Hello and welcome to today's Journal Club Critical Care Medicine webcast. This webcast, hosted and supported by the Society of Critical Care Medicine, is part of the Journal Club Critical Care Medicine series. In today's webcast, we feature two articles from Critical Care Medicine. My name is Thomas Zagmany and I'm a Professor of Intensive Care at Cardiff University in the United Kingdom. I will be moderating today's webcast. Thanks for joining us. Just a few housekeeping items before we get started. First, during the presentation, you will have the opportunity to participate in an interactive poll. When you see a poll, simply click the bubble next to your choice. Second, there will be a Q&A session at the conclusion of both presentations. To submit questions throughout the presentation, type into the question box located on your control panel. Third, if you have a comment to share during the presentation, you may use the question box for that as well. And finally, everyone joining us for today's webcast will receive a follow-up email that will include an evaluation. Please take five minutes to complete this. Your feedback is greatly appreciated. Please note, this presentation is for educational purposes only. The material presented is intended to represent an approach, view, statement, or opinion of the presenter, which may be helpful to others. The views and opinions expressed herein are those of the presenters and do not necessarily reflect the opinions or views of SCCM. SCCM does not recommend or endorse any specific test, physician, product, procedure, opinion, or other information that may be mentioned. And now, I would like to introduce today's two presenters. Jonathan Hinton is currently an interventional cardiology fellow at Bournemouth Hospital undertaking a fellowship in complex percutaneous coronary intervention. Prior to his fellowship, he undertook a two-year period of research at University Hospital Southampton. His research focused on assessing the prognostic role of high-sensitivity troponin assays outside the context of acute coronary syndromes. Dr. Marek Nalos is Director of Intensive Care at Goulburn Hospital and Senior Consultant in ICU at Liverpool Hospital in Sydney, Australia. He graduated and was trained at the medical faculty, Charles University in Plissen, Czech Republic, before moving to Australia in 2002. He was a research fellow at KUOPIO University, Finland, and at University of Ulm, Germany. Dr. Nalos holds a PhD and an Associate Professorship in Critical Care at the Faculty of Medicine, Charles University in the Czech Republic. His interests include critical care echocardiography, research into sepsis, immune function, and cellular metabolism in critical illness. And he has co-authored over 50 articles in peer-reviewed journals. Thank you both for joining us today. Now I will turn things over to our first presenter, Jonathan Hinton. Great. Thanks very much. And thanks very much for asking us to share our work. So, before I start, it's important to note that all the assays used in our study were provided by Beckman Coulter, but Beckman Coulter had no other role in the study design or prosecution or analysis. So, I was fortunate to be part of a fantastic team conducting this work, both at University Hospital Southampton and the Keel Cardiovascular Group. In particular, my supervisor, Professor Nick Curzon, who guided me the whole way throughout this. So, I thought we'd just start with a case, just to whet your appetite about what we're going to discuss. So, imagine an 80-year-old man is admitted to critical care with septic shock requiring modest doses of vasopressor support. He also has atrial fibrillation with a fast ventricular response, but no ECG changes or chest pain. His troponin on your local assay is 20 times the upper limit of normal. So, what is the most likely cardiac diagnosis here? Is it an NSTEMI, type 2 myocardial infarction, acute myocardial injury, chronic myocardial injury, or a type 1 myocardial infarction? So, if you want to vote now. OK, great. Well, that's sort of even split between type 2 myocardial infarction and acute myocardial injury. They're both good answers, but the right answer here is acute myocardial injury, and I'll talk you through why that is as we go through the presentation. OK, so the two real objectives here, really, to talk about explaining a troponin result outside the context of a traditional myocardial infarction, and then to explore the potential role of troponin as a biomarker for risk in critical care. So it's worth talking briefly about the fourth universal definition of myocardial infarction, and there are five types of myocardial infarction. I'm just going to talk about type 1 and type 2, you'll be pleased to know. So type 1 is your traditional N-STEMI or STEMI, and this requires a rise and fall of troponin above the upper liminal with at least one of the following. So symptoms of ischemia, new ECG changes, new myocardial loss on an imaging modality and coronary thrombosis, either on angiography or autopsy. Then when we look at type 2 myocardial infarction, this also requires a rise and fall of troponin above the upper liminal with symptoms of ischemia or new ECG changes or new myocardial loss. So, as you can see, they're very similar. The main difference