Transcript
Speaker: Welcome to Critical Matters, a sound podcast covering a broad range of topics related to the practice of intensive care medicine.
Speaker: Sound provides comprehensive critical care programs to hospitals across the country.
Speaker: To learn more about our programs and career opportunities, visit www.soundphysicians.com.
Speaker: And now your host, Dr. Sergio Zanotti.
Speaker: Administration of intravenous fluids is one of the most common interventions in patients admitted to the ICU.
Speaker: For the last decade, we have debated a broad range of specific topics related to the use of intravenous fluids in critically ill patients.
Speaker: 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.
Speaker: First, does the fluid composition, saline solution versus balanced solution impact patient outcomes?
Speaker: And second,
Speaker: Does the mode of administration, slower infusion versus faster bolus, have an impact on patient outcomes?
Speaker: Our guest today is Dr. Michael Conner, Jr. Dr. Conner is an associate professor and senior physician for critical care medicine and nephrology.
Speaker: 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.
Speaker: Michael, welcome to the podcast.
Speaker: Hi, Sergio.
Speaker: Thank you so much.
Speaker: It's such an honor and a pleasure to join you with this conversation.
Speaker: And I'm looking forward to hopefully some fun for you and me and the listeners as well.
Speaker: Absolutely.
Speaker: 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.
Speaker: So we'll get to that maybe later.
Speaker: But the other topic that probably occupies much of your practice, since you are a nephrologist and an intensivist,
Speaker: is fluids.
Speaker: I mean, you're always probably thinking every single patient, should I take fluids away or give fluids to this patient?
Speaker: 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.
Speaker: Absolutely.
Speaker: 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
Speaker: episode is maybe a debate between the timing of de-resuscitation.
Speaker: But certainly the administration of IV fluids is obviously something we do every day.
Speaker: And I couldn't agree with you more that we have maybe more questions than answers.
Speaker: And before we dive into specifically the questions that we mentioned at the intro, I want to start maybe with a more general overview.
Speaker: And for many years, and I'm a little bit older than you are, but when I was a fellow in training, I
Speaker: much of the debate really centered around crystalloids versus colloids.
Speaker: Could you just give us kind of in a nutshell where we are today and how that has transpired?
Speaker: 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.
Speaker: for most things.
Speaker: 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.
Speaker: 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.
Speaker: 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.
Speaker: 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.
Speaker: So the real question is sort of surrounding albumin and its role in use.
Speaker: 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.
Speaker: But in larger patient populations or in more general patient populations, we really have seen no clear benefit there.
Speaker: 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.
Speaker: 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.
Speaker: So still, I think that we primarily avoid the use of albumin unless
Speaker: you know, there is a special population.
Speaker: 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.
Speaker: And one of the things that came up very clearly
Speaker: was a case against chloride.
Speaker: 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.
Speaker: Can you give us your perspective on chloride and how that might be the case?
Speaker: Yeah, absolutely.
Speaker: 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
Speaker: it's important to recognize we also don't have clear data that it's a harm to patients.
Speaker: 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.
Speaker: So whether or not in those cases there may be a role for some limited albumin use is really unclear.
Speaker: But you're certainly not harming the patient.
Speaker: You're just obviously spending more money.
Speaker: 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.
Speaker: The idea being that
Speaker: 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.
Speaker: And there is quite interesting
Speaker: randomized trials or crossover trials in healthy volunteers that sort of support that physiology.
Speaker: 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
Speaker: increase risk of AKI in patients who got large quantities of chloride-rich solutions.
Speaker: 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.
Speaker: 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
Speaker: we're talking about balanced crystalloids versus saline with maybe higher concentrations of chloride and perhaps a different pH.
Speaker: 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.
Speaker: Yeah, absolutely.
Speaker: As you're
Speaker: 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?
Speaker: So normal saline or 0.9% sodium chloride
Speaker: 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.
Speaker: 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.
Speaker: And so, you know, there's been a few prospective trials, crossover trials and such,
Speaker: 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.
Speaker: So just taking both of those separately briefly, so the SPLIT trial was performed
Speaker: four ICUs at tertiary facilities in New Zealand, both a mixed med surge as well as a cardiovascular cardiothoracic surgery ICU.
