Midazolam vs. Diazepam for At-home Care

History of Cluster Buster Protocols

In 1995 Dr. Michael Podell championed the idea of at-home, rectal diazepam use for canine cluster seizures. In that study, dogs that received rectal diazepam had fewer cluster seizures compared to those that didn't receive the drug. Since then, at home cluster care has become standard practice for many veterinarians.
According to human literature, benzodiazepine drugs (midazolam, diazepam and lorazepam) are the "best" first line anticonvulsant drugs to stop status epilepticus. As is typical, we simply adopted this idea in veterinary medicine without data to support it's use. But...the benzodiazepine drugs do show improved seizure cessation so...they probably help our canine patients in some manner.

Which Benzodiazepine is Better?

Here is where the science gets a bit muddy. We've compared rectal diazepam to intranasal midazolam and intranasal midazolam was superior. We've compared intranasal midazolam to intravenous midazolam and intranasal midazolam stopped seizures faster. However, all of these studies involved few animals and ethically we cannot have a group of untreated animals to determine true efficacy. So, which is better? They all work, but intranasal is perhaps faster and easier than other non-intravenous routes when IV access is restricted.

What are the current recommendations?

At this time, intranasal midazolam at a dose of 0.2 mg/kg up to 3 times in 24 hours is my recommendation for dogs with a cluster or status epilepticus history. Do your best to use a nasal atomizer because this has been shown to be the superior technique compared to nasal-drop application. (I have found them at Midwest Vet:https://www.midwestvetsupply.com/products and also carry them in my car. Ask, when I'm at your clinic, if you need one!).

Nasal drop vs. Atomizer?

The nasal drop technique requires the client to drip the midazolam intranasal slowly during the active seizure while also avoiding getting bitten. The atomizer looks like a conical shaped marshmallow that is attached to the end of the syringe and the client is then able to press the atomizer against the nare and dispense the dose in one "push". Not clear on this technique? Please ask me, I am happy to clarify! I do not have a financial incentive or disclosure for this product, or Midwest Vet Supply. :)

I hope you're enjoying summer and all it has to offer! I am at the Dane County 4-H Fair cheering on my kids so my hours are a bit limited. Please reach out if you need me and cannot find a suitable consult time online. Have a great week!

Abrupt Benzodiazepine Withdrawal in Dogs

Abrupt withdrawal of benzodiazepine drugs can result in withdrawal seizures. A recent report describes withdrawal seizures in 3 young dogs and I thought we could take this opportunity to review this concept.

What is a benzodiazepine drug?

Benzodiazepine class drugs commonly include diazepam, midazolam and lorazepam. These drugs are GABA agonists in the CNS which results in suppression of activity. GABA activation causes inhibition in the forebrain, cerebellum, and in other parts. So, if you activate an inhibitor, you will suppress activity. Got it?

How long is too long?

Abrupt withdrawal resulting in seizures and other signs of CNS overstimulation can occur after constant rate infusion (CRI) use, or chronic oral use. Use of a benzodiazepine drug as a CRI for more than 12 hours usually warrants tapering. The three dogs in the recent report received one of these drugs for 39, 64, and 48 hours, respectively. After abrupt withdrawal of the drugs they experienced ataxia and seizures within 4- 48 hours. A return of the benzodiazepine CRI at a low dose, followed by a 12-24 hour taper, resulted in a successful wean from the medication and no additional neurologic events. All three of these dogs were also undergoing mechanical ventilation, and received other medications, so there is always the questions about a direct link between the benzodiazepine withdrawal and the seizures, however the authors suggest this link follows an expected pattern with abrupt withdrawal in humans and in animals. I agree.

As a general rule of thumb (based on human literature), if I prescribe a benzodiazepine drug for oral use longer than 7 days I taper the medication. Abrupt withdrawal is sometimes called "Jim jams" which, honestly, is a pretty fantastic term but probably not a fantastic feeling. Withdrawal ataxia, cerebellar signs and seizures can be seen from abrupt discontinuation of a benzodiazepine drug.

How do I taper to avoid withdrawal seizures?

CRI:

• Typical dosing range is 0.1-0.5 mg/kg/hr. I reduce the dose by 50% every 12 hours until the pet would be receiving less than 0.1 mg/kg/hr. For example, if we are at 0.25 mg/kg/hr and wish to taper I would start with a reduction to 0.12 mg/kg/hr x 12 hours, then stop, because the dose would then be less than 0.1 mg/kg/hr.

