Introduction to Intensive Care Medicine Podcast
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Welcome to Critical Matters, a sound podcast covering a broad range of topics related to the practice of intensive care medicine.
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Sound provides comprehensive critical care programs to hospitals across the country.
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To learn more about our programs and career opportunities, visit www.soundphysicians.com.
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And now your host, Dr. Sergio Zanotti.
IV Fluid Administration in ICU - Recent Studies
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Administration of intravenous fluids is one of the most common interventions in patients admitted to the ICU.
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For the last decade, we have debated a broad range of specific topics related to the use of intravenous fluids in critically ill patients.
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In today's episode of the podcast, we will discuss two recently published studies, the basics randomized clinical trials, and we will address two specific questions.
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First, does the fluid composition, saline solution versus balanced solution impact patient outcomes?
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Does the mode of administration, slower infusion versus faster bolus, have an impact on patient outcomes?
Role and Expertise in Critical Care Nephrology
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Our guest today is Dr. Michael Conner, Jr. Dr. Conner is an associate professor and senior physician for critical care medicine and nephrology.
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He's the director of critical care nephrology with the Division of Pulmonary Allergy, Critical Care, and Sleep Medicine at Emory Critical Care Center and Grady Memorial Hospital at Emory University School of Medicine.
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Michael, welcome to the podcast.
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Thank you so much.
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It's such an honor and a pleasure to join you with this conversation.
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And I'm looking forward to hopefully some fun for you and me and the listeners as well.
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So we were talking on before the podcast started that we are two baseball fans that are about to be confronted in the World Series.
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So we'll get to that maybe later.
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But the other topic that probably occupies much of your practice, since you are a nephrologist and an intensivist,
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I mean, you're always probably thinking every single patient, should I take fluids away or give fluids to this patient?
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So definitely something that is very common in our practice, yet something that still really has as many things we practice in medicine, so many questions around it.
Crystalloids vs Colloids Debate
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I must admit that I fall on the side of taking fluid away portion of this argument very much so, but that could be potentially an interesting podcast for your listeners for a future
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episode is maybe a debate between the timing of de-resuscitation.
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But certainly the administration of IV fluids is obviously something we do every day.
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And I couldn't agree with you more that we have maybe more questions than answers.
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And before we dive into specifically the questions that we mentioned at the intro, I want to start maybe with a more general overview.
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And for many years, and I'm a little bit older than you are, but when I was a fellow in training, I
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much of the debate really centered around crystalloids versus colloids.
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Could you just give us kind of in a nutshell where we are today and how that has transpired?
Albumin Use in Resuscitation
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Yeah, you know, I think most of your listeners will recognize that at least in the United States and in North America, we primarily use isotonic crystalloids as our fluid of choice during resuscitations, be that acute resuscitations in the ER or in the ICU.
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Of course, obviously, if someone is having hemorrhage or hemorrhagic shock, that blood is still our preferred, or a balance of blood and FFP and platelets in a massive transfusion protocol is still obviously preferred.
High Chloride Levels in Fluids - Observational Data
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And we've had several trials, as you know, that have attempted to try to look at the benefits of other colloids over crystalloids for resuscitation that really have shown no benefit.
Clinical Trials: SPLIT and SMART
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The sort of standing and what I oftentimes teach to our trainees is that the HETA starches are basically, have been eliminated from practice due to some concerns around nephrotoxicity.
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I know there are still a few that debate that, but I think for the most part, people have abandoned the uses of HETA starches.
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So the real question is sort of surrounding albumin and its role in use.
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And I think we can all agree that quite clearly in certain patient populations, especially those with end stage liver disease, cirrhosis with ascites, that there is clearly a benefit to the use of albumin as a significant contributor to the resuscitation fluid in those patients.
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But in larger patient populations or in more general patient populations, we really have seen no clear benefit there.
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is some studies that maybe suggest that albumin has a role as a drug in patients with sepsis or septic shock as an adjunctive therapy.
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But it's not entirely clear that benefits are, that the mortality outcomes are clearly better with the use of albumin in that patient population.
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So still, I think that we primarily avoid the use of albumin unless
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you know, there is a special population.
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And historically, it seems that once we settled that albumin was safe, that perhaps there was no benefits in terms of outcomes in the general population, a lot of research started coming out discussing within the world of crystalloids potential differences among these different fluids.
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And one of the things that came up very clearly
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was a case against chloride.
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And a lot of people showing observational data and making arguments of why perhaps when we give too much chloride, we might be harming patients.
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Can you give us your perspective on chloride and how that might be the case?
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I just quickly though, wanna double back to the albumin and just remind people that while there hasn't been a clear data that it's a benefit
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it's important to recognize we also don't have clear data that it's a harm to patients.
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And we do have to remember that patients who have severe hypoprotonemia for any particular reason, albumin levels below the limit of detection, for example, they're not probably overly highly represented in the SAFE trial or other randomized controlled trials.
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So whether or not in those cases there may be a role for some limited albumin use is really unclear.
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But you're certainly not harming the patient.
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You're just obviously spending more money.
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Turning to the chloride question, you know, there are a lot of observational trials, and in fact, several animal and human model trials where you give volume expansion to patients or healthy subjects even, healthy volunteers, that demonstrate some alterations, especially in renal hemodynamics with the use of chloride-rich solutions.
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The idea being that
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the exposure to high amounts of chloride as a strong anion has effects on the justicomereolar reflex and other renal hemodynamic and auto-regulatory mechanisms that potentially lead to renal artery vasoconstriction and actually a decrease in perfusion.
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And there is quite interesting
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randomized trials or crossover trials in healthy volunteers that sort of support that physiology.
