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So good evening, everybody. Welcome to March's installment of the SI CS evening education updates. Thank you so much for joining this evening. Um So uh I know that many of you will be familiar with SI CS as an organization. But for those of you who are maybe joining for the first time, the Scottish Intensive Care Society is an organization which aims to enhance the quality of care delivered to critically ill patients in Scotland. And really the way that we do that is through three main routes. The first is education through events like this evening, but also other events in that run throughout the year, research and then finally, audit and standards and quality indicators. We have a variety of membership categories. A for all different types of healthcare professionals. A and they include a number of benefits including a reduced delegate rate at her annual general meeting and access to education and a travel bursaries in addition to comprehensive travel insurance for those of you who undertake hospital transfers. Um Just a couple of things to mention that we have upcoming, we have our education bursaries a which are available for anyone who wishes to undertake a period of post graduate study and that's up to the value of 3000 lbs. The application for that is in the application deadline for that is in a couple of weeks. So if you want more information, have a look at the S IC websites. And then also we have our specific nursing and HP bursaries which have just gone live for the first time. So there are two bursaries, the value of 500 lbs each to allow uh nursing staff and all healthcare professionals to access courses or um or undertake a project which is of interest to them. So please have a look at the website if you are interested. Moving on to our speaker for this evening and we're delighted to welcome Dr and Sans to talk to us about clinical toxicology. Is a consultant, clinical toxicologist and is the past director of the Edinburgh Unit of the National Poisons Information Service at the NPS. Provide clinical advice to healthcare professionals across the UK on management of poison patients via the online database. He's one of a small team of toxicologists providing direct clinical care for patients admitted to Scotland's only dedicated poisons unit at the Royal Infirmary of Edinburgh. And he also contributes to the national on call to providing clinical advice to healthcare professionals from throughout the UK. He is someone who's also got a keen interest in medical education and he's an honorary senior clinical lecturer within the University of Edinburgh, who was the assessment lead for Edinburgh Medical School. He sits on the Medical Schools Councils National Standard Setting Committee for the upcoming ML E exam. Um, and we're really grateful. Thank you so much for joining this evening and I'm gonna hand over to you doctor. Thank you very much. Er, it's a pleasure to be here. Um, I'm gonna spend the next wee while talking about, er, therapeutic poisons and recreational highs. Just given an overview, I suppose bringing you up to date with the current issues in toxicology. I will try and keep an eye on the chat function as well for an answer questions all as we go along if you like and, and, and happy to answer questions at the end as well. Give it some context. Poisoning in the UK is very common. Er, there's at least 100 and 60,000, probably more than that, er, ed presentations across the UK and of course many more people self harm or are poisoned either deliberately or accidentally out of hospital. So it's a huge, er, burden, it's one of the top 10 reasons to be admitted to hospital. One of the top 10 medical reasons to be admitted to the hospital and recent studies that we've done locally in Edinburgh and Glasgow suggest it makes up approximately 10% of ICU admissions. I was quite surprised by that. I thought that was quite high. Um, they are generally short stay durations in intensive care or critical care environments, but it's quite a high proportion of our patients end up in critical care. Um We're the guys who provide talk space for the UK. Um So obviously, that's the um first and foremost er gold standard method of poisons information in the UK. We also have the phone line as backup and talks space is a great information resource, but it's also quite a good research tool actually. And we use it for kind of a proxy measure of the common drugs that are out there and the common drugs that people are taking. So if you look at the top 10 drugs er taken in or top 10 drugs accessed on top space for last year, it's a good measure of the top 10 drugs that are involved in poisoning episodes across the UK. And I'm sure looking down this list, uh you won't be surprised to see the common culprits in there. I haven't put in the figures, but to give you an idea of paracetamol outstrips, all of the rest of them by a, by a huge margin. So paracetamol is obviously our first and foremost, most common drug and also not only for the single overdoses, but for every mixed overdose, paracetamol always features. So it's in basically everything. Um The new kind of ones on the block, the ones that are coming up are things like propranolol, um which is particularly common uh in the last couple of years Um So I'll come back to that later on in the talk. Um if we look at a slightly different list. So this is the list of drugs that reaches the consultant referrals for the toxicology. So there's 17 consultants in the UK that back up that tox space ROTA and the national phone line that provide advice for the more complex cases. These are the drugs that get to the consultant referrals. Again, paracetamol is there, II think that largely reflects it's just so common. And so it's in a lot of the calls that we get, although there are still a lot of complex paracetamol decisions. Um but obviously, then drugs of misuse features quite heavily and then it's all the nasty poisons. Um the calcium channel blockers, the toxic alcohols and the other cardiotoxic agents, bites and stings. At number eight, there is another kind of false one on the list. I think it's there largely because that we have an sop within our service that any bites or stings has to um have a consultant referral. And really that's things like adder bites. Um and other poisonous snakes and things. I know we only technically have the adder that's the poisonous, only poisonous snake in the UK, but there's obviously a lot of um exotic snakes and things kept as pets. Um And so we are reasonably busy with, um with that and these always get a consultant referral. So it appears quite heavily on the list, although it only is a small proportion of our calls. Of course, that's all very well. If you know the drug that you're dealing with nowadays, most of toxicology is taught by Toxidrome. Um, and certainly, uh, the people rotating the trainee doctors rotating through our unit, we always try and teach them Toxidrome. Um, because more often than not, you don't know the drug that you're dealing with. Um And so I think this is probably a great slide that you can easily access on Google if you haven't seen it before, I'm sure probably many of you have seen it before, which gives the five main toxic DRS down the side and the clinical features associated with those toxic DRS. Um uh II, unfortunately, this side is American. So the example agents that gives a lot of them are American agents, but you get the idea and it's quite a good pictorial diagram of the features that you should be looking out for. Um And we're developing talk space um all the time. And so we're working towards a situation where we might have a database that you can not only put the drug in, but you can also put in the clinical features and then it will give you an idea of what drugs um it could take you to. So we're gonna spend the next few while giving you basically a whistle stop tour as a brief introduction there of um toxicology. So I'm gonna talk first about cardiovascular talks. Cos I think that's probably by and large, what a lot of end ends up in intensive care is the cardiovascular toxicity. A little bit about recreational drugs. Cos, I think nowadays we can't do a tox talk without, er, giving a talk about to touching on recreational