Good evening, everyone. Welcome to tonight's equine webinar with the webinar vet. I'm Lewis and I'll be hosting tonight.

So, to introduce our speaker tonight, Patrick Burns, following the graduation from the University of Queensland, Australia in 1992, Patrick worked in private practise, an equine referral centre, and his alma mater before completing residency in anaesthesia from the University of Pennsylvania in 2005. He subsequently worked in the USA and Canada at various universities before departing for the University of Edinburgh, where he became the hospital director of the Hospital for Small Animals and head of the anaesthesia Service. His current position is as lead of the equine anaesthesia Service at Langford Vets.

So without further ado, I'll hand over to Patrick. Oh, thank you very much. I'd like to thank, the, excuse me, the webinar vet for, inviting me along to this.

I also need to apologise if I cough. I'll try and, cover the microphone, before I cough, but unfortunately, I'm still suffering from a little bit of a bronchitis. But anyway, let's get started, .

This presentation is concerning the equine standing restraint, optimising the level of sedation. I'm gonna briefly talk a little bit about constant brain infusions, not too much, but just to give you some general concepts to try and follow. Any adjunct therapies that you can add to, the sedation that will help optimise the level of sedation and try to minimise any side effects.

A little. Touch on pharmacology of local anaesthetics, not too much in depth, but . How you can manipulate their pharmacokinetic properties to your advantage, and when things go wrong.

So some of the topics that, don't, aren't really discussed all that often, but to, again, give you a, a little bit of a highlight as to, occasionally when things can go wrong. So, here's a list of indications for standing procedures. My wife happens to be an equine surgeon as well, and, believe it or not, we do tend to get on, despite the barrier in between.

And I find that this list, is growing longer and longer as time goes on. As techniques improve, as equipment improves, pardon me. So this is not an all inclusive list of indications for standing procedures, and I'm sure those of you who are out in the real world, that can add to this list.

So the standing restraint. We've got our advantages and disadvantages, obviously a big one is that you avoid general anaesthesia, I think my wife does this just to avoid calling me. It can reduce your per-operative time, but, the preparation for the standing procedure, etc.

Etc. I sometimes find that that can, really, prolong the the procedure, getting people together, etc. Etc.

The really the big thing, in my mind is that you avoid the, the recovery time. So from a, a workflow perspective, you're not having to, have a number of people recovering the horses for you. And of course they remain standing, so particularly for the geriatric patient that may have other comorbidities, such as osteoarthritis in, in multiple joints, etc.

Or an old non-union sesamoid fracture, etc. Some of the disadvantages, however, I generally find that what's good for the horse is usually bad for us, and what's good for us is usually bad for the horse. You have an increase in personnel risk, and there's always, the risk of over sedation and the horse going down in the, in the stocks, which then, Becomes a different problem.

So the ideal sedative agent is is something that's got a short onset time, short duration effect, a linear dash response. So what I mean by that is if I give a little bit, we have a little bit of effect. If I give a little bit more, I have more more of an effect.

And so it becomes predictable. There's a monoreceptor effect, ideally, short recovery time, easy to administer, minimal side effects and can be antagonised. We're actually not that far off actually from from this ideal.

So if we just conceptualise what generally happens . Is that the surgeon will give a bolus and so our drug levels, On the Y axis will go up very acutely, and then with a single bolus, The drug levels will slowly abate and and be eliminated from the body. What you'll find is that it gets to a point where you need to administer another bolus, and then another one, and then another one.

Etc. And I think you can get the idea. This magical red line is, is the, the level of sedation that's required, this is quite stylistic because as you're doing a a standing procedure, the level of sedation may vary a little bit.

So say for example you're doing a sinus flap on the head of a of a horse. And you've you're just starting and you're creating that little flat. And you're using your osteo osteotomin mallet, and of course you're, you're hitting away on that, osteotome and so the, that vibration going through the head, you're going to need a little bit more sedation at the start, and then obviously once that little flap is open, then, life is a lot better for the horse and so the level of sedation, may be less.

So this red line, red dotted line is a little bit stylistic, but I think it's just here to give you that idea of this is what is happening with multiple bolus. And I generally find that the dose that is required, which you can calculate the dose is the dose under the curve on the dose response curve. So if you look at that area, we've got these little spikes.

And the last triangle that's underneath. But if we were to consider giving a bolus and then a constant rate infusion, you'll see this occurs, so you'll give your bolus, it'll start to wane away, and it'll flatten out. So the purple line, the horizontal purple line that's going out to the right is again stylistic, but that's looking at the ideal level of sedation is for the dose that you're using.

