Great, thank you very much, Bruce. Good to be back. Welcome, everyone.

I hope you are all well and coping with the many challenges thrown up by the current pandemic. I'm sure you all have heard that the latest news on the benefits of dexamethasone administration to help manage, oxygen-dependent patients with coronavirus pneumonia. And most of you, I'm sure are wondering about the risk benefit of giving such a drug to a viral infection.

This is why I love this fascinating group of drugs. They always throw up a a new use, a new quirk or a new challenge, to accepted thinking. And during this talk, I hope to shed some light on the evidence or lack of it behind our current practise with glucocorticoids.

And perhaps ask some searching questions, about how we, we use them. Perhaps at the end, you, you might want to reflect on some of these questions with your colleagues and, consider, consider what, what, changes in your, your, practises that, that you might want to, to think of, because I think, it is, it, there is a lot of art in the use of, glucocorticoids, and it's helpful if we're all singing from the same, song sheet. So I'm gonna start with a reintroduction and then I'll talk about some, things that we need to think about before we start treatments with glucocorticoids, and then how we start treatment and then how we adjust doses, and I'll finish off with a little about when not to use steroids.

And finally, we'll bring a summary altogether. I'm hoping this will take, about 45 minutes, which would give us a few minutes for questions. What are glucocorticoids?

Glucocorticoids are are natural hormones, produced by the adrenal cortex, and, the most, famous of those now is, is cortisol, but it was actually cortisone, the, inactive metabolite that is converted to cortisol and back and forward. It was originally discovered by Kendall Reichstein and hench, hench being that the actually, who first used this, cortisone to treat, patients with rheumatoid arthritis. And it was a game changer.

And, and one of the phrases that came out of that time was therapy is now dated BC before cortisone and AC after cortisone. And that really shows the effect that this, work had. There are other glucocorticoids, naturally produced.

These have much less effect than, cortisol, such as the, the cortisol precursors. Why do we have cortisol? Well, we have cortisol for, have had cortisol in evolutionary terms for a very long time.

very primitive fish have, cortisol, and in those, animals, they use it for, water balance. And, and what's happened over time is not that cortisol's changed, but rather the way animals use cortisol has changed. So that now, we don't use cortisol, for water balance.

We have aldosterone for, for that. But now we have, cortisol as, the, defence against stress hormone, really. the major stresses that, that, animals face, in terms of their survival is starvation and disease.

And cortisol, counteracts many of the harmful effects of starvation and particularly acute inflammatory disease, and you may start thinking, aha, that's why we can use it in coronavirral, pneumonia. As a therapeutic, thing, the, the, the cortisol exists there to protect us against stress. It is your body's natural antipyretic.

Yes, so we have fever, we have pyrexia, cortisol levels rise and limit pyrexia, limit fever, so it doesn't become, a severe hypothermia. We have aesthetic analogue these hormones, prednisolone, very close to cortisol, and prednisone, very close to cortisone. Methylprednisolone, dexamethasone, betamethasone, are, are available as veterinary licence preparations.

Triamcinolone is, is not available as a systemic glucocorticoid, for small animals, but is widely used in, human medicine and in some other, species. Mainly we use prednisolone. I think it's worthwhile just, just touching briefly on prednisolone to say that it is a rapidly absorbed.

These drugs are all rapidly absorbed, but more so if they are in the presence of food. So, it's important to give steroids with food. The absorption is very variable and leads to a wide variation in measured plasma levels.

So, so one tablet of prednisolone given to one dog achieves a very different plasma level to another dog. There is a dose dependent effect, but it's nonlinear, and that is to say that it can take really quite big increases in dose to get small increases in plasma levels. And that's because these drugs are highly protein bound.

But the plasma levels are not that important because it's the amount that gets into the cells and exerts the biological effect that lasts, that, that, determines the length of action. So the, the plasma levels may only last for prednisolone, 4 to 8 hours, but, the clinical effect may last a lot longer. So there's no value in therapeutic monitoring of plasma levels.

We have to measure the biological half-life, of these drugs. What we know is that the biological effects are proportional to the suppression of the hypothalamic pituitary axis. So the more effect that you want, the more effect you get on the pituitary.

And therefore, we can monitor, the, the degree of, effect by monitoring, the HPA . A suppression, which we can do by ACTH stimulation tests, which we can do by ACTH assays. We won't do this in clinical practise, but in terms of trying to work out the pharmacology, these tests are, are more important than measuring plasma levels.

Having identified a steroid, we can then alter those steroids with adding on a methyl group here, fluoride here, something like that to alter these, these drugs, and these can alter quite profoundly, the length of action, the binding to various receptors and so forth. In some countries of the world, prednisone is still the major glucocorticoid used in the clinic. And that's because prednisone is very cheap to make.

It's much cheaper than prednisolone. In the UK, prednisolone is used. Prednisone is a pro-drug and is converted to prednisolone.

But there are species differences in the ability to do that. So cats, for example, do not convert prednisone to prednisolone particularly well. And prednisone, therefore, does not work very well in cats.

And this sort of species difference between glucocorticoids, is important to remember when we start to think about, how much we really actually know about these drugs. If we take the base model of cortisol, and we add, for example, here, a, a, a flu, fluoride molecule, to get betamethasone or dexamethasone, which is structurally very similar, then you can see that, by just really small changes, you can achieve very great changes in the duration of action. prednis alone, is, is, also, also modified and these lead to very different effects.