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And as you know, and as you alluded to, there's a whole host of retrospective and even prospective observational trials that support the fact that there does appear to be a small
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increase risk of AKI in patients who got large quantities of chloride-rich solutions.
Exploring the BASICS Trial
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And so that's really what's prompted several trials now to be performed in larger sample sizes to try to look at that further.
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And I think this is a perfect segment to go into answering that first clinical question that we were trying to tackle, which was, does the type of fluid make a difference
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we're talking about balanced crystalloids versus saline with maybe higher concentrations of chloride and perhaps a different pH.
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And I was thinking, Michael, that we could probably at a very high level introduce some of the first trials, the split trial and the SMART trial, before you talk in more detail about the BASICS trial that was recently published.
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readers will, or your listeners will undoubtedly know, right, the main difference between balanced crystalloids and 0.9% isotonic sodium chloride is the concentration of chloride as well as other cations and anions, right?
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So normal saline or 0.9% sodium chloride
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has 154 milliequivalents per liter of both sodium and chloride and actually has a fairly low pH of around 5.4 effectively, whereas our balanced crystalloids of which there is a whole host of different types of balanced crystalloids, you know, contain a more normal physiologic normal levels of chloride.
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and have some other cations and look a lot more like our serum does with different pHs and potentially some base substrates as well, whether that be lactate or acetate or some other compound to provide base for the patient as well.
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And so, you know, there's been a few prospective trials, crossover trials and such,
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that had been done, and ultimately it led to two centers or two groups really trying to do this in a more prospective fashion several years ago with the publication of both the SPLIT trial in 2015 in JAMA and the SMART trial in 2018 in the New England Journal of Medicine.
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So just taking both of those separately briefly, so the SPLIT trial was performed
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four ICUs at tertiary facilities in New Zealand, both a mixed med surge as well as a cardiovascular cardiothoracic surgery ICU.
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And it randomized patients to balance crystalloid with PlasmaLite 148 versus sodium chloride in critically ill patients.
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And it's actually an extremely well-designed trial.
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They included all ICU patients who received crystalloid therapy.
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Their exclusion was end-stage renal disease or AKI requiring dialysis within the next six hours.
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And their primary outcome was the development of acute kidney injury based only on serum creatinine information.
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And the trial was designed in these alternating periods of seven weeks where
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an ICU was assigned to use a blinded fluid, either fluid A or fluid B for all fluids during that given seven week period.
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And then after seven weeks, they would switch to the other ICU and they went, or to the other fluid.
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And they went back and forth like this for a total of four exchanges or 28 weeks.
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And patients who were assigned to fluid A remained on fluid A
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if they were still in the ICU over the crossover point.
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So there was really little crossover between the two groups.
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The trial ended up enrolling a little bit more than 2,200 people.
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And in short, it showed no difference in AKI rates between these two groups, which was a little bit surprising on the surface when this trial came out, because it was really the first trial that had
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prospective trial that had shown no difference in AKI rates, showed no worsening for any one group, but basically superimposed lines of survival.
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When people dug a little bit deeper into this trial, there were some interesting
Balanced Crystalloids vs Normal Saline Debate
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things that people noted, which led some people to wonder whether or not this really answered the question that they were intending to answer.
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So specifically, most of these patients were admitted after elective surgery.
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The mean time in the ICU was only one and a half days.
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Only 65% of patients were on the ventilator, and the mean amount of time that patients were on the ventilator was only 15 hours.
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And then the average fluid amount that was received in the first day was less than two liters.
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people concluded that this probably, while an extremely well done trial, didn't really address the question per se because they tended to enroll patients who were probably quite low risk for acute kidney injury in the first place.
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And then they didn't particularly get exposed to a particularly high amount of the solutions.
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And so, you know, if you have a solution like 0.9% sodium chloride that may be
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a bit nephrotoxic, for example, if it has a low toxicity, but the toxicity is there, if you're only exposed to a small quantity of a fluid that has a low amount of toxicity, that it may not really, you may be blunting your effect size.
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And so, you know, while the authors concluded that there was no significant difference,
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I think that more correctly, it's probably more correct to say that there's no demonstrable risk of 0.9% saline when used in small quantities to critically ill patients at low risk for AKI.
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At least what I feel like is the better conclusion for this trial.
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And it really doesn't help you if you're talking about patients at high risk for AKI
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with getting large quantities of solutions.
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So, you know, the patient with fluorid sepsis who's getting five liters of fluid and has a high risk for AKI, I don't know that this trial really addresses that.
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And I think it's important because it also illustrates how challenging it is really to design large scale, high quality clinical trials that answer all the clinical questions we have at the bedside
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with some individual patients, right?
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And the problem is that that patient that you described is a patient that we all know, but that in order to enroll thousands of patients under those circumstances, you probably require a monumental effort in terms of the sign of trial.
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But let's move on to SMART because obviously SMART came a couple years later, larger trial and some interesting findings here.
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Yeah, so the SMART trial,
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again, in New England Journal 2018, was ultimately, importantly, a single center trial, but involved five different ICUs at that center with a wide range of different types of patients because these were all subspecialty ICUs.
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So you had your medical ICUs, your neuro-cardiac trauma and surgical ICUs as all sort of separate patient populations.
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And they did a very similar sort of crossover trial where a given ICU was assigned to use a particular type of fluid, either 0.9% sodium chloride or a balanced crystalloid, which could be either LR or plasmalite A. And they would use this for a month at a time.
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And then the entire ICU would move over into the other fluids.
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It was not blinded, importantly, whereas the split trial was blinded in terms of which solutions they were using.
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And their outcome was a composite outcome of death by 30 days, new development of renal replacement therapy, or persistent acute kidney injury,
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And so that composite outcome is used quite a lot in the nephrology literature, and it's called the MAKE-30 outcome, which is major adverse kidney events at day 30.
