All right, so now that we know what sepsis is, we're going to talk about how to treat it. So I do want to mention—and again, this is, again, borrowing some of the slides from the first talk—as we think about, you know, shifting our concept and our definitions of what sepsis is, it's in—I think it's important—the terminology is important, but we can't get lost about what we do at the bedside, right? And ultimately, sepsis is a—something that exists along a continuum. So dichotomizing it is always going to be arbitrary, right? And so whether we use the 2005 old nomenclature, the sepsis three criteria, or now the new Phoenix definitions, patients are going to present with what they present with, right? So some patients will present with severe organ dysfunction, and it's easy for treating sepsis or septic shock. And some patients will present early, right, and have some features that are a little concerning, look a little inflamed, look a little sicker than the average patient with an infection. And so what are you doing at that point? Are you treating early sepsis or you're preventing sepsis? You know, semantics, really. Don't get lost in that. And then lastly, what do we now do with the patients who have some degree of organ dysfunction that's measurable, previously would have been called sepsis or severe sepsis, and now don't fall into the Phoenix criteria? Again, not super important to worry about as a clinician. Makes it harder maybe to communicate as we're talking, but don't get lost in that. All of these things are kind of on the continuous spectrum. All right. I am going to use the Surviving Sepsis Campaign as the guide. It was published in 2000, or sorry, 2020, and so it's been out long enough now that I think you'll start to see direct examples incorporated onto the boards. The first thing that the Surviving Sepsis Campaign does is it recommends systematic screening. And so that's important because multiple studies have shown that it helps people recognize sepsis earlier, provides more timely therapies, and improve outcomes. The question is how do we actually do that screening? And the reality is there's no right way that's ever been shown. And people use lots of different things. So you should do whatever your local organization uses. Some combination of infection, shock, organ dysfunction, and maybe even some features of inflammation. Lactate is one that commonly comes up. And the Surviving Sepsis Campaign actually suggests against using lactate as an initial screening marker. It's important for tracking and monitoring therapy, but is limited in its ability to screen for sepsis. So if it's high, that's helpful. But actually most patients with high lactate actually do well as long as they're treated appropriately. But there are many patients who have low lactate that isn't actually reassuring. And so this is an example from a study that was published by Halden Scott out of the emergency department where you can see different levels of lactate. And even many patients who had normal lactate levels less than two still had ICU length of stay, still had some degree of mortality. And so really lactate can be helpful as a way to assess what's happening and follow it over time, but don't use it as a screening tool, at least per the Surviving Sepsis Campaign in and of itself. I think it's also important to differentiate definitions from diagnosis. So I talked a lot in the pathophysiology talk about what defines sepsis and now the Phoenix criteria. And that's important for understanding prognosis and who's at risk for poor outcomes. We really want to be treating patients before they become somebody with a poor prognosis and a bad outcome. And so diagnostic criteria tend to be a little bit earlier. So we want to be picking up patients as early as possible. And so these are more operational features which haven't changed. These are the same criteria with or without meeting Phoenix sepsis criteria. All right, so moving more into direct treatment. So this is the Surviving Sepsis Campaign algorithm. So we talked about systematic screening. And then once you kind of screen and assess and you decide, hey, this patient has clinical features of shock, then you have about an hour to get things going. So why an hour? So I'll talk about that in a little bit. But there are six key steps that you want to do. IV access, blood culture, antibiotics, measure of lactate, again, to help you guide therapy, but you already decided the patient's in shock. You didn't need lactate to tell you that. Fluid and then vasoactives. If you assess a patient and you're like, okay, they're not in shock, but I am worried, then you suspect sepsis. And these are patients you should do the exact same things for, but you have a longer period of time. Because you may learn some information from an expedited diagnostic evaluation that says, oh, this patient actually doesn't have sepsis or doesn't need antibiotics and they have something else. And so you don't need to go on all cylinders right away if they're not in shock. But you should still be working quickly. And if at any point they develop signs of shock, then you obviously move over to the left side. All right, so the times are really, the one in three hours, really come from the antibiotic data. And so the Surviving Sepsis Campaign has two recommendations about antibiotics. The first is that if you have septic shock, you should start antibiotics right away. And then sort of do your expedited diagnostic evaluation concurrently. If you have sepsis but not shock, or suspected sepsis without shock, then you have some time. So you can proceed with your expedited diagnostic evaluation. And as soon as it becomes indicated to give antibiotics, or it becomes clear the patient needs antibiotics based on your evaluation, then you should give them. And you have up to three hours to kind of make this decision. And then, of course, any kind of other source