Speaker: And it randomized patients to balance crystalloid with PlasmaLite 148 versus sodium chloride in critically ill patients.
Speaker: And it's actually an extremely well-designed trial.
Speaker: They included all ICU patients who received crystalloid therapy.
Speaker: Their exclusion was end-stage renal disease or AKI requiring dialysis within the next six hours.
Speaker: And their primary outcome was the development of acute kidney injury based only on serum creatinine information.
Speaker: And the trial was designed in these alternating periods of seven weeks where
Speaker: an ICU was assigned to use a blinded fluid, either fluid A or fluid B for all fluids during that given seven week period.
Speaker: And then after seven weeks, they would switch to the other ICU and they went, or to the other fluid.
Speaker: And they went back and forth like this for a total of four exchanges or 28 weeks.
Speaker: And patients who were assigned to fluid A remained on fluid A
Speaker: if they were still in the ICU over the crossover point.
Speaker: So there was really little crossover between the two groups.
Speaker: The trial ended up enrolling a little bit more than 2,200 people.
Speaker: 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
Speaker: prospective trial that had shown no difference in AKI rates, showed no worsening for any one group, but basically superimposed lines of survival.
Speaker: When people dug a little bit deeper into this trial, there were some interesting things that people noted, which led some people to wonder whether or not this really answered the question that they were intending to answer.
Speaker: So specifically, most of these patients were admitted after elective surgery.
Speaker: The mean time in the ICU was only one and a half days.
Speaker: Only 65% of patients were on the ventilator, and the mean amount of time that patients were on the ventilator was only 15 hours.
Speaker: And then the average fluid amount that was received in the first day was less than two liters.
Speaker: And so, you know,
Speaker: 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.
Speaker: And then they didn't particularly get exposed to a particularly high amount of the solutions.
Speaker: And so, you know, if you have a solution like 0.9% sodium chloride that may be
Speaker: 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.
Speaker: And so, you know, while the authors concluded that there was no significant difference,
Speaker: 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.
Speaker: At least what I feel like is the better conclusion for this trial.
Speaker: And it really doesn't help you if you're talking about patients at high risk for AKI
Speaker: with getting large quantities of solutions.
Speaker: 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.
Speaker: Excellent point.
Speaker: 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
Speaker: with some individual patients, right?
Speaker: 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.
Speaker: But let's move on to SMART because obviously SMART came a couple years later, larger trial and some interesting findings here.
Speaker: Yeah, so the SMART trial,
Speaker: 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.
Speaker: So you had your medical ICUs, your neuro-cardiac trauma and surgical ICUs as all sort of separate patient populations.
Speaker: 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.
Speaker: And then the entire ICU would move over into the other fluids.
Speaker: It was not blinded, importantly, whereas the split trial was blinded in terms of which solutions they were using.
Speaker: And their outcome was a composite outcome of death by 30 days, new development of renal replacement therapy, or persistent acute kidney injury,
Speaker: at 30 days.
Speaker: 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.
Speaker: And that always includes death by 30 days, new requirement of dialysis, or persistent acute kidney injury.
Speaker: And so in the SMART group, they had these unblinded, they had these solutions going back and forth
Speaker: every month.
Speaker: I may have misspoken.
Speaker: I apologize.
Speaker: I think I said it was an unblinded trial.
Speaker: I think it is actually a blinded trial.
Speaker: I apologize that I said that incorrectly.
Speaker: But they had access to unblinded solutions if needed based on some sort of decision by the ICU team.
Speaker: And ultimately, this trial did show a difference in MAKE-30 composite outcome.
Speaker: It's a very small difference.
Speaker: of around 1% difference in rate.
Speaker: The study did reach statistical significance, although just barely.
Speaker: And they had actually enrolled about 16,000 patients, which is really quite remarkable.
Speaker: And when you look at it all told,
Speaker: It was primarily driven by a small decrease in death and a small decrease in the need for new dialysis before 30 days.
Speaker: 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
Speaker: and showed a small but statistically significant difference.
Speaker: 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
Speaker: that you may have one patient who has a better outcome.