here is that the type 2 myocardial infarction is precipitated by an imbalance between myocardial oxygen supply and demand, and it's unrelated to acute coronary thrombosis. So here are just a few different causes of type 2 myocardial infarction. As you can see, there's a wide range, and this is by no means a complete list. But it does get a bit more complicated because if you've got increased demand, you might have a troponin leak if you've got unobstructed coronaries. But some of our patients won't have unobstructed coronaries. They will have coronary artery disease that's stable or chronic. So it's important to consider that some of these patients who have an acute myocardial injury might well have underlying ischemic heart disease. Also, a sort of side note, coronary artery dissection and coronary artery spasm are also included in the type 2 category at the moment. So, unfortunately, it does get a bit more complicated. So, there's this term called a myocardial injury, and the fourth universal definition splits it into acute myocardial injury, which describes a troponin rise and fall with one level above the upper limit of normal without any evidence of ischemia. And this has very similar causes to type 2 myocardial infarction. And as in the case that we discussed, the man didn't have any chest pain or ECG changes and therefore most likely fits in with an acute myocardial injury. Chronic myocardial injury is a stable troponin elevation that doesn't really change with time and there's no evidence of clinical ischemia. And we often see this in patients with chronic kidney disease or severe aortic stenosis or a chronic cardiomyopathy of some variety. So, thinking about critical care, this is a graph of a number of the studies looking at standard sensitive troponin in critical care. And on the y-axis is the percent of patients who have a troponin above the upper limit normal, and on the x-axis is the year that the study was published. The size of the circle demonstrates the size of the study. And as you can see, there's a very wide range from sort of just under 20% to up to 90% of patients. But that was with the standard sensitive troponin and most places have now moved to high sensitive troponin. So, I just thought I'd talk briefly about why change. It's important to note that it measures exactly the same substrate as standard assays. It's just it has improved discrimination at lower concentrations. And this allows us to set a lower limit of normal than would be possible without that same level of discrimination. And it can, because of this, it can reliably exclude myocardial infarction much quicker between one and three hours, depending on the protocol you use. And the error under the curve for diagnosis is 0.96 compared with standard assays of 0.76 at three hours. And this clearly has, you know, important implications for resource-scarce healthcare settings in particular, and also for the speed of turnaround for your patients. So, our research group did a study where we recruited 20,000 consecutive patients at our institution, and we added a troponin onto their sample. These were inpatients, outpatients, and patients presented in the emergency department. And what we did was, we took these samples and then we looked at the overall trends. As you can see here, the upper limit of normal for this particular assay is 40. And there's a significant proportion of patients around one in 20 had a troponin above the upper limit of normal. And these were patients in whom the clinician was not expecting to have an acute coronary syndrome or a type 2 myocardial infarction. So, it's common to see acute myocardial injury in these patients. And then we went on and looked further at these data and sub-categorised them into where the patients were when they had their troponin taken, and then looked at the percentage of patients who had a troponin above, a high sensitivity troponin above the upper limit of normal. And as you can see, in cardiovascular and thoracic, excluding those patients with myocardial infarction, 15%. But if you look at critical care, you know, over one in three of these patients had a troponin above the upper limit of normal. So, we wanted to look at this in a bit more detail. So, there were two aims to our study. The first was to describe the distribution of high sensitivity troponin across two adult critical care units within our institution, so both general and neuroscience critical care. We then wanted to evaluate the association between high sensitivity troponin concentrations and their critical care outcome. So, this was a prospective study which enrolled consecutive patients admitted to either of those two critical care units over a six-month period. We were given special dispensation to perform the study without obtaining consent in order to ensure that we had an entire population and that we weren't missing cohorts, so that we could truly assess whether the high sensitivity troponin assays are of any benefit. We then added high sensitivity troponin testing onto biochemistry samples from admission, day one, day two, and then every alternate day until the patient was discharged from critical care. High sensitivity troponin testing was performed regardless of whether there was any clinical indication and the results were