drugs. And then we're often asked about kind of weird and wonderful cases that we get in on the top on the national ROTA. So I thought I'd add in a few of those slightly more unusual cases towards the end, more for interest. Really cos they're fairly unique. So we'll start telling you about Lisa. Lisa's a 42 year old er, lady and history of hypertension, gout and depression, a fairly classic tox scenario found surrounded by tablets and alcohol, unknown time of ingestion and you're just faced with a lot of empty packets and these are the pills that were found. These are all cases um that I've been involved in locally here in Edinburgh. Um, so Cocodamol, omeprazole, benzo fluide, doxazosin, ibuprofen, simvastatin, dilTIAZem, allopurinol, Mirtazapine, Lisinopril zopiclone and isosorbide mononitrate. So quite a lot of drugs um to work your way through in terms of s standing in a kind of resource environment and this was on admission, she was drowsy and vomited once prior to coming in and was pretty sweaty. Um, P 60 BP on the low side, given we're talking about cardiovascular toxicity. That's probably unsurprising er, Aporia and SATS were fine and a metabolic acidosis on the gas and the ECG just showed a sinus bradycardia. So you're faced with this list of drugs. Um And it's, this is actually one of the commonest calls to. Um our service is we've got a massive big mixed overdose. If you look up talkspace and start printing off all the sheets, you'd be printing off half a rain forest of information. And where do you start and what to concentrate on? And I think that's quite a, that's a very reasonable phone call and we can help direct as to what are the important ones to concentrate on. But if you are faced with a list like this, um and hypertension is the main problem. Clearly, there are a lot of anti uh antihypertensive drugs in there. The take home message is if there's a calcium channel blocker or a beta blocker involved at all, then you can pretty much ignore the rest of the drugs and just concentrate on those medications that either the calcium channel blocker or the beta blocker because they will be the toxic agent. They're associated with such a small percentage of all poisonings, but they have such significant systemic toxicity and mortality that if you deal with those, you'll probably be ok at dealing with the rest and that the management will deal with the rest of the drug. So I would always concentrate on one of those drugs. So in the list on the previous slide that obviously dilTIAZem was there. So that is the kind of top space entry I suppose to follow. So why are they so toxic? Talk a little bit about the pharmacology. So calcium channel blockers, um they obviously block calcium channels um both in the cardiac myocytes and nodal tissue and in the vascular smooth muscle. So the net effect of that when you take them in overdose is you get negative inotropy, chronotropy and peripheral vaso dilatation. But interestingly, they also block the calcium channels in the pancreas. And so the net effect of that is it reduces insulin secretion and you get a state, a hyperglycemic state and a relative hypoinsulinemic state. And that's important when we come back to talking about um high dose insulin, which is obviously one of one of the treatment er arms that we use. Nowadays, there are the two types of calcium channel blockers, the dihydropyridines and the non dihydropyridines. And I think people traditionally think of verapamil and dilTIAZem as as a kind of more toxic drugs than amLODIPine and Nifedipine. Um and that family of calcium channel blockers, but in fact, when you take them in super therapeutic doses as in an overdose, that selectivity of the central versus peripheral effect is is often lost at high doses and you can get both central and peripheral effects. So I think from a to point of view, I would just think of them all as calcium channel blockers and treat them effectively in the same, in the same way. So in terms of treatment, first line treatment, you're in recess. Obviously, cal calcium is one of the first things we would reach for. Um depending on the salt that you have, either calcium gluconate or a calcium chloride, I would have to say from experience the responses to calcium are variable. Um People may have had more positive responses. Um I wouldn't be surprised if you've had variable responses. Um And they can often, if somebody's very toxic with a big calcium channel blocker overdose, they can also the the calcium treatment can often feel quite suboptimal. There isn't really any dose response relationship, either it kind of works or it doesn't. Um But it's a good first line agent because it's easy to hand, it's very quick to get. Um and you can give that while you're getting the next treatment prepared. It's important to be a bit aware of the adverse effects. Um They are rare but they can be serious. So particularly with calcium chloride, there's the risk of extra, obviously, that's what it's talking about in the top picture there. And the bottom case is a, a very rare but very awful case of a a fatal case of iatrogenic hypercalcemia in the treatment of a calcium channel blocker overdose. And this poor patient was given so much calcium, got the calcium up to 8.07 millimoles per liter. Um uh uh before having a cardiac arrest. Um So it's important, obviously, it's a timely reminder to yes, give calcium but, but monitor the calcium level and, and certainly don't overstep the mark and being overly zealous in that treatment. The next kind of thing or another easy access thing that we would often reach for is Glucagon. Um and Glucagon is known to have a, a positive inotropic and chronotropic action and it increases the method by which it increases the cyclic A MP via a beta receptor independent pathway. So it's often kind of traditionally thought as a, a kind of first line antidote for beta blocker poisoning. It has actually got, there are, you know, it has got some evidence in both beta blocker and calcium channel blocker um toxicity. So it has been used for both beta blockers and calcium channel blockers again a bit like calcium. Um, the effects if they are positive, they're often transiently positive and you often get a kind of good initial effect and then it just rapidly wears off. It's very much associated with nausea and vomiting. But the, the commonest difficulty with giving it is um, supplies of it because obviously it's only produced in er, the smaller mini jets. And for this purpose, we need quite a large supply of it. So I'm sure um, you've been in the situation where your kind of hospitals potentially running out or certainly your ward is running out of um, Glucagon and your your pharmacist is sort of panicking about where to get further Glucagon supplies. You may be aware as well. There's a current national shortage of Glucagon. And so, in fact, we've slightly adapted our, um, to based advice. Um, and actually we have very much belittled the use of Glucagon now. And in fact, if I'm phoned on the national rota about a calcium channel blocker or a beta blocker overdose, I would advise against giving it because the evidence is so limited for its efficacy. Um Given the situation with the current national shortage, it should really be reserved for hypoglycemia. And so, in fact, um the slide is really here just to say I wouldn't bother with Glucagon and I would move on to the next agent. So you're going back to Russ back to our patient at recess. We've given some fluids, obviously, um we've given some calcium, we've not given Glucon for the obvious reasons. Um The blood pressure's come up a little bit but 86/48 it's not fantastic, certainly a relative bradycardia as well. The gas is still um a an acidosis and, and those are the sort of blood starting to come back um from the labs and we've got a glucose of 13.2. And that's the next important thing to, to kind of highlight this patient is not diabetic. So they have a relative high paraly. And that is important because we now know uh we know that serum glucose concentrations have been shown to correlate directly with the severity of the calcium channel blocker intoxication. Um And we use this as a marker to s so to see how sick the patient is and you know yourself, when you're in the kind of recess environment, the