we were asked to do a piece of work working together with with uh some of our anesthetic colleagues about patients that were taking Exogen exod steroids and again um I'm not sure I'll be able to offer Solutions but I thought I'd try and give you a little bit of background in terms of um some of the the guidelines that have been developed and really highlight issues where I think we're we're we're really lacking evidence and I think that perhaps is is is is the is the main problem you'll all be very familiar with this is the the hypothal adreno a is centrally driven lots of central triggers that uh ultimately regulate the release of cotop and releasing hormone that then acts on the anterior p on the catro cells of the anterior pituitary um to release act which then acts on the on the adrenal cortex um and to to release cortisol and then there's the negative feedback loops that you're that that you're very familiar with there so you know you're all over you know very very familiar with the hypothal p AIS we know that cortisol fundamental hormone essential for Life regulates many many crucial actions not just metabolic but in terms of maintaining blood pressure response to stress all these sort of things um and what we also know and again that the the the terminology gets gets a little bit confusing I think it's important just to rehearse that we have primary adrenal insufficiency whereby that's a a defect of the adrenal gland itself um you have secondary adrenal insufficiency which is a defect of the pituitary where we see and again we spend a lot of our time in clinics looking at patients with pituitary disease and then there's this concept of of of tertiary adrenal ins sufficiency which by and large um certainly in the context of this talk will be about iatrogenic adrenal efficiency that's exogenous steroids causing suppression at all the different levels of the hypothal adrenal axis resulting in endogenous glucorticoid deficiency and the key test that we often use again I put it here you'll be probably be familiar with this is the short sting test the reason putting it here is because a lot of the data I'm going to present uh uses the short and acting test which is not a perfect test but it's the test that we currently use most commonly to assess whether there is integrity of the hypothalamopituitary adrenal axis and how does we Implement that well it's a baseline cortisol uh 250 micrograms of synthetic H which we tend to give IV and then a 30- minute cortisol and clearly if you have got a a functioning adrenal gland that isn't shriveled isn't at trophic then you would expect a a response at 30 minutes and again different centers have different levels of cortisol and we can discuss that if you wish so that's the the basics that's how we assess it and that's broadly speaking how it can go wrong so this is a a problem that I've become progressively more and more interested partly from a research angle but also with within our clinics you know I I have to say that of all the clinics that I do probably you know two or three patients a week I'm seeing um that have got theogenic gluc gotic I'd be it from Rheumatology be it from respiratory but it's a real a real problem um and we know this is data from the UK the US 2 to 3% of the population prescribed glucorticoids highest in the elderly and again most commonly for a there a slightly hazy graph you can see here um but what you can see here as as age increases you can see that the prevalence of for gluco good use increases significantly um and it's across all the different uh the doses but actually most commonly um in for for for medium dose and in the elderly and it's perhaps the elderly that are that are more prone to the adverse consequences of that glucorticoid excess if you correct for underlying disease the glucorticoid itself is still associated with increased cardiovascular cerebrovascular disease and and and heart failure that that's relatively historical data from uh probably 15 20 years ago this is more recent data from from from from Denmark actually and um it takes looks at both the prevalence of uh glucorticoid use but also the incidence a new new users so the top two graphs A and B here are are are the are the prevalence going back to uh 1999 over the last 15 years and again you can see that actually it's reasonably steady and again it's that's here up to you know between three and 4 perent of actually within with within Denmark but hasn't really changed dramatically over those 15 years or so however when you divide it by age what you can see here is that actually in in those patients above 80 that's in this the the the dots up here you can see that up to 10 % of patients are using um glucorticoid and there does appear to have been a little bit of an increase around about sort of you know early 2000s um such that now about 11% of the population of Denmark over the age of 80 are using steroids and again that's also reflected in the in the incident so you know in the LD this is the bottom graph D here you can see that actually there perhaps is a trend to more new users of glucorticoid 3 to 4% um on average per 100 patient per person years so this is a a big problem I see it in my clinics and as stevea said and certainly talking with with anesthetic colleagues here and and and and further a field it's clearly a big problem for for you guys in your in your speciality as well one of the big things that we have to think about is you know we get very OBS endocrinologists we I think we're as we'll see a little bit later I think we're quite a risk averse group of individuals um and we get very worried that we're going to miss adverse outcomes um but what we do know is that primary dream efficiency that's a primary defect of the adrenal gland is associated with with with the mortality and part of that will be adrenal crisis when beby you don't get sufficient glue corticoid at times of intercurrent illness or or or stress and so again a variety of different studies these are standardized mortality ratios um with reasonable numbers of patients not huge but reasonable numbers showing that really across the board the standardized mortality ratio is significantly increased in both men and women in patients with primary adrenal insufficiency what about secondary ADR efficienc this is work done by by by Mark Sherlock colleag in Birmingham um so