withheld from the clinical team and the patient unless they were specifically requested by the clinical team, in which case they were released. We monitored the use of organ support, length of stay, and death in critical care. So, just to note, the assay used in this study was the Beckman Coulter Access high sensitivity troponin assay, which has an upper limit normal of 18 and performs as a true high sensitivity assay. During the six-month time frame, we enrolled just over a thousand patients into the study. We excluded 15 of those who were diagnosed. We excluded the 15 that were diagnosed with a type 1 myocardial infarction in critical care, and that left us with 750 patients in general critical care and 283 in neuroscience critical care. So, first, we look at the distribution of troponins in these patients, and as you can see here, this is the entire cohort, so both general and neurocritical care, and the x-axis is the high sensitivity troponin concentration, which has been logged to the base 10 transformed. As you can see, there is significant proportion with troponins above the upper limit normal on admission and highly positively skewed distribution. And then if we look at each individual unit, so if we look at general critical care units, again, a very similar pattern, as you'd expect, and almost two-thirds of these patients had a troponin above the upper limit normal on admission. Then when we look at neuroscience critical care unit, a smaller cohort of just over 280 patients, and again, a significant proportion with troponins above the upper limit normal, just over a third. Sorry, this is quite a busy slide, but this essentially looks at the patient's pre-ITU demographics. So, the left-hand column shows the demographics of patients whose troponin levels below the upper limit normal, and then the right-hand column shows the demographics of patients with troponins above the upper limit normal. As you can see from the right-hand side, these patients who had troponins above the upper limit normal were older, and they had more cardiovascular and non-cardiovascular comorbidities, which I guess isn't surprising. So, you know, those patients with troponins above the upper limit normal had more cardiovascular disease and risk factors. So then we looked at the features of their admission, and again, on the left is the features for patients with troponins below the upper limit normal, and on the right, those with troponins above the upper limit normal. As you can see, all highly statistically significant in terms of their admission criteria being more complex. So, patients with troponins above the upper limit normal had higher Apache scores, they had worse renal function, higher white cell counts, lower haemoglobin, higher C-reactive protein, and higher lactates on admission. So, I guess not really surprising, those patients with higher troponins were the sicker patients. And then we looked at what happened during their critical care stay and the need for invasive ventilation, need for filtration, vasopressor support, and the length of stay. And again, you'll see that those patients with troponins above the upper limit normal were much more likely to need any of those organ supports and also had longer lengths of stay. So again, they had more complex admissions. Then we looked at critical care mortality, and the black bars on this graph show the mortality for patients who had troponins above the upper limit normal on admission. And you can see much higher mortality during their critical care stay for those patients compared with those with troponins below the upper limit normal. And then when we looked at the peak troponin, again, a similar pattern, much higher mortality for those patients whose peak troponin rose above the upper limit normal compared with those who had normal troponin concentrations. So, we then wanted to look at splitting these troponin concentrations up a little bit more to see where there was a stepwise increase. So, the smallest bar, the light grey bar here is troponins below the upper limit normal, and then going upwards, we go up to up to 5 times the upper limit normal, up to 20 times the upper limit normal, and then above 20 times the upper limit normal. And as you can see, there's a stepwise increase in the risk of critical care mortality just based on this one admission, high central troponin concentration. And in neuroscience critical care, if you had a troponin greater than 20 times the upper limit normal, your mortality was over 40%. So, then we wanted to look at the area under the curve for mortality for these patients. So, this area, this ROC analysis looks at patients in general critical care unit, and they're comparing the admissions, high central troponin concentration with the Apache and SOFA scores. And as you can see, the lines are very similar. And on analysis, there's no statistical difference between any of these markers. And actually, the troponin concentration performed well with an area under the curve of 0.82, which, given it's a single marker, was quite an impressive result. And then if we look in neuroscience critical care unit, again, we see very similar lines. And again, there was no statistical significant difference between any of those markers for discrimination for critical care mortality. And