Oral dosing

• Typical dosing is 0.25-0.5 mg/kg PO q8-12hours. If the dog receives the drug for more than 7 days, I would recommend a 50% taper for 3-5 days, followed by another 50% reduction for another 3-5 days and the stop. Cats are at risk of acute hepatic necrosis with oral diazepam administration so I rarely use this medication. However, if you find yourself treating a cat on chronic benzodiazepine drugs, a similar taper can be employed.

Thanks for reading and enjoy your summer! Remember, if you're working with a dog or cat with neurologic disease, I'm an email or telephone call away! Better yet, schedule a consult and we can work through the case side-by-side.

https://onlinelibrary.wiley.com/doi/epdf/10.1111/vec.13221

Update on Acute Seizure Management

"Doc, The Dog is Having A Seizure!"

No one likes to hear those words (not even neurologists). You rush into the exam room and are faced with a convulsing dog on the floor. Here is your preemptive stop and think moment (yay!):

Why do we want to stop seizures, anyway?
Prolonged seizures can result in hypertension, tachycardia, acidosis and hyperthermia with secondary neuronal cell death and hypoxia. These changes negatively affect the brain and may have systemic effects as well. The goals of acute seizure management are to stop the seizure as quickly as possible thereby limiting secondary brain and extra cranial organ damage.

Give me the "Go-To", Barnes!

Look no further than your Benzodiazepine class of drugs. Benzodiazepine drugs (Diazepam, Midazolam, Lorazepam) were introduced in the 1960s for human status epilepticus. A recent human meta-analysis identified that benzodiazepines are the “best” first line IV drugs and identified the therapeutic concentration to be between 150-300 ug/ml. To date, there have not been any veterinary studies identifying which drug is ‘best’ for acute seizure management. We’ve always used benzodiazepines so we continue to do so.

• Rectal, at home care: Home care with liquid rectal diazepam is often recommended for patients at risk for cluster seizures. Compounded suppositories are not currently recommended. Rectal midazolam and lorazepam are not! We also know that chronic phenobarbital use reduced plasma concentrations of diazepam. With this knowledge we recommend dosing rectal diazepam at 1-2 mg/kg if the patient is receiving chronic phenobarbital therapy.

• Intranasal diazepam and midazolam: Intranasal diazepam, using an atomizer, resulted in detectable levels in about 2.5 minutes which makes this drug a viable alternative for at home anticonvulsant care. Midazolam was even more rapid and had a better outcome than rectal diazepam in one study of epileptic dogs so it is currently my drug of choice for at home (or non-IV) care.

All the "cool kids" are using levetiracetam. Should I?

Well, maybe yes, maybe no. Levetiracetam is still considered a new anticonvulsant drug, however its use has been documented in veterinary medicine since 2004. It is considered a relatively safe drug, with few reported side effects. This drug is typically used as an add-on or alternative to intravenous benzodiazepine therapy for acute seizure management at doses ranging from 30-60 mg/kg IV. Adding diazepam and levetiracetam together resulted in improved seizure control in epileptic cats so this is currently my recommended way to give IV levetiracetam. (Unless diazepam is contra-indicated such as with hepatic failure.)
Rectal levetiracetam may be on the horizon according to one study in 2014. However the first sampling time was 10 minutes therefore it is unclear if this drug will be useful in acute seizure management.

Is Propofol Still Used?

Yes, but there isn't any new information. We all like shiny, new things, but propofol does have a place in acute seizure management. There are a small number of published studies addressing this use in veterinary medicine. This drug is only recommended for intravenous use. Care must be exercised when using propofol due to its respiratory suppressive effects. Occasionally, intubation may be required if apnea is encountered during bolus therapy. Propofol withdrawal may result in distal limb twitching which may be difficult to distinguish from seizure activity. Extended exposure in cats to propofol may result in Heinz body anemia therefore a CBC analysis is recommended every 24 hours during constant rate infusion of propofol with cats.

Have a topic suggestion for TidBit Tuesdays? Please reach out!

Need a consult?
Email: barnes@barnesveterinaryservices.com
Telephone: 608-597-0077
website: www.barnesveterinaryservices.com

Happy Father's Day to all of you lucky Dads! Hope you have a safe, relaxing day.

Midazolam vs. Diazepam...Which Drug is Better for At-Home Cluster Care?