first thing that's often done when a patient comes in is a blood sugar. Um And certainly when I'm on the calls, taking the calls, I ask what the blood sugar is and I'm often told, oh, it's, it's fine. It's ok. Um, people think I'm asking to check the patient's not hypoglycemic, but I actually want to know the actual number. And if you actually ask what the number is, often it's relatively high and if it is relatively high, um, then clearly that shows the sign of the patient's very sick and often just before they, um, have any sort of cardiovascular collapse, the glucose starts to climb as well. Um, so you can use that as a good marker of, of how sick the patient is. And that brings us on to high dose insulin, new glycemic therapy, which, um, is, I think it's still thought of as a kind of new treatment. In fact, it's been around for, um, 20 years, um, almost 20 years. Um, but it's still very much thought of as a kind of new thing and people are, people are often uncomfortable using it for obvious reasons and I think entirely appropriate reasons because it's such high doses of insulin. How does it work in? Nobody really knows. There are various theories of how it works and it all centers on these three mechanisms and it's likely a combination of all three of them increased inotropy, increased intracellular glucose transport, which is the main kind of hypothesis and peripheral vascular dilatation. Um But essentially, we're talking about heroic doses of insulin. So that's the protocol that we have on the left side, left hand side there. And it's been relatively recently updated again, just to make it more clear because it's such a common source of query about this because everything, all your traditional training is telling you not to give these doses of insulin. So we would give a bolus dose of one unit per kilo intra intravenously over 2 to 3 minutes and then titrate it up, er, start an infusion, sorry and titrate it up to a maximum of about 10 units per kilo. We have a nominal maximum of about 10 units per kilo per hour. Um So in a 70 kg man, that would be 700 units of actrapid an hour. And in fact, I've had a few memorable cases recently where I've, I've certainly been involved in, in, in pushing it beyond the 10 units and I've gone up to kind of 1215 units per kilo. So you're talking kind of 1000 plus units of actrapid an hour. Um So they are eye watering amounts of insulin. Um, people often ask about adverse effects. Um, I've put the main adverse effects there and in fact, the relative, er, risk of adverse effects is, is surprisingly low hypoglycemia is obviously the main one that you'll find or you should find. If the patient is very toxic with the calcium channel blocker, they are relatively resistant to hypoglycemia and you can actually use a relatively resistant, I should say to the insulin. And so hyperglycemia is, is reasonably rare and you can use that as a, as a marker to guide pro progress. So as the patient clears the calcium channel blocker, they will require more and more dextrose to maintain their um blood sugar. And that's a sign that they're clearing the poisons. So you can use it as a, as a proxy measure of how they're getting on. Um You always have to give them potassium because um they're at risk of hypokalemia with the big doses of insulin that you are infusing. And then just a word about stopping it when the patient gets better. Often it's used in either in isolation or in combination with other inotropes. If it is used in combination with other inotropes, we would wean those first before uh weaning the insulin and we now know through a lot of experience of using it that the because you're using such high doses of the insulin, it hangs around for a long, long time. Um When you give it in such super therapeutic doses. So, rather than the kind of traditional weaning approach, we would literally um advise halving it. And then if the BP maintains, then halving it again and just essentially getting off extremely quickly. Because after you discharge the patient and step them down to the medical ward, we do run into problems with the patient having recurrent hypoglycemia from the insulin that has been administered in intensive care. Um So it would just be um it would just be helpful, I suppose when you're discharging patients particularly or stepping them down to the ward, if they have been on high dose insulin to, to make a note and give warning to the ward staff to monitor the blood sugars. Um quite closely certainly for the 1st 24 hours. What about your kind of standard? And I say this in the politest possible sense, knowing my audience but standard inotropes and vasopressors that you guys are much more familiar with than me. Um Really they have the advantage that you're very familiar with them that you use them every day and you like using them. Um II don't have a particular preference as to which agent from a tox perspective. The only thing that we would say is for a calcium channel blocker and a beta blocker overdose, we would very much recommend high dose insulin as the first line agent. Um And then if you need something in addition to that add in whatever agent you're familiar with in your unit, I'd, I'd much rather you guys are familiar with it for all other hypotensive agents, non calcium channel blocker beta blocker agents, then um high dose insulin is not first line. So your normal, your standard inotropes would be first line for non calcium channel er, calcium channel blocker beta blocker poisonings. So that's talking a little bit about hypotension. Um I now want to just move on to the kind of ecg aspect, the arrhythmia aspect um of cardiovascular toxicity. Um This is a different case. Um This was Laura again, classic to scenario found drowsy surrounded by empty packets of propranolol. And I felt I needed to include a propranolol case because I think nowadays I II really think I can't get, I wouldn't have a, a night on call for the MPS without getting a very severe propranolol. Um call, there's just so common now came in with a heart rate of 78 and a BP which was hypotensive um came up a little bit with fluids. You might suggest that that heart rate is quite fast for um propranolol overdose. And in fact, just from experience, we often see that they're not always that bradycardic with propranolol. So she was cool, cool peripherally and a bit of a metabolic acidosis. This was the ECG on admission, um which is not massively exciting, but certainly does have a prolonged QR S er complex ABA broad QR s complex relative for her age. Um And again, just to emphasize the point, it is not particularly bradycardic. So, what about propranolol? So it's considered um I ra I put one of the most, it's probably considered the most er toxic um of the beta blockers and it's quite specific from other beta blockers actually in it, in its toxicity. Um There's been quite a lot of medical presser highlighting the dangers of propranolol. And we know that prescriptions are increasing admissions with propranolol overdoses are increasing and deaths are increasing right across the UK. Um So prescriptions have gone up in the region of kind of 400% particularly since COVID. Um And that's largely because of primary care and prescribing more of it and because of anxiety and things particularly since the pandemic. Um and I think GPS are caught really between a rock and a hard place because they're advised not to prescribe benzodiazepines for the addictive aspect of it. And propranolol gives patients very good symptomatic relief um but it is exceptionally dangerous in overdose. But in fact, there was a safety report from the HSI B um organization in England highlighting the potential under recognize risk of harm from the use of propranolol. And if you look at the date on that when it was published, it was February 2020. So it was just before the pandemic. So things were starting to be noticed about propranolol before the pandemic and certainly, since the pandemic, it's got significantly worse. Why is propranolol so toxic? Um Well, it's obviously a beta blocker. So it has all those beta blockade effects, but it also is a strong sodium channel blocker. Um and a sodium channel blocker in the heart. Um And in the brain, so if you think of amitriptyline, it gives the same sodium channel