secondary adran sufficiency that's a a p problem act deficiency and again what you can see here this is the the the your mortality relative relative risk here and markers could be compared if you've got a normal act or if you're deficient and you can certainly see that those patients who are deficient in act with secondary adrenal insufficiency have an increased uh standardized mortality ratio here um and that's not the case if you're TSH or if you're going to add a troping deficient and if you look at the panel here over on the right hand side um marks divided this up by by by daily dose and I think that's something that will'll come to in in in a minute and you can see here that actually that if you're on a a higher daily dose of hydrocortisone your standardized mortality ratio is a little bit higher suggesting that over replacement is also not such a such a good thing and that's even broken down a bit further with a bit more granularity here such that if you're on a hydrocortisone dose of greater than 30 physiological replacement dose around about 20 uh milligrams per 24 hours you can see that your standardized mortality ratio is is higher so um you know clearly in the context of replacement too much and too little is is is is bad and that is also reflected in this this is the um I think probably today the only really metaanalysis that has actually tried to look at outcomes in um prescribed glucocorticoids this was done by by Paul Stewart and his team in Sheffield um uh sorry in Leeds um and it looked You' use a CPR as a primary care database and it identified you know 70,000 patients who have prescribed all glucocorticoids and it stratified those to those who had either evidence of adrenal insufficiency or patients that had evidence of glucocorticoid excess and if you really cut to the quick if you look at the the the the IR that's the incidence rate ratio of death effectively um and you can see that in the far right hand panel here certainly those patients on glucorticoids when he Compares with those not on glucocorticoids have an increased uh mortality and that's true whether you've either got excess so that's with gluco induced Cushings here 2.24 or with with gluco induced adrenal insufficiency accepting that the numbers here are are pretty small so again we know now evidence from from primary care that too much and too little glucorticoid prescribed GL quod is associated with an adverse outcome so again a few years ago we just began to down on the um the types of glucocorticoid and evidence of adrenal insufficiency there there was a um uh and again I hope I'm not offending anyone here but there used to be a trail of thought that said well if you're draw on an inhaled steroid um that doesn't cause a green Lance efficiency doesn't get into the circulation um I would like to think that everyone's now aware that that is actually complete rubbish um but but and again some of the evidence of that there's lots of evidence to to suggest that that is absolutely true um but here's just some of the evidence that we generated a few uh a few years ago and we took about uh 2 or 3,000 patients that had caon test and we pulled out those ones that had had glucorticoid treatments and there were some that were gluc naive some that were on predus treatments and some that were on current and this is the percentage that were failing the short s test so if you currently on glucorticoid 30 to 40% of people were failing the short short acon test not a great surprise there but when you drill that down by glucorticoid root yes all was the worst but still a significant proportion on in topical intranasal um steroids were all failing the the the short syn acon test um and again I think there isn't a single route um of administration that hasn't been in some study associated with adrenal sufficiency um including the joint injections which are are are particularly potent of causing his drainal suppression we draw down a little on fluticasone again commonly used potent inhale glucorticoid and you can see here once you're on to sort of you know reasonably Punchy doses 2 50 micrograms a day 50% of people are failing caon test and when you look at the data actually it Maps out quite nicely so with increasing flu TI own daily doses your basil cord disol Falls and your 30 minute cord disol Falls what about prednisolone or prednisolone so again we used to think that um that that if you're on you know five milligrams of predisone that's a pretty safe dose we don't need to worry about adren sufficiency I'm not entirely sure that's the the case this is again data from um from uh from leads and you can see here this is patients on increasing doses of predis loan 5 5 to 7.5 and over 7.5 and even at five getting on for less than five 30% of people or so are failing a short sment test when you're at 7.5 70 or 75% are failing the um failing the the short sting test this is all quite dirty data there are lots of problems with it it doesn't necessarily look at previous exposure so um but I think it just highlights that if you've got a patient in front of you and may happen to be on a dose of inhaled or predis alone at that time then their risk of adren sufficiency is is potentially significant how can we try and rationalize you know we can't suggest for one moment that every patient needs to have a short Sy acon test and again this is a busy complicated complicated slide um and and I'll try and summarize it because what we were trying to do with this data was say is there a simpler way whereby we can assess whether someone does or doesn't have adrenal insufficiency see based on effectively just a morning cortisol and so what we tried to do in is take all our patients that were either un inhaled or or allal glucocorticoids and set the specificity and sensitivity of our morning cortisol such that we didn't want to miss anyone so 100% specificity here would be when we didn't miss anyone that subsequently went on to fail the syac test so we picked up everyone that was adrenally insufficient and by and large if if you take your threshold of the morning call around about 340 um then you picked up the vast vast majority of patients who had an intact hypothalamo pituitary adrenal axis similarly if you drop down to below 100 everyone fail the syon test so you can begin to rationalize a little bit and again this is now these sort of data again with