Speaker: And so, you know, it still is potentially clinically meaningful even though the difference is quite small.
Speaker: 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.
Speaker: And would it be fair to say, Michael, though, that even though the primary finding was different,
Speaker: They're definitely not incompatible considering that a smart had seven times more people, right?
Speaker: It was significantly larger.
Speaker: 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.
Speaker: Would that be fair to say that it could be explained in that way?
Speaker: 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
Speaker: but ultimately executed somewhat better to answer the questions that were being asked.
Speaker: And while the difference was small, there was a difference there.
Speaker: 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
Speaker: saline.
Speaker: 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.
Speaker: 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.
Speaker: And it
Speaker: 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.
Speaker: So 100% normal saline versus 100% balanced crystalloid versus areas in between.
Speaker: And so, you know, there's, it's, I think most people ultimately said split was a really well-designed trial,
Speaker: 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.
Speaker: And I think SMART and its companion trial, which was the SALT-ED trial done just in emergency department patients,
Speaker: 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.
Speaker: And remind me, Michael, the amount of fluid at an average the patients got in SMART, that was close.
Speaker: I mean, it wasn't a large amount either, right?
Speaker: I mean, I'm sure with 15,000 patients, it averaged out probably to something not too far from split.
Speaker: Is that correct?
Speaker: 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.
Speaker: 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.
Speaker: If you look at the types of patients that were enrolled,
Speaker: there was a far greater percentage of patients in SMART trial that were enrolled through the emergency department.
Speaker: More than 50% of the patients came from the emergency department for the SMART trial.
Speaker: And there was a high proportion of patients with sepsis as well.
Speaker: And those that did have surgery were much more emergency surgeries rather than elective surgeries.
Speaker: So it was, generally speaking, a sicker patient population, which is why you may have seen
Speaker: a difference with a similar exposure to fluids.
Speaker: Yeah.
Speaker: And I think that it's an important point, right?
Speaker: 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.
Speaker: Now that might be a discussion for another day.
Speaker: What the right amount of fluid is we can talk about that some other episode.
Speaker: But those are two things that obviously, like you said, split and not really tackle in the way it was designed.
Speaker: Excellent.
Speaker: So now we have a new study, Basics, and they actually published recently two separate studies that address two separate questions.
Speaker: So very well organized and you had the opportunity to write the editorial.
Speaker: 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.
Speaker: If you could tell us more about this basics trial.
Speaker: 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
Speaker: 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.
Speaker: BASICS did a very similar thing, which is that patients were randomized to two different arms.
Speaker: And so it was sort of like a two by two trial.
Speaker: 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.
Speaker: And then they also got randomized into receiving their bolus solutions quickly versus receiving their bolus solutions at a slightly slower
Speaker: rate.
Speaker: And so they analyzed these two things separately and published one article on each of those two things.
Speaker: So all the patients participated really in both sides of the trial.
Speaker: And so the initial trial that we're at least discussing right now is the one that's comparing the two types of fluids.
Speaker: And so again, this was a randomized trial.
Speaker: They received blinded solutions
Speaker: 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.
Speaker: And the primary outcome in this trial was not a composite outcome.
Speaker: The primary outcome was
Speaker: 90-day mortality.
Speaker: 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.
Speaker: They also enrolled a huge number of patients, around 11,000 in total.
Speaker: And this was spread across, I think, almost 70 ICUs in Brazil.
Speaker: 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.
Speaker: Absolutely.
Speaker: 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.
Speaker: That is unheard of in our field.
Speaker: 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
Speaker: scientifically justified and designed trials, which hopefully move, move our field a little bit forward.
Speaker: 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?
Speaker: Yeah.
Speaker: So ultimately, you know, their results were, um, were, uh, that there was no difference in mortality between these two groups.
Speaker: Um,
Speaker: 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.
Speaker: So this trial, you know, sort of fell along with split, sort of saying that there was no real demonstrable difference between
Speaker: these two groups in terms of the primary or most of the secondary outcomes.
Speaker: 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
Speaker: 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.
Speaker: 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.
Speaker: Yeah.
Speaker: And I think that, like you said, you mentioned this is a secondary endpoint.
