That's great. Well, thank you very much for the introduction. And, yeah, this, this final week I had at the start of the course intended to keep it purposely blank so that we could have, a little bit of audience, contribution to, to say what you wanted to, to learn about.

And last week, the audience spoke, and so this is, the outline for today's webinar, the, the topics that we're gonna cover in a little bit more detail in terms of what do we do with them, special considerations, and sort of some of the nuances of, of how we manage them. So, It's actually interesting looking at these topics, because they're all topics that are on the VPIS top 10, reasons that they receive calls. So, it's nice that we haven't picked too, too obscure a topic to kind of cover as well.

So hopefully we'll see, learn things that we can apply to cases that we'll see on a, on a daily basis. Before we move on, we had a really good question at the end of the webinar last week where we've been talking about paracetamol toxicity, and it's a great question. Somebody asked what the mechanism of the facial and the poor edoema that we see in that, that poisoning was, especially given that these patients aren't particularly hyperalinemic and they, they have this sort of specific location.

And, it's a great question. I didn't know the answer, so I thought, I'll, I'll look this up. And, in, in summary, whenever I was a resident and I, I asked a question and nobody really knew the answer, the answer that always came back was something along the lines of the mechanisms poorly understood or or something similar, or it's multifactorial or complex or one of those things.

And I'm afraid I'm gonna have to pull that line on you this evening. As in, I've, I've looked and looked, I couldn't really find anything, as to specifically why this happens in those locations. I looked on, on then and there's some of the, the toxicology diplomats on there, and, and they also didn't know.

So I think we're just gonna have to go with the mechanisms poorly understood, or magic, whichever of those two you want to go with. So yeah, really interesting question. Maybe we'll find out at some point in the future.

So, not really an answer to the question, but maybe a sort of tying up of, of loose ends from last week, perhaps. So on to the things I do know a bit more about, hopefully, starting with metaldehydes. So this is one of those common intoxications or, or things that our pets get exposed to.

And as we probably all know, it's a commonly used molluscaide as in something that we purposely use to kill slugs and snails, etc. Which it does buy, out of interest, a sort of combination of, of dehydration and, and paralysis. So usually works pretty well on, on those mini beasties.

Comes in lots of different formulations, so typically it's the, the greenish blue pellets that you can see this particularly brave creature I'm encountering in the top right of the screen here, but it comes in other preparations as well potentially. But where these different formulations are, are relevant to us is that certainly the the pellet preparations are often formulated with cereals and things like bran and or molasses as kind of sugar. With the aim being that adding that to the bait is supposed to make it more attractive to the snails and slugs, but of course, doing that also has a side effect.

It's making it more palatable to, to typically dogs are sort of the more indiscriminate eaters that we come across as well. So, kind of maybe explains in part why, why this sort of intoxication is relatively common. We've talked a lot during the course of this course that about how important the full toxologic history is.

And again, it applies to this poisoning because oftentimes these products may well have some additional herbicides and various other things in there. Often carbamates are quite common compounds that come up. And so if we know if the owner has the packet of, of the product that they've kind of put down in their garden, it's really good if they can bring that in with them and just so we know that all of the aspects of the exposure have been covered that we're treating all of the things that we possibly can.

So what happens in, in toxicity with metaldehyde? Well, it, it is a common cause of fatality in dogs. Certainly, if, if untreated, then it's, you have to try pretty hard to, to not have a fatality from that.

But of course, we've probably all had those cases that we have had fatalities even in patients that we've treated as well. So quite a, quite a serious, quite a challenging toxicity to, to deal with. And the biggest problem by far is the, the fact that the way that the toxin works is that it readily crosses over the blood brain barrier.

And in doing so, we can see really, really severe, both muscle tremors and, and seizures, and that's the sort of biggest manifestation of this toxicity. For interest's sake, how does that actually come about? Well, again, it's one of those things we don't know fully why it happens, but there's some evidence to say if, if you're sort of interested in, in this, kind of stuff that There is, you do get a decreased brain concentration of GABA, which causes signs because normally that has an inhibitory hole rip inhibitory role, sorry, in, in the sort of general excitation of the neuron.

And there are again studies that show that the lower your GABA level, then the higher your mortality. So it certainly seems that that's a big, has a big role to play. But there's various other neurotransmitters involved as well, that actually can lower your seizure threshold, by alterations in their levels.

So it kind of makes that the GABA effect even worse. So it's actually quite a clever toxin from a slug and snail perspective, but obviously not so helpful and that is applied to our, our clinical patients. Another really big contributing factor to the morbidity and mortality we see in these patients is the hypothermia, and the most likely is due to this really intense muscular activity that we get from the, the tremors and or seizures.

And certainly this hypothermia can reach the level where you can start to get cellular necrosis, and clearly you can't have too much of that going in the body without starting to get organs fail. And again, that's a sort of one-way path once that starts happening in any great amount. So that's a sort of secondary complication but actually can be as big a problem as the, the tremors and seizures themselves.

And we also know that the metaldehyde can affect acid base balance. It's something that I really like talking about, but probably one of the least relevant things on this slide in terms of the overall, pathophysiology, this toxicity, as in, it can cause changes to breathing and we'll touch on this a little bit later. But usually that's something that will just resolve by itself.

So the other things that we've talked about, are the, the most, most significant things in this poisoning. One of the kind of difficulties, and certainly I find with dealing with this toxicity is that time isn't really on our side. And if we have a patient who's ingested a metaldehyde containing substance, we can see clinical signs of that and toxicity really quickly, as in literally within a few minutes of ingestion, which I find pretty incredible, but it's, it's published, it's out there and, and we do see that.

Can take up to several hours, but by several hours we're talking maybe 2 to 3. And so we, we're dealing with quite a short window in which we can have a patient go from normal to quite severely affected. And so that's kind of one of the inherent difficulties that we, we have.

In terms of initial signs that sort of listed here, there's, there's quite a spectrum of them, largely related to the central nervous system signs that become clinically progressive, but also some GI signs to start with and kind of putting these together in the benefit of hindsight, you can look at this and say, well, that's clearly Matalda high toxicity, but if you're ordinarily or in practise if somebody brings in their anxious tachycardic dog with some hyper salivation, there's, there's plenty of other things that that can be. So, Thinking about the progression and, and that sort of focus on progression neurologic signs can be a really helpful clue to say these are clinical signs and consistent with metaldehyde, metaldehyde and toxicity. And of course, we know that as things progress, we do get this really severe muscle tremors.

These patients can be really pretty rigid, and the seizures may be intermittent, but actually can be continuous in severe cases. They can present as if they're, they're in status or looking very, very similar. So it can be a really severe clinical manifestation.

And I should say that all of this that we've just been mentioning is is relevant to the dog. Cats do sometimes ingest this stuff. They're not the, not the most known for being indiscriminate eaters, certainly in comparison to your average Labrador, for example.

