Thank you. I'm Rana Hijar, I'm an intensivist at University Hospitals in Cleveland, which is an affiliate of Case Western Reserve University. My major interests are actually in clinical education, and I practice there predominantly in the medical intensive care unit. I do have a financial disclosure with Intellects Healthcare, which is we're looking into AI applications into safety into intensive care medicine. I act as a clinical consultant. Another disclosure, which is not financial really, is because I'm a medical person, I drift towards medicine predominantly. So it's going to be, I chose for you three articles that may impact our practice at the bedside. The first one, as you all know it, it's Clover's. It started off in 2018, had a little bit of a halt sometime in the 20s, in the 2020, I believe, which is a very interesting study really. Had a little bit of a controversy in relation to the ethical background with this study, whether it was justified for one, and whether patients were informed of the risks that they were facing in it. So the halt happened through the NIH until they changed the protocol a bit and changed their consent form and the disclosures to patients. The hypothesis was regarding a restrictive fluid strategy versus a liberal fluid strategy, and they defined it very well in the protocol. They would recruit patients into it after initial resuscitation, which is between one to three liters of fluids that they give, and their primary outcomes was all-cause mortality by 90 days, and they had a bunch of secondary outcomes. The interesting part here, which may lead to a lot of bias really, is at any point in time, people could, the primary care team taking care of the patient would withdraw the patient. And though they screened a lot of people, there were a lot of people who met the inclusion criteria and actually met eligibility for the study, but only 1,500 were recruited. I would like to highlight that there was very significant under-representation of the most problematic patients, and that's the heart failure patients and the renal patients. And the severity of the illness and the patients who were recruited was very mild. The majority of, I mean, we're talking about SOFA scores of three, which is barely make it into the ICU, actually, in some ICUs. The other thing, this is way into the emergency department. This is like the bulk, which is fantastic, actually, for an emergency department study from there. And the two groups were resuscitated almost equivalently. It's clear that the restrictive fluid strategy was going to be leading towards more use of vasopressors, which is clear. And there was a big difference at six hours between the two groups of the liberal people took far more than the restrictive people. And at 24 hours, it was even furthermore. And by the 24 hours end, everybody will go back to usual care. The interesting part also is there was no mandate to put center lines in everybody. So there was a lot of peripheral access, and many patients got vasopressors through a peripheral access. There's no highlighted things here. The two groups kind of fell on top of each other, and there was absolutely no difference in any of the markers that they were getting. The DSMB board said you have to stop because of futility, and the study stopped. When they looked at the subgroup analysis, perhaps there was a hint of renal people, renal patients getting a, having a better outcome if a restrictive strategy was used. The issue here is we cannot make such a distinction, obviously, because they were truly, truly underrepresented. So would that impact our clinical practice? And I really said maybe, and the reason why I said maybe is because the way the study was conducted is just give fluids and see what the results you get. It doesn't really look into whether the patients needed fluids or not, and whether our practices are going to change the stars a little bit more objective measures of whether patients need which strategy is better. So in reality, we have to still go back to the bedside and say how much fluids we're going to say just enough, and this enough is a big question to answer, and perhaps needs a little bit more physiologic data to be assessed at each level. This is not a strategy that can be used without a functional assessment of hemodynamic assessment, but in reality, research has to get us to that. Functional hemodynamic monitoring is something that has a lot of controversy currently, and I know there are a lot of devices that are being promoted and sold, but in reality, none of them have made a major impact on survival, and we have to be very careful in what to pick. So the groups of patients outlined have to be studied better, and to impact their survival, we have to be a little bit more physiologically oriented. The second study is kind of a fascinating one, and it's the use of hydrocortisone in severe community-acquired pneumonia, the Cape Cod trial, as they call it. Steroids have been in the literature for years and generations, and they will keep on coming. It goes a la mode. Older days were, oh, they're great, and then they got, no, they're not great, and now after recovery with COVID, they became great again at reasonable doses, and the Cape Cod trial was, hey, we probably should consider it, and people with the severe community-acquired pneumonia, the hypothesis of the trial was that early treatment with hydrocortisone reduces mortality, and the outcomes was death within 28 days, and secondary ones are later on, three months later, use of mechanical ventilators, safety, and