So if we take hydrocortisone, which is, which is cortisol, essentially, and we look at prednis alone, then we can see that there's immediately an increase in glucocorticoid effect with a commensurate fall in the mineralla corticoid effect. And the equivalent dose, therefore needed to achieve the same effect comes down. If you fast forward to, to betamethasone and dexamethasone, you can see a dramatic increase in glucocorticoid activity and an almost complete absence of mine.

A corticoid activity and a much increased duration of action. So it really does matter which, which steroids we choose. It really does matter.

the small structural changes, in terms of receptor binding and we'll come on to talk about how that is. Leukocorticoids have a wide range of effects on the metabolism. They get their name from their ability to antagonise insulin.

and that relates to their ability to, or their, or their function, should I say, in acting as a defence against starvation. If you're starving, the last thing you want is insulin to be active. And so you, you use glucocorticoids to counteract that that effect.

It has, they have effects on protein and fat and calcium, on other hormones, almost everything that they need to get, the body through a period of starvation or, or disease. They will have some, water and, an electrolyte, effects, particularly, when you start looking at, the, the aldosterone, of course, but even cortisol has some effect on water and electrode homeostasis, and of course, suppressing, immunity, suppressing particularly inflammation. The effect of steroids on the immune system varies considerably with which part of the immune system you're looking at.

So for example, T cell memory is probably rather poorly affected. Dogs that are vaccinated. Retain the ability to mount a response and the face a challenge even when they're given steroids.

And that's why it is, it is not unreasonable sometimes to administer steroids to animals with or humans with viral infections. Our use of steroids, is, probably they're probably some of the most widely used drugs in, in clinical practise. I don't think, the only thing I can think of would come close would be antibiotics.

in 200 Peter Hill did a survey and found that 20% of dermatology consultations ended with the administration or the prescription of steroids. I find that result almost surprising, not because it's high, but because it's as low as that. And if you look in the literature, in the textbooks, and in the, in the, in the human pharmacology textbooks, there's actually an enormous amount written about the chemistry of these drugs, about their action, and about their, they, they use, but very few conclusions about how one should go about using, .

in the more general case. And, steroids are without a doubt, the drugs that drugs that are given for the widest variety of reasons, by the widest range of routes and by the widest range of doses. We use antibiotics, for, for many different conditions, many different routes, but the doses tend to be, static.

we use very variable anaesthetic doses, but, the reasons are always the same. Analgesia, same thing. Steroids are some of the few drugs that actually combined both a wide range of reasons and a wide range of doses.

And whenever I, I talk to vets about steroids, we always have to talk about the cost-benefit analysis. Little dogs like this coming in, that, that have got, extensive signs of calcinosis, cutis, hydrogenic Cushing's syndrome, all down to, veterinary, veterinary prescription of, steroids, are, are, are not on. Common, and we recognise that there is a, there are risks.

We have a kind of love hate relationship with steroids. Let no dog die without steroids is often heard in the practise pharmacy, but equally well, oh my God, don't give it steroids. Whatever you do, don't give it steroids.

And on top of this, there is a big influence of the human medical literature. Human beings are very sensitive to steroids. Dogs are moderately sensitive and cats are relatively insensitive to steroids, and we tend to forget that when we, we look at cases like this that actually really serious outcomes according, due to, to, to steroid overdose are actually relatively uncommon.

In humans, chronic steroid use is associated with significant side effects in, in very, very many people. This fear of roids is because we recognise a group of dose and time dependent side effects. These are predictable.

Dogs will develop polyuria. They will develop polydipsia. This is dose and time dependent and when we reduce the dose, then the effects get less.

There are also, we have to remember, some non-stochastic, some random effects. These may not be dose dependent. They may be individual dependent.

I'm sure people who have used steroids a lot will have had the experience of having started a dog on a moderate dose of steroids, only to find two weeks later the dog has gone into diabetes mellitus or has collapsed. Or has developed a, a, a profound GI ulceration or has developed massive polyuria polydipsia, or sudden and severe alopleia. And these horror stories stay with stay with us.

How dangerous they are compared to other drugs, I, I, I, I leave you to, to, to question because if we say we use steroids, so much, then it's probably quite likely that we're going to have some, some horror stories, to tell anyway. It is a huge subject. I just did a survey this morning, looking at the, the literature.

I didn't read all 228,817 references on glucocorticoids, for this talk. I didn't read all the ones on receptors, 25,000. I haven't read all the 13,000 on glucocorticoid action, but I would draw your attention to the fact that the receptor ones, all of those 25,000, most of these are molecular papers looking at the molecular level of glucocorticoid receptors, whereas the glucocorticoid action is about the clinical effects, and it's an interesting comparison between those two.

What about glucocorticoids in the dog? Well, actually, the number is really quite small. And if you take actual action, then it becomes a very small group of papers indeed, and some of these are experimental.

There are actually very few good papers on the use of glucocorticoids in the dog. Most papers compare steroids. In the clinic to another drug.

With steroids, so it's not actually comparing steroids against another drug, it's comparing steroids with Papers comparing doses of steroids, comparing types of steroids are very rare, and the justification for a particular dose in a particular situation is virtually unknown. Here's a sort of classic example, really. This is a very, well known paper looking at the use of no prednisone.

It's it's an American-based pay, or prednisolone with metronidazole for canine IBD. These authors are highly respected people in their fields, no criticism in the paper. But it stated in the paper that these dogs were given 1 milligramme per kilogramme prednisone twice daily for 3 weeks.