But if cats do ingest this stuff, maybe again it's kind of sweet with some of these additives we talked about. They do get similar clinical signs, but their degree of nystagmus is is a lot more pronounced. So that's something that's a little bit of a species difference, but again, it's a central nervous system bias for the clinical signs.

Other clinical signs is this really marked hypothermia that we, we talked about and is obviously something that we can measure, pretty straightforward to do. But if we start exceeding temperatures at which we can get cell necrosis as we talked about, we'll get heat stroke and potentially organ dysfunction of which the clinical signs of that are gonna vary depending on the, the sort of system affected. Further down the line, we might get clues as to kind of other, other organs that have been injured and something that isn't necessarily super well known, but in potentially up to about 5% of cases, they may well get some secondary liver failure 2 or 3 days after exposure.

And so again, we might see clinical signs of that. And as a clinical signer of toxicity, death's a pretty bad one, I think we can agree. And so for all of the reasons that we talked about, it's certainly possible that that is a relevant, relevant clinical sign that we're trying to prevent against right from the get-go.

So how do we diagnose actual Mataldehyde toxicity? Well, If we're thinking about is there a definitive test that we might well do, well, yes, there is, and obviously that can be quite, quite helpful, but it's after the fact, as in we can send away various samples and and things to the toxicology labs that we've kind of talked about accessing it in previous webinars, but There's inevitably going to be a delay to those results. And if we're saying we can get clinical signs within minutes to hours, it's just not gonna be fast enough for that to be meaningful for us in terms of treating the patient at the time.

Postmortem findings clearly not very helpful to treating a clinical patient, but actually fairly non-specific for this kind of intoxication too. So it seems like definitive testing isn't really that helpful. And so largely for me, the diagnosis is based on a history of potential exposure, not necessarily having to be seen to be eaten it, but just being in the environment that they could have gotten into, combined with an acute onset of, of consistent clinical signs.

So typically neurologic signs as we talked about. My index of suspicion goes up a little bit if when you induce emesis if appropriate, or with gastric lavage or even if you see faecal material that these patients pass. If you see blue or green pellets, then again, that means it's a toxin, let's face it.

And if again, that fits with consistent clinical signs, then for me, that's enough to say, let's proceed and treat this as a sort of metaldehyde toxicity. Other things that might raise our suspicion of Mataldehyde over some other toxins are potentially the time of year and what's actually kind of interesting, this is a May webinar being recorded now. Is that 50% of the cases reported to the VPIS occur at this time of year.

I guess this is the time at which the the vegetable patches are starting to look nice, the flowers are coming up, etc. And so there's potential for more exposure, usually around this time of year, and the other peak looks like it happens around October sort of time. So again, it's supposed to be on, on the lookout for appropriate clinical signs at this point in the year as well.

And then I mentioned that I really like acid-based kind of stuff. The other kind of little cheat that that affords you if you're, if this is something that you're routinely measuring on these patients, is that if you have a patient come in with, a metabolic acidosis and neurologic signs and you're not convinced that it fits with it being an ethylene glycol toxicity, then pretty much metaldehyde has gone to the top of the list. So, It's a nice little cheat.

It depends if you're kind of measuring the stuff routinely so that it's second nature interpreting these. But metaldehyde is actually, an acid compound itself, given I think the, the, the first slide had mentioned that it was, a sort of, Made of all of these acetoaldehyde components, and which are a little weak acids. And so if we have too much of that added to the system, that's why we get a metabolic acidosis.

So again, not the necessarily the definitive proof that we might necessarily feel comfortable with, but just clues kind of adding up to the big picture to say, is it likely to be Matilda high toxicity. And there's lots of things that, that we have on our differential list for toxins that can cause neurologic signs of which I've listed just some of them here. So the chemoogenic mycotoxins, and the sort of chocolate derivatives and those sorts of things, remetholin, some illicit drugs, the amphetamines, some of the other things that we talked about, as well.

And so, Hopefully we'll have some kind of idea from other clinical signs of these patients, from sort of toxologic history as to sort of potential exposure to these various things to say, well, we think metaldehyde's most likely. But again, it's kind of good if we can try and narrow this down so we can make sure that we're decontaminating, appropriately and safely, and that the signs of toxicity we're seeing a sort of fitting with the toxin that we think that it is, and also we can advise on prognosis, etc. So, So I said lots of things that can cause neurologic signs, but hopefully as we go to kind of talk about the metaldehyde can hopefully raise its hand and say that it's, it's the most likely in a given case of poisoning.

So what do we do sort of initially, we've got a patient who's been exposed to metaldehyde, and they've come in. Well, In my mind, because the clinical manifestation of this toxicity is, is really quite so bad. And the fact that it's really hard to quantify exactly how much a patient has eaten of this, like they've eaten some pellets in the garden, it's, it's really impossible to know what the sort of the exposure has been.

It's for me, it's a case of saying that all of those patients would benefit from emergent, urgent assessment, because we've been thinking about avoiding our worst case scenario, then that is really irreversible brain injury and, and various complications that we've mentioned. So we need to kind of see these patients as soon as possible and need to kind of manage them to, to guard against that worst, worst case scenario. In an ordinary toxicity, we'd be thinking about assessing the patient being stable and then thinking about decontamination, induction of emesis.

But we've kind of stressed previously that that's only appropriate in asymptomatic patients. And if we're saying patients can get neurologic signs within minutes of exposure, there's a really, really small window in which induction of emesis is, is going to be appropriate. So, I think it's rare that we'll, we'll do that in these patients.

I'm always a little bit worried that if I have an asymptomatic patient, that they might become symptomatic whilst I'm getting my appomorphine ready. And so I have to say there's not that many of these that, I felt I was in that right window for induction of emesis, but again, that's sort of individual patient assessment based on your sort of judgement at the time. If you've got a symptomatic patient or one that for whatever reason we just think induction of emmesis isn't appropriate, then once they're stable enough to do so, then we're thinking about how else can we decontaminate them and typically we'll be thinking about a gastric plus or minus a colorectal lavage just to try and eliminate as much of this toxin from the GI tract as possible.

And this also affords us the opportunity to deposits a dose of activated charcoal as well just to kind of make sure that we're decontaminating it as thoroughly as we possibly can with these guys. One of the kind of the major focuses of emergency treatment of these cases is to get really good, quick, control of the neurologic signs, these, these tremors and seizures. And it makes sense the longer they go on for, the worse the neurologic injury is going to be, the worse those kind of secondary, complications are gonna be.

And we know that seizures are more likely to trigger more seizures, so it's just gonna get worse rather than better. So getting this sorted as soon as possible is in, in everybody's best interest, clearly. Things that we can do I kind of run through the next few slides as to kind of approaches you can take.

And what you'll notice from this is that this isn't really prescriptive as in do this, then do this, then do this because If you have, it would be a pretty bad day in the office if you did, but if you had 10 of these patients and present to you, they'd all have different requirements in terms of drugs that they'd respond well to or or would need. So there's just kind of ideas and kind of suggestions as to things that you can do. One of the things that's often overlooked is making the environment as kind of calm as possible.