So if we calculate the area under the curve for the purple area, you'll see that it's actually less because we don't have those little tall spikes, for the, as, as you can see on the multiple bolus. So the area under the curve here, as, as I whip my arrow around, hopefully you can see that on the screen, is less than the area of the curve where we've got these tall spikes that are going above the red dotted line. So quite often with a constant fusion.

You can often get away with a lower total dose over time. So when we look at the alpha 2 adrenergic agonists, this is the cornerstone of any sort of standing sedation. We have a number of options available to us.

Thylazine, dine, remiphidine, meatomidine, dexametomidine. Melatoninine is sort of slowly going off the market and it's being replaced by dex melatoninine. There's some subtle differences between the two.

But, excuse me, xylazine, in terms of my experience in North, America was probably the most commonly used. There's some pros and cons against it, and I'll explain a little bit more about that, shortly. And has short duration of action.

Some of the cons are, however, are you've got ataxia, head tosis, so they're they're dropping their head down and the potential for paradoxical excitement. Dodomaine is, is probably another one, that's commonly used in, in, ambulatory practise. It's longer duration, prolonged cardiovascular effects, and it does accumulate.

It's the one, however, that, in the, in the literature that's probably been studied the, the most, just partly because it's, it's relatively old compared to some of the newer drugs like ramiphidine and, dexamenotoinine. But it also has some advantages and disadvantages to use. Remifeine and now being in the UK and in the EU.

It's probably the most commonly used, and it has the advantage of having less ataxia and less hetosis. However, for a constant brain infusion, to me it's not the ideal same with ditomidine in that the long duration of action after one bolus of of that drug, and if you use it as a constant infusion, you will have, signs of, accumulation, so over time the sedate level of sedation will, will increase. There are ways around that, but it does require you to to be manipulating the dose.

Xinomidine, in my mind is probably the most ideal. It's got a shorter duration of, of action and onset. Even compared to metaomidine, because the levo meatomidine that is in with meatomamine metaominine is a mixture of levometatoamine and dexmeotominine.

The levo meatomamine is biologically inert. However, it does compete with dexmedoominine for metabolism. And also interactions with the receptors.

So Theoretically, the dose of dexametotomidine that's required should actually be a little bit less than 50%. However, clinically we don't seem to sort of see that advantage. So I generally recommend about 50% of your metaomamine dose is what you're going to use for your dexametotomatine.

The other thing I should mention is that in the UK, dexam melatoninine, . Is not on the list of drugs for use in horses, so it is off-label, so it doesn't quite follow the the cascade. This next slide just lists a whole stack of ready rechners for you to calculate your loading dose, your infusion rate, and it's making the assumption that you'd like to see an infusion rate of 1 drop per second.

And if you're using a 10 drop per mL administration set to a a theoretical horse that weighs 450 kg. If you are using dexam melatoninine rather than melatonin, again, I would just halve these doses. But that's just there for you to have some idea of how much drug you're gonna need to, to use to be added to your infusion bag.

If I just talk a little bit about deomidine for a moment, this is the one that's been reported and the one that, appears in the literature, at least in North America, the most, you're adding 25 mcg per kilo, to a 250 mL bag, and then you're giving a bolus of 5 to 10 mcg per kilo IV, and you start your infusion at 8 mLs per minute. And then every 15 minutes you're halving it, so the reason for halving it every 15 minutes is to try and compensate for the long duration of of effect. You could do something fairly similar with remiphidine.

However, no one has really sort of studied ramifiine as an infusion rate, at this stage where they're, manipulating the dose. What I've seen so far is that people are are tending to keep the dosage of, of remiphedine the same. That may actually be a bit of a moot point anyway, because when I'm doing a a clinical case.

I'm actually looking at the horse and, and seeing what the response is and asking the surgeon, what do they need to do next, what level of, of discomfort or noise that they're going to do, how much pulling and pushing they're going to be doing. And I try and manipulate that. So sometimes I'll actually slow the rate down and then just before the, the, more critical point, I'm going to increase my rate, get them to a more happy place of level of sedation, and then I'll back off again.

So part of this could actually be a bit of a moot point anyway. Again, this is making the assumption that the level of sedation that's required is, is actually stable. And that quite often that's not the case.

So alpha 2 adrenergic agonist tends to affect just about everything in the body from cardiovascular, respiratory, CNS, liver, kidneys, endocrine. So I'll just mention some of the, the side effects, going on. I think most of us know, in, quite intimate detail about the cardiovascular effects, so I won't go out with that too much, but obviously you get hypertension due to the vaso constriction.

And as a consequence, you may also see secondary AV block. The respiratory effects are usually fairly minimal, you get a slight reduction in your in your ventilation, and that's a central effect, i.e., it's a direct effect on the brain.