again, another high area under the curve of 0.83. So, the troponin concentration is quite effective at discriminating critical care mortality. So, I guess the key question here, and where the money's at, is an independent relationship. But we first looked at the stepwise troponin concentration across the whole cohort. As you can see from here, from the odds ratios, the odds ratio for mortality in critical care gradually climbed with increasing high central troponin concentrations. We then looked at the log to the base 10 transformed high central troponin concentrations, both in neuroscience critical care and general critical care. And as you can see, in general critical care, a statistically significant result. And you can see the other variables that were included in the multivariable analysis. So, we only included variables that were associated with mortality in this multivariable analysis. And again, in neuroscience critical care unit, again, a highly significant result. So, just thinking about this study, it has some advantages. It's the largest study like this to date. And the great thing about the study is that we perform testing regardless of indication. We have a consecutive cohort of patients. So, we don't worry that we're missing a whole cohort. And it's pretty consistent with previous data, which have also suggested similar results. And there are some limitations with the study that we're thinking about. Certainly, this is a single centre analysis and therefore has all the limitations that a single centre study would have. There were a few patients in whom we didn't have all the APACHE criteria in order to calculate admission APACHE, because other than adding a troponin on, we didn't do any other testing on patients. And then, of course, we've used two different critical care units here. And, of course, that somewhat dilutes our ability to analyse them individually. So, in conclusion, high sensitivity troponin elevation taken outside the context of conventional indications is very common in the critically ill. These elevations were associated with increasing age, comorbidity, illness severity and the need for organ support. The admission of high sensitivity troponin concentration is an independent marker of critical care mortality and has similar discriminative ability to the APACHE score. And this may represent a novel prognostic biomarker on admission in non-cardiothoracic critical care settings. So, thinking about the future, I guess at the moment we have a marker that demonstrates risk. But what would be really nice to know is if it's associated with longer-term outcomes, because if it were associated with longer-term outcomes, then potentially we could look at these patients in the future and say, should we do a study to see whether any medical therapy can alter their long-term outcomes? These data are awaited. So, thank you once again for inviting us to speak. I'll take some questions at the end, but I'm very happy if people want to contact me in the future to discuss. And I'll hand over to our next speaker. Good afternoon, everyone. So, I'll present our paper association between pre-morbid beta blocker exposure and sepsis outcomes, the so-called BEAST study. I have no nothing to disclose and no conflicts of interest related to this study and I'd like to acknowledge the work of Dr. Kai Kwan Tan from Singapore and Dr. Martin Harazim from the Czech Republic who helped a lot with this study and also the other co-authors. So we all know that sepsis is a large problem and the most common diagnosis in intensive care patients and we've also recently heard of the concept of decatecholaminization with beta blockade in septic shock patients trying to improve patient's outcome. We've looked at the role of beta blockers in septic patients before, performed a systematic review that showed that, interestingly, if patients are taking beta blockers before the septic episode and admission to intensive care, they seem to have reduced odds of dying. And so we look at this study as an extension of the systematic review to see if that actually does apply. So we performed a multicenter study. We looked at data from the Nipian Hospital in Australia, from medical intensive care at the University Hospital in Pilsen in Czech Republic and to increase our sample size we also collected data from the publicly available eICU collaborative research database which I'd like to acknowledge here. We looked at adult patients admitted to ICU for sepsis between January 2014 and December 2018, so four year period, and patients were included if they met the sepsis 3 definition in the hospital cohorts and ICD-9 diagnostic code from the eICU database. Patients were excluded if they had another admission with sepsis, so multiple admissions and multiple beta blocker prescriptions. As for outcomes, we looked at intensive care and hospital mortality and we also tried to explore the mechanistics behind any possible effects. So looking at the frequency of dysglycemia, which we know is associated with outcome, the peak lactate levels, SOFA scores as a proxy for organ dysfunction. We looked at the frequency of septic shock, overall mechanic ventilation rates, renal replacement therapy rates, and the length of stay in intensive care. We had to convert the Apache