blockade effect, that amitriptyline does. So you've got the hypertension and bradycardia and that's the beach blockade effect. You've got the QR S prolongation and the ECG and that's the sodium channel blockade effect. And then the convulsions um again, that's just down to the sodium channels. It's always important to know whether it's an Mr preparation or not. Um And because it affects the half life and therefore the length of time that the patient's going to be sick for and therefore, how long to keep an eye on them. So, in terms of treatment priorities, um I've concentrated on the QR S aspect first because I think this is the, the bit that gets often um forgotten about and ignored and this is the bit that's really toxic that causes all the deaths. Um So obviously, you get QR S prolongation if you block those sodium channels, um then you block the depolarizations. You've got the um the action potential diagram there on the bottom left with ECG trace just below it. And if you block the sodium channels, then you prolong that QR S complex left untreated, um you'll develop a broad complex tachycardia and then VF and death. So the treatment for that is sodium bicarb, um high dose, um high concentration sodium bicarb at least kind of 100 mils if the um complexes are long at all, even in the absence of acidosis. And actually, what we're trying to do is drive the patient to be alkalotic. So we want the patient to be kind of a ph of about 7.5 maximum 7.55. Um And the reason for that is it reduces protein binding and reduces it sort of increases protein binding and reduces the amount of free drug that's around um and overcomes that sodium channel blockade. So it essentially renders a degree of cardiovascular protection by driving the patient to be um alkalotic, try and aim to get the potassium and magnesium at the high end of the normal range as well while you're doing that. And so beware that when you give um the bicarb, you're gonna need to watch the potassium, particularly if you end up giving repeated doses of bicarb and very much, you know, give the bicarb and do a, do an E CG and look at the QR S give the bicarb, do an ECG, it's very much cause and effect. And you'll see, hopefully see the QR S complex narrow the beta blockade effect um is obviously fluids, atropine of the R particularly bradycardic. Although that is not commonly a massive issue with propranolol. Interestingly enough. Um Glucagon, arguably that should be in brackets from what I've just said, you know, glucagon has been used, but I can't think in the current situation, we'd probably advise against it but move rapidly on to high dose insulin as we've just been talking about. And then the convulsions again, as I said before, that is secondary to the, the sodium channel blockade. Um So we would treat, treat the convulsions with benzo ASPs for fortunately, they're normally short lived um uh and relatively rare. Um And so we would treat them normally with actually good with any seizures with benzos. And the important thing I guess says that phenytoin is contraindicated. I think phenytoin is really rarely used nowadays anyway. Um but it is a sodium channel blocker in it in its own, right? And so if you um if you've given all the bicarb to treat the sodium channel blockade, and then the patient has a fit and you load them with feto and then you're kind of back to square one with the sodium channels again. Um And so we would always advise not to give phenytoin and Kras fine if I mean, kera is being increasingly used nowadays in this kind of scenario. Um And Kra itself is not a sodium channel blocker. So it doesn't have, doesn't have that same risk. So I'm gonna um rapidly move on to recreational drugs, leave cardiovascular toxicity er behind um for the minute, but by all means, if there's any further questions or any questions at all about cardiovascular toxicity, we can come back to it. So a little bit about recreational drugs. Um, obviously in Scotland, we have a fairly horrendous record when it comes to um, recreational drugs and particularly the drug deaths. Everyone's very familiar with the, the drug death data, which is um heavily, um as rightly, heavily publicized and there's a lot of um funding going in to try and reduce the awful figures that we have from a top space point of view. And I guess from a poisons information point of view, what are we phoned about? Really these three agents? It's opioids, benzos and stimulants and probably by and large is very much about the benzos at the minute. Um in terms of what the common drugs out there are. Um in Scotland, these are just the official figures from the national records of Scotland showing um obviously the the rising drug deaths since the mid nineties. Um There is sort of encouraging scenes, I think to the most recent data showing that things have turned the corner it obviously very early yet say that this is all, you know, this is great things are finally coming down, but certainly for the last few decades, it's the first time that there has been a downward trend, there are various hypotheses why that's happened. Um But I suppose time will tell as to whether that is that persists or not, when you look at the type of drugs um that are involved. Again, it's um commonly, more than one drug, first and foremost, um opioids are most common and, and take up the majority of um the drug deaths or are a result of the majority of the drug deaths. Um But the proportion that involve a benzodiazepine has significantly increased from about 2014, 15 onwards. Um when it, when there was a sharp rise, uh and they've all reduced, as I say in recent data. But really, the benzos is where there's been a sharp rise. But still, it's most commonly about the opioids in terms of the actual deaths. I'm often asked about um the situation in America and whether we have the, the the problem of the synthetic opioids here, you'll, you'll be familiar from the news about the, the major problem of fentaNYL. Um and the other synthetic opioids in, in the States and the significant rise in deaths associated with synthetic opioid use there. Um We don't have the same degree of problem um clearly of the synthetic opioids, but we do and we are starting to see more synthetic opioids on the streets and coming into hospital, clearly not anywhere near the degree as over there, but they are starting to come. Now, um on the left hand side, um this is a um a, a relatively recent paper showing um some of the new synthetic fentanyls, they're all given chemical names around rather than the kind of um street names um down the left hand side and I've highlighted one column there. You'll see at the top, it says relative potency compared with morphine. So it just gives you an idea of how potent these agents are. Um go anything from, you know, a little bit more potent than the morphine up to. You'll see, car fentaNYL about two thirds of the way down, which is 10,000 times more potent um, than morphine. And it was carfentanyl that was repeatedly used in the Moscow State Theater attack by the Russians a few years back. You may remember that they pumped apparently carfentanyl into the state theater at the time to render everyone unconscious. Fortunately, a lot of these very, very potent drugs haven't made it to the UK. Um, you may have been aware on the news recently and public health Scotland have publicized um quite heavily, the niacine er, er, compounds that are, have made it onto the streets of Scotland. Um, and we've certainly seen in our poisons unit quite a few admissions recently with NTO exposures. So the nicotine are a group of, of opioid drugs which are being, are being sold as um er, other agents on the street or heroin or counterfeit tablets is oxyCODONE. Um, and they are particularly potent um opioids and we've, in fact, we've had some of our regular um, opioid users come in um unconscious with respiratory arrest because they've been exposed to um what they would describe as dodgy drugs. But it turns out to be the, the NZ, the NZ component uh N compounds. There's a lot of chat in the talks literature about whether we need to, you know, we've got a wonderful antidote in naloxone. Everybody, everybody recognizes how good naloxone is. But there's a lot of chat about whether with the rise of the synthetic opioids, whether