lots of other studies all the studies have already come up come around saying by and large if you have a morning cortisol of 300 350 um that is a very good indicator that you've got an intact hypothalamopituitary adrenal AIS um and again that's now been incorporated into recent guidelines that I'll that I'll talk to you about in in a minute so that's the sort of some of the background some of the work that that we doing but what about what happens under under stress and again this is now moving into into into your realm rather than mine and this is a uh data from one of my colleagues V caralt in Birmingham and she looked to uh assess the degree of hyper calmia that you get at times of stress and under and patients undergoing elective surgery so again if you look at the the um the uh the panel here on on the left hand side you can see that your your morning cortisol level is around about 2300 in patients but quite a big spread we know that it's very variable and you're clearly aware it has a a Cadian Rhythm when we look at patients under for example compact Str uh combat combat stress these were soldiers in the military unit within um with Birmingham or under elective surgery your your levels of cord are two or three times times higher um interestingly they go through the roof in in in sepsis in acute trauma um perhaps less less impressive than you might have might have expected and these are also reflected in changes in free cortisol level again as you'll all be aware what we measure in the vast vast majority of assay is total serum cortisol of which 90 95% is bound to bound to protein so high levels of cortisol new in in patients having elective surgery um and then there are question is okay well if you were considering supplementing or replacing steroids how might you do that um and there are various ways that you can do that and again V and her team explored that you know and and looked at cortisol levels if you dose people orally every six hours and you can see there are sort of Peaks and troughs the sort of the uh the the orange bars here are sort of where you like but you might like to see the level so sometimes if you give it orally you know above and below it's not dissimilar if you see uh if you give it intramuscularly intervenous these similar patterns but if you give a 24-hour continuous in uh infusion again these are the same doses you can see you get quite a nice sort of flat flat flat profile um so certainly an infusion gives you perhaps the smoothest of um uh the smoothest of profiles as we'll come to towards the end of this end of this talking in in in a few minutes time it'll be very clear what we don't have is outcome data and that's absolutely what we need in terms of do any of these supplementations regimens make a difference to outcome but we'll come back to that um so it's all very well and good I think endocrinologists often fall foul of just trying to get numbers looking looking good um and the hyperth pituitary adrenal axis is incredibly complicated um because it's not just simply a question of you know CR act cortisol going to a tissue doing some stuff because there's a whole host of things that are that are sort of going on and especially if people are either un well they're stressed or they're having operations so we know that there are Central issues in terms of how your hypothalamus in your Pand respond in terms of your ability to use CR or act there's relative act resistance at the level of the adrenal gland if you're if you're unwell your cortisol production as a consequence of cholesterol that can impact if your liver metabolism is not quite as uh good as it as as it would be there are changes in the periphery so that we know that there's alterations in the metabolism of cortisol again one of the enzymes that we've been working on here this 11b hsd system your glucorticoid receptor expression changes with with illness um the transport cortisol binding globulin is and your your free cortisol changes so there are lots and lots of issues it's not as as simple as saying well we just need to replicate a specific level in the blood because that doesn't tell us what's going on within within the tissues so that's the sort of the the the background of where we're at and again based on a a case that went to the coroner um um who sadly sadly died who was a patient on glute corticoid and and and didn't get supplementation we sat down with some of your anesthetic colleagues um and proposed this is this is a group of anst and endocrinologist that we came together at the Royal College um to say okay how can we try and prevent those sorts of issues happening happening again um and we freely admitted as you as you will you'll know if if you read the guidelines that this is very much an evidence-free Zone and I think we all felt that we probably had to act in a safety first way and therefore after significant and and lengthy discussion um across the table we came up with the the the uh the recommendations here that actually that are times of major surgery that we would recommend that people got a uh if they if they had evidence of adrenal insufficiency and here we stated it have been a PR predone equivalent for five milligrams or greater for more than four weeks we'll come on to that a little bit in a moment but patients will be given 100 milligrams of the induction of anesthesia and then 200 milligrams over 24 hours um which we were sort of slightly relaxed is that is that yes you could use an infusion um but there were other Alternatives and that you could use uh 50 milligrams 6 hourly um if if if an infusion wasn't deemed to be deemed to be practicable and again similar sorts of things for other body Body service of surgery and things requiring general anesthesia um much more recently in fact just this year the European science of Endocrinology um has published a guideline on the diagnosis and the treatment of glucorticoid drenal insufficiency again I wasn't involved in in drafting up these guidelines but I think they're quite helpful and and again um you you'll see if you if you if you dig into those guidelines how little evidence they are based upon and you can see sort of here there that based on sort of good clinical practice but no real evidence and what do they recommend well they recommend that um uh with patients with glucorticoid in induced adrenal insufficiency