scores because the different cohorts used different scoring system. Apache 4 scores in the eICU and Australian database and Apache 2 scores in the Pilsen database. We performed multivariate logistic regression. The covariates were age, gender, the Apache score, ICU type, and admission weight. And we also did a sensitivity analysis looking at the propensity score matching, trying to match patients with and without beta blocker prescription in their chronic medication, and then match them as close as possible. And we also performed a survivor analysis using the Cox-Hazard regression and Kaplan-Meier curves. So there's overall, we identify almost 13,000 patients who had sepsis in those data sets. About 4,000 patients we were able to include, mostly from the eICU collaborative database. We had to exclude two-thirds of patients because there was no notion of their pre-morbid medication data in the databases, and we excluded only few who had concurrent prescription of more than two beta blockers. Septic shock was present about 12% of patients, and about 38% patients in the data sets were actually prescribed chronic beta blocker medication before their septic episode. And most commonly these drugs were metoprol and kepedilol. So this is the baseline demographics of the patients. As you can see, most of them are males as is usual for patients. The patients who were prescribed beta blockers before sepsis, as you would expect, were a little bit older, and they had somewhat less incidents of septic shock. The outcomes. So looking at mortality, the exposure or chronic prescription of beta blocker medication was associated with decreased ICU and hospital mortality. And the adjusted odds ratio for ICU mortality were about 0.8, and for hospital mortality 0.84. Both significant on the adjusted, but not significant on the non-adjusted analysis. Looking further at the data, trying to figure out what beta blockers were mostly associated, we found that it was actually, surprisingly, the non-cardioselective beta blockers that were associated with better outcome rather than the cardioselective beta blockers. And the most association, or the strongest association, we could see was with kepedilol followed by metoprol. So for the matched analysis, we created about 1,555 unique pairs of patients. And again, the results were similar, even somewhat slightly stronger. And the baseline characteristics didn't really differ in those matched and unmatched cohorts. And you can see here, the Kaplan-Meier curves for the unmatched and matched cohort. And you can see that the patients who were taking chronic beta blockers before they got septic had slightly better outcomes. And here, again, looking at the Cox's Heart regression analysis, you can see that beta blocker prescription is associated with better outcome, whereas the severity of illness, as you would expect, is associated with worse outcome. When we looked at each cohort separately, we could not find any difference in mortality, presumably because of the lower number of patients included in each separate cohorts, which just shows that the sample size is important in trying to find small but important outcome differences. And again, the association was stronger in patients who were not in septic shock, perhaps because there was not that many patients overall in the database that were in septic shock. As for the organ dysfunction, we looked at SOFA scores on day 1 and 3, which represent in about one third of the patients, one quarter of the patients. And what we could see is that the patients who were on chronic beta blockers had somewhat better PF ratios and so better oxygenation. They had somewhat slightly higher creatinine levels, perhaps associated with the fact that these were slightly older patients. And surprisingly, they had lower noradrenaline requirements on day 3 and somewhat higher GCS scores. Knowing that that's not very reliable as a SOFA descriptor, interestingly, it was the mean anterior pressure was somewhat higher on day 1 and 3 in the patients who were taking chronic beta blockade. And overall, there was no difference in the pooled SOFA scores or change in SOFA scores between day 1 and 3. We also could find that there was reduced mechanical ventilation rates in patients who were taking beta blockers prior to sepsis. As I mentioned, reduced frequency of septic shock. There's no difference in the use of renal replacement therapy. And there were no significant differences in the rates of either hypo or hyperglycemia. And we couldn't see any association with the serum lactate levels or length of ICU stay. To discuss these results, really, what we could show is that if patients are prescribed chronic beta blockade therapy, the outcomes are somewhat better. What could be the reasons? We know that catecholamine excess in septic patients or in critical care in general is present, and it's due to the adrenergic stimulation, which may be due to pain, inflammation, stress, or hypervolemia. We also know in sepsis that catecholamine is produced quite early by the autonomous nervous system, by the gap and white cells. And, of course, we know that stimulation of beta 1 receptors leads to increased heart rate, myocardic contractility, and oxygen consumption. Whereas beta 2 receptor stimulation leads to vasodilatation