And certainly if we're dealing with a stressful situation, just being mindful of that can be, really important to try and have a quiet environment if we can dim the lights a little bit, if we can put cotton wool in ears. It's kind of really simple stuff like that, but just trying to minimise stimulation of these patients, and can really do a lot to kind of, not eliminate, but to reduce their drug requirements, which can only be, a good thing. It's also good if we can get intravenous access and IV catheter up front, but, clearly if they're seizuring, tremoring, rigid that we've talked about, probably not the best time.

So if that's the case, then I'll just go ahead and say, let's, let's give some diazepam as our, our kind of first drug of choice. But I'll go ahead and give that recally. And if we do that, we'll typically double the dose that we give.

So, I typically give around one week per cake and Whilst you can get the little specific rectal diazepam tubes. If you don't have that, you can just use the regular injectable diazepam, but I typically dilute it with a little, little something just to increase that volume to help it be kind of absorbed across that rectal mucosa. And that can work really nicely just to get them a little bit more still so the IV excess is, is more likely to be successful.

Once that's in, I'll go ahead and, and typically consider giving a, a, a bolus of IV diazepam again, kind of Zappa is obviously the TBM kindly sponsoring this really probably go to drug there. Lower dose because it's IV, so typically around 0.5 mg per gig.

And this is, is helping, but it's really incredibly unlikely that this is gonna be enough to sort out the problem as a sole measure. So this is very much a case of trying to get control. It's those first steps to kind of getting control of these neurologic signs.

But it's buying us time to kind of think about what's coming up, in this patient's future. So we can repeat that bolus once or twice, but realistically, that's not as, as kind of sustainable drug approach for these patients. And if it, if I find that this drug is, is working, but then the effect is wearing off, then what can be quite a nice thing to kind of step up to as the sort of plan B, if you like, is a constant infusion of something like midazolam, kind of suggested doses written here for, for that.

Tends to be tolerated, tolerated well from a sort of intravenous infusion perspective with less thrombophlebitis than might otherwise be seen with some other preparations of diazepam. And that can work nicely to kind of get a bit of a steady state and kind of translate that intermittent bolus effect to more of kind of a, a prolonged and controlled response. But again, it's, it's a pretty good day in the office if that's enough to kind of control the clinical signs of these dogs.

It definitely helps, but it's unlikely to get us that, that absolute control that we wanted, that complete cessation of tremors and seizures. So we're thinking about, other agents that, that might be necessary. And then I've listed quite a few things here.

I have to say it's a pretty extreme case that you're going to need all of these. I have seen them and they've been really quite challenging, but it's not my usual experience. It's usually picking maybe one or two things off this list that you might need, but at least you've got options depending on how a patient responds or, potentially based on, what drugs you have in stock at the clinic at the time as well.

One of the drugs I really quite like in these metaldehyde dogs is, is propofol. And if I'm using this, then it's generally in, in addition to the benzodiazepines that we just mentioned. And my strategy will be to go ahead and give a small bolus, intravenously to effect and then follow that up with a, a really low rate of a continuous rate infusion.

And I should say that can be either with a syringe driver, which is, you know, the easiest way, you just draw it up and then you programme your stringe driver. But if you have a drip pump, you can dilute the propofol in, in, in fluids, put it in, you know, insert it into kind of your drip bag, obviously make sure your concentrations all all checked and double checks, but then deliver it like a sort of intravenous fluid, as a sort of another way of getting this drug in as well. And the aim of the propofol is really, it kind of makes sense that we want to titrate what we're giving to the really lowest possible dose.

And This drug makes me nervous and for somebody who does emergency and critical care all day every day, it takes quite a lot to make me nervous, but having patients on propofol, CRIs is, is up there. We know what can, what can happen if this goes wrong, and so, If we have a patient, these patients require intense monitoring anyway, let's face it, in terms of severity of signs that we're dealing with, but If we're having them on a constant infusion of a drug that we know causes respiratory depression, cardiovascular depression, as well as neurologic depression, then we, we really have to monitor them super closely. So monitoring them, getting into that lowest effective dose to try and minimise side effects, but enough that we're getting good seizure control, is, is a sort of finely tuned art that requires a lot of tinkering, basically.

So this patient's needs might well change over the course of time. Another drug that may be considered in these patients, again, not necessarily in all of them is, is phenobarbitone. And if we have a, a patient who, generally speaking, these are healthy animals who've just eaten something they shouldn't, so it's unlikely that they'll be on pre-existing phenobarbitone therapy.

To get them up to therapeutic levels, we'll have to do a so-called phenobarbitone load. So that basically is, is where we give them incremental doses and to get them up to that kind of steady state as, as soon as possible, so within a 24 hour window. And the general strategy with this is that over kind of a 24 hour period, we'd aim to give them somewhere, somewhere in the region of between 20 and 24 makes per cake of this sort of cumulative dose.

How you do that varies. I have seen people give that as a single bolus. I would not recommend that.

It tends to cause massive sedation, if not other adverse effects. What's probably a safer way of doing that is thinking about smaller bolus in the region of, around sort of 4 megs per kg is like a, often a sort of sensible starting point. And then I usually give that every, usually every 4 hours or so, .

Monitoring them to make sure that they're not too sedate, that they can handle it, that I'm, I'm not gonna cause more harm than good by giving it. And sort of keep on going until I've sort of given those, those 6 doses of that. If the patient's tolerating it well and I'm really trying to get more quick seizure control, I can give that more rapidly as, as determined by the patient.

But again, it's very sort of patient dependent as to how long they're, they're tolerating it. One kind of consideration with using this drug though is that there's historically cautions being given for using barbiturates in general in these patients, since there's some theory that they might compete with the enzyme that's responsible for metabolising the acetaldehyde, this kind of active metabolites that is sort of causing all of the trouble. But I think for me, in this case, if I've got a patient who's seizuring in front of me, then that kind of wins in terms of, what's most important.

And there is some debate as to whether or not this ace acetaldehyde is actually the, the only kind of, well, the main toxic principle in this, in, in this poisoning. So for me, if I need to use phenobarbitone, then I'm gonna go ahead and give it. I think getting that seizure control, as you said, is the most important thing.

If this isn't working and or not available, whatever may be happening, then we can think about giving Keppra, kind of suggested doses here, or isofluorine anaesthesia also has been used really quite effectively, in these patients, as well. So hopefully there's something on this list that we'd we'd have that we could use that, that would kind of work in these patients. But Depending on the exact patient, we might need to think about a couple of those on that list.

That's OK. Some sometimes they just need that for that kind of period of time. But while we're kind of setting all of this stuff, we do need to be aware that these patients might well need to be in this kind of sedated or anaesthetized state for around the sort of 1824 hour mark.

And so thinking about planning ahead, is that something we can manage in our practise? Do we have the 24 hour care and would it be better to get a, get a good window of control and then transfer them to sort of, you know, the sister practise, whatever that might be, just the kind of longer term planning as to how we're going to manage these patients. Another kind of class of drugs that I really, really like for these patients is muscle relaxants and specifically, methocarbamol, which, some of you may well have used before or you may well recognised from when we talked about the vets now BPIS tox box in in week one, then this is a drug, the trade name is Robaxin typically.

