Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. This podcast Narrator - ? 00:11 is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice, and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk, Episode 92 I'm your co host, Dr. Kane. I'm Dr. Schuman, and today's episode title is why you should stop using abnormal saline, normal saline versus lactated ringers for IV fluids. And today, we're basically discussing some new evidence supporting the concept that maybe normal saline is, in fact, nephrotoxic to patients. This is an IV solution that we've been using for many decades, and it just so happens that relatively recently, we have some data comparing normal saline versus another IV fluid called lactated ringers, and that new data suggests that we should probably change our kind of standard practice away from normal saline, right? Speaker 1 01:12 So, so Dr. Kane, I practice mostly in an outpatient setting. So what are some examples, then, of maybe when I as an introduction, when are IV fluids generally used in hospital? I know a little bit from when I teach my nutrition when I teach my nutrition lectures, but in kind of general practice, what Dr. Sean Kane 01:26 do you see them used for? Yeah, so basically, there's like two main modalities of why a patient might receive IV fluids. One is for maintenance. IV fluid, meaning that the patient isn't taking adequate po or can't take oral anything. It could be that they have an ileus, they have surgery coming up, or they just had a surgery, or they're nauseated, they're vomiting, for whatever reason, you're basically trying to maintain their hydration status, and you do that by giving maintenance IV fluid. Now the other thing that we do is IV boluses. So instead of kind of giving a continuous rate over a long period of time of an IV fluid for someone who is hypotensive, someone who's bleeding, someone who, you know, is extremely dehydrated, that needs to kind of get a lot of IV hydration very quickly. We can give them IV boluses, and this is very commonly done, especially in more critically ill patients. And the reason is that for low blood pressure, we have to give IV fluids. For other therapies like vasopressors to work. Vasopressors won't work if you don't kind of tank up the patient with an adequate hydration through IV fluids. So IV fluids are incredibly common for hypotension, dehydration, and then people who can't take po and we have a variety of different IV fluids are that are available, but historically, normal saline is one of the most common IV fluids that we use, both for the hydration and boluses, but also even mixing drugs to give them IV normal saline is a very common diluent that we'll use to maintain tonicity in an IV product, but be able to mix it with another drug that we're trying to give the patient. Speaker 1 02:57 Yeah, and so again, when we look at what is available, I remember in school, something that you learn about, but don't talk about as much, is the idea about these, these Crystalloids and colloids. So can you tell me a little bit of those two? Dr. Sean Kane 03:07 Yeah, so crystalloid just basically means it's like a salt solution. So mostly this is going to be sodium and chloride making up the crystalloid component. But this is an electrolyte salt solution that you give to a patient, and those electrolytes have some degree of osmolarity, and that osmolarity maintains that fluid inside the vasculature. So, for example, with normal saline, it has an osmolarity of 308 milliosmoles per liter. That means that when you give that patient that fluid, that sodium, that chloride, will stay in the blood, and it keeps that water and that IV fluid inside the vasculature as well. Now, in contrast, colloids, an example of a colloid would be albumin or certain types of IV starches. These use oncotic pressure, as opposed to osmolarity, to basically stay in your blood. And we basically don't use these very often because they're quite a bit costlier than our crystalloid counterpart. And we we have some evidence that actually some of these colloids, like starches, can be harmful for patients. So basically, when we're using colloids, we're effectively talking about albumin, and because of cost, we don't use it that often. We use a lot more Crystalloids, and for that reason, in the scope of today's podcast, we're really restricting our discussion only to IV Crystalloids like normal saline, right? Speaker 1 04:22 So again, normal saline is going to be your standard default crystalloid. And so normal saline or point nine are also written as as ns, and that's been the standard IV crystalloid for a long time, particularly, I know, in non surgical patients, yeah. Dr. Sean Kane 04:36 And you know, historically, there's a big fight between the medical specialty and the surgical specialties, in terms of what is the best IV fluid, normal