You'll see mild increases in your PACO2 and a mild decrease in PAO2. However, if you're adding in, say something like brophenol or methadine, or morphine. These, the level of increase or decrease of the PA CO2 or PAO2 respectively, will increase, as the, opioids are a more potent respiratory depressant, they'll, they'll decrease or reset the trigger point for the respiratory centre.

And we'll also talk a little bit about some of the adverse effects later on, on how the alpha 2s affect the respiratory system. It also causes hypo hypoglycemia due to the inhibition of insulin and all the increase of, of glucogen. Click it on That in itself may cause osmotic diuresis if your glucose levels get higher than 12, you, you're, you're breaching the 12 milli per litre, you're breaching that renal threshold for for glucose, and so you'll start to see glucose in the urine and so you'll get this osmotic diuresis.

But as you can see on the list, there's actually other mechanisms that causes polyuria as well. We have reduced ADH release of production, inhibition of ADH on the collecting tubules, increased excretion of sodium, and reduction of Brennan. So there are multiple mechanisms which cause polyuria.

And some of these individuals, If, if your procedure is going for a period of time, when, say for example, an hour or so, you may need to consider, postoperatively some IV fluids for a little while, particularly in the older animals that, might be a little bit hard to compensate for, it might be a hot day as we have at the UK at the moment, and may pre pre predispose them to dehydration. The other problems that you'll see are ileus and. Excuse me, impactions as well.

So in in order to try and minimise the level of sedation by the alpha 2 adrenergic agonist, we can also add in other agents such as buorphenol. I've listed the, the dosage that I normally use, down there. I've put a question mark.

He tremors, people talk about buorphenol and causing head tremors. I've also seen head tremors associated with the use of xylazine. They'll get quite the head tremor, they'll be bobbing their head backwards and forwards.

So people tend to blame it on butterphenol, so Holly's got the butterphennil head shakes, but this also happens with thylazine as well. You could also use Ace promising, I find that this is quite good, particularly for the older patient, the little poodle, the little poodle, the little pony that's got, metabolic syndrome, these guys have got high levels of, of, lipid in their, in their system. These guys are prone to blood clots, they're hypertensive already.

So in other words, to try and, and blunt that response, a little bit of aromazine beforehand. You'll still get a hypertensive response, but it won't be anywhere as high. So that's why I sort of talk about that for the geriatric patient, that Ace Pradnizine is quite handy, .

To to use for that regard. Morphine or methadine are are are other options. The only problem with these agents is the excitement, so we generally start those after the sedation has kicked in, and then I'll give them slowly.

I have used a morphine IV and interesting enough, even say during an induction for general anaesthesia. So the horses are actually relatively sedate. I've seen some horses, become more aware, more responsive of the surroundings after the morphine.

So I've sedated them, I've given them the morphine, and then you literally see their eyes start to widen, their ears start to prick up, and they'll lift their head a little bit. So that's something that you might, you might see. Again, some ACE romaine beforehand may help counteract some of these apparent increased awareness.

Another option is is lidocaine. I must admit it's something that I haven't done as frequently as some of the other therapies. Again, if, if you are gonna use lidocaine.

As a CRI, a consrate infusion, you do need to be aware of your total toxic dose, so you need to calculate that so that you don't go over, particularly if you're doing a lot of infiltration of the subcutaneous tissues and and muscle layers, be aware that, If you're injecting a lot and then you decide, yes, we will add in some lidocaine, it's very easy that you might overdose. So if you do see signs of overdose, at low concentrations, if we look at the diagram on the right hand side, you'll you'll see some muscle twitching, a little bit of agitation is what you'll, you'll generally see, that'll lead on to unconsciousness, convulsions, coma, respiratory, arrest, and CNS, cardiovascular depression and death. It's, like we always say, death is the end result.

So if you do see those signs of agitation, stop the infusion. Generally that's, that's all that's generally needed. If, however, if you've missed the mark on that and you've been concentrating too much on, on your surgical procedure.

Then you can give them a little bit of diazepam or thiopental, or another reason that might happen is that accidentally the infusion may run in faster than what you're you're hoping. So give them some diazepam thiopental to control the the the agitation, the the twitching and and potential convulsions. And then treat them, just as supportively.

So if they need, need, dibutamine or phenylephrine to increase their blood pressure again, some IV fluids, and, they usually come out of that fairly, fairly easily. Thank goodness, pardon me, I haven't had to do that, all that often. Sorry, pardon me.

So there are a number of different ways you can obviously put the drugs into a bag and drip the drug into the into the horse, but if you are gonna use some adjunctive therapies, you, you could, particularly if you're just going to use a set rate. Then particularly some of these devices work out quite well, and you can use these in addition to the gravity feed. So here's a little little product that that I used to use back in Australia, it's the spring fuser, it's literally just a spring inside these.