um naloxone is as effective. Uh and whether we need higher doses, whether it's effective at all. Um And there's certainly a lot of discussion in the literature from the states about the efficacy of naloxone for these synthetic opioids. Um I think the take home message is that um naloxone is effective uh is effective for these agents, but you may well need higher doses. Um And so I would urge you, I suppose if you're seeing these patients and particularly you guys are gonna be called because the airway is compromised if you are seeing these patients, um ensure they've had a good dose of naloxone because if they've been exposed to something like the nitidine, it is likely naloxone will be effective, but it's likely that they may need um higher doses than you would normally be expecting to use. Um So it's just to reassure you that um er again that naloxone is entirely effective and, and we're very heavy users of it as you can imagine. But what about the Benzodiazepines? Because the Benzodiazepines is, is ii think where it's all at in terms of on the, the recreational drug scene in Scotland at the minute. So Scotland has a strong relationship with Benzos for a number of years. Um, way back when, you know, benzos were started to be used quite commonly in primary care. It's because they were, they were kind of advertised or promoted as a safer alternative to barbiturates at the time and really as prescribing is increased, um you, you get that diversion to the illicit market and then the rise of the internet has made things just obviously much more accessible. Um and then you can now get them, you know, delivered in an Amazon package to your, to your front door. Um It's all been about er Xanax, which is Alprazolam and Etizolam in Scot, certainly in the Central Belt, particularly in Edinburgh. It's been about Etizolam and alprazolam. And recently things are starting to move on to slightly different benzodiazepines. Um More recently, they're just um oo other drugs of the same family. They often have extremely long half lifes and much more so than, you know, standard diazePAM or LORazepam. Um And so they can hang around for a very, for a very, very long time. Um And this brings me I suppose nicely on to flumazenil. Um So when I was training, um I was essentially told never give flumazenil um for fear of either seizures or arrhythmias. Um And so it's very difficult to kind of get around that because I think a lot of medical teaching for so long has been avoid flumazenil, particularly in a tox patient. Um, but there's been quite a lot of work done recently looking at flumazil and actually trying to establish well, what actually is the risk of flumazenil. Um And if you go back to the original studies in the early nineties and things when flumazenil was been increasingly used, then, um the instance in the literature of the of adverse effects is is relatively low. And if you actually look at the top population at the time that all the studies were done in using flumazenil tricyclic antidepressant toxicity was massive at the time. So most patients that flumazenil was used on for all the trials, uh and all the case reports and all the case studies that were done at the time had ingested tricyclics, which is, which are highly associated with seizures similarly or additionally, um huge doses of um flumazenil were used as opposed to the doses that we would use nowadays. So there is a feeling there's a kind of slight changing of the guard that FMA it's maybe not the, the nasty drug that we always thought it was. Um And we're, we've, we've very much tempered the tox space in vice recently. And so we, and because Benzodiazepines are so common now in Scotland that we've rather than it being a big. No, no. Um we've, we've ad adapted it to say it should be considered certainly to avoid intubation. Um We have put caveats around it. You know, it shouldn't be used as a diagnostic test. It shouldn't be used if there's any risk that the patient is taking drugs which are highly associated with convulsions or any evidence of a drug with sodium channel blockade. So example, for example, propranolol or something like that, that causes that QR S prolongation because then that would suggest there are higher risk of convulsions. So I accept, there are a lot of caveats to it, but it's a perhaps a, a baby steps towards increasing use of flumazenil. And one of my colleagues, er, here in Edinburgh is about to start a randomized controlled trial for patients coming into the Royal in Edinburgh where we're gonna give er, patients blindly flumazenil um along with naloxone to see if we can try and develop um some more confidence with using flumazenil. And who knows it? One, it, one day might be a step towards um take home flumazenil in the way that we have take home naloxone. I've just seen a question about opiates. How do you know if it's, if it's the nits that you've taken um clinically, er, the clinical tox screens that we do from a clinical perspective, don't test that differentiation of the or they don't currently do. Um, there may be developing tests to do that. But currently, for example, in Edinburgh, we can't isolate tis versus other opioids. Um, forensic labs do and research labs do and the police do in terms of the tracking the drug use, but on a clinical basis you don't. Um, so all the patients that I talk about in basics, it's very uh sorry in our unit, it's very much presumptive if you know, they have just required much higher doses of naloxone. And it hasn't really been a clinical picture that we're um that we're used to in terms of waking up quickly. And the patient feels that I've normally managed that dose of heroin. And this, you know, this time I had respiratory arrest, it's very much presumptive. So in terms of clinical tests, um louise, you can't get a ra readily access to a clinical test for me diseases. What about stimulants? Stimulants is the last group that we get called about. And I suppose stimulants is the one that patients are, are properly sick. Um very, very unwell in the kind of critical care environment, um which you guys are, are much more as opposed to see much more of in terms of the recreational group. And really, we worry about serotonin toxicity or serotonin syndrome, um which is the triad of autonomic dysfunction, neuromuscular excitation and altered mental status. Um The little thumbnail there is actually a video which didn't work on the PDF when I obviously, when I flipped it for the slide show. Um But it's just as a reminder to check for clonus whenever you see these patients, clonus is one of the hardest signs, hardest physiological sign of serotonin syndrome. And you just flick the ankles and they'll have sustained clonus if they are sick with serotonin toxicity. Um and they often have nystagmus pouring with sweat, big dilated pupils and a very low BP and look extremely sick. Um But we flick the ankles in all of our patients because even actually, I've been caught out quite a number of times the patient can look physiologically ok from the end of the bed and then you flip the ankles and they're, they're, they've got sustained clonus and it's quite a good sign just to indicate they're still potentially quite toxic from the drug. Why does it cause so much problem? It causes so much problem because of the temperature and the uncontrolled hyperpyrexia and all the downstream effects. The D IC, the rhabdo, the multi organ failure has all been linked back all as a result of that uncontrolled hyperpyrexia. Um initially when the patient first comes in. And so we would do everything we can to try and get that temperature down and that will help the prognosis of the patient. It's very much supportive. Um There is no kind of uh antidote or magic cure. It's just supporting the patient through it, but trying to control the temperature and bring it under control. Um So how do we do that? Obviously, we get them out of um our general wards up to you guys as early as possible removal of any precipitating drugs. Um And this would be AAA reminder just to say, avoid any fentaNYL type drugs. And so fentaNYL, you know, if, if you remove all the recreational drugs and then you start them on fentaNYL as part of their um anesthetic regime. FentaNYL has been associated with uh serotonin toxicity as well. So