seizures, blindness, and death.  

The gene is considered autosomal dominant with incomplete penetrance, so dogs with two copies of MDR1 will exhibit multidrug sensitivity. Some dogs with 1 copy of MDR1 may also exhibit multidrug sensitivity, though often to a lesser extent.

(Incidentally, up to 10% of German Shepherds can also carry the gene mutation!)

Some common drugs that are listed as 'MDR1 drugs' are: Certain anti-parasitics (ex: Ivermectin, Moxidectin, others), Ondansetron, Loperamide, Digoxin, certain chemotherapy drugs, Galliprant, Maropitant (though this drug has such a wide margin of safety, at the 1mg/kg dose we use it is not really a concern), Acepromazine, and…Butorphanol!

Important to know:  Cats can have the ABCB1/MDR1 mutation too!!  It is much less common than in dogs, but can be present.

What does that mean for our patient?

The suspicion that this patient may have some Australian shepherd present in its genetic profile, and the fact that she was taking longer than normal/expected to wake up after anesthesia suggested that it was possible she may be experiencing exacerbated sedation from the Butorphanol due to possibly having the MDR1 gene mutation.  It was decided to attempt to reverse the Butorphanol with Naloxone, and this resulted in a rapid arousal and extubation.

Does this mean you should never use Butorphanol in MDR1 mutation patients?  No.  If there is an alternative opioid that could safely be used, maybe go with that.  Otherwise, it is suggested that in heterozygous dogs, the dose of these drugs should be decreased by 25% and homozygous dogs, by 50%.  We don't always know if our patients have this mutation so sometimes you just have to use your best judgement.

A list of dog breeds that are commonly associated with the MDR1 mutation can be found here.

A question for you

Who can tell me, besides the MDR1 mutation link, what Loperamide and Butorphanol have in common? 

Send your answers to Questions@vnioc.com with subject line "Answers for Anesthesia Blog." 

Thanks for reading! 

Remember, Make Good Choices!!

-ERR