This is a drug that is included in that tox box. And for me, this is one of the toxicities where this is, is really helpful. And what this drug is, it's, essentially acting skeletal muscle relaxant.

I have to say I, I've had a lot of success with this drug. And when I worked in the States, we actually have this as an IV formulation. I, I really miss having that, to this day, but I, my experience was using it, routinely in cats with permethrin toxicities, where it just worked beautifully.

I can't tell you how well this stuff worked, and I've been a big fan of it ever since. In the context of Mataldehyde toxicity, in the UK at the present time, my understanding is we can only get hold of that in a tablet formulation. So sadly, we can't get the, the, the IV form.

But it doesn't stop us using it. We can, give the suggested doses here will typically if it in sort of mini bolus titrated to effect with crushed up tablets delivered, rectally with the hope that that's being absorbed. And this is a drug that can be repeated up to a total cumulative dose of 330 mg per gig per day.

So you can see there's quite a number of bonuses that we can sort of get throughout the day to do that. This is the sort of label maximum dose that you can exceed if necessary. I have to say I haven't done it, so this will be kind of uncharted territory, but in, in human medicine, signs that tend to be seen at the sort of really high doses are really profound, CNS and depression.

Potentially seizures and hypertension. So for me, I'd need a good argument as to why I needed to go there, but certainly up to that 330 mg per day doses is really quite accepted, quite safe, and quite reasonable to try. Could we consider lipid therapy?

I've kind of been talking about this as one of the sort of greatest developments in, in toxicology. Is there a role for this? Well, There's kind of conflicting evidence as to how lipid soluble metaldehyde and actually is.

And it's one of those things that we do know that this drug crosses the blood-brain barrier, goes into a lipid rich environment, and most sources claim that it's poorly water soluble. So for me that would imply some degree of lipid solubility. But there just isn't literature really supporting its use, which I think is quite telling for quite a common toxication.

Why isn't there the same breadth of literature as we see with permethrins and ivermectins and the kind of situations we know where it works really well. And a kind of search, this week, to my knowledge, there's just a single case report describing its use in a dog, with Matilda high toxicity that hadn't responded to other therapies. But if you get to that point, maybe you're at the point where the dog would have been kind of coming out of the toxicity anyway, so it's hard to kind of show cause and effect.

And there's potential downsides that, the lipid therapy will bind indiscriminate to anything that's lipid-soluble and a lot of these anti-convulsant medications we've been talking about are as well. So, do we give it but risk making, our seizure control more difficult, hard to kind of make an a strong argument for giving it at the moment. So I'd kind of put that on my, my plan, maybe JKL whatever kind of letter we're up to all of these options and, and kind of think about the other things we talked about first.

It's really, really important that we monitor these patients. They are anaesthetized patients effectively, and if we're giving enough of these drugs to depress the neurologic system to get the seizure controls we talked about, it's inevitable we are going to have cardiovascular depression. We need to monitor them for, bradycardia, hypertension, those kind of depressive effects.

We need to monitor their respiratory system in terms of making sure that they are oxygen, oxygenating adequately, that they don't have too much respiratory depression in terms of respiratory rate and effort as, as really potentially common side effects that they might have. And we also need to prevent them getting secondary problems, and this has happened to me in, in a few cases. I have to, have to say that really severe metaldehyde patients that have needed, a, a concoction of drugs to sort of get their seizures under control.

And in doing so, it makes them more prone to aspiration pneumonia. So I've kind of learned from, from kind of those cases and something that I'm really, sort of diligent about doing now is, is monitoring these patients, really frequently for the presence of the gag reflex or if there's any kind of impairment of that. And as soon as there is to say, you know what, if I have to sedate them so much that they've lost their gag reflex, I really need to protect that airway because it, it, to put it bluntly, it really sucks to lose these patients from pneumonia as opposed to kind of the toxin that they, they came in for.

So intubate them we'll have a nice cough tube that will really lessen the risk. And then we just need to be mindful about handling these patients, ideally wearing gloves to kind of handle these, these tubes if they're gonna be in for a period of several hours to kind of prevent any acquired pneumonias, as well. The good news is that if they did have a metabolic acidosis, this is one of the other major things that we talked about is usually that just goes away by itself as this toxins eliminated.

So that's the kind of the good news I wanted to kind of throw in as we're talking about these patients. One of the other big treatment priorities is managing hypothermia that we talked about, and we mentioned how we can get organ failure that pick an organ system and it can basically fail if you have heat stroke, which I'd much rather treat a patient without all of these abnormalities that can happen. Just some of them are listed here, just makes life a whole lot easier.

And so just aggressive cooling if these patients are hypothermic. I like to kind of douse them in, in a sort of tepid water and then apply fans, to kind of Help get that temperature down and giving them fluid therapy with room temperature fluids, nothing too ice cold because that can actually conversely cause some heat retention. And again, getting that sort of muscular activity under control is, is really helpful, in this regard as well.

For me with these patients, it's relatively easy to keep on adding in medications to get them to stop tremoring and and seizuring. I always find the trickiest part is getting these patients weaned off the medications, ultimately. And again, there's no kind of one recipe fits all.

It really is based on the individual patient, how they've, how bad a dose of this they've had, how they've responded, what drugs they've needed to be kind of escalated onto. But I would say in terms of general kind of suggestions, it's unlikely to be successful if we just go cold turkey and turn these drugs off. My experience is they need more of a kind of gentle recovery.

So I'll be trying to kind of wean the drugs that they've, once they've kind of achieved stability and I'm happy that they've been seizure or tremor and free, everything's kind of plain sailing, then I'll, over the next sort of 6 to potentially even 12 hours, start the process of weaning drugs off and My strategy is generally may well depend on stocking and what I kind of running out of. But if I had them on inhalant drugs, I'll try and get them off those first, so they're a bit more mobile and that's just a bit easier once they're off those. Get them off anything that's having more potential for adverse cardiovascular effects, such as propofol and sort of incremental reductions, one kind of suggested dosing regimen here.

But I'll try and reduce the things sort of step wise, and keeping the benzodiazepine infusion to last given that sort of quite cardiovascular sparing, minimal rest or depression, etc. Have that as my last thing and then sort of get rid of that. And the really tricky thing I find about this is, as you're kind of taking these drugs away, they have been under prolonged anaesthesia.

It's normal that they can have some kind of paddling during recovery and trying to assess these patients to say is that return of tremoring activity versus kind of what we'd expect as we come out of this kind of drug coma. That's the tricky thing for me and it might well be trial and error to kind of see what, what happens, what the general kind of progression is. But I said, this is kind of the tricky part that oftentimes we just, we just have to go with how the patients sort of tolerating things.