No reference, no justification. It's just accepted. That's what we, we, we would do.

And given that this was a number about 54 dogs or things, the chance that every one of those dogs responded in the same way to that one make the keg is fairly unlikely. So we have a, a conundrum here where accepted clinical practise now has become accepted clinical practise simply because it's accepted clinical practise and actually challenging the basis of that proves very difficult. And the question I ask and I see these papers is why that dose?

Why that duration? Why not, adjust the dose according to clinical effect? If we're going to talk about glucocorticoids, it is important that we understand how they work, and, this is something that, has, has received a lot of attention, in, in the human field, but relatively little in, in the, the veterinary.

Inside the cytoplasm of cells are glucocorticoid receptors, which are held in the cytoplasm by some chaperone proteins. They cannot go through the nuclear membrane with the chaperone poetry proteins. Glucocorticoids, being fat soluble, will diffuse through into the cell.

And when the glucocorticoids bind to the receptors, the chaperone proteins become dislodged. And then the glucocorticoid receptors with their cortisol are able to pass through into the nucleus where they dimerize. In that dimerized form, they combine two genomic elements.

And this direct binding alters the transcription. And promotes the transcription of certain things, and they promote anti-inflammatory proteins. So they, they, they are promoting things like annexing one and all the things listed there, listed there.

They can also bind to things and promote things like osteocalcin, keratin, pro opium lanocortin, the production of ACTH, and by, by the suppressing these, sorry, they suppress these things, they block them. This leads to the decrease in ACTH. It leads to the decrease in keratin.

It leads to the decrease in bone density by their negative effects. They can also in their single form, bind to corticoid, binding protein and then bind to other glucocorticoid responsive elements. And these are the ones that produce the inflammatory.

Components like cytokines and so forth. These glucocorticoids, and their receptors are actually blocking the action of, cytokines like NF kappa beta. Which would normally promote inflammation.

So they are both positively anti-inflammatory on the, the green box. They block inflammatory on the orange box. And they promote negative things in the red box.

These actions Explain why glucocorticoids have such a wide range of effects on the genome. But looking at this, the one word that fits this more than anything else. This must be a slow process.

To get an effect on glucocorticoids will take you hours or days. To achieve anything with these. And yet we know That there are some faster interactions.

We know, for example, if you have a dog with steroid responsive meningitis and you give it intravenous dexamethasone, you'll see an improvement within an hour. It can be that dramatic. You know that if you have a dog with anaphylaxis and you give it steroids, the effect is dramatic, so it can't explain it all.

So there are some sort of rather poorly defined non-genomic effects. Which are yet to be properly considered. The other thing that we know is that chronic exposure to glucocorticoids actually changes the DNA of our cells in the way that we fold the DNA.

And it causes chromosomal changes. These chromosomal changes explain why in some instances you can use steroids to cure a disease. Because you can actually turn it off.

So for example, immune-mediated hemolytic anaemia may be triggered by something, but it may be idiopathic. And if we use steroids, we can actually see with chronic steroids, these animals will recover, but then when you take them off the treatment, they stay recovered even in the face of stimulus. So the assumption must be there that we've actually changed, we've reset the body's immune system using glucocorticoids, and this is almost certainly due to the chromosomal effects.

So steroids have a wide range of effects, a wide range of mechanisms of effects, which explains the range of actions that they have and the side effects. So before we start, a dog or a cat on glucocorticoids, I think we need to just talk about the indications for glucocorticoids and then about the concept of what is your plan. Glucocorticoids are, are used at a range of, of conditions, but probably the, the most obvious one is where you haven't got any glucocorticoids.

So here we have a dog with Addison's disease, and we're using glucocorticoids as a maintenance dose to, to help this dog, survive. The most common use in, in practise probably is as anti-inflammatory. Here we have a dog with atopic dermatitis.

And this use to the inflammation that we can see here in this dog's skin. We use them as immunosuppressive agents. This is a dog with another skin condition, but this is Penhagus foliacious.

This dog will not respond to an anti-inflammatory dose. It needs immunosuppression. It's, it's immune system needs to be suppressed more generally than just an anti-inflammatory dose.

We use this as an anti neoplastic treatment as well, cutaneous lymphoma here and steroids will reduce that. We use it occasionally for its anti-insulin effects. So here is a dog with an insulinoma, and we're using steroids to stop the insulin causing the hypoglycemia.

And we also use it for anaphylaxis and here is a dog that's had an anaphylactic reaction, to potentiated amoxicillin, and we're giving it steroids, to, to help with that anaphylaxis. These are probably the single most useful drugs in pharmacy simply because of the range of things that they can do. Almost immediately they started using steroids in human beings.

They started to realise that there were side effects. And, about 15 to 20 years after, after they first started using these, these drugs, an author called Thorn in the New England Journal of Medicine, published this really, important paper that, that defined a lot of, of thinking about why you should think about steroids before you use them. How serious is the disorder?

How long are you going to treat for? is the patient likely to be disposed to complications? So are they diabetic, for example?

What is the anticipated glucocorticoid dose? What preparation are you going to choose? What other types of treatment have been used to minimise the dose?

And here you say again, the idea that we will use the, the smallest dose that we can. To keep the side effects under control. And the last thing they asked is, is an alternate day regimen indicated.

Now that was in the 1960s. a lot of this still, pertains. I'm not sure I would ever start, a dog on alternate day regimens.