Speaker: So if anything, it should generate further evaluation and studies.
Speaker: as opposed to a conclusion that's definitive, but it also illustrates the complexity of the topic, right?
Speaker: 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.
Speaker: So again, just showing you how complex and terogenous our critically ill patients are
Speaker: And that ultimately it might be hard to say blanket statements, this versus that for some very specific patient situations.
Speaker: Right.
Speaker: 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.
Speaker: Granted, a very small proportion of these patients
Speaker: in those who receive saline compared to balanced crystalloid.
Speaker: And so there are some questions and concerns about that, and you're absolutely right.
Speaker: And it's not the first trial to ask that question or to have some signal of potentially harm in those with neurologic insults.
Speaker: The idea primarily being that the osmolarity of 0.9% sodium chloride is slightly higher than the osmolarity
Speaker: 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
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.
Speaker: And we tried to say in our editorial that we agreed that this is concerning and, you know, potentially needs more study.
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.
Speaker: Michael, could you tell us a little bit more about the bound solution that they used in this basics trial, the PlasmaLite 148?
Speaker: Yeah.
Speaker: So PlasmaLite A and PlasmaLite 148 are actually really very identical solutions in terms of their composition.
Speaker: They both contain about 140 milliequivalents of sodium per liter, 5 milliequivalents of potassium.
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.
Speaker: In the United States and in Canada, plasmalite-148 and plasmalite-A are slightly different with regards to their pH.
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.
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.
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.
Speaker: And that maybe the difference in pH explains the difference in the results of these two trials or these three trials.
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.
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.
Speaker: And that in Australia, New Zealand, and in Brazil, Plasmalite 148 actually has a pH of 7.4.
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.
Speaker: And additionally, the authors of these various trials did not include in their manuscripts or in previously published methods papers
Speaker: what the pHs were of the solution that they were using.
Speaker: And so we incorrectly just assumed that plasmalite 148 in these countries had a lower pH.
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.
Speaker: Excellent.
Speaker: And we'll talk a little bit more about ultimately the clinical implications as we close.
Speaker: But before we get there, Michael, I wanted to tackle
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.
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?
Speaker: And where does this question really come from?
Speaker: Yeah, it's great.
Speaker: I actually was really pleased that they did this portion of the trial.
Speaker: I think this asks and answers a really important question.
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.
Speaker: But I'll admit that when I'm in the cardiac intensive care unit, I certainly have seen patients who have suffered from
Speaker: RV dysfunction from too rapid volume expansion with a cold solution, be that blood or crystalloid or anything else.
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.
Speaker: and obviously not what any one of us are trying to do when we volume expand a patient.
Speaker: And there's really never been a great study that actually looked at how fast do we need to give the fluids?
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?
Speaker: And how does that impact outcome?
Speaker: And so the other portion of this trial
Speaker: you know, randomized patients to either a liter an hour for resuscitation speed.
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.
Speaker: And again, it was the same patient population.
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.
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.
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.
Speaker: Just getting the fluid in in the first place is really
Speaker: sort of the important aspect of that.
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?
Speaker: And especially in the ICU, I think we might feel that urgency.
Speaker: But like you said, I mean, it demonstrated that there was no significant difference.
Speaker: And perhaps, I mean, obviously you need to give the fluids not over two days, but
Speaker: where you give it at 999 or like they did at 233 mls per hour, probably not a big impact.
Speaker: Yeah, but I think that's important, right?
Speaker: Because I think we oftentimes rush to give a bunch of fluids.
Speaker: We feel like they have to have these large bore central lines and they have to get this all in very quickly.
Speaker: rather than just getting it started through the IV that you have and getting them going on something.
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.
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.
Speaker: Whereas when we're giving it really fast,
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.
Speaker: Yeah.
Speaker: And are there other possible concerns about bolus administration versus a more measured infusion in terms of other physiological problems or endpoints?
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.
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?
Speaker: And I think those are all
Speaker: important questions.
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.
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.
Speaker: No, no.
Speaker: And I was just curious in terms of are there other things that have been published or I wasn't aware.
Speaker: But like you said, I was also very excited when I saw
Speaker: that they actually did the second R because I think it answers a very commonplace and practical question.