And then just to finish up this section, if these patients are potentially recumbent for a period of several hours and so they've got quite intensive nursing management requirements, whether that be, eye care, oral care, turning, managing a bladder, checking body temperature, to make sure that they haven't got too cold with cooling, that they're not starting to get hot again if they're having kind of minor muscular tremoring that we're trying to get on top of. And ongoing fluid therapy to make sure that we're sort of keeping those kidneys happy, and that we're monitoring for any organ dysfunction if we think that that is something that, that could well happen as a result of the toxin, as well. If you're interested in this, this is a paper from the vet record in in 2012, but this was an interesting reading.

It's a retrospective study of over 700 cases of suspected metaldehyde poisoning reported to the DPIS these are literally cases being seen in in first opinion practises. It's a lot of kind of reading there, but I took this, this table out of there because it's, for me, it's quite a handy guide to kind of know how patient I need to be with these, these, these poisonings. So the table shows the onset of the various sort of clinical signs, and the duration that these signs tend to last.

So it just shows how quickly things can come on, but potentially how prolonged some of those things could be, especially with regards to, If we're monitoring patients for becoming symptomatic, if we're kind of waiting to see when are they at the woods, this is, this, I find this quite sort of helpful to, to know where I'm up to. And then what's the prognosis for these, these guys? Well, Generally, it can be good if they get, I think that 1st 24 hours is the tricky one.

And if they've got through that 1st 24 hours, that most challenging bit, they've side skirted any kind of organ failure from hypothermia. We've managed to get seizure control, then that, for me, that feels like we're sort of heading towards a win, but It is possible you can still lose these patients, and most often it's due to hypothermia or respiratory failure or cost of treatment. These things that the level of monitoring and this kind of the polypharmacy cases can be really quite spendy.

So there's potentially areas where we can kind of lose them. You said these, these maybe patients we're dealing with for sort of 24 hours or so and we can have sort of complications down the line as well. So, we really want to know is the patient gonna get better and ultimately, we don't necessarily know it's a sort of time will tell sort of thing.

Moving on to kind of the, the latter two toxins that we, we talked about and starting with the non-steroidal toxicities. We know that these are, are really widely used drugs in, in human and veterinary medicine. We know they're quite a heterogeneous kind of group of drugs.

There's probably lots of these drugs that we can think of at the top of our heads. And we know they're kind of good and bad cops. So we know the, the good things we use them for the anti-inflammatory, antipyretic analgesic effects, but we do know that there are some adverse effects as well.

So we do know that they can, in general terms, decrease any sort of protective mucus layer in the stomach and small intestine. We know that we can get basic constriction of gastric mucosa, so specific to the GI tract. And we know that they can inhibit renal blood flow.

So we know that if there's intoxication, there's potential for these organ systems to be injured. And I think what I would say about this is that all of these different non-steroidal anti-inflammatory drugs can have different, kind of clinical manifestations during a, during a toxicity. So some of them, might be more, prone to causing GI bleeding, some might cause more GI perforation, some might be more kind of kidney manifest in their clinical signs.

And so typically, given that signs can vary depending on dose as well as drug, then it's really a a good idea just to kind of get back to VPIS other kind of source of information to say for this exact patient, what is the kind of expected sort of toxologic profile that we're we're looking at in the future. We most likely see intoxication in animals exposed to excessive dosages. So, you know, the, the dog who's found that the remodel is indeed quite palatable and has gone ahead and eaten that, for example.

But patients may have it worse than others and certainly patients with preexisting, volume depletion or hypertension, those kidneys have kind of already primed to have a hit, or if there's pre-existing, underlying disease, again, a sort of toxic effect might be, might be kind of worse. We can potentially see bleeding tendencies, but not because these drugs can affect hemostasis as well as we saw in the previous figure, but usually it's an isolated finding, not terribly common. And whilst you can get sort of quite rare idiosyncratic hepatic injuries with, in, in dogs, specifically carrofem being one of the listed, drugs that has been associated with that.

It's this hepatic injury isn't really in a prominent feature of acute intoxication, so that's quite a, a good thing that we just have to worry more so about the, the renal and, and the GI. With exposure to a non-steroidal anti-inflammatory, we can see vomiting at any dose. But then typically we'll start to see worsening clinical signs with increasing doses.

So vomiting will be the kind of most of them will, will have some degree of that and that will typically progress to signs of GI ulceration and then renal damage. And then we can occasionally see central nervous system signs at at sort of really high doses of some of these agents as well. So clinical signs listed here that we might see potentially quite varied depending on how that toxin is manifest if that be the ulcerative effects, if that be the acute kidney injury effects.

So, quite a sort of range of clinical signs that we might see. And similarly, we might have varied sort of findings on any blood work or other sort of lab work we run on these patients. They can have variable degrees of, of anaemia because of, of GI blood loss.

Same with, any azotemia, which again can vary depending on how much GI haemorrhage we have that sort of affects the urea more so than creatinine. So that may well be very depending on what the patient's doing. And then if there is any renal injury, then we'll kind of see signs consistent with retention of those sort of renal toxins and evidence typically of tubular injury because of how these sort of toxins are working as well.

I think for me that, I mean, there's lots of worst case scenarios if we think about non-steroidal intoxication, but probably one of the not great ones is if we have secondary gastrointestinal perforation. So it's reported to occur as a consequence of, of this toxicity, either with overdose or just it's worth kind of mentioning that we can see this also just with normal dosage, in sort of our clinical patients anyway. So it's kind of same approach might apply to, to those guys as well.

And what's kind of important to know about this is you, if, you know, if I say gastrointestinal perforation, you think septic peritonitis, you think, you know, painful abdomen, vomiting, really, really, really unwell patient and you wouldn't be wrong in the majority of patients, but Because oftentimes the perforation we see here is, is of the upper GI tract, where there's less of a bacterial load in the stomach, we might see quite vague signs initially, certainly something like anorexia, lethargy and appetences. Really quite vague, but could be quite a, a serious, consideration in this sort of patient population, given it could well be a sort of marker of this, this patient, having septic peritonitis and, and therefore being, a surgical emergency. Just very briefly, how do we pick up on this, you know, to make sure that we're not missing our sort of worst case scenario.

Well, if we take abdominal radiographs, then the presence of a pneumo peritoneum, meaning sort of free gas in the peritoneal cavity is, is really patinnemonic to say that if you haven't stuck a needle in there to kind of do a belly tap, in which case it really hard to interpret. But if these are radiographs taken before you poked anything and there's free gas, then something has sort of ruptured inside and, and that really is sounding more surgical and not. So the two yellow arrows here are showing really quite nicely some gas accumulation in the cranial abdomen.

This is typically the area that it's easiest to see. And what you'll see is just more detail than you'd normally expect because you have, air contrasting the soft tissue really quite nicely. So this is, was actually an ibuprofen toxicity dog, that had a gastric perforation.

So this is literally what these patients can look like. Something that can be more of a sensitive marker for looking for evidence of sepsis is, is looking for free fluid. So I think people are quite routinely doing FAT scans to kind of look for free fluid in these patients and if there is free fluid, then getting a sample of that, is really, really important to.