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And that always includes death by 30 days, new requirement of dialysis, or persistent acute kidney injury.
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And so in the SMART group, they had these unblinded, they had these solutions going back and forth
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I may have misspoken.
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I think I said it was an unblinded trial.
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I think it is actually a blinded trial.
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I apologize that I said that incorrectly.
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But they had access to unblinded solutions if needed based on some sort of decision by the ICU team.
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And ultimately, this trial did show a difference in MAKE-30 composite outcome.
Complexities of Fluid Management in Critical Care
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of around 1% difference in rate.
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The study did reach statistical significance, although just barely.
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And they had actually enrolled about 16,000 patients, which is really quite remarkable.
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And when you look at it all told,
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It was primarily driven by a small decrease in death and a small decrease in the need for new dialysis before 30 days.
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So this was a trial that enrolled far more patients than the split trial did and had a similar design but a different primary outcome
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and showed a small but statistically significant difference.
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And while we don't usually get too excited about a 1% absolute risk reduction or 1.1% absolute risk reduction, given the number of patients per day that we're giving IV fluids to, you can see where if you're treating 90 patients with IV fluids, then it's every day or every couple of days that you may
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that you may have one patient who has a better outcome.
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And so, you know, it still is potentially clinically meaningful even though the difference is quite small.
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So we had these two trials that showed two very different things and it's sort of difficult to sort of make clear assumptions or decisions based on these two.
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And would it be fair to say, Michael, though, that even though the primary finding was different,
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They're definitely not incompatible considering that a smart had seven times more people, right?
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It was significantly larger.
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And second, it also had a broader endpoint in terms of using that make 30 as a composite endpoint, primary endpoint versus mortality and AKI.
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Would that be fair to say that it could be explained in that way?
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Yeah, I think for the most part, most people who feel strongly about these various topics and who follow these topics felt very much as you said, which is that the SMART trial seemed to be maybe similarly well-designed
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but ultimately executed somewhat better to answer the questions that were being asked.
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And while the difference was small, there was a difference there.
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And I think people who, I mean, people who believe that chloride is dangerous would say, hey, you know, let's use chloride-poor solutions or balance crystalloid solutions and sort of avoid
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And in the interim, you know, between these two trials, there were lots of other retrospective trials that also came out that supported this too.
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You know, like in sepsis, there was a big trial that came out that looked at how much balanced crystalloids you received and showed a pretty linear decreased risk of mortality as the percent of balanced crystalloids for which you were exposed to went up.
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and it was divided into, you know, various quintiles and just showed a continuous improvement in outcome with more and more exposure to balanced crystalloid, not total quantities, but percentage.
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So 100% normal saline versus 100% balanced crystalloid versus areas in between.
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And so, you know, there's, it's, I think most people ultimately said split was a really well-designed trial,
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But because it didn't end up enrolling patients that were particularly high risk for the outcome in question, and they were really exposed to quite a small amount of fluid, that despite its excellent design, the results really don't help us in any way.
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And I think SMART and its companion trial, which was the SALT-ED trial done just in emergency department patients,
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you know, showed the same thing, which is that it seemed to be that there was this make 30 outcome that was better with balanced crystalloids.
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And remind me, Michael, the amount of fluid at an average the patients got in SMART, that was close.
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I mean, it wasn't a large amount either, right?
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I mean, I'm sure with 15,000 patients, it averaged out probably to something not too far from split.
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Yeah, I think, I actually don't have that number directly in front of me, but I think you're right on that, that it's very similar quantities, maybe half a liter more total.
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So it's not, you know, still, you're not dealing with large quantities of solutions, but you were dealing with a patient population that was much higher risk to start with.
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If you look at the types of patients that were enrolled,
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there was a far greater percentage of patients in SMART trial that were enrolled through the emergency department.
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More than 50% of the patients came from the emergency department for the SMART trial.
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And there was a high proportion of patients with sepsis as well.
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And those that did have surgery were much more emergency surgeries rather than elective surgeries.
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So it was, generally speaking, a sicker patient population, which is why you may have seen
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a difference with a similar exposure to fluids.
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And I think that it's an important point, right?
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Because like you said, two variables that are very important for us in the discussion when we deal with very sick patients are risk for AKI and death, which the sicker, obviously the higher, but also we always feel that we're giving patients a lot more than a couple of liters of fluid over a short ICU stay.
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Now that might be a discussion for another day.
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What the right amount of fluid is we can talk about that some other episode.
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But those are two things that obviously, like you said, split and not really tackle in the way it was designed.
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So now we have a new study, Basics, and they actually published recently two separate studies that address two separate questions.
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So very well organized and you had the opportunity to write the editorial.
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So I know that you are very familiar with these studies and would love to tackle maybe the first one of the studies which tries to address the question of the composition of fluids, balanced glycella versus saline.
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If you could tell us more about this basics trial.
00:24:48
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Yeah, well, importantly, it's important to realize that while this was published as two separate articles in the same New England journal, it was all done as one
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And so, you know, it's similar to another famous trial in critical care where that was the FACT trial where there was this sort of two by two design where patients got randomized to conservative versus liberal as well as randomized to a PA catheter versus a CVP line.
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BASICS did a very similar thing, which is that patients were randomized to two different arms.
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And so it was sort of like a two by two trial.
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randomized to either, excuse me, randomized to either balanced crystalloid versus a 0.9% sodium chloride with the balanced crystalloid being plasma light 148, which we can talk about a little bit later.
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And then they also got randomized into receiving their bolus solutions quickly versus receiving their bolus solutions at a slightly slower
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And so they analyzed these two things separately and published one article on each of those two things.
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So all the patients participated really in both sides of the trial.