of skeletal muscle vessels and bronchodilation. And that stimulation of alpha receptors leads to arterial vasoconstriction in the kidney, gut, and skin, the non-vital organs. So how could beta blockade be beneficial? Perhaps chronic beta blockers might protect from the catecholamine surge that is seen in sepsis. In terms of cardiac function, it may decrease myocardial oxygen consumption and perhaps improve diastolic dysfunction that is present in behalf of septic patients by prolonging diastole and chronic perfusion. In terms of vascular effects, the beta 2 adrenoceptors have only small modulatory effect on basal tone. And, in fact, blocking beta 2 receptors leads to a small degree of vasoconstriction in many vascular beds, apart from skeletal muscle. And there's some work showing that beta blockade may reduce the nitric oxide expression that leads to vasodilation in sepsis. And, interestingly, in old papers in the 60s, beta blockade was tried as a treatment for septic shock or endotoxic shock in dogs. And they could see that on autopsy of these animals, they could not see splinting and pulmonary congestion that was present in animals that were not treated with beta blockers. What is the evidence against beta blockade? I guess it's mainly the experience we have with patients is that patients in sepsis often have a high cardiac output, especially if they've been resuscitated with fluids. And beta blockade may reduce cardiac output in these patients, especially those in septic cardiomyopathy. We know that if patients are hypovolemic, they are very sensitive to the effect of beta blockers, and that may result in hypertension and cardiovascular collapse. And it may impair vasodilation in skeletal muscle and impair bronchial small muscle relaxation and increase airway resistance. It may also be that the effect on inflammation can be quite rare with beta blockade. And traditionally, beta blockers are stopped in septic patients, the chronic beta blockade therapy on patient's admission to hospital. So as I said, we have previously done a systematic review of work that was done in observation studies looking at pre-morbid beta blocker prescription. And we did find a similar effect to our study. The odds ratio are reduced in patients who take pre-morbid beta blockers. Interestingly, there's also a recent trial in patients who had cardiogenic shock. And the elders say that they actually primarily thought that beta blocker use will be associated with more early death and more cardiovascular dysfunction. But in fact, they could find the opposite. And the chronic beta blockade prescription didn't even seem to attenuate the effects of dobutamine in these patients. And these patients had a better outcome again when they were on chronic beta blockade therapy. And similar outcomes seem to have been better in patients who had out-of-hospital cardiac arrest with non-shockable rhythms. All this is very recent work. And to look at the possible effects of why beta blockade may be associated with improved oxygenation in septic patients, there's one study that looked at patients with stroke. And again, they could see that the incidence of nosocomial pneumonia is reduced in patients who were prescribed beta blockers either before episode of stroke or when they actually suffered stroke. Interestingly, we also observed the effect of Kavadil was the strongest in our cohort. And so we looked a little bit more closely at the effect of Kavadil. And to at least my surprise, there's quite a lot of work in the 90s about Kavadil and its effect. And it has quite a potent antioxidant properties, especially its metabolites. And there's some experimental work looking at the lipid peroxidation induced injury in the liver, which was reduced with the use of Kavadil. There's some neuroprotective effects and renal protective effects in diabetic nephropathy. And there certainly has been some protective effect in splenic ischemia reperfusion model. And Kavadil pretreatment seemed to have depleted, restored depleted renal antioxidant enzymes and improved renal dysfunction in a septic model in rats. And it also seemed to be protective in skeletal muscle in ischemia reperfusion model of limb ischemia. Again, all just animal studies. So what is the take-home message from our study? Well, it is an association study. It's a retrospective study, so we can't be certain about causation. There's always risk of bias. The patients were a little bit older and slightly less sick at baseline. Maybe that could be a selection bias in these patients who prescribe beta blockers. They may be treated a little bit earlier because they are a bit more frail. And that is certainly a possibility in our data set. We still don't know whether giving beta block A in septic shock is important or not, or associated with better outcomes. And there's certainly studies coming up looking at that issue. Although most of the planned studies, I believe, are viticardioselective beta block A with short-term or ultra-short-term beta blockers. So a recent discussion on this topic in the journals is that decatecholaminization is probably important, but whether this should be done by beta block A or by stimulating vagal nerve or vagal system, as was done in animals, in research that was done at the Pilsen University Hospital