But I that was considered. The way I like to think thing is, first of all, I don't like try this and see. I'm not sure I I wouldn't say that to the owner.

I probably would say that to the owner, but I'm not thinking this. I'm not thinking try this and see. I'm thinking that we're going to make a plan, going to plan how we're going to use these steroids, starting dose, how long we're going to, to use it for, and then particularly, when are we going to recheck?

When are we going to look at this animal again and think, has it worked? And if it hasn't worked, How are we going to do, deal with it? And if it has worked, how are we going to reduce the dose?

And having a plan is important because it allows colleagues to come on after you and to see these cases. It's important that plan is written down. Dwight Eisenhower, the, the, the, the, the general who later president who, who led the D-Day, D-Day landings, famously said in preparing for battle, I find that plans are useless, but planning is indispensable.

And what he's saying there is writing the plan is more important than actually following it. Thinking about it before you do it, and then adapting, and the idea that then we, we, we put a steroid plan in place before we use them, and that plan is only 5 words perhaps, but at least it is a plan that allows you and the owner to agree when to stop and when to increase and when to decrease the dose. And in starting the treatment, I, I, the thing I, I see more than anything else is, that it's important to inform the client what we're doing.

I think it's important to say why you're using it, why it'll work, to tell the client what improvements you expect. And the minimum improvement that you will accept. To talk the client through side effects.

It's really important. A number of times I've come across dogs and I'm sure you've had the same, same conversation with owners. They've come in, you've given them steroids, and they said, oh, but he's drinking a lot.

He's urinating a lot. I'm really surprised about that. And why might that be?

And although you know you've told them. Clearly the message doesn't always get through. So it's important that we try to get the message through and, and at least at Glasgow, we, we use these client information leaflets on steroids, which we find very helpful.

It's if, if I, if I was given steroids by my doctor, I would get some sort of information sheet that would tell me about the side effects of steroids. I think it's reasonable for us to, to do that. And we need to talk about the time, how long these, animals are going, both the, the absolute time, maybe we, you know, we're gonna try 2 weeks, 4 weeks, or the relative time, we're going to try this dose until your dog stops itching.

We're going to try this dose until your dog's anaemia is controlled. These sorts of relative time frames, giving the clients the idea that there is a time frame for this, and at the same time then emphasising the need for rechecks to keep these cases under control. I sometimes challenge people with the question about how high would you be prepared to go on a starting dose.

and, most people, will start talking about, there isn't one starting dose. There's several starting doses, and that's, that's fair enough. A lot of people carry around the idea that, that, maintenance, steroids, is equivalent to a dose of prednisolone of 0.2 mg per kg a day.

But that's based on the assumption that cortisol is produced at 1 mg per kg per day. It is now clear that that figure was a gross exaggeration. The dose is, the maintenance production of cortisol is probably closer to 0.4 mg per gig per day, but there is huge variation individual to individual, even in healthy people and healthy dogs.

The production of cortisol varies a lot. It varies day to day, but it also varies between individuals, over, over, an average. So there are people who and, and dogs who have a high cortisol users, and there are people who are low cortisol users, and I emphasise these people are, healthy.

So if we're going to talk about, for example, maintenance in an Addisonian dog, but although we may start on 0.1 or 0.2 makes per kg a day.

We're going to bring it down quite quickly, and this, this goes a long way towards explaining why many out of so many dogs only need a small amount of prednisolone with their DOCP. The anti-inflammatory dose is said to be about 0.5 to 1 MB per kg, but again, big variation.

Immunosuppressive doses are said to be 2 mg per kg, once a day, but with cats because, they seem to be relatively steroid resistant, you may need double that, so 4 migs per kg per day. Don't forget dexamethasone is 7 times more potent than prednisolone, and so if you're using dexamethasone, you do have to cut the dose, proportionally. But how high, but is 2 mg per kg a high dose?

Well, not really. If you look at Penthigus treatments in human beings, there are protocols for enhagus which start, give 10 mg per kg. But just for 5 days.

And the idea is then to achieve remission quickly. And when I see dogs like this Newfoundland with panhagus, then I can understand where the human dermatologists are coming from. And the thinking goes that actually total prednisolone dose ends up being lower with less side effects than the lower doses.

Being used for longer. This has been tried, in a few dogs, back in the 80s. It never really caught on.

But, certainly when we talk about, for example, the treatment of feline immunemediated hemolytic anaemia. I, I, I have often gone up at least to 5 to 6 to 8 megs per gig per day quite comfortably to achieve control. And, and I think we need to now stop thinking about these doses as being fixed, but simply think of them as being the starting dose, which we will then increase to achieve remission of the condition.

And it may be that we have to go very high indeed. Of course, the problem with dogs is that Migs per kg doesn't really work, when you're talking about the difference between a chihuahua and a Great Dane. So should we look at metabolic body weights for, for, for doses?

And, and, I mean, . If you look at 2 mg per kg, then that's equivalent to a 30 mg per metre squared in a Pomeranian, but it's 80 mg per metre squared in a in a St. Bernard.

So I'm very cautious about 2 mg per kg in very big dogs, whereas in the very little dogs, I'm actually quite blase and I will quite happily go up to 4 makes per kg in a Pomeranian. But in the St. Bernard, I might start a name a suppressive dose as low as 1.5 mg per kg.

And that's shown there by that 40 migs per metre square dose when you start looking there. Thing you start to see the sort of difference of of, of effects that that that gives you. Be aware, however, that Better metabolic body weight dosing is no more accurate than body weight dosing in a dog that is binding the prednisolone to steroids.