saline was kind of the flag bearer for the medical specialties, whereas lactated ringers was more the go to agent for the surgical specialties. Speaker 1 04:53 So it's interesting. I know Dr. Kennedy, you mentioned that you know, talking about what's what's considered normal and it's interesting. Saying, if you look at, you know, calculating it out, we look at the actual amount of sodium that is a normal saline, you're looking at 154 mill equivalents per liter overall, which technically is hypernatremic. If we're considering a plasma concentration somewhere between 135 and 145 as normal. So it's maybe not as normal there exactly. Dr. Sean Kane 05:19 So if a patient receives too much normal saline, they will become hypernatremic, because the sodium content of normal saline is too much sodium versus what your body prefers. So that is absolutely a problem with normal saline. Interestingly, though, the bigger problem is actually the chloride content, and in this case, the chloride content is 154 milliquivalence per liter, but your blood is around like 98 to 107 or we'll just effectively call it like 105 and this is a much bigger discrepancy than that sodium content. So if, again, we give too much normal saline to a patient, they will become hypernatremic, but they'll actually get very hyperchloremic. And we think that that excessive chloride load is actually one of the things that causes some of the harms associated with too much normal saline. Interesting. Speaker 1 06:05 You also mentioned in terms of osmolarity, that it's a little bit different there too. So 308 milli Osmos per liter would be what's considered for normal saline compared to in the body. Isotonicity is defined as 275 to 300 so again, a little bit of a difference. And interestingly, as well, I believe, is pH difference too, within the plasma pH of 7.4 but with normal saline pH of 5.6 is significantly more acidic in that Dr. Sean Kane 06:32 environment, exactly. So one of the big problems is that we love to give normal saline for, let's say, a septic patient, and in sepsis, it's very common these patients will form anion gap, metabolic acidosis from their lactic acidosis. It's ironic that they already have an acidosis, and then we give them liters and liters of this IV fluid that is also acidic and hopes that their acidosis will get better. Clearly, that doesn't make a lot of sense. So unfortunately, between its hypernatremia, its hyperchloremic nature, and its acidic pH, normal saline is really not that normal, and some people have kind of jokingly called this abnormal saline because of the fact that it does create electrolyte problems, especially if you give too many liters of this IV fluid. Speaker 1 07:13 Now, Dr. Kane, I'm pretty sure I know the answer to this, but if we're talking about how maybe problematic normal saline could be there's got to be some sort of other type of crystalloid that may be available, right? Dr. Sean Kane 07:24 Exactly, and this is where that surgical specialty comes in. They've really hung their hat on the concept of using lactated ringers or LR as their preferred crystalloid of choice. And they've really fought the medical specialties for decades, saying that they think that their IV fluid of choice is better than the medical specialties, normal saline. Speaker 1 07:42 So it's interesting. You hear the name, so maybe ringer's lactate, lactate? So is ringer a person? Does ringer have to do with the formula? What is the ringer part? Dr. Sean Kane 07:51 Yeah, so basically, a physician by the last name of Ringer was the first person to come up with what we now basically call today as lactated ringers. So ringer's lactate is probably a more proper name for it, but by convention, we've kind of called it LR or lactated ringers instead. And then what happened was another physician, a pediatrician, actually by the last name of Hartman, actually modified that to what we now have today, which we call LR lactated ringers. So some people call this lactated ringers or ringers lactate. Some people will use that second physician's name and call it Hartman solution. This is a little bit more common in other countries, outside of the US, but that's basically where that name comes from. LR, Hartman solution comes from the two physicians that were involved in the development of this IV fluid, Speaker 1 08:35 and Dr. Kane. Since you mentioned that some of the concerns with the were about some of the breakdown of sodium chloride osmolarity and patients maybe start with their comparison. So how does this look in terms of sodium content versus normal saline? So this one Dr. Sean Kane 08:48 is actually hyponatremic. So it has 130 milli equivalents per liter of sodium, whereas your blood is closer to 135 to 145 so as opposed to making you hypernatremic, if you get too much of this, this could potentially actually make