00:26:15
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And so the initial trial that we're at least discussing right now is the one that's comparing the two types of fluids.
00:26:23
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And so again, this was a randomized trial.
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They received blinded solutions
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Patients were enrolled basically 24 hours a day through all the different participating ICUs, and they received blinded fluids in 500 ml bags, and they received that same fluid throughout their time that they needed in the ICU, or the time they stayed in the ICU.
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And the primary outcome in this trial was not a composite outcome.
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The primary outcome was
00:27:01
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And they had a whole host of secondary outcomes, which obviously included many things that people are interested in, such as acute kidney injury, development of dialysis needs, SOFA scores between these two, as well as, you know, length of stay, ICU length of stay, mortality, and other sorts of things.
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They also enrolled a huge number of patients, around 11,000 in total.
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And this was spread across, I think, almost 70 ICUs in Brazil.
00:27:37
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So it's really, you know, the authors should be really commended for doing such a tremendously large study at many different sites, you know, which obviously helps the generalizability of the results.
00:27:55
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And I think that also just what just hit me and that is worth remarking is that we're talking about a total of just three large studies of 30,000 critically ill patients being studied on a topic.
00:28:08
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That is unheard of in our field.
00:28:11
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And really, like you said, not only the basics team, but all these teams have really put forward an enormous effort to really do very robust scientific research
00:28:24
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scientifically justified and designed trials, which hopefully move, move our field a little bit forward.
00:28:31
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So ultimately what, what did they find and, and, and what, what, what's your take on this part A of the basics trial and how do you fit that into what we talked about with split and smart?
00:28:43
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So ultimately, you know, their results were, um, were, uh, that there was no difference in mortality between these two groups.
00:28:54
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And if you look at all their various subgroup analyses or other secondary endpoints like acute kidney injury or, excuse me, or dialysis needs, there was no difference really in any of those outcomes.
00:29:12
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So this trial, you know, sort of fell along with split, sort of saying that there was no real demonstrable difference between
00:29:23
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these two groups in terms of the primary or most of the secondary outcomes.
00:29:27
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Now, importantly, they did show that in the a priori decision to look at patients who had traumatic brain injury, that there was a statistically significant difference in survival in, excuse me, a statistically significant difference in patients with traumatic brain injury as defined
00:29:50
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not by survival, but as defined by a difference in sort of neurologic SOFA score or Apache score between these two, suggesting at least that maybe traumatic brain injury patients had potentially some risks being exposed to balanced crystalloids as opposed to being exposed to normal saline.
00:30:15
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And there's a lot of reasons why that could be, but it's important to recognize that this is a secondary analysis using an imperfect scoring system as the outcome in question, being the Apache 2 Glasgow Coma Scale SOFA score type of scoring system for the neurosystem.
00:30:34
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And I think that, like you said, you mentioned this is a secondary endpoint.
00:30:39
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So if anything, it should generate further evaluation and studies.
00:30:44
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as opposed to a conclusion that's definitive, but it also illustrates the complexity of the topic, right?
00:30:50
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Because in general, if you would say post-SMART, the pushes towards balanced crystalloids, if anything, and now you find a subset of patients in whom perhaps that is not the right answer.
00:31:04
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So again, just showing you how complex and terogenous our critically ill patients are
00:31:10
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And that ultimately it might be hard to say blanket statements, this versus that for some very specific patient situations.
00:31:18
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And I think, you know, similar to how we have to say that there are specific situations where colloid may be better, you know, that might be the case here as well, that survival was better in those with traumatic brain injury.
00:31:33
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Granted, a very small proportion of these patients
00:31:36
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in those who receive saline compared to balanced crystalloid.
00:31:39
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And so there are some questions and concerns about that, and you're absolutely right.
00:31:43
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And it's not the first trial to ask that question or to have some signal of potentially harm in those with neurologic insults.
00:31:54
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The idea primarily being that the osmolarity of 0.9% sodium chloride is slightly higher than the osmolarity
00:32:06
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plasma light or LR and so if you're using a solution that is slightly hyperosmolar to the CSF or to the serum you're going to not potentially move as much fluid into this central nervous system and potentially worsen any sort of CNS edema you know so that's sort of the underlying physiology behind that but
00:32:29
Speaker
You know, again, like you said, whether this is just hypothesis generating or enough data to really say to avoid that, you know, I think is a bit unclear.
00:32:37
Speaker
And we tried to say in our editorial that we agreed that this is concerning and, you know, potentially needs more study.
00:32:46
Speaker
But in the short term, probably we need to be a little bit careful about indiscriminate use of balanced crystalloids in patients with central nervous system issues, like particularly traumatic brain injuries.
00:33:00
Speaker
Michael, could you tell us a little bit more about the bound solution that they used in this basics trial, the PlasmaLite 148?
00:33:10
Speaker
So PlasmaLite A and PlasmaLite 148 are actually really very identical solutions in terms of their composition.
00:33:21
Speaker
They both contain about 140 milliequivalents of sodium per liter, 5 milliequivalents of potassium.
00:33:30
Speaker
98 of chloride, 3 of magnesium, and then gluconate and acetate that serve as the buffering agents or the bicarbonate sources in these solutions.
00:33:47
Speaker
In the United States and in Canada, plasmalite-148 and plasmalite-A are slightly different with regards to their pH.
00:33:58
Speaker
Plasmalite 148 in the United States and Canada has a pH that ranges between around 5.5 to 6.5, depending on the country, whereas Plasmalite A has a pH of 7.4.
00:34:11
Speaker
And you're able to adjust these pHs by adding very small quantities of either hydrochloric acid or sodium hydroxide, such that you don't really affect the actual concentrations of chloride or sodium in the fluids.