Sort of get the, get the scoop on, on what these patients are, are doing. And certainly doing CAT scans early and later to kind of look for changes and accumulation of fluid over time, is a really helpful way of monitoring these patients, the kind of development of leakage during a period of hospitalisation as well. Ultimately, if we do want to diagnose septic peritonitis, then looking at fluid cytology or free abdominal fluid, is, is up there in terms of diagnostics that's, that we can do, that we can get immediate results from.

And The textbook answer to how do we diagnose septic peritonitis is that we're looking for gene neutrophils with intracellular bacteria is kind of seen nicely on the the cytology figure here, but These patients aren't always the ones that have read the textbook and given that we're talking about upper gastrointestinal tract injury, a known area where we've got probably a low bacterial load because of the natural stomach acid. We might not always see those bacteria. And so they can be a bit of a challenge.

We need, might need to think about other reasons. They might have free fluid. We might need to think about general clinical progression in these patients to say, are they recovering, in which case maybe we'll monitor it, or are they not and therefore we need to maybe be more concerned about this.

But it's, it's oftentimes not as easy to diagnose these kind of perforations as your typical, small intestinal lesions. And whilst in other, sort of sepsis talks, I'm often talking about sort of paired glucose and lactate measurements and various other things that you can do to kind of confirm sepsis. These haven't really been evaluated in this specific population of upper GI tract, lesions.

So it's not something I'd personally feel that confident kind of relying on to, to diagnose that. So how do we manage these patients in, in more general terms for gastrointestinal signs that aren't sort of like that perforating stage? Well, kind of very early on in proceedings, we're thinking about routine gastrointestinal decontamination with charcoal.

Again, bearing in mind that not all of these drugs are created equal, so some of them certainly naproxen is, is one of the kind of the, the baddies, if you like, of the non-steroidals. It's, got a really prolonged half-life in dogs and it has really massive ultrarogenic potential, but it also is really quite markedly, enterhepatically recirculated. So we might need more repeat doses for that than, say, we did an exposure to carprafen.

And we said that vomiting is kind of an early sign in these kind of dogs, . We talked about how normally we'd say that a vomiting dog doesn't need emesiss induction. Well, perhaps if it's a recent exposure, we might get more of a gastric emptying with induction of emesiss if there's no other contraindication.

So again, patient by patient assessment. And early on for kind of treating just gastrointestinal signs in, in general, we're clearly thinking about fluid therapy to treat any volume deficits and reassessing these patients, of course, to make sure that it's our our therapies hit the market's doing what it's supposed to do. Or specific medical therapy for gastrointestinal tract lesions.

Well, this is where the use of misoprostol comes up, and we could have mentioned this potentially in the webinar where we talked about antidotes because this is kind of an antidote for a non-steroidal anti-inflammatory toxicity. And what this drug is, as a sort of reminder is that it's a synthetic prostaglandin analogue that the evidence base behind its use comes in the literature with overdose of aspirin specifically, where it's been shown that it can prevent adverse GI signs and the formation of gastric ulceration. So that sounds pretty good and that has been shown to be effective with aspirin exposure.

We kind of take it a step further ahead and say, well, the same pathophysiology should apply for any kind of non-steroidal anti-inflammatory drug, and we kind of use it in all of these other drugs as well. But it's important to kind of bear in mind that where that kind of literature, where that sort of indication for it comes from. But as it is, we do kind of apply this to toxicity with, with any of these drugs.

Well the most important fact about this drug, if we're thinking about using it, is that it's absolutely contraindicated in pregnancy and prostaglandins and viable pregnancies is not going quite so well together. And so as an absolute rule, pregnant women just should not be handling this drug at all. And so that's a really important consideration.

Dosage wise, if you kind of look this up in a formulary, there's a bit of a dosage range, so between sort of 2 and 5 mcg per kilo orally every sort of 8 to 12 hours. But as a general rule, I'm, I usually stick to around a 3 mcg per kilo limit because at higher doses you can see more adverse GI side effects, so nausea and vomiting and all of those things that we'd be kind of hoping to be getting resolving over time, not getting worse. So I'll typically stick to that sort of 3 mcg per kilo limit and then hopefully that won't sort of confuse matters.

And then less specifically, but also important are proton pump inhibitors, so omeprazole therapy, and antiemetics if indicated and making sure we're keeping up with any ongoing fluid losses as well in these guys. We said that some of these non-steroidal drugs had a tendency to cause more GI bleeding, certainly naproxen, being one of the big ones, but I ibuprofen, and also having quite a decent amount of potential to cause GI bleeding. And so again, based on the toxin and what the patient's doing, then making sure we monitoring the patient's PCV and to sort of get a number on that, but probably more importantly, any clinical signs of anaemia, in terms of heart rate and pulse quality and all of that kind of good stuff.

And this, is some really quite unpleasant looking vomit from a dog who'd received some ibuprofen. I think they'd had an unwell dog gone online, got some good old doctor Facebook advice as to what they should treat their dog, and they'd given us a little bit too much ibuprofen, and this was the, the dog's vomit. And so we can see from this bleeding can be really severe.

To the extent that for some of these toxicities, not all of them, but some of them we might need to think about transfusion therapy to replenish them with, with red blood cells with kind of similar guidance as to we talked about with the anticoagulant rodenticides, as well. So monitoring these patients is, is really important and bearing in mind that Once they've eliminated all of the blood, it's pretty obvious that they have GI bleeding, but these patients can sequester a whole lot of blood in their GI tract, both upper and lower, for quite some time. So if you've got one of these patients really quite unstable, just kind of have a think about could they have sort of, significant, haemorrhage and, usually it will, it will find us eventually if we haven't found it.

And then the kind of the other big injury that these drugs can cause is acute kidney injury as well as we kind of know this kind of poorly looking kidney in the picture here I quite like. And so this is something that's quite common. We'll probably have an idea from a suspected dose if we can figure that out as to whether or not kidney injuries is possible or not.

But what can be really helpful is right at sort of time 0 if we're worried that kidney injury, is a potential consequence is to get a baseline correctly measurement, so we know where this patient kind of sits normally and then we can kind of look for changes over time. Simily with body weight again, can really help us with fluid therapies we'll talk about shortly. So getting this as a baseline can be really, really helpful to kind of build a picture on.

Most of these drugs do undergo more, hepatic transformation in terms of their metabolism rather than renal metabolism. So we're not really using fluid therapy to help eliminate them, but we are using it for sort of renal protection to say, If these kidneys are at danger of, of sort of being injured, then making sure that they're adequately perused is can only be a good thing. So treating them with fluids for around the sort of 48 hour mark, or as needed sort of clinically can be really helpful.