This little container, and if you look here, there is a lower lock on the syringe. You attach the fine bore tubing. Down below, this bit, the blue end goes onto the syringe, you've already preloaded your syringe with the amount of drug that you want to give over 1 hour, so in this instance, the flow control tubing will run in 10 mLs over 60 minutes.

So if you have a certain dose that you want to give, you put that in your 10 cc syringe and then dilute that to 10 mLs. You attach the fine bore tubing, the flow control tubing. It's just a a a piece of tubing that's a very, very tiny radius on it, so that creates a lot of resistance, so it goes, it counteracts the spring, you then push, The the plunger of the syringe into the spring fuser.

And then give it a little twist as you're going in and it locks it in place, and away you go. So, on the small animal side, I used to put in my dose of fentanyl into the the syringe, and that would then be delivered over an hour. So it works really great for drugs that, that you'd want to give just for as a concentrated fusion, so you're setting the dose and then moving on.

Obviously if you wanted to get fancy, you could use a an electronic device. So there are many on the market. I just, this Baxter one is, is a, a favourite of mine, it's fairly rugged, fairly hair, and, you can programme the drugs that you use, into the machine, so you, you don't have to keep calculating the doses off the top of your head.

I don't expect anyone to sort of do a procedure without doing some form of local or regional anaesthesia on the horse. However, just to sort of state the obvious, it improves the level of analgesia, reduces your dose of sedation. But also one thing that I just wanted to point out is that it also blocks the stress response.

The stress response is a, when you have no susception or or pain, it'll it'll go in to the brain at the subcortical area, and that subcortical areas, those, those nuclei will then spread that information up to the higher centres in the cerebral hemispheres so that the horse can perceive and acknowledge where the pain is coming from. However, you don't actually need those higher centres for you to have a stress response. The subcortical.

Nuclei will then start to create that, response, without even requiring the higher centres. So what I'm trying to say is is that even horses that have got general anaesthesia on board, Where we've anaesthetize their higher centres, their cerebral hemispheres, they can still have a stress response. So this is very, very important, so a stress response, if severe, will interfere with the utilisation of energy substrates, increase the rate of metabolism.

Increase the risk of, poor wound healing, wound breakdown, etc. So it is a deleterious effect that we can have on our patient and if we don't attend to their analgesic requirements can have, can contribute to to a poor outcome. I just wanted to talk a little bit about local anaesthetics for a second.

On how they work. One thing to appreciate, not everyone realises this, but the the local anaesthetic, if we look up the diagram. When you inject it from the bottle, it is in the ionised form, that's the BBH plus, it gets into the interstitial space.

Once in the interstitial space, it's buffered by the the buffering system within the interstitial, and then dissociates to the non-ionized form, that's the, the letter B and the hydrogen. It's the non-ionized form that then diffuses across into the cell, intracellularly. And then once inside the cell, the pH intracellula is a little bit more acidic, so then it goes back towards the ionised form, and in actual fact it's the ionised form that then blocks the sodium channel from inside.

So they're not local anaesthetics are citing channel blockers, but it's not blocking it from, from the exterior part of the cell, it's blocking it from the interior part. So that local environment, the acidity of the local environment is very, very important. If the outer Environment, the extracellular environment is quite acidic, will actually favour the movement towards the ionised side of the equation, thereby slowing the the rate of diffusion into the cell, or inhibiting it altogether.

So if the, if the tissues are inflamed, or there's very poor perfusion in in that area, that will create a hypoxic environment. And that will lead to accumulation of acids, and that acid environment will affect your local anaesthetics. So that might be one reason if you've got that situation where there is a pulp fusion or or an infected area, why your local anaesthetics may not work.

It's just that acidic environment is inhibiting the, the, the movement of the non-ionized portion of the drug into the cell. So it's a little bit on the, on the complicated side, but I just wanted to point that out to you that that's one thing that you need to consider because the equine veterinarian is so dependent upon local anaesthetics, we just sort of need to take our knowledge up a little bit when it comes to the pharmacokinetics. Of local anaesthetics.

I think I might just leave it at that for the time being. So one way that you can manipulate local anaesthetics, particularly lidocaine. Is that you can add bicarb, 8.4% to your lidocaine.

There's also sodium bicarb 5%. Basically with the sodium bicarbonate at 5%, you just, Double the the volumes that I'm talking about here. By combining that small amount of sodium bicarb, it will change the proportion relative proportions of the ionised form to non-ionized.

It will favour the formation of non-ionized lidocaine. Thereby it'll speed up the rate of onset, it'll neutralise the pH of the solution. Now by the way, the pH of of lidocaine 2% is around about 33.5%.