we would often try and say just avoid fentaNYL. Um and morphine and midazolam is totally fine. Um And that's the kind of combination that we would prefer in this kind of patient group, active cooling ice, Arctic sun, whatever method doesn't really matter, just whatever you can do to get the temperature down. The only thing that has been shown to have good effect, the only evidence based treatment is active cooling and benzodiazepines. So get them on a Midazolam infusion um which has been shown through lots of studies to obviously reduce agitation, which will indirectly reduce temperature and reduce BP, reduce heart rate. And also it has been shown to independently reduce temperature as well. There are some specific treatments that we might advise from time to time. Um Cipro heptadine is the most obvious one which is a five HT two antagonist. So a serotonin antagonist. So logic would tell you it would be effective. Um It's used for migraine normally. Uh a couple of problems with it. It's only available orally. So it has to be given by an NG tube and absorption is often a problem in these patients. Um So you, you can give it, um there's no problem to giving it. It doesn't really have any adverse effects. The evidence of benefit is variable and it, it, you know, it's often given in amongst loads of other things that are given. It's very difficult to know whether it has any actual beneficial effect. But I find myself increasingly giving it um for want of wanting to do something to help. I, I'm never totally convinced whether it has a massively positive effect or not. ChlorproMAZINE also has um five ht five ht antagonistic effects. Um The problem with chlorproMAZINE is it also has lots of other effects on other receptors. Um uh it is available IV so that is a benefit. Um but IV chlorproMAZINE is associated with significant hypotension and these patients often have such a low BP which prevents them from getting from being able to tolerate that er treatment. So there has been some studies in the past and you will find papers out there that advise using Chloroma, but we very, very rarely advise giving it. Um And it's actually quite difficult to get hold of as well at the minute in terms of IV chlorproMAZINE. So really your options are fairly limited to cooling uh benzos and potentially Cipro heptadine and then it's just very much supportive care and trying to support the patient through it. Uh, I'm just gonna end, hopefully, uh, I'm aware of time. I'm, I'm a, I'm acutely aware, I've also rattled through this but, um, II wanted to, um, to, er, get through a reasonable amount to me. Hopefully keep it interesting and give you some, a, a few slightly more unusual cases. I've got three cases that have been particularly interesting recently. They've all happened locally, um, over the last, um, few years. So the first one is a 54 year old male. These kind of tick the box of the weird kind of tox cases. 54 year old male intravenous drug and alcohol misuse a good going history of that. And he was going through a very, um, er, bad time in life and, um, did some deliberate self harm to his wrists in the shower, um, with a knife with the intention of trying to make himself bleed out in the shower. Um, and he collapsed and his wife called an ambulance. He came in, um, conscious, lightheaded and breathless into recess in Edinburgh and he was obviously pretty anemic. His liver and kidney function was normal. Um, and er, he was assessed by, um, vascular and orthopedics and things and his, it was described to me as his tendons were flapping in the wind in his wrists. And so he needed to go to theater and prior to going to theater, he had a chest X ray and Russ and this was his chest X ray. And so the doctors went back to him and said, you've clearly been doing something else. What have you been doing? And at that point it emerged that he had injected metallic mercury into hi. Yes, absolutely. Metallic mercury into his groin. So he worked as a lift shaft engineer um, in the eighties, er, and Lyft used to use mercury tilt switches, which is a picture of one there. And his job was to change all the mercury tilt switches into electronic switches. And he at the time thought the mercury tilt switches were in inverted commas cool. And so he kept them uh so he removed them from all the lifts and kept them. So he had a whole supply of mercury tilt switches in his house. And then when he became unwell, he decided to smash all the mercury tilt switches onto the kitchen table, get a needle aspirate up the mercury and inject it into his left groin. Um So you can see in the Abdo x-ray at the top where he injected it and he inject, he injected it by stabbing it multiple times, um just willy nilly into his leg. Um and he um obviously had mercury in his ankle there and you can see in the ct of his head, he had mercury in his head. Um and that was his mercury concentration with the reference range and brackets. Um when we got it back. So this has clearly caused a lot of excitement within the talks unit as we've never seen. There's only about, um, there's very few cases of this and there are, there are, there are cases in the literature, but there's about um about 15 or 20 cases published in the literature before in the world. And so, um this caused quite a lot of constipation and he, his x-rays appeared on lots of x-ray meetings in the hospital at the time because everyone was quite interested in his x rays. Um Unfortunately, I can't show you a moving picture of his echo um because it's a PDF, but this was his heart and a massive bit of mercury sitting in this tricuspid valve inside his heart, which was flapping around. Um And so he started to develop heart failure and things in, in, in the ward. And he had, you know, there was a lot of discussion nationally. So we involved in all of our consultants across the UK and how to treat this. What does mercury do? It won't bore you with the details, but it basically causes mitochondrial injury at a cellular level and shuts everything down. Um And he, he had heart failure, liver failure, renal failure and actually gut failure and he ended up his gut just um he ended up having uh relentless diarrhea and really difficult metabolic disturbance because his gut just effectively shut down. Um We tried to chelate him. So we gave him D mps, which is an IV chelating agent. Um As you can see, the red bars along the bottom are the days in which we gave him the IV chelating agent. The blue line is the urine mercury that we managed to bind and he peed out and the red line is his blood mercury level. So you can see that despite us giving chelation, it did absolutely nothing to his blood mercury level because it was just so high that despite the fact that we were getting rid of some, all of the mercury was just redistributing um from his um extravascular space and, and bones and things and into his blood. And it really made very, very little difference. So we got less than 0.2% of the total body load of mercury out. Ultimately, he actually got discharged at about a month. Um was well that DMS A is the oral version of chelating agent and we sent him home with tablets to take. And so we sent him home w inverted commas well, at a month and he, he was readmitted a month later, exceptionally unwell and unfortunately, then had a, a six week admission at which he died at the end of it. Um really due to the effects of of cellular shutdown throughout his entire body, a multiorgan failure. And he died in one of the medical wards. There is a slightly black humor ending to this story, um whereby I was, I looked after him for the whole time and I was very keen and it was an awful, one of the junior doctors described it to me as a kind of three month suicide. It ended up being awful um because he really regretted the actions and he got better mentally, but there was nothing that we could do to prevent his kind of demise from the mercury. Um And I wanted to learn from it and was very keen to get a post mortem to establish exactly what was going on. And actually, I'd had a chat with him as well and he was keen to for his case to be published and, and, and you know, for, for us all to learn from it. Um but I discussed his case with the pathologists and um we raised, they raised concerns about the safety of the