And all the time watching for anything that could make these kidneys be more injured, so avoiding any possible hypertension or other injury to the kidneys, thinking about other drug therapy they might be on, making sure there's nothing else that could have a kidney side effect, just because we want to sort of stop the situation from getting worse. And then we really, one of the kind of earliest things that we'll look for these patients, that would be a sign that their kidneys have taken a big hit and that they are in acute kidney injury is if there's a change in urine output, whether that be excessive amounts of urine, so polyurea, in which case we need to know so we can keep up with fluid therapy, or a decreased urine output, which is, potentially a bit more common. And so really high-risk patients, I'll think about, do I just put in a urinary catheter and have a close collection system and I measure it and then I know exactly what urine output is versus the ones that I'm worried about, but maybe just monitoring, do I just go outside with them with a jog to kind of clutch their urine if they'll sort of Permit that versus do we get them to urinate somewhere specific and try and kind of weigh incontinence sheets, or do we just weigh the patient several times a day and say that if their body weights change, that probably reflects changes in their sort of total body water as opposed to kind of lean body weight changing over time.

So lots of ways that we can kind of monitor these patients invasively or or less invasively, luckily enough. And then with kidney injury, we'll typically think we'll give them fluids. And that's absolutely the case.

We said that there's an indication for giving these patients fluids, but we really need to make sure that we're giving them enough but not too much. And this figure is something that I find really helpful to when I'm approaching these figures that It basically offsets intravenous volume along the X-axis here and rate of complications along the Y-axis here. And we were looking for this kind of optimal spot where we've got a good intravenous volume and that's associated with the low rate of complications.

In terms of our fluid therapy and these guys, we don't want to be over here where we're low on volume and therefore having high complications, but most of the time we think about kidney injury, we give fluids, it's unlikely we're gonna be on this side of the curve. But a real potential risk is that we say they've got kidney injury, let's give them fluids, that's gonna help flush the kidneys out, that's gonna help, you know, maintain perfusion. We'll give them more fluids.

But they go into a fluid overload state, which is actually associated with loads of complications as well. So, whilst we said about we're monitoring urine output, we really need to be mindful of how much fluid is leaving the body in the, in urine versus how much is, is going in, and just making sure that we're not on one of those kinds of extremes of, of the curve there. And simply in general principles, managing these patients and avoiding any hypertension that we can see with acute kidney injury, but There's quite a lot of information out there to say that having a patient being volume overloaded, so having sort of too much fluid having gone in as opposed to kind of come out, is one of the prime reasons why these patients can develop hypertension with acute kidney injury.

So we can potentially save one of these problems from happening with our, our fluid balance, as well. And then to finish up this section, we're gonna be monitoring blood work as well. We said if we have a sort of baseline creatinine, we can kind of see if that's changed over time.

And that's a really important thing to do, but it's worth mentioning that having a creatinine go up is actually quite, it's a sort of functional marker of, of kidney injury as opposed to kind of telling us about early injury. So, This figure is kind of on the, the units used more, more in the states, but if we kind of look over on, on this part of the curve here, we've got creatinine extending on the X-axis and, and GFR so our ultimate kind of marker of of kidney function. We can see in this, this area here, we've got really quite a marked decline in GFR.

We've dropped by sort of, you know, 2/3, but our creatinine is actually just crossing over into being a little bit above normal. So once, what I'm kind of trying to say with this really is once our creatinine started going up, then we've actually got quite a drop in sort of kidney function. So any increase in creatinine in these patients is something that we need to sort of take seriously and, and It's a bit too much outside of the scope of this talk to kind of talk about the ins and outs too much of how we manage these, but they might need more aggressive medical management than just fluids to kind of sort them out if they get to this state as well.

And so a little bit of overlap with that with the kind of the last topic of the day today, which is the, the grape and the the raisin toxicity. And again, this is a toxin that's associated with more with acute kidney injury in dogs, but there are some anecdotal reports of cats ingesting raisins getting renal injury which I have to confess I've never seen but it's worth bearing in mind. And people have looked into this an awful lot to kind of see what the exact cause of this is.

And it seems like grapes from various sources have been implicated, whether that be, sort of private vineyards, organic grapes, commercial grapes, seeds, seedless, all of that sort of stuff. They've, they've all been implicated. But what we don't know is sort of what the toxic principle is.

We know that it affects the sort of function of the proximal tubules and they stop working, which isn't a good thing, but the cells start dying, that kind of all of those cells then, kind of fall into the inside of the, the renal tubules, form casts, block them, stops that kind of nephron working. So it's really quite severe injury that can occur. Potentially it is reversible based on what we know about sort of histopathology, but we do know that some dogs may take several weeks to get renal recovery and the challenge is trying to sort of manage them with that kidney injury to sort of allow that kidney time to, to recover.

And that's the kind of the potential challenge with these patients. The other big challenge is just this very simple question of what actually is a toxic dose of these. And I don't know, is the, the honest answer.

So we, we don't really know what causes the toxicity. We think it's probably something water soluble within the kind of the, the body of the grape rather than the kind of the skin, but lots of theories as to exactly what the toxic principle is. We still don't really know at the time of this webinar.

There also doesn't seem to be a good dose response relationship and we know some dogs that eat a really small amount that have a massive problem, some dogs that eat, you know, live on vineyards and eat grapes as a snack and they're fine. So that doesn't really help us figure it out. And so ultimately, we don't really know what a toxic dose is, and that makes a little bit of a challenge to sort of manage these patients.

And as such For that reason, we sort of have to recommend that gastrointestinal decontamination is recommended after any exposure, regardless of how big or small that might be. As we talked about in an earlier webinar, because these, grapes and so on may well stay within the stomach for quite a long period of time, we might be able to get some yield with emesis up to sort of 6 hours or so after, ingestion. That's worth bearing in mind as we talked about repeated charcoal may be effective too.

And then It's a very kind of similar approach to what we just talked about, so it's kind of nice to kind of group these two together, but we'll think about fluid therapy, potentially for enhanced elimination since we don't really know exactly what's going on inside these guys, but also to kind of protect those kidneys, and thinking about getting baseline readings again. Clinical manifestations of this tend to kind of start with vomiting with, with GI signs, but they may progress to the doctors becoming generally unwell, potentially abdominal pain. And then typically if we're gonna see an acute kidney injury and changes in urine output, usually that's the sort of 48 to 72 hour mark.

And blood work that we'll see if you're kind of watching this happen, then we'll tend to see, changes in, calcium and phosphorus, creatinine being elevated aotemia being seen within 12 hours. And then we might well see hyperkalemia, later on as well. And again, a little bit outside the scope of this talk, but, Although having an acute kidney injury clearly isn't great, this is probably the life-threatening aspect of this toxicity.

And so monitoring for that, is, is gonna be really important. And also treating, accordingly. And I've put this in here just as a, as a reference to say that there's lots of things that we can do to manage that hyperkalemia.

And again, it's about kind of keeping these patients alive long enough to kind of see if we can get some kind of renal recovery as well. So lots of lots of options, thankfully, that we can use to sort of treat these patients. In terms of ongoing treatment, then we said we'll kind of give repeated doses of charcoal if it's safe to do so ongoing fluid therapy, supportive care.