control procedures, including antimicrobials beyond antibiotics, such as antifungals or even some antivirals, would be important this time as well. All right, so why these two recommendations? Well, the first is that there's a very clear linear association between delays in antibiotics and poor outcomes. So this was a landmark trial done under Canada, adult sepsis patients. But every hour increase from the onset of hypotension to the delay of initial antibiotics was associated with a 7% increased odds of mortality. In children, we see a similar but less profound relationship. So on the left is data from a single center at CHOP. We see that same stepwise increase, much smaller sample size, didn't reach statistical significance until three hours. And on the right is a much larger study, multicenter out of New York State, which prioritized antibiotics as part of a bundle of care, but didn't show any direct difference between mortality when patients were given antibiotics within one hour or around three hours. So the bundle in totality did matter, but the antibiotic timing less so. So it doesn't seem like there's as a strong association. But the patients who did benefit in these two studies from early antibiotics had shock. The ones who didn't didn't have shock. And so that's why that allowance of up to three hours was put into place. Doesn't mean you should wait three hours. It means that the outcomes aren't going to be worse if you delay the antibiotics while you do your evaluation to make sure they, in fact, do need antibiotics. The balancing metric is that you're not giving antibiotics to patients who don't need them. All right, so that's that. And the other five pieces of those other key management steps, those other five flowed from the timed antibiotics, right? So that's where their one and three hours came from. All right, in terms of fluid, three recommendations here to know about. The first is that in health care systems where intensive care is available, there's a suggestion to give up to 40 to 60 mLs per kilo of bolus fluid in the first hour, titrated to clinical markers of cardiac output and discontinued if signs of fluid overload develop. So this does not mean every patient needs 60 per kilo of fluid or 10 per kilo of fluid or whatever. It means that you should be considering fluid up front as long as it's helping improve cardiac output and the patient doesn't have signs of fluid overload. Health care systems with intensive care means the United States, right? No matter where you're located, right? Even if you're at a community hospital that doesn't have an ICU, that obviously doesn't apply to anyone in this room who all work in an ICU. But if you're getting phone calls from your referring hospitals and they say, we don't have an ICU, therefore we're not giving fluid, that's not the right reason to not give fluid. I'm not saying you should give fluid, but that's not the right reason to withhold it. It's really in health care systems where you have no access to provide intensive care medicine, whether that's in a formal ICU or not. So that means you can't give advanced modes of ventilation, vasoactives are limited, and so on. In that environment, there seems to be a benefit to withholding bolus fluid unless you're frankly hypotensive. If you're frankly hypotensive, then you should give bolus fluid. If you're not, then maintenance fluids seem to have some benefit. I'll show you that data in a moment. And then there is a suggestion to use balanced crystalloids over saline, and I'll show you some of that in a second. All right. So why do we say give fluid? Well, there's many association studies where patients get at least some amount of minimal fluid do better, at least in health care systems with access to ICU care. This was a study from Joe Carcillo in the 90s that showed increased survivors if you got at least 40 mLs per kilo. However, we do know that too much fluid is also pathogenic, and Jerry alluded to this earlier. And there are multiple studies that also show an association with excessive fluid administration and increased mortality. So finding that right balance is really important, which is why titrated fluid administration is recommended. There's good data from the FEAST study, which made the Surviving Sepsis Campaign issue that warning about giving fluid in low-resource settings. And so in this study, patients were randomized to either albumin or saline up front versus no bolus, and the patients who did not receive a bolus, only maintenance fluids, had a lower risk of mortality at 48 hours. Many of these patients had anemia. Some had malnutrition, although severe malnutrition was excluded. But importantly, all patients who had frank hypotension were excluded from enrollment in this. Right? So that's been forgotten a little bit, but that's why that recommendation by the Surviving Sepsis Campaign, frank hypotension, you should reverse the hypotension with fluid. All right. So which fluid to give? There are lots of options. Which one should we use? Well, if we look at crystalloid fluids, which are recommended, there's not been any study that's definitively shown that colloids up front are beneficial, and they're certainly more expensive and more difficult to store and deliver. So crystalloids are generally the first-line therapy, but there's several different options. The main difference between saline and your balanced or buffer fluids, which is lactated ringers or plasmalite or Hartmans, is that saline has a super-physiological amount of chloride, right? Because it only contains two things, sodium and chloride. So it's isotonic with sodium, but therefore hyperchloremic as a result, whereas the other fluids are more balanced or buffered with a non-chloride anion buffer, right? That's why they're referred to as buffered or balanced. Saline will induce a hyperchloremic metabolic acidosis, whereas the balanced and buffered fluids will not. And