Welcome to this chapter in the Society of Critical Care Medicine Hemodynamics Masterclass, Fluid Resuscitation. Once again, my credentials, my contact information, please feel free to reach out to me. My conflicts of interest are all here and may play a role in your evaluation of what I have to say. I want to emphasize that any figures that I use here are for illustration only and I am not advocating for any specific product or class of products. So this is a pretty straightforward case. I'm using it to make a point. As in much of clinical medicine, most of the diagnosis is in the history and physical exam. I think most of us would give this patient IV fluids without much hesitation. And without the need for more monitoring. But more often in critical care medicine, the situation is a lot more complex. The physical exam doesn't really do a lot to help us resolve the clinical dilemma. And preliminary laboratory analysis suggests ongoing organ failure. This is a very concerning situation. And within a very short amount of time, blood cultures show growth. Chest X-ray also doesn't really help us make decisions. There's sort of a large cardiac silhouette. There's large-ish right ventricle loss of the left atrial concavity. Maybe some increased civilization of the blood vessels. So what do we do to resuscitate this patient? Do we give fluids? And to help resolve this question, do we use additional monitoring? So as we discussed in the previous talk, sometimes we frame this clinical question as, is my patient wet or is my patient dry? And in this particular case, it's hard to tell. And as we discussed, we're often concerned about the adequacy of tissue substrate delivery. So in this patient, is tissue substrate delivery sufficient? I think we'd argue that it's probably not. There's signs of organ failures. But what do we do about it? So the best ICU monitor would tell us how those cells and tissues are doing, but we don't really have that yet. So right now we use capillary refill time, blood lactate levels to help us understand what's going on at the tissue level in terms of perfusion and substrate delivery. Remembering that shock is a condition in which oxygen and substrate delivery is not enough to meet tissue oxygen demands, we can keep in mind that IV fluids act on the cardiac output part of the oxygen delivery equation. When we give IV fluids to increase the blood pressure or to increase urine flow, what we're really doing is trying to increase renal perfusion by increasing cardiac output, hoping that increased renal perfusion will improve kidney function and urine output. Same goes for trying to take care of a high lactate. We're trying to improve perfusion of the tissues and cells to try to get those cells out of anaerobic metabolism and back into aerobic metabolism. So this is the arm of the oxygen delivery equation where fluid administration works. Like we said, what we're really doing is asking several questions in series, not is my patient wet or dry. If I give IV fluid, will left ventricular stroke volume increase? And if the stroke volume increases, does cardiac output increase? That is, is my increase in stroke volume going to be offset by a decreased heart rate? And then if cardiac output increases, does oxygen delivery increase? And does oxygen delivery lead to improved organ function? As we said, it's hard to answer some of those questions. We should also be asking ourselves, what kind of fluid is fluid harmful and when do I stop? And it's important to remember some of the adverse effects that fluid can have. There are a lot of data to suggest that too much IV fluid can be harmful. It's important to recognize that these data are from retrospective studies, so it's hard to infer causality. But certainly they raise the question about whether IV fluids or excessive IV fluids may hurt. In some randomized controlled trials, IV fluids for sepsis were associated with worse outcomes. The patient populations in these studies may be very different from the patients we tend to treat in North America, so whether we can extrapolate these results to our populations is highly uncertain. Let's remember that the indication for giving IV fluid for shock resuscitation is to increase left ventricular stroke volume. IV fluid loading will only increase stroke volume if ventricular function is on the steep vertical part of the Frank-Starling curve. The problem is, individuals have many Frank-Starling curves depending on many, many factors, and it can be hard to know whether patients are on the steep or horizontal part of that curve. In the previous talks, we discussed using functional hemodynamic monitoring to understand fluid responsiveness and what the physiologic basis for fluid responsive or functional hemodynamic monitoring is. It's crucial to remember that fluid responsiveness does not imply that fluids are going to be beneficial. It's also crucial to remember that eliminating fluid responsiveness is not a goal of resuscitation. So how well does using functional hemodynamic monitoring help us make decisions about fluids? This was a retrospective study from the University of Kansas. The Cheetah-Nycombe device, which is now known as Starling SV and is marketed by Baxter, was used to help clinicians identify which patients were fluid responsive. Some clinicians decided to use the device and others didn't. The study compared outcomes between two patient groups, patients who underwent monitoring with the device received less fluid, and there was some evidence of improved outcomes associated with the use of this device to guide fluid prescriptions. You can see lower length of stay in the ICU, lower risk of mechanical ventilation, lower duration of vasopressor use, and a lower risk of needing acute dialysis. In a meta-analysis, fluid responsiveness monitors used to guide IV fluid prescription were associated with several improved patient outcomes, including a lower risk of death. Except for one study, these studies were mostly in surgical patients, including operating fetal resuscitation and postoperative resuscitation. In