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.
Speaker: But I agree with you.
Speaker: As we close on the basics comment, I guess the other things that I found interesting
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?
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.
Speaker: And also it seems that it was a very wide range of patients.
Speaker: Yeah, yeah.
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.
Speaker: I mean, they should really be commended for doing this trial and for succeeding at doing the trial.
Speaker: But I think
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.
Speaker: Only 20% or 22% of the patients are coming from the emergency department as an unplanned admission.
Speaker: You know, sepsis is only affecting about 20% of the patients in this 11,000, 12,000 cohort of patients.
Speaker: And so again,
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?
Speaker: Elective surgeries, if 50% of your patients are elective surgery, you shouldn't be seeing a lot of those patients die.
Speaker: And so if your primary outcome is mortality, then you really, if you're going to see small differences in an outcome,
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.
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,
Speaker: have more of a problem.
Speaker: Theoretically, you could look at high-risk patients who had fast normal saline versus slow normal saline.
Speaker: Did those patients have a difference in outcome?
Speaker: Or normal saline versus balanced crystalloids in the particularly high-risk patient populations in these groups?
Speaker: So I think it suffers from some of the same challenges as split in trying to answer this.
Speaker: But that being said,
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.
Speaker: But I think the question still is out there a little bit as to
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?
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?
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.
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.
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?
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.
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.
Speaker: And he demanded I change it to Ringer's lactate.
Speaker: at the time, obviously, I just thought, oh, whatever, rolled my eyes and did it.
Speaker: But maybe he knew something I didn't know.
Speaker: Maybe he had a point.
Speaker: Well, I'm a little bit younger than you, not much younger.
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.
Speaker: And we both thought each other were crazy.
Speaker: But, you know, and I think that
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?
Speaker: Maybe we weren't really hurting a lot of patients, but we may be hurting some.
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?
Speaker: I mean, the prices are basically the same, right?
Speaker: I mean, these solutions are really cheap.
Speaker: And even if PlasmaLite A
Speaker: is more expensive, you're talking about $8 instead of $2.
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.
Speaker: I don't think we should be too worried about that.
Speaker: So I see the argument to say, okay, there's not a huge benefit of balanced crystalloids.
Speaker: Maybe, maybe that's really the case.
Speaker: I don't know yet in the very sick patients that needs five liters of fluid.
Speaker: I tend to still use balanced crystalloids in that situation.
Speaker: But the counter argument I think is also there is, well, why do it?
Speaker: Because no study shows that saline is better.
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?
Speaker: I agree.
Speaker: And to close, I mean, the discussion, the clinical part, I think it's always a
Speaker: important to remind ourselves that the ultimate goal of research is action, not knowledge.
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?
Speaker: Well, I will be guilty of having said maybe a few years ago to my resident, you know,
Speaker: geez, why did you use normal saline at all?
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.
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.
Speaker: I tend to still use balanced crystalloids for most resuscitations, again, because I don't
Speaker: see many clinical situations unless the patient has been vomiting and has actual hypochloremia.
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
Speaker: over some of the other options that we have.
Speaker: So I tend to lean on plasma light.
Speaker: I also think balanced crystalloids are great for other things, right?
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
Speaker: and recovered your serum bicarbonate levels.
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.
Speaker: So I think there's a lot of reasons why balanced crystalloids provide us potentially benefit, but
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.
Speaker: Yeah.
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.
Speaker: But it does seem
Speaker: One way that I look at it is, obviously, it's hard to teach old dogs new tricks.
Speaker: And there's a lot of this that we've just been ingrained in us.
Speaker: Normal saline has always been the to-go for medical trained clinicians, like you said.
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.
Speaker: And one is clearly more expensive than the other.
Speaker: Let's go with the lower cost one.
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.
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.
Speaker: Why don't we just use the balanced crystalloids?
Speaker: Yeah, you know, that's a good summary.
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.
Speaker: So, but the point is, is that no trial that I'm aware of
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.
Speaker: Again, maybe in a traumatic brain injury, but in general, that saline is clearly better, NO trial has shown that at all.
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,
Speaker: at least that's my own interpretation.