Sorry, a pH of about 3.5. So by adding in a little bit of bicarbonate, it'll have less pain on the injection.

So this works quite well, but particularly for horses that are a little bit, flighty, a little bit upset, and so you want to minimise the discomfort, particularly during the injection. You could also add adrenaline, 5 mcg per mL, and that'll double the duration of action of lidocaine. This is partly because your vasoconstricting the area in which it's being injected in, so the uptake away from the site is slowing down.

If you do the same thing with buppivica, this has minimal effect on the duration of action of bupivvica. The reason for this is because the duration of action on buppivica is actually longer than the duration of the effect of the adrenaline which you're adding, so you don't get that, benefit from it. So most people generally are adding adrenaline to, to your lidocaine.

One other thing that I forgot to mention is that, you can't just mix the bicarbonate with your lidocaine and then just leave it in the bottle, and then, you know, go to the next case and, and do the same thing again. You, you, you really do need to mix these up in the, in the syringe as you're going, because it will affect the stability of the lidocaine, by the way, so that's part of the reason why in the bottle, the, the pH is 3.5, is that That favours almost 100% of your lidocaine is in the ionised form, so that's the more stable form of lidocaine.

So, and that'll prolong your shelf life. So as I've already mentioned, if you have inflamed tissues, or poor perfusion in in that area, local anaesthetics may not work quite well because the, acidic environment that's in the interstitial space. So I'll just move on to when things go wrong.

I'm gonna talk briefly about the following topics, paradoxical aggression, ascitement, acute respiratory distress. Did I use water for injection, in other words, you're not seeing an effect that you want. I talk about a case study on on overdose, and lastly, human exposure.

This is the, the last topic is is one thing that, is definitely not many people are talking about, and I just want to raise some awareness for everyone out there on human exposure to alpha 2 agonists. So paradoxical aggression. This is when you, you're giving an alpha 2, and instead of becoming sedate, your horse becomes aggressive, it starts to bite you, it becomes a little bit more aware, .

And it's a little bit more stimulated rather than . Being sedated. So don't forget that with the alpha 2 adrenergic agonists, they do also affect your alpha 1 adrenergic receptors.

So if we look at xylazine, It's got a relatively low alpha 2 to alpha-1 selectivity. I'll show you some numbers in a second. The other thing that makes Zylazine different from the the other drugs is that it's not an imidazoline receptor antagonist agonist.

So, when you're considering this, I've, to be honest, I, so far I've only really seen it with Xylazine. I can't recall a case where I've seen it with ditominine or remephidine or dexametlaominine. But I'd, I'd love the the audience to, to give me any feedback if they've seen it.

I think part of that is is because I, coming from North America and and being in the UK for the last 3 years. I haven't, I've used mainly silenzine in North America and, and so far being in the UK I've used mainly reniedine, . I haven't seen any paradoxical stimulation or slash aggression with using remiidine, certainly not with domidine, but.

I surmise that some of the reasons why I'm, I'm only seeing it with xylacine is, is this, low alpha 2 to alpha-1 selectivity, and perhaps the other possible cause is that xylazine is not an imidazole receptor agonist. Imitazoline receptor agonist, which is basically the rest of the alpha 2s, also have some analgesic properties as well. So that could be part of the underlying mechanism, but we don't really know.

If you do see paradoxical aggression, you can just wait for the horse to become calm again before, or to be calm before sedation, . You can combine it with aramazine and butterphenol. Or you can use another alpha 2 adrenergic agonist if if you're seeing this type of behaviour, .

I have seen one case of this when I was at . The University of Montreal in Quebec, and what we did is we gave the the horse a combination of aromazine, brophenol and some diominine, and that calmed the horse right down, to the point where we, we could, get closer to the horse and manage the situation. So that's something that you might see, doesn't happen all that frequently, but it occasionally happens.

One thing that I have seen on a few occasions, in a number of places that I've practised is acute respiratory distress. It's commonly associated with fever, and it has been reported in other species as well. Small ruminants, particularly sheep, there are certain strains of sheep that are very, very sensitive to alpha 2s.

And regardless of the of the dose in in some spec in some breeds of sheep, you'll start to see signs of respiratory distress, even using very low doses. What is happening is that you're getting activation of the pulmonary macrophages. There are alpha 2 receptors on the pulmonary macrophage.

And it's causing degranular activation and degranulation. Of the macrophages, and that's causing an increase in permeability of, of the capillaries within the lungs, and so you're getting these massive fluid shifts across, And so the the compliance decreases and these animals are breathing harder and they're developing signs of pulmonary edoema. So they become tachynic, dysic, you'll hear inspiratory crackles and and agitation.