as well, showed some impressive data in preventing organ dysfunction in sepsis, or whether we should just simply reduce the amount of inotropic support that we use, that all requires further research. And we are looking perhaps at doing a pilot, randomized, double-blind study using beta blockers in selected patients in sepsis and septic shock, and those who are not hypovolemic, and those who perhaps can receive dementia rather than intravenously in small doses. So with that, I'd like to thank you, and I'll now hand over back to Dr. Tamar Sakmani for starting the question and answer session. Thank you very much. Thank you very much for both presenters for the talks. We've got a number of questions, so I will start off, and the first one is going to Dr. Hinton. It is about the test and how can we use troponin. What do you think, what should be the threshold for ordering this assay so we get the most out of this, that we minimize the confounding and perhaps guide appropriate treatments? Thanks, great question. And I guess the first thing from my perspective and my clinical practice is that we have to split that automatic reflex where we see an elevated, or certainly in the UK, we see an elevated troponin, and therefore the assumption is that that is a type 1 myocardial infarction and therefore the patient needs to be treated with antiplatelets. And so I think it's, you know, part of this is about educating our colleagues that we need to shift our mentality, and actually a troponin can be immensely helpful in critical care and in lots of other situations in terms of giving us a guide of prognosis. But it has to, we have to switch our focus from thinking that it is a type 1 myocardial infarction rather than just seeing it as a marker of that. Thank you. The next question is to Dr Nalos. It is really interesting to see that there are different improvements in different organ-specific outcomes. How could you explain the better outcomes in the respiratory outcomes? Is it really related to the reduction of venous, sorry, pulmonary congestion that you have mentioned, which was found in the animal studies? Yeah, it is very interesting, and we were quite surprised with some of the results. And it is possible that the chronic beta blockade may attenuate the effects of catecholamines on the pulmonary vasculature and the congestion that is seen in septic shock patients or in sepsis patients. The animal studies, certainly the autopsy studies in the 60s were quite specific about this effect. And also the recent observation study in the stroke patients is in the similar direction. So association, and it is something to be explored further. Thank you. Dr Hinton, we are going back to this question of how can we interpret the results? And how can you communicate this troponin rise within the team? So if you receive a result which is greater than the upper limit of normal but less than the 99% percentile, how can you make it actionable at the bedside, if it is possible? Yeah, thanks. Another good question. I guess perhaps I didn't make it clear at the beginning. So the upper limit of normal is defined by the manufacturer and that's based on their 99th percentile for that assay. But that 99th percentile is based on a young, healthy population. And so I think we have to try and translate that into what we're seeing in front of us. And we've done a number of studies where we've sort of tried to show what the 99th percentile is in a certain cohort. But of course, that's very much dependent on that cohort. And it's very much dependent on the assay that you're using. So the first study that I showed you used a different assay to what we did in our current study. And of course, there are more and more assays developing. So it's very difficult to give people a specific number. But I think when we're interpreting these results, we have to look at the age of the patient and their demographics, particularly their cardiovascular risk factors, and then thinking about the illness severity in order to try and interpret them. I don't think it's easy. And I think particularly in critically unwell patients who can't give a history of chest pain, it is challenging. OK, thank you very much. Dr. Nallos, if I remember correctly, you said that the mean arterial pressure was higher in the group which was pre-treated with beta blockers. Is it possible that the beta-blocker group had better outcomes because they received less catecholamines during their stay? I'm referring to the 65 trial which hinted at this. Yes, look, it is possible. And as I said, the physiologic effect of beta blockade is that it blocks both beta-1 and beta-2 receptors. And the blockage of the beta-2 receptors actually leads to a slight vasoconstriction. And so, yeah, these patients seem to have slightly higher mean arterial pressure. And again, whether this is that reason or because these patients are obviously prescribed beta blockers for either hypertension or heart failure and therefore their baseline blood pressure is higher and drops to a higher level with sepsis, that's also entirely possible. Thank you. We will stay with Dr. Nallos. And just to expand on the limitations, because again, when we look at the confidence intervals and the ORs, they are very, very close to not being significant. And you had