patients hyponatremic instead chloride wise, this is spot on. And again, the chloride was the big problem with normal saline. In LR, we have 110 of chloride versus physiologic — it's about, we'll say, 105–110, somewhere around that range. So this is much more physiologic than the 154 of chloride that normal saline came along with it. Speaker 1 09:21 And then furthermore, believe it also has some potassium component as well — so 4 mEq/L, which is around a normal range for potassium. And then I'm assuming that there's some sort of lactate involvement too. Dr. Sean Kane 09:35 Exactly. So, as the name suggests, they add lactate to the IV fluid — this is 28 mEq/L. And basically what happens is that lactate will eventually turn into bicarbonate in the liver. So that lactate hits the liver, turns into bicarb, and some component, maybe not all of it, will get converted into bicarb. It depends on how efficient that conversion process is, but you can kind. Think of it as if you give 28 molecule events of lactate to a patient, some of that, or all of that, could be potentially converted into some number of molecular events of bicarb in the patient. Speaker 1 10:10 And then if you look at pH as well, we're talking 6.2 so it's still not exactly on there, but maybe a little bit closer to physiologic compared to normal saline, 5.6 Dr. Sean Kane 10:21 versus six point Yeah, so way better. Maybe not exactly at 7.4 which is the pH that we would love to have. But this particular product is not as acidic as normal saline. And then finally, the the last thing in here is calcium. So it has six milligrams per deciliter of calcium in it, which is low compared to your blood, which normal blood is around eight to 10 of calcium, but it still has more than zero. And one of the reasons why the surgical specialty really likes LR is because you do need calcium to help your clotting factors work. So especially in that bleeding patient, that trauma patient, sometimes that calcium can be nice to have, although we can always give extra IV calcium if we need to as well. Speaker 1 11:01 I believe there are other Crystalloids on the market as well too. So what are some of these other things we can maybe consider too? Dr. Sean Kane 11:07 Yeah, so there are a number of other Crystalloids that are very similar to lactated ringers, and we call lactated ringers. And these other Crystalloids balanced Crystalloids, meaning that physiologically, they're similar or balanced to what normal plasma should look like. Some of the examples of these branded products include Plasma-Lyte, Isolyte, Normosol. There's a bunch of other ones on the market. And then many of those products also have very similar names, but slightly different concentrations of ions. Mostly the pH is a little bit different. So for example, we have Isolyte S and we also have Isolyte S pH 7.4 and that latter product obviously has a pH of 7.4 versus Isolyte S without the pH designation has a slightly more acidic pH. So again, basically all of these are very, very similar. The nuances are the pH and the exact electrolyte concentrations, but all of these are more physiologically balanced to be more similar to your plasma as LR is. The difference, basically, is that we've used LR for a very long time, whereas these newer products, these are products that are formulated by different companies and have slightly different variations, and typically, to be honest, they don't have as much IV compatibility data, which is one of the reasons that we don't immediately grab these all of the time. Speaker 1 12:23 And so similar to the other types of Crystalloids we mentioned, these can be given both as maintenance IV fluids as well as an IV bolus. So something may be along the lines of 80 to 125 milliliters per hours, a continuous IV which would be about two to three liters per day. And again, also the option in cases where you need to push it a little faster as an IV bolus, maybe one liter over an hour, maybe a little bit less, depending upon your IV access. So nine or nine, nine mils per hour, if the IV pump can't, can't handle that. That four digits at 1000, but yeah, we can go ahead and give it a bolus, maybe even give multiple boluses at the same time, if we need to. Dr. Sean Kane 12:58 And if you look at, you know, especially some of the earlier septic shock literature, depending on how sick the patient is, they may get up to, let's say, 10 liters of IV fluids in the first day. But I would say, for the most part, most literature is moving toward a resuscitation volume of a couple liters is going to be what you'll typically give for that sick patient, and then beyond that, that's where you start reaching for vasopressors, for example, in that patient who is still hypotensive after that. But for the most part, I think we over complicate the dosing of these IV Crystalloids. You give a couple