there's some evidence that hyperchloremia can be particularly harmful, especially for the kidney. And there have been now multiple, very large, randomized controlled trials in adults. This is the meta-analysis of those trials, which do suggest a suggestion of a benefit if you decrease mortality if you use balanced or buffered fluids, although in this meta-analysis didn't quite reach statistical significance. But if there is any benefit, it's probably in the patients with sepsis. So that's why the Surviving Sepsis Campaign issued that week recommendation. Of course, we have an ongoing randomized controlled trial in children now, which will be finished in about a year, and hopefully we'll know a little bit more about children. All right, two last things, vasoactives and steroids. So vasoactives, so the Surviving Sepsis Campaign says you can use epi or norepi rather than dopamine. It's reasonable to start vasoactives after you've given 40 to 60 mLs per kilo of fluid, or sooner if you have fluid overload or evidence of myocardial dysfunction, say on a POCUS exam. And you can safe to administer these through a peripheral vein. Why epi or norepi versus dopamine? Two head-to-head clinical trials, both showed clinical improvement. If you use epi rather than dopamine, epinephrine is probably a better inotrope and has fewer off-target adverse effects. There's never been a good head-to-head trial of epi versus norepi. So that's why they're thought to be equivalent. In terms of physiologically, a lot of people like to say, well, I'd like to use epi for cold shock and norepi for warm shock, so I can use an inotrope in cold shock and a vasopressor in warm shock. I think there's good rationale for that. The problem is, and the Surviving Sepsis Campaign warns against doing this, because we're not very good at actually figuring out the physiology based on our clinical signs alone. This was a study that was conducted that looked at classification of shock and the associated clinical signs. Everybody uses the things that are obvious. If you put your hand on the patient and they feel cold and their cap refill is sluggish and their pulses suck, that's cold shock. But they ignore the fact that they have a wide pulse pressure and a low diastolic blood pressure. What drives us to make that determination are things that maybe aren't entirely consistent with that type of shock. So that's why there's a little bit of a warning from the Surviving Sepsis Campaign that, while conceptually a good idea, just be careful that you might be wrong based on your clinical bedside evaluation alone. More helpful would be to do a point-of-care ultrasound. So embedded in the guidelines are to assess cardiac function early, and that can really be very helpful. If you see severe myocardial dysfunction versus not, versus hyperdynamic cardiac function, you might choose epi versus norepi differently. What about vasopressin? No great studies in children, but pretty good evidence in adults. This is from the VAST trial, that if you give vasopressin, that you can at least reduce the amount of catecholamine that you need to give. And so there is some evidence that vasopressin, which has harmful side effects. So vasopressin might be useful, at least as the catecholamine-sparing agent in patients who have refractory vasoplegia, despite other catecholamine vasopressors. And then milrinone, on the other side, as an inodilator, very good at augmenting cardiac output and offloading the left ventricle. And so there appears to be at least physiologic benefit of adding milrinone in those patients. Other causes of shock need to be considered if the patient's fluid refractory. I'm not going to go into those, and I'll close with steroids. So currently, steroids remain an area of controversy. There is an ongoing randomized controlled trial in children alone, but the current guidelines say if you are able to achieve hemodynamic stability with fluids and vasopressors alone, no steroids. But if you can't, dealer's choice, and so either use or don't use. Other adjuvant therapies I don't have time to go into, but are, I think, nicely explained in the Surviving Sepsis Campaign guidelines when to use these and for what circumstances. And I think these are probably fair game for the boards, and so I would have a read of those guidelines to look at that. I'll skip that. And then lastly, as I mentioned, the pathophysiology subtypes. The problem is, just remember, we have this one set of guidelines, and we're trying to apply this to this huge group of patients and expect that outcomes are going to be better. The problem is sepsis is not itself a diagnosis, it's a syndrome. There's many different components of it. And so it's really important that we actually think about how to treat these patients individually. And so now we are finally doing trials that are trying to exactly do that. So we know that there are patients who are hyperinflammatory, even more so than this graph shows, so I drew it in here. And these are patients in this trial who are being randomized to anti-inflammatories. Other patients don't need anything, right? And in this trial, they're just being observed. And other patients we know are immunosuppressed, and these patients actually need an immune stimulant. And so doing trials and doing clinical care that's more thinking about what's going on in front of you, as opposed to just applying a set of protocolized guidelines to that patient, I think will be the future of sepsis management. So points to take away, screen, think about sepsis. When you begin your resuscitation, remember those six key management steps. And then if we do things in a way that's at least consistent across patients with some individualization, that's when we tend to have our best outcomes. All right, so thanks very much, appreciate your time.

sepsis treatment

Surviving Sepsis Campaign

antibiotic administration

fluid management

vasoactives