to exclude a quite sizable population from your study. Because you didn't have data. Do you think that if you expand this to an even wider population, then this might change? Or how confident are you with your results? Well, I think we can be as confident as our data, which means it is borderline confidence. Having said that, we have done the system deck review looking at other studies that explored similar issues. And the effect has been quite consistent. There is also since some other studies that looked at similar, a study from Taiwan. And again, they found a similar effect, even though their population was smaller. And it is certainly something that, as you know, there are several groups who are trying to look at the effect of actually starting beta blockade for septic shock patients, especially those one with hyperdynamic circulation. And so I believe that there is some true effect in beta blockade for sepsis. But how big that effect is and how it can be applied to patients with sepsis, that certainly is a challenge. Thank you. Dr. Hinton, we got a question about how could we use the high-sensitive troponin assay in polytrauma patients to rule out subtle cardiac injuries? Do you have any experience of this? That's a really interesting question. Certainly the centre that we perform the study in is the major trauma centre for the region, for the South Coast, effectively. So it does receive a large volume of trauma cases. And so certainly some of those in the study were polytrauma. I think it certainly is helpful to look for myocardial injury as a result of contusion. And certainly going back to the beta blocker study, there was another study looking at patients who had polytrauma with a standard sensitive troponin. And they found that quite a few of those had small dissections as well resulting from it. I think, again, it all depends on the history. And then adding in other things, I think an echo in this circumstance can be really helpful to look for regional wall abnormalities in particular and whether the myocardium is thinned in that area to sort of guide you to the chronicity of whether it's an acute event. But, again, it's difficult to differentiate. And often what we do in clinical practice is to look at the troponin, perform an echo, and then wait for recovery to decide whether further investigations need to be undertaken or not. Thank you very much. And I think one of the last questions is that, to Dr. Hinton again, is that if the troponin is a risk biomarker, as you had mentioned, have you looked at integrating it with others? For instance, infection risk biomarkers, or is that too far-fetched? No, I like the sound of this. To be honest, we didn't look at combining it specifically with infection risk markers. We did look at various iterations of the Apache score with adding the troponin data in, but we couldn't improve on the Apache score by adding the troponin data in. So I think certainly there's room to look at this further in future. Thank you. And as I said, it's the last one. It's not the last one because another question came in to Dr. Hinton again. What would be your troponin threshold for a coronary angio in the critical yield? I think that's a really good question. I mean, of course, it all depends on the patient in front of you. You know, sometimes I get asked about patients who are quite elderly with multiple comorbidities and, you know, who are on high doses of vasopressor support. And actually, in that context, I would expect their troponin to be quite high. And the more we do these studies, the more we see that actually it's quite common. I mean, personally, I would have a relatively high threshold for coronary angiography just because, you know, there are lots of other things going on here. The addition of contrast and antiplatelet agents and all the heparin that we give, you know, that all in the critically ill patient has implications. So I think, you know, I would have a relatively high threshold for doing it in someone who's critically unwell. But certainly once patients recover, I think, you know, we need to think carefully about whether they've got underlying coronary artery disease. As I said before, some patients who have a type 2 myocardial infarction or myocardial injury will have a lower threshold to develop that because they've got underlying coronary artery disease. So I like to think about after they've got better from their critical illness, what are their cardiovascular risk factors? And then combine that with the echo and consider whether we need to look further. But it's a difficult balance, I think. Thank you. I think this concludes our Q&A session. So I would like to thank both of our presenters, and I would like to thank the audience for attending. Again, everyone who joined us for today's webcast will receive a follow-up email that will include an evaluation. Please take this five minutes to complete the evaluation as your feedback is greatly appreciated. And on a final note, please join us for our next Journal Club, Critical Care Medicine, on Thursday, October 28th. This concludes our presentation today.

troponin

biomarker

risk

myocardial infarction

high sensitivity troponin assays

critically ill patients

pre-morbid beta blocker exposure

sepsis outcomes

chronic beta blockers