liters IV bolus very quickly, within an hour or two, for hypotension and for maintenance IV fluid, you're basically picking a number between 80 or 83.333 which is two liters a day, all the way up to 125, which is three liters a day. And that's a typical hydration for someone who's not taking po Speaker 1 13:50 and so again, I think at this point, just to highlight some of the differences we mentioned, as you said, there's, there's nothing quite normal. With normal saline, we're talking about higher sodium content, definitely, definitely higher chloride content, more acidity and so maybe not as balanced as some of these other more balanced Crystalloids, as you Dr. Sean Kane 14:08 mentioned, exactly. And again, lactated ringers is the main thing that we've used, just because we've had it around for a long time. There are other products out there now, but these balanced Crystalloids are just better in terms of the physiologic balance of electrolytes that they have in the pH that these have. It's more similar to your blood and Speaker 1 14:26 Dr, can you make it sound like this is something again, this is not a surprising fact. This is something that's been known for a while. So what has kept individuals, maybe, from embracing lactated ringers comparatively Dr. Sean Kane 14:36 to others? So the number one reason is that if you're a medical specialist, and you were trained with normal saline, and you like normal saline because you're comfortable with it. Your argument is, show me the data. And for decades, the argument was, if there's no data that says Normal saline is causing trouble, why would I switch? That's how I trained. That's how I learned, and I want to continue doing, you know what I've done. And basically that was factually correct. For a very long time, decades, actually, where we didn't know whether the imbalances and abnormal saline actually caused a clinical difference, or if people were just getting worked up about clinically irrelevant numbers in a bag that you know, your body can handle some degree of chloride. It can handle some degree of an acidic pH solution. The argument was, maybe the body can adapt, and it doesn't cause a clinical difference in outcome, right? Speaker 1 15:25 So I'm guessing then we'd have some new data available that we can jump right into. We do all right? Dr. Sean Kane 15:30 And the two trials that came out relatively recently, within the last year, the two trials are named smart and salt Ed references are in the show notes. Again, this is episode 92 at HelixTalk.com but these were kind of parallel trials done at the same institution, so they're very similar in design, but they looked at different patient populations. Basically the design of the trial was comparing normal saline versus balanced crystalloids, and most of the time they used lactated ringers. They used a small amount of Plasma-Lyte/Isolyte products, but for the most part, they used lactated ringers. So effectively, this was a normal saline versus lactated ringers study, two studies, actually. Speaker 1 16:08 And so this was, again, for both trials, really a single center, unblinded, which just does bring in some, some considerations, pragmatic interest. So they really only control the one aspect of patient care. Everything else was up to the clinicians. That's again, interesting that obviously, you know, you patrol for the main thing, but then there's probably some confounders that that could introduce. Dr. Sean Kane 16:29 And if you think about it, normally, single center is not a good thing. You want it to be very applicable to a bunch of different centers. Usually, unblinded is not a good thing. But one of the reasons that they were able to achieve the numbers that they did, which we'll talk about in a second, is that they did make it unblinded. They made it very pragmatic, where they didn't dictate all elements of care. It was just if you want an isotonic IV fluid for maintenance IV fluid, or for IV boluses, you have to pick this particular product. Everything else about patient care, from when antibiotics are given, what kinds of antibiotics, what you do for blood pressure, goals, everything else was basically left up to the clinician. And that's okay, as long as you have a ton of patients where kind of any random noise and chance is diluted out, because you have 1000s of people which, which they did. And one of the reasons that they were able to do this was that they did a what's called a cluster randomized study, which means that instead of randomizing each and every patient, consenting them saying, Hey, we're running this study, we want to give you this IV fluid or this other IV fluid. Instead of doing that, they randomized an entire unit. So either the ED or the ICUs were completely randomized to either get normal saline or LR for an entire month, and then they swapped back and