00:34:30
Speaker
Now, we commented in our editorial that maybe this difference in pH because if you're using PlasmaLite 148 versus PlasmaLite A, SMART clearly use PlasmaLite A and LR, which have a higher pH potentially than PlasmaLite 148.
00:34:51
Speaker
And that maybe the difference in pH explains the difference in the results of these two trials or these three trials.
00:34:58
Speaker
We did, however, and it's very important for me to let your listeners know that we did actually make a small mistake with that comment in our editorial.
00:35:09
Speaker
It was not known to us at the time that Plasmalite 148 actually has a different pH in many different countries around the world.
00:35:19
Speaker
And that in Australia, New Zealand, and in Brazil, Plasmalite 148 actually has a pH of 7.4.
00:35:27
Speaker
Why the manufacturer would have the same product name with a different pH in different countries around the world is unclear to us, and it seems to be ripe for possible mistakes or misinterpretations.
00:35:44
Speaker
And additionally, the authors of these various trials did not include in their manuscripts or in previously published methods papers
00:35:55
Speaker
what the pHs were of the solution that they were using.
00:35:59
Speaker
And so we incorrectly just assumed that plasmalite 148 in these countries had a lower pH.
00:36:05
Speaker
So clearly, pH is not of the fluid is not differences in the pH of the fluid is not really what's explaining the differences in these results.
00:36:16
Speaker
And we'll talk a little bit more about ultimately the clinical implications as we close.
00:36:21
Speaker
But before we get there, Michael, I wanted to tackle
00:36:25
Speaker
the second basic study and the question regarding does the mode of fluid administration, a faster bolus versus a slower infusion make a difference.
00:36:35
Speaker
So before we talk about what they did in the trial and what they found, could you just give us a overall context of what are the theoretical concerns of potential implications of giving somebody a big bolus very fast versus infusing it a little bit slower?
00:36:51
Speaker
And where does this question really come from?
00:36:56
Speaker
I actually was really pleased that they did this portion of the trial.
00:37:01
Speaker
I think this asks and answers a really important question.
00:37:04
Speaker
So I, like many people, tend to give our boluses really rather rapidly, either on an IV pump or by gravity or on a pressure bag.
00:37:15
Speaker
But I'll admit that when I'm in the cardiac intensive care unit, I certainly have seen patients who have suffered from
00:37:24
Speaker
RV dysfunction from too rapid volume expansion with a cold solution, be that blood or crystalloid or anything else.
00:37:34
Speaker
And so, you know, the theoretical risk here is that when we give a lot of solution cold quickly, that we can cause some RV distension and RV dysfunction and sort of potentially exacerbate cardiac dysfunction and hypotension or shock.
00:37:52
Speaker
and obviously not what any one of us are trying to do when we volume expand a patient.
00:37:57
Speaker
And there's really never been a great study that actually looked at how fast do we need to give the fluids?
00:38:04
Speaker
Do you really need to give these patients fluids very fast, or is it just as well to give it quite slowly or more slowly?
00:38:14
Speaker
And how does that impact outcome?
00:38:18
Speaker
And so the other portion of this trial
00:38:20
Speaker
you know, randomized patients to either a liter an hour for resuscitation speed.
00:38:26
Speaker
So any resuscitation or boluses they got was run at a liter per hour versus running at a third of a liter or 333 mLs per hour.
00:38:35
Speaker
And again, it was the same patient population.
00:38:38
Speaker
And there are some questions about this patient population, which we can talk about in general for basics enrollment, but it was the same patient population.
00:38:49
Speaker
And they showed no difference in outcomes between fast versus slow infusions, no difference in any sort of meaningful outcome such as dose suppressors or AKI or mortality or anything else like that.
00:39:03
Speaker
So I think that this, in my opinion, was almost a more useful result because it helped us know that we don't need to be too concerned if the fluid isn't running in very fast.
00:39:16
Speaker
Just getting the fluid in in the first place is really
00:39:19
Speaker
sort of the important aspect of that.
00:39:22
Speaker
And it's interesting because it kind of makes us pause and think and reconsider a very common tendency that we have in life in general that faster or more is always better, right?
00:39:36
Speaker
And especially in the ICU, I think we might feel that urgency.
00:39:40
Speaker
But like you said, I mean, it demonstrated that there was no significant difference.
00:39:44
Speaker
And perhaps, I mean, obviously you need to give the fluids not over two days, but
00:39:48
Speaker
where you give it at 999 or like they did at 233 mls per hour, probably not a big impact.
00:39:56
Speaker
Yeah, but I think that's important, right?
00:39:58
Speaker
Because I think we oftentimes rush to give a bunch of fluids.
00:40:02
Speaker
We feel like they have to have these large bore central lines and they have to get this all in very quickly.
00:40:09
Speaker
rather than just getting it started through the IV that you have and getting them going on something.
00:40:15
Speaker
And if that means they need a little bit of vasopressors for a couple of hours until you've gotten enough fluid in, then that's fine.
00:40:21
Speaker
And that you're not really harming the patient in that way by doing it a little bit more deliberately, which I think is good because if we're more deliberate, we also will have more time to, I think, assess how much more fluid does this patient really need.
00:40:37
Speaker
Whereas when we're giving it really fast,
00:40:39
Speaker
We sort of order them, and before we know it, four or five liters are in, and maybe the patient really only needed two or three liters.
00:40:46
Speaker
And are there other possible concerns about bolus administration versus a more measured infusion in terms of other physiological problems or endpoints?
00:41:01
Speaker
Well, you know, there's concern, obviously, that the more rapid exposure to the high chloride solutions could potentially be, you know, an interesting question.
00:41:11
Speaker
You know, does the kidney, if you're giving a whole bunch of chloride really quickly, is that more problematic on the kidney than doing that same amount of chloride a little bit slower?