It still is a non-linear dose response curve. So you still can't, can't, can't predict the outcome using this sort of thinking. Practically what it does mean, of course, is that you do have dogs with low levels of protein.

It's important to cut the doses in those, you will get more side effects. reduce the doses if there are liver problems, reduce the, dose of prednisolone if the animals on phenobarbitone or other steroids, which are also protein bound because they will, displace those and may cause side effects. And in dogs like this hypoalbumic, dog, then clearly the lack of body fat is also important to take into consideration because that will also affect the pharmacology, of, of prednisolone.

So having decided our starting dose and understanding that that itself is complicated enough and accepting that our starting dose is just that, a starting dose, and we're going to adjust the dose and we're going to titrate to effect, how do we go about doing that? And then having achieved the effect, how do we taper the dose and the important role of other treatments? So this is Robert the First, Robert the Bruce of Scotland, who, who, whose battle motto was if at first you don't succeed, try, try, try again.

I think there's a Robert may have been a great general, but he was a lousy vet, and, and a very poor pharmacologist. If at first you don't succeed with prednisolone, by, by that, I mean, if it hasn't worked in 5 days, it's not going to work. You either have to change the drug or the dose, or you have to try something else altogether.

The one comment I would make is that if there are no side effects, then don't expect an effect. The pharma kinetics of the Side effects are the same as the side effects as the as the pharma kinetics of the effects. And therefore, You can keep on increasing the dose until you have achieved polyuria polydipsia, until you have achieved maybe some lethargy, maybe some polyphagia.

Once you know you're getting those, then you know you're getting at least some effects going on. The problem with steroids is that the longer we go with the higher the dose, with certain formulations being particularly a problem, then the hypothalamic pituitary axis becomes suppressed. There have been very few studies looking at this, but one of the pivotal ones was one by Mourin Hone in 1992, which looked at the effect of a 0.5 mg per kg twice a day dose for 35 days.

I note this was prednisone, so that would be equivalent to a 0.25 mg per kg. Of prednisolone.

So you've got to be a bit careful here that, the, the, the American and UK literature do differ a wee bit. After 14 days, there was already a marked effect on the AC tape stimulation. There was already an effect on AC tape, but sorry, but it wasn't marked.

After 28 days, it was a marked effect. That is to say, after 28 days when they did their AC tape stimulation test, there was, there were dogs that were behaving as if they were Addisonian on that test. The implications of this is that if you see a dog and you need to stop its prednisone or you you want to stop it, then if the animal's been on for less than 14 days, you can just stop it.

Just stop. There's no need to wean them off. But if you are more than 14 days, then you need to wean them off.

But that weaning off can be quite dramatic. You can go down from 2 MBs per kg down to 0.08 megs per kg down to maintenance because they only need maintenance.

So you can decrease them quite quickly. The other implication of this is that at least with prednisolone, it takes a time to make a an estimation about whether you've had an effect and to reduce the dose more frequently than every two weeks. Is not, not, not much point in doing that.

So every step down that you go, should be done every 2 weeks, and you should use markers for when to reduce doses. So if the animal's poretic, it's very easy. Ask the owner how much it's itching.

If the dog's not itching, you're OK to decrease. There may be some markers such as the platelet count. So in immunerated thrombocytopenia, you may, just monitor the platelet count if it's, if it's good, then you're safe to decrease the, the, diseases.

It's harder for some diseases such as meningitis, and very hard for other diseases like pemphigus where by the time you actually see, the, the disease, coming back, then it's, it's, it's, it's often quite far advanced. In Glasgow, we've been using C-reactive protein as a marker for many of these inflammatory diseases now, so immunity polyarthritis, steroid responses of meningitis, and so forth, to try to predict the point at which we can decrease steroids. And this has worked quite well.

We find that we are able to decrease the steroids on a, using the CRP and predict when these animals are likely to relapse if their CRP starts to go up. And that's a good example of a, of a surrogate marker being used there to, to adjust steroid doses. In that paper by Mark Lowry from 2009, they identified 4 cases out of their initial group which had CRP going up but had no clinical signs, and when they didn't do anything about it, those animals came back with the disease.

So practically, we want to adjust our steroids according to objective parameters, the itching, the PCV, the platelet counts, acute phase proteins, wherever we can. If we can't, then we have to just simply type right down to find the lowest dose at which clinical signs. .

If you need to stop suddenly, you can go right down from high doses down to low doses very quickly, and, and by low doses, I mean maintenance dose of 0.08 or 0.1 there, of, prednisolone.

Now, what about this concept of alternate day steroid therapy? First say this is absolutely accepted clinical practise. It was first advocated in the 1960s, and has remained a benchmark ever since.

But it was developed in the 1960s on the assumption that the effects and the side effects. Have difference in their kinetics. So that is to say that you're getting the good effects on the first day you gave.

And he allowed the, good effects would carry on, but the bad effects would wean off and so you'd allow recovery. This concept has never been studied in dogs. Nobody has ever shown that that's the case.

Indeed, they've never even shown it's the case in humans. Nearest you get is in 1979 with Trustan and Graham, who took three groups of, of dogs. They gave them, once a day, once a day, and, every other day doses.

All the dogs got hypothalamic pituitary suppression. The dogs on the single daily dose of 0.2 mg per gig had no clinical signs.

But the dogs that were getting 0.5 once a day versus the dogs that were getting 1.1 twice every other day.