forth every month, and that allowed them to basically give the study drug, the crystalloid, to all of their patients when they needed IV fluids. Again every other month, they're switching off that unblinded nature of it allows them to be able to enroll a ton of people and give their study drug to a ton of people. Speaker 1 18:00 All right, so just now to look at some of the breakdown of the individual studies. So as the first one I think you mentioned was the smart study, so critically ill ICU cohort, five ICUs a Vanderbilt. And I think you already mentioned this. This was a very, very large study, 15,000 that right? Dr. Sean Kane 18:15 15,802 people enrolled. This is gigantic for ICU studies. And again, the reason that they could do this was simply the fact that they had this cluster, randomized design, pragmatic design, and they included a ton of different kinds of ICU patients. So I would be hard pressed to find a larger ICU study than this. This is like cardiovascular research territory here in terms of that number. So what was the primary endpoint they looked for? So in the smart trial, the primary endpoint was what they called major adverse kidney events within 30 days. And major adverse kidney events basically meant that you died, you went on dialysis, new dialysis, or your SCr doubled. Speaker 1 18:54 All right, so let's, let's look at the results there. So ended up with with normal saline, 15.4% of individuals met that primary endpoint compared to 14.3% lactated ringers — may seem like a small difference there, but P value 0.04, so statistically significant, Dr. Sean Kane 19:11 where the number needed to treat of only 91 which is really pretty good. So the absolute difference was just above 1% difference. That's where that number needed to treat comes from, effectively, kind of proving or demonstrating that there is a clinical difference between normal saline and lactated ringers. And most of that difference actually was born out of the fact that normal saline was more nephrotoxic than lactated ringers. Was another Speaker 1 19:36 interesting point to look at is, is the amount of the food. So again, if if you think it is a problem with the solution itself, then then you know more of it would be considered to be more problematic. And so one thing they note is that relatively small amounts in the study, so median of 1000 milliliters given with an interquartile range of up anywhere from none to 3500 milliliters. Dr. Sean Kane 19:57 And of course, if you think about it, if the median was 1000 that means that that roughly 1% absolute difference we're observing is with roughly about a liter of fluid, right? So you'd expect that the amount of nephrotoxicity that you should observe is going to be a lot more for that patient that gets like six liters of fluid in that first day. I would view this as very applicable to many, many patients, because it doesn't take that much IV fluid to observe this difference of primarily nephrotoxicity. Speaker 1 20:26 Now what about, I guess, thinking about other end points, what about as far as mortality? What did this do towards the patients there? Dr. Sean Kane 20:33 Yeah, so they looked at 30 day inpatient mortality, and they were so close. So normal saline had 11.1% versus LR had 10.3% the p value would make a statistician cry. It was 0.06 so they were so close, but not quite there in terms of showing an actual mortality difference among this critical care cohort. Speaker 1 20:53 And then were there any important subgroups they looked at? I know you're big on sepsis, so what happens in that population? Dr. Sean Kane 20:59 Yeah, so of that 15,000 patients, about 15% of them were sepsis patients. And again, sepsis patients tend to get a lot of IV fluids in that first six to 24 hour period. And what they found was the 30 day inpatient mortality of that sepsis cohort was normal saline, 29.4% versus LR, 25.2% that was a significant P value of point 02, with a number needed to treat of 24 again, this is a hypothesis generating subgroup, meaning that this doesn't change our standard of care for sepsis patients, but it does kind of argue the point that there may be certain patients that would benefit more from switching from normal saline to lactated ringers, or just never using normal saline period, Unless there's some compelling reason that you really need to use normal saline in those patients. Speaker 1 21:44 All right, so we've kind of talked about the smart trial, which is critically ill ICU cohort. Now you said the other one was salt ed. I have a guess as far as what population this one was in, exactly. Dr. Sean Kane 21:54 So this is our non critically ill emergency department cohort, and at Vanderbilt, they only have one Ed, so this was a single center, one unit study. But again, I wouldn't beat them up too much for that, because they actually had 13,000 