So the treatment for these is try and recognise the the the situation as as quickly as possible, use an alpha to antagonist to reverse the sedation. However, that, if you've got signs of overt pulmonary edoema, that is not going to change the pulmonary edoema. The only thing that's gonna do that is oxygen for supportive care if you've got it, or furizamide.

So the, the reversal of the sedation is to prevent the ongoing effects and the oxygen and the rosamide are targeting the pulmonary edoema. And what you'll typically see is the horse has been sedated, and I'll quickly get a call about 10 minutes after, saying that the horse has got developing acute respiratory distress. So what I, I do here, this is one situation where I'm using the reversal agents off label, and I'm slowly giving my reversal agent IV.

So, to put that into perspective, Adamazole, the usual reversal agent dose on that is 60 mcg per kilo. The dosage that I'm usually using in this situation is around 2 to 5 mic grammes per kilo. These horses are breathing like a freight train very, very quickly, so I want to try and get them back to a a a a place where their their breathing is, is a lot a lot more relaxed.

I did have a video for that, but I, I, I was afraid that if I tried to stream it via the webinar, that that may slow the webinar down. So but basically you'll see flaring in the nostrils, fast heart rate, increased effort. And what the video was going to show is that within 5 to 10 minutes of of using the antiamazole, the small dosage of adamazole, and even that dosage I, I give slowly to effect because I know that I'm using it off-label, so I want to avoid the adverse effects of the alpha 2 adrenergic antagonist.

And that seems to work quite quite well, and touch wood, so far I haven't had a problem with signs of agitation induced by the alpha 2 adrenergic antagonists. Another situation is, is where you have failure to sedate. The reasons for that might be that the horse is a bit too excited, you've under underestimated the weight, which I've certainly done on more than one occasion.

Your dosage may have been a bit too small for the clinical situation, or there might be a storage problem. So in other words, if you've got it in the in the in your truck, and it, it's not being stored in, environmentally controlled conditions, and it's a hot day, again, coming back to the UK it's a bit of a heat storm, a heat wave over there, . You might get some degradation of of your of your product, due to the heat.

So if you are getting failure to ate, you might consider adding in some other therapies like Aceramaine. You can go slow, so in other words, give the drug a little bit more time to to kick in. Postpone it for another day, consider another bottle, obviously, you could try domidine or or remiinine, some, another, alpha 2 agonist.

And possibly add in an opioid like brophenol or or methadone or methadine, methadone, sorry, or morphine. depending upon what you've got in, in your kit. Just moving on, this is a a a a case study that was written up in the literature, it was based on a pony.

And it was given dittomiine 0.2 milligrammes per kilo IV. I usually use between 0.05 to 0.01 milligrammes per kilo most of the time.

Occasionally you'll go up to 0.02 milligrammes per kilo, but they're usually well and truly sedate on that dose. So this is at least 10 times the highest dose that I'd ever use or consider using the domidine.

The treatment that was given was Adipiazole, 1.1 milligrammes per kilo, I be slowly. Again, if we go back to what I said just previously, the typical antagonistic dose of Adipiazole is 0.06 milligrammes per kilo.

So this is quite a lot higher. And in theory, you want to try and match up your alpha 2 adrenergic agonist concentration that you're giving to equal the tissue concentration of the alpha 2 adrenergic agonist. So you're trying to match those two up, so in other words, all I'm trying to say is, if the, if the animal's been given a higher dose, you want to sort of match that up and give them a higher dose of, of your prednisone.

Again, in these life and death situations, you want to give the drugs slowly, . You could either go the the the the safer legal route of giving them I IM, but if, if needs be, I have given this IV, and you can drip it in. If, if, if you want another alternative instead of giving multiple small little doses, put it in a bag and then just slowly drip it in and, and wait for the desired effect.

If you do have an overdose, you need to consider that you may need to elevate the head because the sedation will cause nasal edoema. With the head being dropped all the time, the nasal cavity will, will swell up. And so that may prevent them from breathing because since they're obligate nasal breathers.

So don't forget that you may need to elevate their head. You'll need to monitor their body temperature because the up to agonist cause a disruption to the thermoregulation. As well, .

So it depends on the environmental conditions as to whether they'll end up going cold or whether they'll go hot, but you need to keep an eye on on what's going on with their, their body temperature. So if you need to, you may have to cool them down or you may have to warm them up, depending upon the scenario. And you'll need to monitor them for signs of ileus or an inaction, so they may need IV fluids, particularly if they've got a longer acting, alpha 2 on on board.

So just talking briefly about the alp two adrenergic antagonists. There are different alpha 2 to alpha-1 receptor affinities. Theoretically you should be able to, should match the agonist with the antagonist, but that is not necessary, to be honest, because the part of the problem is, is, is that you've got, in your practise, you, you don't want to have to have multiple reversal agents, etc.