In asymptomatic patients, I like to get a sort of recheck creatinine, a few hours in as kind of listed here just to make sure that they haven't developed an aotemia that, that I've kind of missed. And again, that kind of monitoring if you're an output monitoring creatinine, just exactly as you talked about before and really doing everything we can to kind of stop that volume overload. Kind of signs of overhydration.

It happens. We, you know, it's, I, I know I've done it. I know we, we see it, it happens, we give fluids to these guys and maybe they just don't handle them as, as well at some point.

These are all kind of common signs that we'll see with that, whether that be nasal discharge or chemosis, peripheral edoema and probably it's hard to kind of describe this in kind of a, a webinar, but these patients will often have a sort of gelatinous kind of edematous feel to the skin kind of feels a bit flobby is my non-technical description of this, but they might well see weight gain as we talked about or sort of third spacing of, of fluids as well. And we do know that this volume overload, especially, there's evidence to say in this specific toxicity that it actually will worsen renal function. If you imagine if you've got too much fluid in your body, it's got to go somewhere.

And that well may go into your, your renal, your kidney cells themselves, which stops them working and can turn a patient into one who was producing urine that we can deal with into one who actually has had an extra kind of hit to those kidneys and now isn't. So. If in doubt, if you think that you're putting in more fluids and it's coming out, then it's always worth kind of stopping those fluids and sort of reassessing.

And just find a couple of slides just to finish up. What's the prognosis for this toxicity? Well, again, it's variable.

It seems like the more I look into this toxicity, the less I kind of know about it. So prognosis variable depending on decontamination, how they respond. If they get to the point that they're making urine, making, urine or not still.

If they do have toxicity, then the literature would support sort of around a 50% recovery rate, but we do know that these patients, can have residual renal damage and some degree of chronic kidney disease. So if you do get them over this, if they had that bad acute kidney injury, you do get them kind of over it. They may not be out of the woods in terms of having, sort of chronic, chronic issues on later on anyway.

And if you're interested in this, there's quite a bit of stuff out there in the literature about this toxicity. This was one of the kind of the biggest studies in JaVIn quite a few years ago in, in 2005, but, kind of abstract here if you're interested, again, saying that they around a sort of 50% survival for these severely affected patients. But for me, more kind of useful take home messages is to say that 100% of these affected dogs, who developed acute kidney injury, develop vomiting within 24 hours.

So dog developing vomiting really to get them in to kind of have a look at them. No difference as to how bad things were for grapes or raisins doesn't seem to make a difference. And there were some things that came out of this study that were associated with the worst outcome that we kind of would kind of make sense to us if you're severely hyperkalemic, if your urine output drops, then you've kind of got it worse than somebody who's still making urine, etc.

But it shows that there's quite a sort of variety of treatments out there as well. It does show that some of these are bad enough to actually need more aggressive, medical management to kind of get them through it, of which some can survive that, but sadly, some don't. So quite a severe toxin, but hopefully, early decontamination awareness, all of that sort of stuff will make it less common.

And That's all I've got for you for tonight and for this series, but if there's any questions now if you've got time, then I'm, I'm definitely happy to to take them. Lindsey, as always, that was absolutely fabulous. Thank you so much.

No worries, I'm glad you liked it. Daniela asks, how about using midazolam IM or intranasally without the initial dose of rectal diazepam. This was when you were talking about Mattel died.

Yeah, that's a great question. And actually, I have to confess, I've never done it because I'm a bit scared, is, is the honest answer, Daniela. So there is actually literature out there to say that intranasal midazolam is as effective, if not maybe more than rectal midazolam.

Similar kind of dose, I'll typically use kind of double what my intravenous bolus dose is. But I'm just a bit nervous by the snappy end. I guess I'd kind of rather go with it, the more of the messy end, but actually it can be really, really effective if you can get a good shot.

But yeah, absolutely worth a try. And yeah, as I said, the evidence is there to say it's probably quite a good option. Yeah, I'm glad you mentioned that.

Thanks for bringing it up. Cameron's got a rather long question, but the basis of it is, when you've got gastric haemorrhage, what is the rationale or the logic between combining drugs like omeprazole, misoprostol with sacrofrate then ranitidine, does it work or doesn't it? I mean, there seems to be a conflicting a lot of evidence recently.

Yeah, absolutely. And I think the honest answer is there isn't. There's evidence coming out, which is great, but I don't think it's really answered the question for me to say what is actually sort of best practise at the moment.

So I think I, rightly or wrongly, kind of go with what I was trained, what's kind of the latest that we have. So I'll, I'll typically do omeprazole twice daily and say that that is ether antacid and tidine, and I tend to use ranitidine more for if I want kind of more prokinetic type effects, but we use for antacid. We used to use cross all because I feel like that's the most specific thing it kind of reversing the the toxin and then the I I'm, I think Oh dear folks, we seem to have Developed a sound problem with Lindsay.

Lindsay, I'm not sure if you can still hear me. We, we held everything together right until the end there. I can hear you.

I've just switched off that microphone, so hopefully I can hear you through my computer now. Yeah, a bit on the omeprazole and misoprostol side of it. Yeah, hopefully, I think I was saying that I'll typically prioritise the, yeah, the omeprazole and the misoprostor because I can see more of a rationale for kind of those two and I feel like that's more specific to the kind of the damage that toxin is causing.

If I can fit in sacralfate whilst not impairing the absorption of those, I will, but I figure that's kind of less of a, less of an important thing. And given the other thing I kind of forgot to mention is the misoprostol is given orally. So if I'm got a patient who I'm who I kind of got nausea, vomiting that I'm working, working to control, and if I'm going to give something orally, I'd rather that the misoprostil get in rather than the crafate.

So it's again probably. Probably individual patient as to kind of what I can prioritise and get in, but it's it's a bit of a bit of a minefield, to be perfectly honest. I think you just have to kind of get in there what you can and then hopefully you'll find out a bit more with an evidence base at some point in the future.

But, yeah, great question. Yeah, I think as you said, you, you've got to take this patient by patient because there's so many variations and there isn't any one thing that's guaranteed to work in every single patient. Exactly, exactly, and I mean, it's to be honest, it's a little frustrating because it would be nice to have a, this is what works in this case, but I guess we'd all get bored at some point, wouldn't we, if that were the case.

So yeah, it is, it is exactly patient by patient and you see something new every day, which is great too. Excellent. Loads and loads of comments coming in saying great webinar.

Thank you so much. Absolutely wonderful. Sorry it's the last in the series and so it goes on.

So thank you, Lindsey, for your time. We really, really appreciate you being here with us for this very, very interesting series on on toxicology. Fantastic.

Well, thanks for having me and yeah, hopefully, hopefully it was useful. Thank you very much. Os, just one last thing to say thank you to TM for their kind sponsorship and remember, let's support the companies that support us, to the webinar vets and Dawn, my controller in the background.

Thank you for making everything possible for us. And for myself, Bruce Stevenson, it's good night until the next one.