Had slightly worse side effects, but only very slightly. There was hardly any clinical benefit to the double the dose every other day. And, other studies have produced some conflicting results, but I think the, these, these, reasonable, things say that the difference between a single dose once a day versus double the dose every other day is pretty much 0.

So the consequence of that is that in fact, every other day dosing is just another way of cutting a dose by half. It's important to remember that the concept of alternate day therapy relies on daily therapy to control the initial clinical disease. Nobody ever advocated alternate day therapy for anything other than maintenance.

That maintenance phase. Is a phase that allows the animal to control the disease subclinically before achieving health, and something's got to happen during that alternate day therapy period for the subclinical disease to go and for the animal to become healthy. This concept again has been rarely tested in and never tested in dogs and rarely tested in humans, but the, the implication is if you're going to go down long-term steroid therapy, steroids do not cure diseases very often.

They need other things to help them. So, alternative day therapy does not cure a disease. It simply suppresses the clinical signs, whilst other drugs or possibly the body corrects the underlying problem, which begs the question, is alternative a steroid therapy even necessary?

And the answer to that is probably not. So we only use alternate days, alternate day steroids when the disease is under control. If that dog is itchy, if that dog is anaemic, if that dog has other problems, there's no point going to alternate day therapy.

And in fact, alternate day therapy may cause problems if you do it in those stages because they may actually lose effect at that point. It's obviously important to use shorter intermediate acting glucocorticoids. There's no point using dexamethasone, on an alternate basis.

And there's no point in the short term. I hear people sometimes they, they start the dog on steroids for 2 to 3 weeks and then they switch to alternate day therapy for a week before coming off. And that is absolutely crazy.

There's no need for that at all. Just cut the dose. And keep it on daily therapy because it's more likely that the animal will not miss the dose if it's on daily therapy.

Always in alternative therapy, if you're using it, think what else am I doing? Maybe you're suppressing the immune system, so maybe you're going to use mycophenolate or azathioprine. Maybe you're treating the allergies, so maybe using immunotherapy.

Maybe you're just using an antibacterial shampoo to control the low grade pyoderma, and that will be enough. It doesn't really have to be very complicated, but something other than just alternate day steroid therapy. It's certainly not an essential thing.

It's just another way of lowering the dose, and therefore, it does not have to be done. We've talked a lot about how to use them. There are sometimes when we don't want to use them.

Osteoarthritis, degenerative joint disease, the effects of steroids chronically on the joints are worse than the anti-inflammatory benefits that you get in the short term. So although in the short term, you could use steroids, long term is not a good idea. Not even in the short term with inveral disc disease.

Unknown tumours, most oncologists would say are very unlikely to respond to steroids. And, if you know it's got lymphoma, which is the, the one that will respond, then really you should be using something else, on, on top. the, the cost of monitoring these drugs is, is more than, the cost of the drugs.

We'll talk a little bit about, shock in, in a, in a moment, about the effects of that, but, I would regard steroid use in shock as being an abuse by and large, and we'll talk a little bit about relative adrenal insufficiency. I ask the question, should steroids be given to the first presentation of any undiagnosed disease? If you have a diagnosis, however, level that is, if you have a diagnosis, then yes, steroids may be indicated and for a very wide range of diseases.

But if you don't have a diagnosis, then I question whether you should ever give them. OK, relative adrenal insufficiency. The, the old logic in, in, in, in the emergency room when something like cortisol is essential survival for disease, the more severe the disease, the more cortisol you need.

High cortisol, is correlated with high mortality. Therefore, if we can, this increased cortisol may be helping some patients. So increased giving glucocorticoids may increase survival, and that was the sort of 1970s logic.

And it's the logic that people apply when they say, Give dexamethasone IV to a dog in shock. That's the logic. It is completely out of date.

It is wrong and the simple fact is, steroids reduces the survival of shocked patients. If you look at all patients with shock, And you look at their use of steroids, steroids make the outcome worse. We shouldn't be doing that.

The only exception to that, of course, is if you think the dog's got Addison's. -huh, said the ICU clinicians who really want to give steroids. It's not that the problem, with all shocked people.

It's actually just a few patients. Who have insufficiently high cortisol. They're the ones we need to supplement, and they pointed to a group of septic patients who were dying because they were hypertensive, who had low cortisol, and they said, let's try those, so they gave those people hydrocortisone, and they survived.

And it's brilliant septic patients, hypertensive, septic patients. Low cortisol, gave them cortisol and they appeared to survive and thus was born the relative adrenal insufficiency argument. And to assess this, these ICU clinicians, without discussion with any endocrinologist, came up with a measure of delta cortisol, which is the difference between pre and post ACTH cortisol.

So they would regard an ACTH stim that went 150 to 440. As being a high delta cortisol and therefore does not need steroids, whereas a delta cortisol of 80 caused by a PR 413 of 510 is not a sufficient rise and therefore that would be an indication for them to give steroids. And so this new idea came out of, we're going to use stress doses of glucocorticoids for these patients, which is what they wanted to do in the first place because they just wanted to give steroids.

What's the evidence for this? Well, the evidence is still not very good, I'm afraid. This, this was an idea that someone had that they promoted quite heavily.

The trouble was that the septic patients who were hypotensive, they had low cortisol because the drugs that they were using etomidate to treat the hypotension lowered cortisol. So in effect, they were giving the septic patients Addisons. And surprisingly then, if you give an Addisonian septic patient steroids, they tend to do better, but that's hardly a fair comparison.