people enrolled. Again, gigantic study. This is cardiovascular research territory in terms of the end here, which is really impressive. Speaker 1 22:15 It's important thing to look at as far as the endpoint. So little bit different here, primary endpoint, days alive and free of hospital within 28 days. Dr. Sean Kane 22:24 And I'm not a huge fan of this particular endpoint. Basically, they're trying to prove that you stayed alive and out of the hospital. And there was no difference here. The median days out of the hospital within 28 days and alive was 25 days in both groups. Basically everyone spent a median of three days in the hospital, and then they were gone. So again, and the smart trial, they primarily looked at major adverse kidney events. In this salt Ed trial, the primary endpoint was actually a failed endpoint, looking at basically being out of the hospital, right? Speaker 1 22:55 So as you mentioned the secondary endpoints, they didn't get rid of the major adverse kidney events. They just made that a secondary endpoint here, in this case. So death dialysis or doubling of a serum creatinine found here, normal saline, 5.6% versus lactated ringers, 4.7% so again, right around a 1% difference statistic, significant P value, point 01, number needed to treat here, 111, Dr. Sean Kane 23:17 and you know, even though this was a secondary endpoint in a trial with a failed primary endpoint, this is a very different endpoint, and I think that it's reasonable to look at this, especially in the context of the smart trial showing less nephrotoxicity. So we're effectively seeing a similar treatment effect here in terms of less nephrotoxicity using lactated ringers, both in critical care patients, which was the SMART trial, and then non-critically ill patients in the SALT-ED trial. Speaker 1 23:44 Now in both studies, again, in this case, they also looked at mortality here. And so similarly, it was, you know, p value, not significant. So 1.6% mortality rate with normal saline, little bit lower, 1.4 lactated ringers, P value, point three, six. So nothing there. Dr. Sean Kane 23:59 And to be fair, I don't know that you would expect to see a mortality difference. Just to put it into context, we're talking about one and a half percent of people dying overall in the salt TD trial, versus in the smart trial, about 10% of people died, and in the sepsis cohort, about 25 to 30% of people died. So this is clearly like a very underpowered mortality endpoint we wouldn't expect to have a dramatic effect on mortality in these non critically ill patients, but it's great that they still looked at it. Speaker 1 24:26 So as we mentioned, another important thing to look at is going to be the amount of fluid that was administered. Because obviously the more given with normal saline, then potentially the more problematic. So here in median with similar 1000 milliliters with a range of one to 2000 Now it's interesting. It looks like that they excluded individuals receiving less than 500 mils from analysis in this study, which was a little bit different than in the prior study. Yeah. Dr. Sean Kane 24:51 So if you look at the interquartile range for the smart trial, some people got literally no fluid versus in this particular cohort, they excluded you if you got less than. 500 mls, knowing that a number of these non critically ill patients would not get that much IV fluid before they left the ED so knowing that they got rid of those outliers that got very little IV fluid. Still, we're observing this difference in nephrotoxicity with roughly about a liter of IV fluid as a median, which again emphasizes that if you have that patient that's getting two to three to four plus liters, there's probably a dose dependent toxicity with normal saline, and we should be even more cautious to use normal saline in those patients. Speaker 1 25:29 All right. So what can we learn if we kind of combine these two studies and make a big picture analysis? Dr. Sean Kane 25:33 So in both trials, they did look at the surrogate endpoints of basically what happened to your Chem seven. So they looked at your sodium, for example. And if you got randomized to the normal saline arm, you had higher serum sodium levels versus lactated ringers, which is kind of what we would expect, because normal saline has 154 mEq/L of sodium. They also saw a higher chloride concentration, which is, again, something that we would expect with normal saline. Even though lactated ringers has potassium in it, four milli equivalents per liter, they did not observe a difference in potassium. And again, that lactate and lactated ringers is going to be converted to bicarb. And they actually did observe that people who got randomized to lactated ringers had higher serum bicarb levels than the normal saline cohort. Speaker 1 26:19 So I think, as you've said it, and I'll say, you