00:41:19
Speaker
And I think those are all
00:41:21
Speaker
important questions.
00:41:22
Speaker
I'm not really too aware of a lot of other real concerns about the speed of it other than its sort of effect on hemodynamic function and RV function.
00:41:31
Speaker
But, you know, I'd be keen to learn from you if there were any other concerns that you've gleaned from having too rapid of an administration.
00:41:40
Speaker
And I was just curious in terms of are there other things that have been published or I wasn't aware.
00:41:45
Speaker
But like you said, I was also very excited when I saw
00:41:48
Speaker
that they actually did the second R because I think it answers a very commonplace and practical question.
00:41:56
Speaker
And that often is not the focus of a lot of these clinical trials for many reasons in terms of how these are designed, funded, et cetera.
00:42:05
Speaker
But I agree with you.
00:42:08
Speaker
As we close on the basics comment, I guess the other things that I found interesting
00:42:14
Speaker
that I would like your comments is that when you look at the type of patient and the amount of fluid, this looks closer to split than anything, right?
00:42:23
Speaker
Lower amounts of fluids, even in the bolus versus Thor infusion, the medium was 1.5 liters, which is probably lower than we're gonna give most of the people that were trying to resuscitate, at least in terms of what I see in practice.
00:42:36
Speaker
And also it seems that it was a very wide range of patients.
00:42:41
Speaker
Again, and I agree with you on that, that, you know, the criticism, I think, of this trial, and again, I want to use that word very lightly because the authors really did a fantastic job designing a trial, enrolling a bunch of patients across many centers.
00:42:58
Speaker
I mean, they should really be commended for doing this trial and for succeeding at doing the trial.
00:43:05
Speaker
they ultimately had a similar challenge in their baseline characteristics that SPLIT did, which is that, you know, these are 50% of the patients are being admitted after elective surgery.
00:43:18
Speaker
Only 20% or 22% of the patients are coming from the emergency department as an unplanned admission.
00:43:24
Speaker
You know, sepsis is only affecting about 20% of the patients in this 11,000, 12,000 cohort of patients.
00:43:34
Speaker
I think one can make the argument that this is not a particularly high risk group for acute kidney injury or for that matter, death, right?
00:43:43
Speaker
Elective surgeries, if 50% of your patients are elective surgery, you shouldn't be seeing a lot of those patients die.
00:43:50
Speaker
And so if your primary outcome is mortality, then you really, if you're going to see small differences in an outcome,
00:44:00
Speaker
from an intervention like this, you need to be enrolling a patient's sample that have a really high risk of death compared to a planned or elective surgery cases.
00:44:11
Speaker
So it'll be interesting over time, I think, when people go back and look at this and maybe in some other post hoc analyses, you know, sort of parse these patients a little bit more to try to get a better sense of, you know, did the higher risk patients,
00:44:29
Speaker
have more of a problem.
00:44:32
Speaker
Theoretically, you could look at high-risk patients who had fast normal saline versus slow normal saline.
00:44:40
Speaker
Did those patients have a difference in outcome?
00:44:43
Speaker
Or normal saline versus balanced crystalloids in the particularly high-risk patient populations in these groups?
00:44:50
Speaker
So I think it suffers from some of the same challenges as split in trying to answer this.
00:44:57
Speaker
But that being said,
00:44:58
Speaker
I think in total, if you look across these trials, I think we can fairly safely say that normal saline doesn't provide a demonstrable harm to the patient when used in not particularly high quantities to patients who don't have a super high risk of death.
00:45:19
Speaker
But I think the question still is out there a little bit as to
00:45:24
Speaker
you know, in those with very high risks, you know, do we need to be at least using a combination of balanced crystalloids and normal saline?
00:45:35
Speaker
One other point I just want to point out before is that, you know, I have a lot of people who argue, well, why use balanced crystalloids at all based on these?
00:45:44
Speaker
And I would take the argument the other way, which is to say, we have no studies that have demonstrably sown a harm from balanced crystalloids.
00:45:53
Speaker
So there's no study that has ever showed that even if it's not statistically significant, that the summary box plot supports normal saline over balanced crystalloids.
00:46:05
Speaker
So yeah, you may not be able to say that balanced crystalloids are clearly any better, but when they cost about the same as normal saline, the counter argument is, why would you use normal saline when there's clearly no advantage of normal saline in most patients, right?
00:46:22
Speaker
It's a fascinating point, and I'll share with you something that has kind of stuck with me for a long, long time.
00:46:30
Speaker
When I was an intern, this is a long time ago, I got chewed up by a surgeon for starting a patient who was going to go to the OR just for acute appendicitis on normal saline.
00:46:45
Speaker
And he demanded I change it to Ringer's lactate.
00:46:49
Speaker
at the time, obviously, I just thought, oh, whatever, rolled my eyes and did it.
00:46:54
Speaker
But maybe he knew something I didn't know.
00:46:57
Speaker
Maybe he had a point.
00:46:59
Speaker
Well, I'm a little bit younger than you, not much younger.
00:47:02
Speaker
And when I was growing up, we had a very similar thing, you know, that surgeons use balanced crystalloids and medicine doctors used saline.
00:47:11
Speaker
And we both thought each other were crazy.
00:47:13
Speaker
But, you know, and I think that
00:47:17
Speaker
you know, we don't have strong data, but we also have no real data that the medicine doctors, you know, that I trained under were right on this, right?
00:47:25
Speaker
Maybe we weren't really hurting a lot of patients, but we may be hurting some.
00:47:31
Speaker
And if we can't predict which ones that may not really, that may be harmed by normal saline, then why use it at all?
00:47:40
Speaker
I mean, the prices are basically the same, right?