post mortem. So if you swallow mercury and pull it out, mercury doesn't cause a problem. If you inhale mercury, that is the most dangerous way to be exposed to mercury. Clearly, you inject it. It's not good either, but the most dangerous is if you inhale it, it's raised the very important that once they would put their, their saws and drills, heat would create heat coming in contact with the mercury in his body would create a vapor and vaporize the mercury and really put them at risk of mercury poisoning. Uh And so the decision was made um between us and the pathologist and the procurator fiscal cos obviously, the death had to be reported that the risks of the post mortem were too great. And so his death certificate just said mercury poisoning. Um and we didn't really get a, a clear understanding of what was going on um on a, on a kind of pathology level. Um It still wasn't the end, however, because I then I had this kind of pregnant pause at the end of that conversation and said just out of interest, is he being cremated? Uh And there was a slight pregnant pause at the end of the phone. And um there was absolute, I can only describe it as absolute panic because his cremation was planned for the next day in Edinburgh. And they were saying, well, if the post mortem was too dangerous because of the mercury vapor and they were about to cremate him. Nobody was quite sure the safety of the, of the, of the cremation. Um And in fact, I discovered to my knowledge that um to my education, sorry that um a few of the crematoria in Edinburgh have mercury, mercury filters on them for mercury amalgam fillings in your teeth. Um And so they felt that this, this one patient would put them well over their year annual restriction of mercury. Um But he was cremated the next day in a crematoria that had a mercury filter on it. Um But if you're living in that area of Edinburgh, I'd suggest there might have been a mercury cloud over that, um, crematoria that day. The second case. Um, I'll be very quick so I'm aware of time. The second case, er, was a 55 year old British National who, um, went to, er, Serbia, he was a power technician. Um, and, er, to you and I, that's a fireworks expert. He went to Serbia to do the New Year fireworks display in Serbia. Um, and on hogmanay, there was an accident and he got significant burns to his um, torso and lower limbs and he remembers the firework going off. Uh and then he remembers walking to the ambulance and then, and doesn't remember anything after that. And he went to the, he went to the local hospital and then he got transferred to the British Army base in, in Serbia. And so that was obviously staffed by um British doctors who obviously normally use to basin. So they phoned us and I happened to be on call and they phoned us in the UK and said what they were dealing with and he got taken to theater to sort out sort out all his wounds. But his main problem um was he had profound hypokalemia and significant cardiovascular instability and muscle weakness were his kind of three primary complaints. Um And you can see he had continuous potassium infusion right throughout the day. And in fact, for, for full 24 hours and his potassium never got above 1.5 despite continuous potassium infusion. And so there was a lot of sort of um chin scratching about what was going on and we established um that he had, it was a green firework that had exploded. In fact, it was a green and red firework that had exploded right beside him. And barium is putting green fireworks to make them green. And strontium is putting in red fireworks to make them red. And he had barium poisoning from massive systemic absorption or dermal absorption from the barium uh firework. So we know that barium induces significant hypokalemia. And there are a few case reports of this equally. Um again, and it blocks the potassium uh rectifier channel and you basically get intracellular trapping of potassium which leads to the depolarization and paralysis. Um And so he was essentially paralyzed. Um He required ventilatory support. Um but he got aggressive potassium replacement and then ultimately, he got dialyzed and dialyzed dialysis resulted in I II significantly improvement. I mean, he got better within kind of 12 hours um of 22 sets of four hours on the on the dialysis machine. And he was massively better. It just removes all of the barium and then you get me the metabolites all, all all normalized. After that, the progress is he's, he's from, he's from locally from here in Edinburgh. And, and so this obviously happened on the first of January 2018 and you can see his barium level there and the reason the bottom two are in red is because of the bottom two are the ones that we did back in the UK. Um, in clinic here, the black ones are the ones they did in Serbia. Um, and you can see his barium level has come, has come right down. He's also got strontium a, a relatively high strontium level. Uh, that doesn't really do any er cause any toxicity. Um but the barium level is, is significantly dropped. Last one, a couple of slides, er I couldn't end without giving this case. This is very local. It only happened very recently, 17 year old uh female inpatient psychiatric patient in our local psych hospital, she ingested e needles from the tree um and then did the on a home visit um and then came back to the psych hospital and ingested the e needles at about midnight one night. And then in the middle of the night vomited had a seizure and the um emergency team were called and she was transferred to the um to the recess er of the adult hospital of the medical hospital where she had episodes of PVD and got ro um with one shock at that point um and then progressively deteriorated following after that. And no, there are people on this call who are involved in that case, quite a memorable case. So what is, what is you the Yew tree is probably the most toxic plant in the UK. You'll find yew trees everywhere, particularly around graveyards. And that's because the medieval days were known to be um poisonous. And so they were planted around graveyards to keep it toward away evil spirits. All parts of the yew tree are toxic, particularly the red berries which you'll see in autumn which kids often pull because the yew branches grow very low. Kids pull them off the tree and eat them. If you don't chew and you just swallow the berry and pull it out the other end hole, you'll probably be ok. But the problem is if you chew down into the berry um and release the toxins inside and it obviously, as you can read in the slide there, it causes significant cardiovascular toxicity. All of the use is poisonous. In fact, she collected up needles and ingested the needles and you don't have to ingest very many needles to have significant toxicity. You can see from her ECG S um she was in a bad way. Um and her echo um was fairly awful um showing severe LV impairment. Um what I would say about this case, um particularly, I mean, obviously all the treatments down there on the left hand side, on the right hand side, you can see the people that were involved and it's kind of admirable. Actually, the, the the the massive team that was assembled very early in the morning. Um to give this patient the best possible care um for a quite an unusual case. So she had lots of BICARB cos that's our standard treatment for the broad complexes. I have to have, I have to be honest. Um I think the feeling from the clinical team at the time was that the BCAR didn't make a massive amount of difference. She had adrenaline, obviously an amiodarone and, and shocks when required. There is some data to say that digi fab is helpful. She didn't require it or she didn't get it on this particular occasion. Um, er, ultimately because I think she was started on ECMO and that kind of took over things, but there is some evidence to say that deab because of the, the similarity with um, er, with Fox Club and cardiac glycoside poisoning that may be of benefit, but ultimately, she was put on ECMO and in the interest of time, I'll just basically summarize what was a five day admission, but effectively, she got very much better quite quickly on the ECMO and by day two was extubated neurologically intact. Um, she unfortunately developed a DVT um secondary to the ECMO line. Um, but she was