Midazolam vs. Diazepam for At Home Seizure Care

History of Cluster Buster Protocols

In 1995 Dr. Michael Podell championed the idea of at-home, rectal diazepam use for canine cluster seizures. In that study, dogs that received rectal diazepam had fewer  cluster seizures compared to those that didn't receive the drug. Since then, at home cluster care has become standard practice for many veterinarians. 
According to human literature, benzodiazepine drugs (midazolam, diazepam and lorazepam) are the "best" first line anticonvulsant drugs to stop status epilepticus. As is typical, we simply adopted this idea in veterinary medicine without data to support it's use. But...the benzodiazepine drugs do show improved seizure cessation so...they probably help in some manner. 

Which Benzodiazepine is Better?

Here is where the science gets a bit muddy. We've compared rectal diazepam to intranasal midazolam and intranasal midazolam was superior. We've compared intranasal midazolam to intravenous midazolam and intranasal midazolam stopped seizures faster. However, all of these studies involved few animals and ethically we cannot have a group of untreated animals to determine true efficacy. 

What are the current recommendations?

At this time, intranasal midazolam at a dose of 0.2 mg/kg up to 3 times in 24 hours is my recommendation for dogs with a cluster or status epilepticus history. Do your best to use a nasal atomizer because this has been shown to be the superior technique compared to nasal-drop application.  (I have found them at Midwest Vet:https://www.midwestvetsupply.com/products). Essentially nasal drop technique requires the client to drip the midazolam intranasal slowly during the active seizure while also avoiding getting bitten. The atomizer looks like a marshmallow that is attached to the end of the syringe and the client is then able to press the atomizer against the nare and dispense the dose in one "push". Not clear on this technique? Please ask me, I am happy to clarify! I do not have a financial incentive or disclosure for this product, or Midwest Vet Supply. :)

Hope you enjoyed the glorious weather a bit last week. I will be closed Friday October 16th, Saturday the 17th and Tuesday the 20th as we celebrate a collection of birthdays in my family. (Including mine!) 

Have a good week! 

Metronidazole and Vestibular Signs

Today is the first day of Fall 2020!
In honor of this awesome season, I thought we'd talk about another type of fall...vestibular disease! :) 

How Does Metronidazole Cause Vestibular Signs?

It is not 100% certain, but it appears that modulation of GABA at the level of the cerebellum is involved. Stay with me...!! GABA is an inhibitory neurotransmitter and there is LOADS of GABA in the cerebellum because it is a largely inhibitory part of the brain. (I like to think of the cerebellum as my mother. As a mother, my job is to "modulate" the activity of my children so they don't get hurt! When you take a step, I tell you how far, how wide, etc. so that you don't trip on a stair. See my point?) Okay, so if the cerebellum is inhibitory to movement, and you remove inhibition, movement gets exaggerated. (Hypermetria, intention tremors, truncal sway!) The cerebellum helps to keep balance in check as well via various mechanisms. Getting back to metronidazole, if we inhibit GABA, then actions become more exaggerated. 

Signs of Metronidazole Toxicity

DOG: Signs of cerebellovestibular disease including head tilt, nystagmus, positional strabismus, truncal sway, hypermetria, intention tremor. 
CAT: Okay, cat's don't play by the rules. They show forebrain signs such as seizures, blindness and mentation changes. Let's not talk about cats today, okay?

Diagnosis of Metronidazole Toxicity

This is both an easy one, and a hard one. There isn't a specific "test" used to make the diagnosis. However, with a history of ANY DOSE of metronidazole within the last 12 hours, one might consider metronidazole toxicity. I have seen several dogs that received metronidazole historically without trouble and developed signs of toxicity on subsequent dosing. I also have seen signs of toxicity at the first dosing sequence at standard doses. It is more likely at higher doses (60 mg/kg/day) but do not exclude the possibility at lower doses. 

Treatment for Metronidazole Toxicity

Stop metronidazole administration! Additionally, you can administer diazepam at 0.1-0.5 mg/kg PO q8hr for several days. Why diazepam? I'm glad you asked! Diazepam is a GABA agonist, therefore it confers more inhibition to the cerebellum. Dogs receiving oral diazepam recovered in 1.5 days compared to untreated dogs that recovered in 11 days. (Evans J, et al. JVIM 2003; 17(3):304-310.) I routinely prescribe diazepam for pets with suspected metronidazole toxicity as a result of this study. 

Whew it has been busy lately!! I hope you are doing well and staying safe. I appreciate what you do to help clients and their pets. Let me know how I can help you manage your patients with neurologic disease.

On site consultation is available Monday through Saturday at variable times throughout the week. Email consults are completed in evenings. 

Have a good week!