00:47:42
Speaker
I mean, these solutions are really cheap.
00:47:45
Speaker
And even if PlasmaLite A
00:47:47
Speaker
is more expensive, you're talking about $8 instead of $2.
00:47:52
Speaker
In the grand scheme of things in the ICU, that's not really enough to write home about, that we have a couple of cups of coffee difference in price between two patients.
00:48:04
Speaker
I don't think we should be too worried about that.
00:48:08
Speaker
So I see the argument to say, okay, there's not a huge benefit of balanced crystalloids.
00:48:15
Speaker
Maybe, maybe that's really the case.
00:48:17
Speaker
I don't know yet in the very sick patients that needs five liters of fluid.
00:48:21
Speaker
I tend to still use balanced crystalloids in that situation.
00:48:24
Speaker
But the counter argument I think is also there is, well, why do it?
00:48:27
Speaker
Because no study shows that saline is better.
00:48:30
Speaker
So, you know, you're maybe not hurting the patient, but why should it be the first thing we reach for off the shelf?
00:48:38
Speaker
And to close, I mean, the discussion, the clinical part, I think it's always a
00:48:43
Speaker
important to remind ourselves that the ultimate goal of research is action, not knowledge.
00:48:49
Speaker
And my question in terms of how does this impact our clinical practice, most of which you've answered, but just to summarize, what's your personal approach to this based on what we discussed, Michael?
00:49:01
Speaker
Well, I will be guilty of having said maybe a few years ago to my resident, you know,
00:49:08
Speaker
geez, why did you use normal saline at all?
00:49:11
Speaker
I think that I will be less dogmatic about that because I don't think I can really stand here and say, okay, they give them a liter of fluid and that liter is somehow poison to them.
00:49:23
Speaker
I will sort of suggest that if we're giving three or four or five liters of fluid that we should use a balanced crystalloid.
00:49:32
Speaker
I tend to still use balanced crystalloids for most resuscitations, again, because I don't
00:49:38
Speaker
see many clinical situations unless the patient has been vomiting and has actual hypochloremia.
00:49:45
Speaker
I don't see a real role for using normal saline where it's clearly giving me an advantage in my general MICU and cardiac surgery patient populations over
00:49:58
Speaker
over some of the other options that we have.
00:50:01
Speaker
So I tend to lean on plasma light.
00:50:04
Speaker
I also think balanced crystalloids are great for other things, right?
00:50:07
Speaker
If you have a patient with horrible DKA that you're giving a ton of fluids to, if you give them a bunch of normal saline, their gap will close, sure, but it'll close because their chloride level's gone up a whole ton, not because you've actually stopped the ketotic process and
00:50:25
Speaker
and recovered your serum bicarbonate levels.
00:50:28
Speaker
Whereas if you give somebody plasma light or LR for your resuscitation, now your gap will close and your serum bicarbonate will go up a lot, but your gap will close not because your chloride has gone up a whole lot.
00:50:40
Speaker
So I think there's a lot of reasons why balanced crystalloids provide us potentially benefit, but
00:50:48
Speaker
I'm not going to stand here and tell you that you're killing your patient by giving them normal saline as much as maybe I would have a couple of years ago.
00:50:56
Speaker
And it seems that based on the evidence that we have, we don't really know as the amount of fluid increases and the risk of the patient of having AKI or mortality increases, what's the danger associated with normal saline.
00:51:16
Speaker
One way that I look at it is, obviously, it's hard to teach old dogs new tricks.
00:51:21
Speaker
And there's a lot of this that we've just been ingrained in us.
00:51:23
Speaker
Normal saline has always been the to-go for medical trained clinicians, like you said.
00:51:29
Speaker
But it seems that when you look at normal saline or crystalloids versus colloids such as albumin, we say, well, it doesn't seem to be a big difference in outcomes.
00:51:37
Speaker
And one is clearly more expensive than the other.
00:51:40
Speaker
Let's go with the lower cost one.
00:51:41
Speaker
Now it seems that it's kind of a different, a reverse analogy where you say, okay, balanced crystalloids versus normal saline, there's not a big difference in pricing.
00:51:53
Speaker
However, there is some evidence, and this is not bad evidence, to suggest that there might be a small benefit in patients in getting the balanced crystalloids.
00:52:04
Speaker
Why don't we just use the balanced crystalloids?
00:52:07
Speaker
Yeah, you know, that's a good summary.
00:52:09
Speaker
I mean, I think the clinic on balance, when we do a meta-analysis of split, SMART, and basics, right, when people do a meta-analysis on this, it's going to undoubtedly come together to show that there was no clear benefit for using balanced crystalloids over that, just because the effect size that was seen in SMART is not going to be, it's not going to overcome the negative effect that you were seeing in those other two trials.
00:52:32
Speaker
So, but the point is, is that no trial that I'm aware of
00:52:38
Speaker
whether it's a retrospective, prospective, or any of these randomized clinical trials, NO trial has clearly shown that saline is definitively better for all patients.
00:52:49
Speaker
Again, maybe in a traumatic brain injury, but in general, that saline is clearly better, NO trial has shown that at all.
00:52:56
Speaker
So since the literature still seems a little bit unclear, if you're giving your patient five liters of fluid and the cost is basically the same, maybe it's better to say, OK,
00:53:07
Speaker
at least that's my own interpretation.
00:53:10
Speaker
I'm gonna switch to balanced crystalloids, rather than do all five liters with normal saline.
00:53:17
Speaker
I agree, I think that's a great point to stop and just remind everybody that despite 30,000 randomized patients in three awesome trials, we still have more questions than answers.
00:53:29
Speaker
And this is something that we do every single day in the ICU and probably don't spend a lot of time thinking about, just shows how complex
00:53:37
Speaker
treating critically ill patients really is and how humble we should remain in terms of what we don't know.