And to be honest, I, I've used mainly, antiamazole. You know, he is, is the drug that I've used, second most frequently. But, from a financial point of view, it's, it's a bit hard to keep having all the drugs, on the shelf all the, all the time.

You also want to consider the degree of metabolism that's gone on of your alpha 2 agonists that you've given. And ideally you want to reverse to to effect. And what I mean by that is you don't have to antagonise, even in life and death situations, you don't have to actually get them back looking normal.

You just basically want to get them back from the edge, such that they're in a safer, clinical scenario. And that they're in in no immediate danger because it's very easy to go too far the other way and create problems with agitation, gut hypermobility, diarrhoea, colic. Particularly if they're painful, you'll have a sudden reversal of, of analgesia and you'll see the stress response, so they can become quite tachycardic.

So this is just to give you an idea of the relative, alpha 2 to alpha-1 selectivity. Again, I, I wouldn't expect anyone to remember the numbers, but just to, to give you an idea of of relatively from one drug to the next. So sylazine, you're gonna have more alpha one activity.

I tend to think of it this way in terms of the alpha-1 activity. So, to sort of try and interpret what you're seeing. If we use ylazine as the example.

For every 1 alpha 1 receptor that it's binding to, it's binding to another 160. Or detominy for every 1 alpha 1 receptor that's binding to, it's binding to 260. So you can see using that logic, thylaine has got the highest activity on the alpha one, that's why I, I sort of hypothesise that perhaps the paradox of excitement is due to the alpha one activity in the brain, the alpha one activity may be coming on, maybe occurring slightly before the alpha 2 activity, .

And if you Given alpha one agonist centrally. You'll increase your state of arousal. Remember that Aceromazine is an alpha one antagonist, so that's why, Aceromazine, a combination of Aceromazine and the alpha 2 might be, a, a nice way to go to try and prevent that, phenomenon occurring.

And you can see that I don't have a number for Remiidine, but I think off the top of my head that it might be 340 and metaominine dex meatomine is up above 1000, 1620. So the numbers themselves don't really matter much, it's, it's more the relative scale from one drug to the next to the next, . The, the, the advantage of, of having such a high alpha 2 alpha 1 selectivity with the metatoamine dex metatoinine is that you've got that selectivity and coming back to the ideal drug, it's knowing that it's working almost purely on alpha 2 receptors, and if I want to reverse that effect, I can bring, bring that effect back.

So, just to touch on a few, highlights and the dosages of the relative, drugs of the alpha 2 androgen antagonists, you've got telazoline is a non-selective antagonist, it'll it'll reverse all the receptors that it's binding to, so the alpha one, sorry, excuse me, the alpha 2. And the imidazoline receptors, whereas yohimbine and antipamazole only work on the alpha 2 adrenergic agonist receptor. You could give this slowly IV, to be honest, that's what I've given, in my clinical practise, or you could do it, repeatedly IM.

The only downside to the IM is, is that it takes you probably about 1015 minutes, a little bit longer. So, and again, remember that IV is not, is off-label use, so you need to keep that in mind when you make your final decision. So I've just listed some of the adverse effects of each of the drugs.

Probably the main thing that I'd like to point out is with telazoline, I, I would strongly urge you not to use tlazine. It's really not recommended for horses. There have been doses, sorry, deaths in horses associated with tlazolline.

There's also another report that came out of Saskatchewan, with a camelid of some death with with tlazolline. It does work quite well in, in bovines, . So that's, that's the only plus for it.

So to be honest, in, in my clinical practise, and my equine practise, I generally use either Yohimbine or antipermazole, and to be honest, I'm usually using antipermazole just because of the simplicity. I've just got +11 reversal agent so I'm not having to think about multiple, reversal agents. And touch wood so far, I haven't had a problem because of the high selectivity of the adipermazole.

So for example, if I'm reversing, xylazine, I'm, I'm, I'm not seeing any adverse effects from that reversal, due to the effects on the alpha one receptor. So looking at another problem that occasionally happens. Is you might accidentally have an intraarterial injection.

This is something that keeps us on our toes in our teaching environment with students, but it can actually happen with, with anyone and the chances of this occurring increases as you move down, the neck, getting lower, getting closer to the thoracic inlet. The onset time, one of the clues to it is, is that the, it's very, very quick. It's less than 1 jugular brain circulation time, which in the horse, is probably around 30 to 45 seconds.

Clinical signs though, it will literally jump backwards and roll over onto their head. You'll see extreme extensive rigidity, tonic clonic type con convulsions. I have seen this once in my career, it was as a student, .