Speaker: I'm gonna switch to balanced crystalloids, rather than do all five liters with normal saline.
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.
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
Speaker: treating critically ill patients really is and how humble we should remain in terms of what we don't know.
Speaker: Yeah.
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,
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.
Speaker: But again, can we definitively tell your listeners that normal saline is definitively terrible?
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?
Speaker: And if we don't know for sure, then maybe it's better to just, you know, use the balanced crystalloids.
Speaker: But to each their own, as you say.
Speaker: Excellent.
Speaker: We'd like to finish the podcast, Michael, with a couple of questions that are unrelated to the clinical topic.
Speaker: Would that be okay?
Speaker: Absolutely.
Speaker: So the first question, and I actually have traditionally three questions, but I have a fourth question for you, only especially for you.
Speaker: Wow.
Speaker: The first question is, what books have influenced you significantly or what books have you gifted often to other people?
Speaker: That's great.
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.
Speaker: It's a book about introverts versus extroverts, and I highly recommend that, and I've gifted that to several people.
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.
Speaker: I would encourage your readers to look at either of those two books.
Speaker: And we'll put those in the show notes.
Speaker: And I really have enjoyed both of these books.
Speaker: And Quiet was actually quite interesting because I think that a lot of times people misinterpret what it means to be an introvert.
Speaker: And I think that people think that somebody who feels comfortable giving maybe a public presentation or somebody who might be jovial,
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.
Speaker: And I am a, the consummate introvert.
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.
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?
Speaker: Oh, wow.
Speaker: Can you say that one more time?
Speaker: Help me understand.
Speaker: I'm sorry.
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?
Speaker: Oh, well, I mean, in medicine, I think it's, you know, de-resuscitate your patients early.
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.
Speaker: But, you know, I think volume overload prevents patient recovery in the ICU.
Speaker: And it's causative of bad outcomes.
Speaker: And so I think, you know, there's still a lot of people who believe you need to swell to get well.
Speaker: So that's what I would say on that one.
Speaker: Excellent.
Speaker: And like you said, that's a great topic for future podcasts.
Speaker: And also something that from 2001 with the early goal-directed therapy by New Rivers paper to now,
Speaker: has really evolved in the way we view and think about this, but it clearly something that requires further discussion.
Speaker: Definitely.
Speaker: The third question is, what would you want everybody listening to us to know?
Speaker: It could be a quote or a fact and kind of like a closing thought.
Speaker: Oh, well, you know, again, the, you need to, you need to protect the kidneys to help your patient survive.
Speaker: So, you know,
Speaker: de-resuscitating and being cautious about nephrotoxins is important.
Speaker: Nephrocentric view of critical care is good for your patients.
Speaker: Excellent.
Speaker: So the final question I have, which is only for you, is what's your prediction on the World Series?
Speaker: My prediction in the World Series will be Braves in six.
Speaker: Okay.
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.
Speaker: Absolutely.
Speaker: And again, this has been just super fun and I really appreciate the opportunity to have such great conversations with you.
Speaker: This is obviously a topic that I love, but obviously you like too.
Speaker: And so I hope we can find a time to talk about other fun, similar fluid related topics in the future.
Speaker: Absolutely.
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.
Speaker: Oh, just critical, just critical beans.
Speaker: Okay.
Speaker: Critical beans.
Speaker: Perfect.
Speaker: That's critical beans, MD, no care in there.
Speaker: It's a, it's a entendre about how important our kidneys are.
Speaker: Excellent.
Speaker: Critical beans.
Speaker: Yes.
Speaker: Sorry.
Speaker: Critical beans, MD and Michael, it was a pleasure.
Speaker: Thank you for taking the time.
Speaker: I know you're in a busy clinical schedule.
Speaker: today and I look forward to talking to you soon and good luck in the World Series.
Speaker: Thank you, you too.
Speaker: All right, bye-bye.
Speaker: Thank you for listening to Critical Matters, a sound podcast.
Speaker: Make sure to subscribe to Critical Matters on Apple or Google Podcasts and share with your network.
Speaker: Sound's transforming the way critical care is provided in hospitals across the country.
Speaker: To learn more, visit www.soundphysicians.com.