know, these two trials support the idea that normal saline can be nephrotoxic. Dr. Sean Kane 26:25 And I think that this was, at least in my mind, a little bit more surprising than than I would have expected. To be honest with you, I would not have guessed that, literally, a meeting of one leader in both critically ill and non critically ill patients could demonstrate a nephrotoxic effect. And these two very large trials, and I think that for pharmacists or even any healthcare provider moving away from normal saline on the basis of these two trials, even though they're single center, I think that given how large they were and how they designed the trial, I think it's reasonable to accept the fact, both from a biochemical basis and also now a clinical trial basis, that normal saline is nephrotoxic Speaker 1 27:02 So, so what are there any barriers? What could prevent people from saying, All right, let's let's do this. Let's just switch completely over. Dr. Sean Kane 27:09 So there are a number of reasons why we don't use lactated ringers as our only IV fluid or IV crystalloid of choice. One issue is that lactated ringers does have that six milligrams per deciliter of calcium in it, and it's great that it has it if you need that calcium to help your blood clot. It's bad, though, because that calcium can cause IV y site compatibility issues. And actually, if you look at one particular drug, ceftriaxone (Rocephin), it actually has a contraindication in the labeling that if you are less than 28 days old, so if you're a neonate, you should effectively not get LR and ceftriaxone at all. Whether it's different times of day or not, it doesn't matter. The reason is that they found that ceftriaxone can precipitate with calcium based salts. And in these very, very young patients, even if they separate the LR from the ceftriaxone, they found precipitates of the calcium ceftriaxone salts within the lung and kidney tissue of these very young children. So why site compatibility is an issue from the range of really, really young kids just shouldn't get both drugs at all, even if you separate the drugs all the way to adults, if you have limited IV sites to give alar to, you may not be able to have enough places to kind of infuse all of your drugs that you need to if line access is a problem for those patients. Interesting. Speaker 1 28:29 So what about, let's say, you know, again, you hear that, you hear the term lactate, and you think, okay, you know, we know certain diseases, things like lactic acidosis. So what if you were to give somebody lactate or ringers if they have lactic acidosis. Dr. Sean Kane 28:41 So in theory, it sounds like a really bad idea, right? So you already have too much lactic acidosis. Why would you give more lactate? And the important concept here is that in a bag of LR lactated ringers, you're not giving lactic acid, you're giving actually it's weak base. You're giving sodium lactate. So this is a weak base that will grab hydrogen ions, it will go through the Krebs cycle and turn into bicarb. So this is something that is a misconception, because even though, yes, you're giving the patient lactate, they convert that to bicarb, and you're giving something that acts as a buffer, it will find h plus ions and soak them up. So this will help, not hurt an acidosis, and it effectively gets turned into bicarb that goes through the Krebs cycle and further helps with an acidosis. Speaker 1 29:26 What about what about hyperkalemia? I know we talked a little bit about the data there. Yeah. Dr. Sean Kane 29:31 So again, LR has 4 mEq/L of potassium in that 1000 mL of fluid that you're giving a patient. Again, we did not see any signal of hyperkalemia in the SMART or the SALT-ED trials — this is a very small amount of potassium, and it's also diluted in a full liter of fluid. So we are diluting that out for the patient, and we're giving a very small amount of potassium. So if there is any effect on the patient serum potassium level, it is very, very, very minimal. And some people actually are. Argue that giving normal saline, which is acidic, could actually make hyperkalemia worse, because as a patient gets more and more acidic, they will basically try to grab those hydrogen ions, put them in their cells, and then redistribute their potassium from their cells out into their blood. So giving a patient an acid can make their serum potassium levels get worse versus LR that has a more basic property to it. Because of that bicarb could potentially make that hyperkalemia better, although, even still, many clinicians are worried to give this potassium containing product to a patient with hyperkalemia. And I get that, but we should understand that if the effect is there, it's very, very minimal, if at all. Speaker 1 30:38 So the one thing that always, you know, the cynic wants to think about is, what about