vasopressors. Inclusion and exclusion criteria were kind of very standard in this setting. The interesting part of patient recruitment, they had a lot of patients with COPD, and as you know, patients with COPD, when they have an infection, particularly if it's in the viral categories, they're going to end up with significant bronchospastic disease, and there were about 25 and 26 patients. There were about 26% of the patients in the placebo group were in that category, but clearly, they were in a very severe range of illness, as judged by the pneumonia score index. The use of vasodilators was also present, and remember these people were picked on as severe pneumonia, but not in septic shock, so there's a little bit of contamination with sepsis, I believe, in this trial. Their outcomes was great. Steroids are fantastic. Mortality dropped. Patients got out of the ICU earlier. The use of vasopressors in them was less, and from a safety profile, the hydrocortisone was not associated with increased nosocomial infections, and was not associated with any increased bleeding. Mind you, the dose of steroids that was used was less or equal to 200 milligrams of hydrocortisone, and when they looked at the subgroup analysis, practically it was perfect for everything, but note, in the isolated germ versus yes versus no, if we isolated the germ, which is usually a bacteria that they were talking about, and they did this in about 50% of the time, didn't make as much a difference as if the germ was not isolated, assuming it could be, could this be like an atypical organism or viral infection. Also, women definitely benefit better than men. Don't know what to make of that, really, but this is just interesting to keep in mind for further studies, because when they're going to revoke the steroid use in the next five years, we'll see which groups will get it. Authors said we should use it, because it's good, and this study was also terminated prematurely, because they believed that if they were to continue on it, it was unethical for the placebo group, because they were not doing as well. Impact in clinical practice, absolutely yes. This is not, however, to be used in the immunosuppressed patients. Not sure if application and aspiration will work as well, and interestingly, as of Friday, just on the 19th, the Society of Clinical Care Medicine published its guidelines on the use of steroids, of corticosteroids, and sepsis, acute respiratory distress syndrome, and community-acquired pneumonia, and acute community-acquired pneumonia said, yes, we have to use it, we should be using it. In those patients. The last study is really very intriguing, and I think it's food for thought more than clinical practice. It's about the use of Langelol, a ultra-selective beta-1 receptor blocker in septic shock. This is coming from the UK. Do they have a rationale behind it? The answer is yes, they do. There has been some animal models and some small clinical trials of its significance. There was a meta-analysis published in 2022 showing a kind of a benefit of use of ezmolol in this setting in survival. And the, like, physiologic basis of it is in septic shock, in patients who are on catecholamines, will have a sympathetic overstimulation that will lead to a worsening myocardial efficiency, being increased work or oxygen consumption, or diastolic dysfunction. So, there is a rationale with it in people who are tachycardia. This was an open-label phase two trial, randomized, with the hypothesis that reducing the tachycardia is going to improve the organ failure. Outcomes was a SOFA score, and the secondary outcomes were related to mortality and other things. Very simple inclusion criteria, very simple exclusion criteria, and they excluded really anybody who didn't have an infection as a cause of their vasodilatory shock. They screened a lot of people. They had the, about 60% of people declined the trial because they were scared of the effects, and they end up having 126 patients divided into the treatment group and the standard group. I would like to emphasize, however, that the norepinephrine dose used is far more than what our standards are as a single vasopressor and septic shock. Majority of us in practice will have a second pressor at here, which is not the case, and these people were very sick. That's kind of like a SOFA score of 10 is getting up there. Steroids were equivalent in both subgroups, the use of steroids, as far as an average dose, but out of the patients receiving it, only half of them were getting steroids in both settings, which is not a standard practice, really. The study was started in 2018. At that time, the standard of care was adding steroids in people in septic shock, which I find interesting and perhaps may have had some impact on the trial. The results are kind of, though there were no statistical difference in anything that they measured, but there was far more side effects, and the number of patients who died were more in the beta blocker group than in the standard group. So, their data monitoring committee advised to hold because of futility, first of all, and second, because of the possibility of causing harm. So, clearly, this is not to be used. This is an absolute no-no at this point in time. However, it's food for thought for further research. Something like this has to go back to the basic scientists to evaluate the role of tachycardia in septic shock with and without the use of beta blockers. With that, I end, and thank you very much. Thank you.

intensive care

fluid management

hydrocortisone

septic shock

personalized medicine