00:53:43
Speaker
And, you know, it's important to remember that, that, that, that we, since we give these things to so many patients, you know, the, the smart trial, the smart trial authors, you know, did sort of say in their, in their conclusion that,
00:54:05
Speaker
you know, since these solutions are applied to millions of patients every year, even though that, you know, you may impact the outcome of one in 90 patients or one in 100 patients, that's still a lot of patients and it's, you know, maybe clinically significant.
00:54:23
Speaker
But again, can we definitively tell your listeners that normal saline is definitively terrible?
00:54:32
Speaker
I would encourage them to ask your listeners to also ask themselves, honestly, what is normal saline giving me that balanced crystalloids is not also giving me?
00:54:43
Speaker
And if we don't know for sure, then maybe it's better to just, you know, use the balanced crystalloids.
00:54:50
Speaker
But to each their own, as you say.
00:54:54
Speaker
We'd like to finish the podcast, Michael, with a couple of questions that are unrelated to the clinical topic.
00:55:00
Speaker
Would that be okay?
00:55:02
Speaker
So the first question, and I actually have traditionally three questions, but I have a fourth question for you, only especially for you.
00:55:11
Speaker
The first question is, what books have influenced you significantly or what books have you gifted often to other people?
00:55:20
Speaker
I would say one of the books that has influenced me most significantly is a book named Quiet by, I think it's Susan Cain.
00:55:29
Speaker
It's a book about introverts versus extroverts, and I highly recommend that, and I've gifted that to several people.
00:55:37
Speaker
I've also gifted a book to a lot of speakers that I invite to different conferences, a book called Talk Like Ted, which gives a lot of really interesting ideas on how to engage adult learners.
00:55:58
Speaker
I would encourage your readers to look at either of those two books.
00:56:01
Speaker
And we'll put those in the show notes.
00:56:02
Speaker
And I really have enjoyed both of these books.
00:56:06
Speaker
And Quiet was actually quite interesting because I think that a lot of times people misinterpret what it means to be an introvert.
00:56:16
Speaker
And I think that people think that somebody who feels comfortable giving maybe a public presentation or somebody who might be jovial,
00:56:26
Speaker
is an introvert, but really the way, what I found Michael is that ultimately it's where you get your energy from that defines that.
00:56:32
Speaker
And I am a, the consummate introvert.
00:56:35
Speaker
And if anything, I think that the amount of time that I've had to myself to think during the pandemic has been the positive several lining, but obviously some people really get their energy from being around other people, but I will definitely put both of these in the, in the show notes and both excellent books.
00:56:56
Speaker
The second question, is it related to somebody that you believe to be true in medicine or in life that most other people don't believe or at least don't act like they believe?
00:57:10
Speaker
Can you say that one more time?
00:57:11
Speaker
Help me understand.
00:57:14
Speaker
Is there something that you believe to be true in life or in medicine in general that most people don't believe or act like they don't believe?
00:57:23
Speaker
Oh, well, I mean, in medicine, I think it's, you know, de-resuscitate your patients early.
00:57:31
Speaker
Fortunately, over my career and maybe with some excellent research that others have done and maybe a small portion of my speaking on this topic, the ideas are changing a little bit out there.
00:57:43
Speaker
But, you know, I think volume overload prevents patient recovery in the ICU.
00:57:50
Speaker
And it's causative of bad outcomes.
00:57:53
Speaker
And so I think, you know, there's still a lot of people who believe you need to swell to get well.
00:57:57
Speaker
So that's what I would say on that one.
00:58:00
Speaker
And like you said, that's a great topic for future podcasts.
00:58:03
Speaker
And also something that from 2001 with the early goal-directed therapy by New Rivers paper to now,
00:58:13
Speaker
has really evolved in the way we view and think about this, but it clearly something that requires further discussion.
00:58:22
Speaker
The third question is, what would you want everybody listening to us to know?
00:58:25
Speaker
It could be a quote or a fact and kind of like a closing thought.
00:58:30
Speaker
Oh, well, you know, again, the, you need to, you need to protect the kidneys to help your patient survive.
00:58:42
Speaker
de-resuscitating and being cautious about nephrotoxins is important.
00:58:47
Speaker
Nephrocentric view of critical care is good for your patients.
00:58:53
Speaker
So the final question I have, which is only for you, is what's your prediction on the World Series?
00:59:03
Speaker
My prediction in the World Series will be Braves in six.
00:59:11
Speaker
Well, I will go with Astros in six and we'll see, I mean, who pays a nice dinner next time we get together in a conference.
00:59:19
Speaker
And again, this has been just super fun and I really appreciate the opportunity to have such great conversations with you.
00:59:28
Speaker
This is obviously a topic that I love, but obviously you like too.
00:59:32
Speaker
And so I hope we can find a time to talk about other fun, similar fluid related topics in the future.
00:59:39
Speaker
And just for our listeners, you can find Michael on Twitter at at critical care beans, MD, if you want to interact with him.
00:59:47
Speaker
Oh, just critical, just critical beans.
00:59:52
Speaker
That's critical beans, MD, no care in there.
00:59:55
Speaker
It's a, it's a entendre about how important our kidneys are.
01:00:00
Speaker
Critical beans, MD and Michael, it was a pleasure.
01:00:04
Speaker
Thank you for taking the time.
01:00:05
Speaker
I know you're in a busy clinical schedule.
01:00:08
Speaker
today and I look forward to talking to you soon and good luck in the World Series.
01:00:14
Speaker
Thank you, you too.
01:00:15
Speaker
All right, bye-bye.
01:00:18
Speaker
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01:00:22
Speaker
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01:00:28
Speaker
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01:00:32
Speaker
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