There's some very interesting work coming out of, South Africa. Johann Schumann, looked at an important group of, of, of, shocked patients, that we see, which are puppies with A parvovirus, and he looked at their cortisols and what he found was that actually cortisol decreases as survivors live. In other words, this was an inherent part of the response to parvovirus, but it diminished very quickly as the animals got better, whereas those that were struggling to survive, they kept on producing cortisol.

There was no evidence of deficiency of cortisol in the in the non-survivors. The problems with relative adrenal insufficiency is that co-medication is a significant factor. This stress effect of cortisol changes rapidly over time.

Cortisol may be high one day and low the next, and given that you can't measure cortisol quickly enough to react to it, that's a problem. And in most studies where they have randomised and carefully controlled for everything, then they found that ACTH stimulation tests do not predict survival. They do not predict response to glucocorticoids.

And in the largest study today, cortico, there's no survival benefit of administering doses of steroids. Indeed, in that study, The steroids that were administered resulted in a high infection, including repeated septic shock in treated patients. These patients were getting steroids in septic shock.

They were getting better, but then they were coming back with septic shock again over and over again. The problem was with Corticus that some clinicians just believed in steroids and would not give them up. Their faith was greater than their science, and they simply wouldn't allow patients into a blinded trial.

So the corticus study was very slow. There are more studies, more recently published out now. The debate continues, but I stand with this reference here, which is that the concept of relative adrenal insufficiency has no clinical utility.

In these cases, administration of glucocorticoids has cost without benefit and with increased risks. So what about the steroids for shock? Bluntly, do not give steroids to animals if they have shock, unless they have electrolyte abnormalities and have been tested for Addison's.

In certain specialist human ICU proteins, there may be a subset of septic shock patients who may benefit. But even in these settings, those clinicians have no way of identifying those patients reliably. So we should not be doing it.

So The golden rules of steroid therapy, 2020. Use enough but no more to control the clinical signs. If you need to use more, double the dose till you have controlled the clinical signs.

If you're not working, if it's not working soon, try something else. Only ever switch to alternate day once the signs are controlled, and once you are on that, use other treatments to reduce the steroid dose. Monitor each animal individually.

The range of responses is huge. When you do lower doses, don't go down by little tiny increments, taper dose in 50% increments, until you are close to twice maintenance and then you can stop. Don't use it as a preventative treatment.

There's no evidence that, steroids prevent anything and don't use in shock or virtual disc prolapse or undiagnosed tumours. So I started the question with, are they the best little white pills in pharmacy? So that is yes.

Unequivocally, yes, they are the best of the white pills in pharmacy providing you use them properly. There is a future there beyond prednisolone. Some of you may have used budesonide.

I, I've tried it. I'm not impressed. You still get side effects.

It's very expensive. But there are things coming through like this one here, Fosdagro Cora. I'm think I'm, I'm never going to learn to pronounce that one properly, where they, they are altering the binding of the glucocorticoids to the receptors.

Such that they end up binding differentially to different glucocorticoid responsive elements within the genome. These are interesting studies. They have done one or two studies in dogs.

It's not on the market yet. It probably will be very expensive when it arrives, but people are looking at alternatives to try this holy grail of dissociating the side effects from the effects. So I hope that you've all enjoyed that whistle stop tour through glucocorticoids.

And I hope that it helps you reflect on clinical practise, and how we use steroids. And with that, Bruce, I'll hand over to you for any questions. Ian, that was absolutely fascinating and I must say you've, You've certainly changed my thoughts on steroids and a lot of aspects.

So thank you so much for sharing your extensive knowledge with us. And I can see now why you like them as the best little white pills in the pharmacy. So we do have a couple of questions.

One of which you've already answered was, what about budesonide? Another one, Sue wants to know, are you saying that atopic dogs should have daily steroids when they're itchy and then stop when they're not rather than alternate day maintenance control. So that that that's, that's a good question.

It's not, it's not quite that simple, but in essence what I'm saying is have daily steroids when they're itchy until they're not itchy. There's no advantage in switching to alternate days in that in that. That part of it After you've made them non itchy.

Then you can switch to alternate days and use something else. To try to make them, less itchy so that you can then wean them off steroids altogether. So something like a topical treatment, a shampoo, or topical treatment, shampoos, maybe it's just a question of time.

I mean, for example, at this time of the year, these dogs may need a daily treatment until they're not itchy. And then once they've you've got the itch under control, then you switch to alternate days and you're in the subclinical disease phase and you can keep going with that over the summer and then at the end of the summer, stop. And that and that's fine, that's using time, it's a plan.

If you simply say, I'm going to treat this dog with alternate day steroids forever, then you may well miss the fact that these dogs actually don't need them at some point, and that'll cause side effects. There's no advantage in that alternate day steroid. It's only a dose reduction.

So if it's easier, you can simply keep going on once a day, but lower the dose and to find the lowest dose you can get. So, you know, the, we hold out this alternate day as being like it's, it's something special. It isn't, it's just another dose reduction.

So, yeah, so, so when you say, itchy and then stop, no, I, I wouldn't stop an itchy dog. I would drop to to a lower dose. Now the lower dose might be alternate, but don't forget, on alternate days, the owners are far more likely to miss a steroid.

They're far more likely to, to end up with, you know, one day, nothing, nothing, then yes, I, I remember it, do it then, do it then, and then forget for another 3 days and 2 days. So the level of control is going is much. It's absolutely clear in any, any human studies that alternate day is really hard to follow.