The only fortunate thing in this situation is that we were actually injecting the horse, with euthanasia solution and so it was going to going to heaven. But, God forbid if this does happen to you, you want to treat the convulsions. So again with benzodiazepines plus minus 5 pento.

11, this is a topic that, that, I would like us all to be aware of and that's human exposure to alpha 2 adrenergic agonists. There are case reports, unfortunately many case reports in the medical literature, some talk about accidental, but sad to say that most of them are talking about intentional exposure where veterinarians have given themselves, alpha 2 adrenergic agonist, either IV or IM. An attempt to commit suicide.

Those accidental exposures, the one that I really want to sort of talk about, I've had one little scam myself, but it it worked out OK. Pardon me. So just realising that you can get exposure via IV IM, ocular, clinical signs surprisingly sound very much like what we see in the horse.

You'll see hypertension, bradycardia, somnolence, hyperglycemia, meiosis, apnea, coma, death. Interestingly enough, when you read the case report on the person, the veterinarian who had the ocular exposure, they, they sprayed xylazine into their eyes, unintentionally. They thought they were washing out their eyes with, with water, and in actual fact they picked up the the wrong syringe.

That person then went on to copiously revise their own eyes. And then continued on working as you normally would try and do, you want to sort of just brush it off. But 4 hours later, that person was, was starting to have clinical signs and they sought medical attention, and, they had to have their eyes bashed, even more.

It will cause blurry vision, so just be aware of that. The treatment for humans, by the way, is mechanical ventilation. Interestingly enough, in in North America, Yhibin and onlyparmoso is not registered as a reversal agent in humans.

So the only course of action that they do is mechanical ventilation. I do apologise, I was going to try and look some of that information up from the UK, European Union. I think there would be a little bit more laxity with people administer administering adipemmazole.

With the Good Samaritan clause, but if you are in that situation, remember that It, it's, it's a, it's a decision that that you have to make, whether or not you are going to self-administer Adipaazole. It's a bit of a touchy subject, and it's highly controversial. Up until recently, if we take a little sidestep over to the opioids, .

I've done also zoological medicine. With some of my colleagues and we'd have this conversation every time we're drawing up some carfentanil oratororphine. Is what, what do you want me to do if if you accidentally expose yourself to these drugs and and up until recently, before the great opioid endemic in in North America.

It would be illegal for for me to administer naloxone to a colleague who has accidentally exposed themselves. In that situation, the, the situation is even more dire because you, you literally only have minutes to make that decision and to administer the drug because the onset time is, is gonna be so short. So this is a bit of a a controversial area as to whether veterinarians self administer adipaazole to themselves.

There has been some recent literature that I've seen where people have given 100 milligrammes of adependazole, just remember that, There's two things that with humans. One is, is that sometimes these exposures are are quite a high dose, but the other thing is that humans are actually less sensitive to apimazole, so the dosage required is is much higher, so. That was in the, in the literature that I, that I read.

There's a recent case review article that's come out in, 2017, 2018, describing, adeppeazole, being administered at 100 milligrammes, as a adult dose. But I'm, getting a little bit off track. I just wanted, people to be aware that if you do accidentally expose yourself, the situation that I had was that, I was dealing with a hole, a fo that, was a little bit rambunctious, postoperatively.

And I was trying to give them a small dose of, of yazine. And they jumped up and and I accidentally squirted the drug out and I jabbed myself in, in the, in the face with the needle, and my my lip went a little bit numb where I poked the needle in. But that was basically it.

My, my wife kept on checking on me and was asking me how my breathing was and what my, eyesight was. But, I, I had effectively, squirted the drug out. So for, for me, it was just the tiniest amount of, of silencing that, was deposited from the tip of the needle.

But please be aware that if you are exposed accidentally, that you do seek medical attention, and preferably get someone else to drive you rather than driving yourself because your vision will be affected. And I think with that I'll open it up to any questions that people may have. Thanks very much, Patrick.

That was a great presentation. I'm sure everyone who is watching found it really, really useful. And thank you so much for taking the time to deliver this for us tonight.

There haven't been any questions that have come through yet. If we just give people a last few seconds just to get any in that they might have. There's been no final questions that have come through, so.

I'm assuming that you've covered everything that they that they'd like to know. Yeah, no, I, I just have to apologise for my cold that I've got. No, don't worry, that's absolutely fine.

Yes, it is an early morning where you are, isn't it? Yes, right, just then in wrapping up, I'd just like to say thank you to Bailey's Horse Feets who are the equine series sponsor. Without them, these webinars wouldn't be possible.

Thank you so much to everyone who's attended this evening. It's been really great. And thank you so much, Patrick, for taking the time to deliver this presentation for us.

That's OK. My pleasure.