ultimately stepped down to the Toxicology ward and transferred back to the, um, psychiatric er, hospital. I would say that um, we actually get a relatively, relatively often calls about, about you poisoning and certainly everyone within toxicology, um, is very familiar with Yew trees being um, very toxic and it's always a worry. Uh, and it's normally Children and it's normally because the berries look so poison. It looks so nice to eat. Um, because they're very brightly colored. So, I suppose it's just a timely reminder about how poisonous plants can be as well as the drugs I'm gonna end there. I hope that was interesting. I am aware that I flew through it. Um, but I hope it was interesting and it was enjoyable. Thanks very much. I've just answered that last we question. Um How did the digi work against the toxicity in classic toxicology? Um Nobody's quite sure it's due to a structural similarity between the taxane to the taxane um toxic component of the re and the cardiac glycoside poisoning of the Foxglove plant. Um And so the digi bind is felt to um bind the toxin. There are, you'll, for every case you'll report, you'll find a positive effect, you'll find equally number of case reports saying it doesn't work. Um But as with all things, when it's a case like that, everything in the kitchen sink is often thrown at the patient in the hope that it might help. Thank you so much, Doctor Sanders. That was absolutely fascinating presentation. Um You've already answered a few of the questions. If anyone's got any other questions, please pop them in the chart. Um I see we've already got one from Owen Smith. Um asking uh what is the training route for toxicology. Er, so it's through, traditionally it's through, um, I'm a physician. Er, so it's through, er, clinical pharmacology. It's part of, it's a clinical pharmacology and therapeutics. Um, and so it's, it forms part of that. There is a move actually that, that toxicology there is a move with the nerve, especially the feeling of toxicology should be a kind of an additional training for people in intensive care, for people in a, and for people in acute medicine because it's really those kind of specialties that see a lot of talks. But at the minute, we're still, we're still within clinical pharmacology and therapeutics. So that was the kind of route I went down. Um So thank you. Um I was just wondering, yeah, it would be good if there was some um component of the CM training and that went through toxicology. Um We've got another question from gen service. Is it only Mr drugs that might result in be traditionally y yes, I wouldn't say only ever it's never 100% of the time. Um I think, I think the worry about bezoars is more, is probably disproportionate to the, the amount of time it actually happens. Um Not, not inappropriately. So, but I think particularly um for the kind of if the patient has prolonged effects, then we get, then we obviously get worried about bezoars. Um The times I've seen it before, the real problem bezoars that I've seen has always been actually recreational drugs potentially causing bezoars. Um And that then that's really tricky because you have no idea really what you're dealing with and patients very unwell. Um We're interestingly on that note, gem, we're updating our whole bile irrigation advice at the minute to try and get around that problem to improve the advice about just washing the patients out. So if there, if there is any concern about Bezos, it's huge volumes of polyethene glycol solution to try and get rid of the substance and wash out before ongoing absorption happens. But to answer the simple question, not always, Mr but probably more commonly. Yes, thank you. No, that was, that's really interesting for me to hear as well. Um We've got, we've got loads of questions coming in now, um, er, has asked, are there any short training courses in toxicology that would be useful for anesthesia, trainees managing the itu I know any kind of resources that you could recommend. Uh Unfortunately, there's probably not any short short training courses. There are training courses available. Um They're not the ones that are available are not short, they're not necessarily always directed at critical care and they're also not cheap. Um, and so for that, for that reason, I wouldn't necessarily advise them for what you're looking at. Um, what I would say on a more personal level is certainly in, in Edinburgh, we are delighted to host any, er, trainees or people that are interested in talks, er, for a period of time and we have in fact hosted a previous IC UST six for a six month post before organized by their TPD S from the West. And it worked exceptionally well. Um, and so we're always open to host people even just for a week or a few days if you're interested to come and spend time and hang out in the poisons unit with us. Um, so that's very informal. There's not really so much that's formal. I'm afraid at the minute. Thank you. And I think that was part of the medicine year as well. Um And yeah, I've heard good things about doing that. Um Gilli is also answered in for that question. There are the SI CS modules for ICU topics that might be of interest to anyone who's watching, um who wanted to do a variety of different topics. Um Jean is asking how high is a high dose of naloxone that we should be expecting to use for the synthetic opioid OD. Uh I wondered if someone was gonna ask that I was aware when I was speaking about that, I deliberately didn't mention doses and that's, that was partly deli it was deliberate, it was a deliberate action on the basis that it's very difficult to know. Um It's very difficult to give you an exact, a precise answer for that on the basis that um with street drugs, you don't know the potency for as we've just explained in the talk. Um We don't know whether it's only just opiates um by and large in the, in the recreational drugs seen at the minute in Scotland, it's probably most likely to be a mixture of opioid and benzos. Um And so you could end up giving big big doses of naloxone. And um and there's still being a benzyl component to it. And so the patient now we really kind of fully waking up. Um II think simple question. It's not that uncommon that we get called on the national ROTA and the patients maybe only had literally only had 400 or 800 mcg of naloxone. And I'm like, no, no, no, you need to at least get two naloxone is not effective. So um just to encourage you, I suppose if you, if there is a strong suspicion that opioids give them at least a couple of milligrams before you're thinking, actually, it's maybe not, it's probably Benzos, but I would, I'd caveat that by saying at the minute, the drug seen at the minute is so heavily towards benzos, there's probably gonna be Benzos in there as well. Um But I suppose on a on a G CS point of view, we have found ourselves managing patients on the and avoiding critical care by almost reversing the opiate component. And the benzo component is means their airway is safe enough to avoid intubation if you see what I mean? So that's how we've kind of managed it. Um We've got another question about the, um, NS showing up on urine screening. Um, unfortunately, from a clinical perspective, they don't show up. They're, they're too, they're too new. Um, at the minute, um, what you find is the clinic and there's also funding as well. At the end of the day, these things are funded from a clinical perspective. Is there any, is there any advantage to knowing it's unseen over another opioid from a clinical perspective? Io obviously, there is from a public health perspective, but from a natural point of managing the patient, um there's arguably not. Um And so at the minute, it doesn't show up in urine screening as separate from other opioids. Um There may come a time that it might, but it's probably too early yet. Thank you. Um I think that might be the last question. Thank you so much for um for tonight and, and that fascinating talk and answering all those questions obviously really popular. Um I can see that Gillies popped the feedback link for everybody in the chat. So if um everyone could fill that out, please and um just watch the space for the next evening update. Thank you again, Doctor S for joining us and I hope everyone has a nice Easter take care.