It's actually, if you're going to do that, it's almost better to say use it weekdays but not weekends, or use it, Saturday, Sunday, Monday, Tuesday, but not during the week when they're out at work, and maybe they don't see the dogs itching so much. compliance of alternate days is known to be poorer than once day. So using a smaller, so, so rather than using a 5 milligrammes every other day, consider using a 1 milligramme every day.

OK. Interesting. Can you please comment on the difference of effect as well as the length of duration and any side effects between Dexaort and Dexarein?

Yeah, so, so this is where the esters come into it, and that, that, Dexedrein is, and I forget the salts, forgive me, I would have to go and check that out. But Dexedrein is, is, rapidly absorbed and rapidly designs that when I say that on my trait that the biological half-life of dexamethasone is 48 hours. I'm talking about Dexedriin.

If you look at dexaort, then that is a different ester and it's stored in the body for longer in the, in the fat and therefore is released more slowly and therefore has a much longer effect. OK. Rose has asked an interesting question.

Do you see steroid psychosis in dogs? right, OK. Yes, now, that, that's a great question, Rose.

That, that's really interesting. Now. Steroids are profound mood altering drugs in human beings.

I have seen dogs whose mood, as best as I can determine. Has been profoundly altered. They become different characters.

When on steroids, it's not common. Certainly, the dogs can get lethargy on this, but, but, I mean, I think when you talk about steroid psychosis, you're talking about really a different dog. I, I've seen dogs that have become very, you know, normal placid family pets who become really grumpy.

And, and if they, if they, the owner goes to move them from their bed, the dogs will try to bite them and things like that. And, and that's not normal behaviour for that dog. So do I think I said yes, I, my, my caveat to that is psychosis is something that a doctor has to diagnose from the symptoms described to them by the patient.

I don't think we can diagnose psychosis in an animal, but I can tell you I have seen profound alterations in behaviour patterns. Which I would refer to as mood altering drugs. So yes, steroids are mood altering drugs, cats, dogs, just as much as, as, as, as humans, yes.

Last one for you and it might even be a whole webinar topic. Could you comment on steroids and COVID? No, I'm not a doctor.

I'm not a human doctor. no, no, that's within the, I, I think it's, it's. Most of us, if we were treating a viral pneumonia, and, and, and for my, for my, for, for my sin, I have tackled a cat with cowpox pneumonia, a few cats with, Kay virus, pneumonia, and I can't think of any dogs that I've treated, but, but I, I, I must have, must have, but.

I can understand it and I can understand why it would work in the extreme cases. So these are the, the important thing about the study from Oxford is where they found the benefit was in oxygen dependent patients. And that makes sense.

In the most severe cases, it's the inflammation that's now become damaging. Rather than the virus, the inf the virus has got into the lungs, the inflammation has gone haywire. There's new evidence coming out on, on COVID showing that your genetic makeup, your personal genetic makeup has a very serious effect on outcome.

Interestingly, if you are type A blood group, you are more likely to come down with coronavirus pneumonia, whereas if you are type O blood group, you are less likely. So, you know, genetics play an important part in this. And so when you, when you, when you hear about the differences between nations and their response, and it's very tempting to blame the politicians, sadly, it may be the fact that there are different genetics and, and that the, the British public and, and the, the American public are, are, are genetically slightly different, slightly different stock to, for example, the Italian.

Public or the German public or the French public or the Spanish public and, and or indeed the Chinese and, and therefore because of the difference in the genetics, we, we are more likely to be, to be affected, which means that that gross inflammation, that steroid thing may work in the UK, but it may not work elsewhere. And that starts to get really interesting at that point. For, for, for me, if you, if you want to go and look up, about, treatments of COVID, the one I'd, I'd be looking at very carefully is Rem Dezavi.

I think that's that's throwing a lot of promise. Yeah. One more question that we have.

I know we've run over here quickly, but I, if you would just bear with us. Carmen wants to know how long would you give steroids to a dog with vestibular disease? Well, if you mean by, by idiopathic vestibular disease, though, those dogs that come in, with, acute, vestibular signs, these are often old dogs, and, particularly where you've got no ability to do advanced diagnostic imaging of these dogs, so we are assuming that these are microhemorrhages.

We're assuming that there is a degree of brain swelling associated with this, and, therefore, there, there, there is a, a, a short term benefit, perhaps, perhaps in giving steroids to these animals. The counsel I would have is that if these, these steroids increase the blood pressure, then they may increase the risk of further bleeds. And steroids do increase blood pressure.

So, so the honest answer is that actually, unless the animals are showing other behavioural changes, it may be better to use anti-nausea drugs. And sedatives than actually using steroids in this, and if you are going to use steroids, it, it, it's a, a 24 hour dose, that, no, no, no, no, no, no more than that. Yeah, so, so very quickly, very shortly, but I would, I would be focusing on, on not antiemetics, but anti-nausea.

So, so metoclopramide is actually better than Moropotent in that circumstance and analgesics, of course. Excellent. Ian, thank you for a fascinating webinar and the interesting insights that you have given us tonight.

As always, it's a pleasure to have you on with us and thank you for your time. Thank you very much, Bruce. You take care.

Bye-bye. Thanks folks for attending tonight and to my controller Dawn in the background. Thank you for all your help to making this work so smoothly.

From myself, Bruce Stevenson, good night everybody.