a prospective randomized controlled trial that I helped design, we tested the hypothesis that using the Starling SV device to guide therapy would result in lower IV fluid prescription. We sought to assess the clinical impact of these prescribing decisions. We tried to model our treatment algorithm in the study on what we believed most clinicians would perceive as reasons to consider IV fluids or other interventions aimed at increasing cardiac output or perfusion. We found that using fluid responsiveness to guide therapy resulted in a smaller net positive fluid balance in the first 72 hours of ICU care. We found similar signals for benefit that were identified in the other studies, lower risk for ventilation and lower risk for renal replacement therapy. In other words, we now have multiple studies that show a consistent association between using functional hemodynamic monitoring with lower IV fluid administration and a lower risk for respiratory failure and renal failure requiring dialysis. Some monitoring devices help us understand when fluids may actually be causing harm by increasing tissue edema. These monitors use dilution technique to estimate the amount of pulmonary edema that's forming. This is an early study that used a fluorescent dye to evaluate edema formation during shock resuscitation. And you can see the treatment algorithm that was used. And the study found that using extravascular lung water as a signal to stop IV fluid loading was associated with a shorter duration of mechanical ventilation and a shorter ICU stay. An important question to ask when looking at what we know about how well IV fluids work for saving lives or achieving other clinically important outcomes in critical care medicine is how well do IV fluids work in achieving the hemodynamic goal that we want them to achieve? That is, how well do IV fluids work in raising the stroke volume and cardiac capillary? Turns out that there are a few interesting studies that examine this question, and this one is one of them. So in healthy volunteers, they crossed over patients to receive either 0.9% saline as an isotonic crystalloid or two forms of colloid infusions, gel fusing, which is a protein solution not available in the United States, or VoluVen, which is one of the marketed head of starch solutions. And they looked at the effects on hemodilution and changes that is represented in changes in hemodilution, in circulating blood volume, and in extravascular fluid volume. And you can see that saline, which is represented by the solid blue boxes here, was much less efficacious at achieving hemodilution and raising the blood volume than either of the colloid solutions that were infused. And the investigators estimated that about 68% of the saline infused escaped from the vascular space into the extracellular fluid compartment within an hour. And that is remarkably close to what we would expect based on the classical physiological teaching of three fluid compartments in the body, intracellular, extracellular, extravascular, and extracellular-intravascular. In a similar study looking at the hemodynamic effects of crystalloid in critically ill patients, Nunez and colleagues measured cardiac index after isotonic crystalloid infusion and found that there was a very temporary improvement in the cardiac index that occurred at about 30 minutes after the volume infusion, but quickly thereafter diminished and returned very close to baseline. It is very close to prior to fluid infusion by 60 or 90 minutes later. These data suggest that both in healthy and critically ill patients that the hemodynamic effects of crystalloid infusions are not very large. As you can see here in this graph, it's about, oh, I don't know, 16% or so increase in cardiac index and not very long lasting. Another very interesting finding comes from a secondary analysis of the recently published Andromeda shock study. The Andromeda shock study, you might not remember, was published in JAMA in 2019. And then this follow-up study was published, you can see, in Critical Care in 2020 shows that the proportion of patients who are fluid responsive when they present with septic shock declines steadily over time where there's a nearly 100% rate or risk of fluid responsiveness at the outset, but that within two hours, only a minority of patients are fluid responsive and by eight hours, almost no patients are fluid responsive. And it's really important to keep in mind as we continue fluid loading or as we continue to consider fluid loading in our patients who have sepsis or other shock states, but especially sepsis, who are hemodynamically unstable, that we may want to reconsider throwing good money after bad, as it were, and continue IV fluid loading for persistent hemodynamic instability. In this very recent publication in the New England Journal of Medicine, investigators compared a restrictive fluid strategy to usual care to try to test the hypothesis that restrictive fluid loading would avoid harm. This was based on all of those things that we considered earlier that found associations of harm associated with intravenous fluid administration. This was called the CLASSIC trial, it was an openly randomized controlled trial that enrolled septic shock patients who were adults, that is over the age of 18. They all had documented or highly suspected infection. They had high serum lactate. They were on vasopressors and had already received at least one liter of intravenous fluid and they were all enrolled within 12 hours of presenting to the hospital. Now I'll just say that as an investigator working on or has worked on several projects where we attempt to enroll patients into the study within a very short amount of time after identification of the disorder of interest, that it often leads to a little bit of bias because you enroll patients who maybe present during the day more so than you enroll patients who present at night because of the availability of investigators and so forth. So just be careful that it may introduce some residual confounding bias when you limit enrollment