cost? How does that influence? Are we looking at big cost barriers if we start to implement the switch? Dr. Sean Kane 30:46 So one of the really exciting things about the smart and the salt Ed trials is that we're basically having a number needed to treat of about 100 for literally no cost to the patient or to the institution. The IV one liter bag cost of LR versus normal saline is literally identical. There is no cost difference. And in fact, you could argue cost savings by avoiding dialysis in some of these patients, by avoiding a kidney injury that could keep them in the hospital longer, and potentially in that critical care cohort, they came really close to showing a mortality difference with LR. So this is a cost neutral, if not cost beneficial, strategy, to take that patient away from normal saline and give them LR instead. All right, Dr. Kane, you've convinced me. Well, we have to convince the rest of America, because this is something that is deeply entrenched in every order set in every hospital in America. This is deeply entrenched in just how we're trained. You know, if you think about it, many of our IV products that we give are mixed in normal saline, because it tends to be fairly stable and it doesn't cause issues with compatibility. So in a patient who's getting multiple IV piggyback writers, they're probably effectively getting a good amount of normal saline that could potentially be causing harm. And we don't even think about that, because we just mix it, and we don't even think about what is the diluent in that drug when we give it IV to a patient. Speaker 1 32:07 All right, so I think now, at this point, we want to kind of sum up some of the things we've already talked about. So the first thing we've said is is normal saline is kind of a misnomer. There's really nothing there that's normal. It has too much chloride, it's too acidic, even there's concerns about the sodium content of it as well. And so even a normal or a standard dose of normal saline can produce electrolyte abnormalities and can even be nephrotoxic compared to balanced crystalloids. Dr. Sean Kane 32:31 And number two is that these balanced Crystalloids, by definition, these are IV fluids that are better matched from a pH or electrolyte standpoint, especially versus normal saline, so they're more similar to human plasma. The most common balanced crystalloid is going to be lactated ringers or LR. But there's a bunch of other products that are on the market, like Plasma-Lyte, Isolyte, Normosol, things like that. These are all very similar in terms of their composition. The main difference is going to be how easy it is to come up with IV compatibility between any of these newer products versus LR, LR tends to have a lot more data with IV compatibility. Speaker 1 33:05 And so again, there are some some concerns if we were to start switching, one of the things we've talked about is compatibility. So because of some of that calcium content, there's potential for IV compatibilities, you know, precipitation. So it can be problematic if you have limited IV access and have to give it through a y site. Dr. Sean Kane 33:21 And finally, lactated ringers has two main misconceptions that people need to be aware of. One, it does not worsen lactic acidosis because it isn't acidic. And two, it does not worsen hyperkalemia because it comes with a lot of free water to go along with that potassium, and it will actually help pH become higher. And so a lack of acidity, plus that free water in the lactated ringers will help it not worsen hyperkalemia. So with that, hopefully we've indoctrinated the HelixTalk audience into favoring lactated ringers over normal saline. I would encourage anyone in the hospital setting, especially to consider changing order sets, changing your practice, identifying patients who are on normal saline that don't have a compelling reason to be on that normal saline and switching them over to lactated ringers. Based on the data that we have, if you just switch 100 patients from normal saline to lactated ringers, you will prevent one patient from having a major adverse kidney event in the ICU setting and even in the hospital setting as well in that non critically ill patient. So this is a cheap, simple intervention that can change patient outcomes. For the listeners who enjoy the podcast content, we're at HelixTalk.com we're also on Twitter, at HelixTalk, if you want to message us with any topic suggestions, those are amazing. So with that, I'm Dr. Kane. Speaker 1 34:35 I'm Dr. Schuman, and on behalf of Dr. Patel, study hard. Narrator - Dr. Abel 34:39 If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store. Search for HelixTalk and place your review there Narrator - ? 34:51 to suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production. Copyright, Rosalind Franklin University of Medicine and Science.