that they should receive stesto coverage when they're exposed to to to stress um that that I think is is very clear but at times of major stress and they include that in terms of general or Regional anesthesia the parental glucorticoid should be should be used they did go on a little bit then to say well okay how can you identify who are the patients because this is part of the issue who are the patients who've got gluco adrenal insufficiency um so what they actually said was that we can't really test everyone and that actually providing people are clinically well that may be sufficient but we should have a degree of awareness in specific groups of patients and it's those patients that have either you know current or recent use of preparations who've got signs and symptoms of adrenal insufficiency that may be you know postal hypertension that may may be fatigue so things that may alert you to a drenal sufficiency if you're on lots of different types of glucorticoid high doses have inhaled high doses of topical for a grade of the year intraarticular glucorticoids are particularly potent causing uh adrenal suppression and those who are on um cytochrome p450 CP 304 Inhibitors now CP 304 is critical for the metabolism of glucorticoids exous glucorticoids and there if if you're on an inhibitor of a sip for you have effectively the steroids that you've been given have a more potent action they have a prolonged half life and therefore are more prone to give adrenal insufficiency so those were the sort of guidelines and again um we we had tried to get some funding with with with with Ben gibon to try and generate some some evidence and and part of the initial um thought processes but behind that was to try and do a survey and many of you may well have been involved in this but this was the the periot replacement of EX exogenous steroids which again you may well have been been been involved with which was trying to assess okay we we've written these guidelines which were published you three or four years ago how well are they being implemented um and I think the results were were were really interesting perhaps alarming and again on the the back of that I was invited to write the editorial which is where the title of this sort of talk came from um so this was nearly 60 trusts 21,000 patients of whom about 1.3% were taking taking steroids and again you can look at the U the I've sort of highlighted some of the the Cru I'm just showing one table because many of you will May been aware of this and there so the analysis was divided into two those who were on uh 5 milligram of prednis loan equivalence or or higher um and those who are on less than than 5 milligrams and what you can see here is that if you look at the the the proportion of people that were compliant uh peroperatively with the the guidance probably only about 30% about 50% for those people um who were on who were on less than five postoperative perhaps even even less for the higher doses 20% um and then in the if you look at the entire pre per and post-operative compliance with the guidelines only really about 9% were compliant fully compliant with the with the guidelines for those over 5 milligrams and about 50% for those less than 5 milligrams um other issues that that that came out of this I suppose were sort of an awareness as well actually you know and that's a problem that isn't you know just restricted to an you know making people aware of guidelines is is important so you know if people aren't aware of them they're not going to read them once you make people aware of them it's about reading them and again there were there were lots of reasons as to why people may not have been following follow following guidance and perhaps we'll be able to discuss some of those so I'm just going to begin to to wrap up there that was sort of setting the scene I you know I don't have the answers because we really do lack a a lot of evidence here but I think we just need to be aware of the situations we know that actually that adren Lance efficiency caused by exogenous steroids is associated with adverse outcome that I think is very very very clear um it's also very common you know um and and we've already mention that that the SST is not a perfect test but even if you define it by the SST then actually we can pick up a lot of adrenal insufficiency questions about how the best way to diagnose it and I think there is consensus now that that we can't do short Sy AC test NM C you everyone on steroids that's just two bigger things so we have to look at those patients at risk and it's those patients who are on lots of medication longer duration higher doses concomitant medication that can exacerbate the potency of glue corticoids in in in our defense the the guidelines for the supplementation were based on on a safety first approach and we all admitted that there was a lack of evidence and I'm sure that's something that may come up in the um may come up in the in in the discussion after after the talk um but you know here we do have a lack of evidence for either harm or benefit with or without supplementation and again we we have tried in the past to get to secure funding to to to address that um and that's some work that we we we're doing with with with bendan in Bristol but sadly wasn't funded um I do wonder and I've put their query hampered by guidelines that now we've published these guidelines is that actually going to make doing research a little bit more tricky because actually if the guidelines say well we should be supplementing this that or the other then how can we then go against those guidelines to do research but I think yeah I think there are ways around that then there are issues about the awareness and implementation of guidelines and again I've just sort of alluded to those and absolutely there's a there's a there's a need for more evidence and we need to think about how we can carefully design studies and acquire data really to see if supplementation with steroids to those patients at risk of a Dre insufficiency makes a difference to outcome and that's the fundamental question because if it doesn't make a difference to the outcome then then we probably don't need to to do it but the we don't have that evidence and therefore we act on a on a safety first principle so I'm going to um stop there I I hope that was interesting and and informative