to the first 12 hours after presentation. So there was a usual care group and there was a restrictive fluid group. The patients randomized to the restrictive fluid group, they were permitted to get fluid in one of four circumstances. They were doing hypoperfusion despite pressors and I think hypoperfusion was defined as persistently elevated lactate, modeling, oliguria, and I can't remember the fourth criteria but it's in the methods of the paper. You could get fluids for replacement of documented fluid losses to correct electrolyte abnormalities such as hypokalemia, hypernatremia, and so forth if the enteral route were contraindicated for additional fluid administration or to ensure a minimum daily fluid intake of a liter. As far as I can tell from the methods of the paper, measurements of fluid responsiveness were not used as part of the protocol to decide which patients might or might not get fluid. As you can see after a day, the patients in the restrictive fluid group represented in the left column got substantially less fluid, a median of less than 800 milliliters of fluid in the first 24 hours and those differences persisted at five days and at 90 days. They also got less total fluid over time. Now I think it's informative to look at what the standard care or usual care group got which is that the median fluids given after 24 hours of presenting with septic shock was 1.3 liters with a range of 500 milliliters to 2,500 milliliters and this study took place in I think 31 centers in Europe where the caregivers, the clinicians may already be predisposed to giving a more fluid restrictive approach when taking care of septic patients because I think in North America, at least at my center at least, to get only 1.3 liters after presenting with septic shock and showing continued hemodynamic instability despite vasopressors, in my experience most patients get more than 1.5 or 2.0 or even 2.5 liters of fluid in those first 24 hours. So that raises questions about how well care provided in this study is generalizable to care as we currently deliver it in the United States or other parts of North America. You can see that by the primary outcome which was death at day 90, there were no important differences between the restrictive fluid group or the standard fluid group and there were no differences in any of the secondary outcomes such as serious adverse events, number of days without life support, number of days alive and out of the hospital. So those are some very recent studies, some of them maybe not so recent, that shed light on the efficacy of IV fluid actually achieving its hemodynamic goals and also whether a fluid restrictive approach is beneficial to patients. If there were one thing that I hope to convey through this talk is that I hope to convey the limits of our knowledge and our monitoring. State-of-the-art monitoring using stroke volume variation or pulse pressure variation or cardiac output variation is very informative in telling us when not to give fluid. We have a much more difficult time understanding when fluid is indicated. There currently, as far as I can tell, is no monitor that can help us understand this. There are a lot of studies that explore why fluids are unlikely to be effective based on what we've just looked at. Many of them have to do with unfavorable pharmacokinetics of crystalloid, especially in patients who may have vascular leak. Put another way, crystalloids just don't result in a very big hemodynamic improvement or a hemodynamic improvement that lasts for a long time. There are, as far as I know, very few studies that look at colloids in critically ill patients that help us understand how long and how big the hemodynamic effect is. We know, and this is not stuff that I've presented here, that head of starch is almost certainly associated with harm. There are a lot of studies that show that head of starch is associated with poorer patient outcomes, especially in patients with sepsis, to the point where the FDA has placed a black box warning on head of starch for patients with sepsis because of increased risk of renal failure and mortality. We also know that a lot of the head of starch literature might be fraudulent. We'll go into that in more detail now. Retrospective studies suggest that there is some benefit associated with albumin, but prospective studies have not underlined that point. Some recent randomized controlled trials suggest slight benefits associated with balanced crystalloids, that is, crystalloids that don't have a lot of chloride in them. But there seems to be uncertainty about whether to give fluids or pressers early for sepsis. So there's a few points that we don't know in a lot of situations, whether fluids are likely to be beneficial, how well they work, and whether we should give them. If there were one thing or a few things that I'd like you to take away, it would be to encourage you to use physiology to help guide your decisions about giving fluid. If you can, try to get a physiologic monitor that tells you, is my patient fluid responsive or not? And if your patient is fluid responsive, don't give that patient fluid. It's like saying, I've got a patient who looks like he has a viral infection, the procalcitonin is low, cultures are negative, I should probably stop the piperosone, vasoectin, and vancomycin. You're just not going to get any benefit out of those things. And if you're going to give fluid, give fluid only, A, when the cardiac output is insufficient, B, when the cardiac output is going to increase when you give fluid, C, when you're pretty sure fluid is not going to cause more harm, and D, when you recognize the limits of our understanding about how good it is to raise cardiac output and how long fluids are going to have that effect. With all that uncertainty, and hopefully with a little bit of new knowledge, I'll take my leave. I thank you for your attention, and I look forward to answering your questions.

fluid resuscitation

critical care medicine

fluid responsive

renal perfusion

functional hemodynamic monitoring

adverse effects