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Show Notes

Pearl 1. Tonicity vs Osmolality: Where Do Fluids Go? 

  1. What is the difference between Osmolality and Tonicity?
    1. Osmolality is the concentration of how much “stuff” is in a solution. 
      1. Tonicity is a measure of how many of those particles are “effective osmoles” and exert osmotic pressure.
    2. Effective Osmoles are those that are able to move or hold onto water in the extracellular space.
    3. For example:
      1. Na and Cl are effective osmoles that help maintain fluid in the extracellular space. 
      2. Urea is an example of an ineffective osmole that diffuses freely among all the fluid spaces and does not contribute to water movement.
  2. Body water distribution
    • Of total body water, two-thirds are intracellular and one-third is extracellular
    • Of the extracellular space, only one quarter is intravascular, and three-fourth is interstitial. 
      • So the intravascular space is one quarter of one third, or one twelfth of total body water.
  3. Where do fluids go?
    1. Isotonic fluids (e.g. Normal Saline, Lactated Ringers): 
      • Tonicity ~280 mOsm/kg, similar to plasma
        • It’s effective osmoles (e.g Na, Cl) maintain the fluid in the extracellular space only
      • Isotonic fluids distribute across the whole extracellular space, 
        • So only one quarter remains in the intravascular space. 
        • For every 1L of NS, only 250cc remains in intravascular space.
    2. D5W or Free water: 
      • Tonicity of 0
      • No effective osmoles, so distributes to all spaces, intracellular AND extracellular spaces
      • Since it distributes to all body water, only one twelfth remains in the intravascular space (see infographic for calculation). 
        • For every 1L of free water, only 83cc remains in intravascular space.
    3. Half normal saline: 
      • Tonicity ~154 mOsm/kg
      • Behaves like half isotonic fluid and half free water. 
      • For every 1L of half NS, ~167cc remains in intravascular space.
    4. Caveat: In patients with inflammatory states and increased vascular permeability, fluid remaining in intravascular space may be even lower

Pearl 2. Hypotonic Fluids: Water or Sugar?

  1. What is D5W?
    • Free water with 5% dextrose, or 50g of dextrose per liter.
    • Dextrose added to make the solution initially isotonic to prevent red cell lysis. But dextrose is rapidly metabolized, and it becomes free water with a tonicity of 0.
  2. How much sugar is that?
    • 50g of sugar is about 2 candy bars. 
      • Another way to put it: One pint of Ben and Jerry’s ice cream is 6.5L of D5W.
    • Provides minimal nutrition beyond a few candy bars a day
    • It may raise the serum glucose slightly in diabetics. But in patients with significant free water deficit and no enteral access, usually prioritize free water repletion and adjust insulin as needed
  3. Does D5W cause volume overload?
    • The pulmonary interstitium has a few safety factors to prevent pulmonary edema, including an interstitial matrix structure that opposes fluid diffusion and more efficient lymphatic drainage that decreases interstitial protein and decreases the interstitial oncotic pressure.
    • In most cases, pulmonary edema is caused by increased hydrostatic pressure in the pulmonary vasculature, so it is driven primarily by intravascular volume 
      • Remember from Pearl 1: for every liter of D5W, only 83cc remains intravascularly. Only one third as much as an isotonic fluid like NS or LR
    • Unless given in large volumes, D5W rarely clinically causes fluid overload or pulmonary edema
  4. What about 1/2 NS?
    • Half NS is essentially half isotonic fluid and half free water
    • Use when patient is both hypovolemic and hypernatremic and trying to fix two things at once
      • ½ NS has some tonicity to contribute to intravascular volume and help with resuscitation and less sodium content/more free water to help with hypernatremia. 

Pearl 3. Isotonic Fluids: NS or Balanced Solutions?

  1. Contents of isotonic fluids
    1. Normal Saline: Just salt and water
      • 154 mEq of sodium and 154 mEq of chloride
      • Significantly more chloride than plasma Cl, which is ~100 mEq/L
    2. Balanced solutions: try to match normal plasma
      • Main examples are Lactated Ringers and Plasma-Lyte
      • Have sodium, chloride, and potassium concentrations similar to plasma, as well as a buffer (see Page 3 infographic for exact numbers)
      • Buffers are different–LR uses sodium lactate and Plasma-Lyte uses gluconate and acetate–but both buffers are metabolized into bicarbonate
  2. Normal Saline vs Balanced Solutions–does it really matter?
    1. SALT-ED and SMART trials:
      • Large single center studies in the ED and ICU comparing NS vs LR for resuscitation. They showed decreased mortality and better renal outcomes with LR
    2. BASICS and PLUS trials:
      • BASICS: Multicenter study in ICU patients in Brazil comparing NS and Plasma-Lyte, found no difference in mortality or renal outcomes
      • PLUS: Multicenter study in ICU patients in Australia and New Zealand comparing NS and Plasma-Lyte, found no difference in mortality or renal outcomes
    3. Meta-analysis
      • Large meta-analysis pooling 13 RCTs and >35,000 patients comparing NS and balanced solutions in ICU patients found a trend toward improved mortality and renal outcomes with balanced solutions, but did not quite reach significance 
    4. Proposed mechanisms of difference: too much chloride!
      • High chloride in NS causes non-gap metabolic acidosis
      • The macula densa in the distal tubule uses chloride delivery as a proxy to measure flow in the tubule. Supraphysiologic chloride delivery “tricks” the kidney into thinking flow is very high, causing tubuloglomerular feedback to reduce GFR
    5. Given possible improved outcomes, many providers now favor LR and other balanced solutions over NS, but more data is needed
  3. Truths and Myths for when to avoid LR
    1. Hyperkalemia: The 4mEq/L of Potassium in LR is a drop in the bucket compared to total body potassium, minimally affects serum potassium
    2. Elevated lactate: LR contains sodium lactate, not lactic acid. While sodium lactate is also measured by the lab value, it is actually metabolized into bicarbonate and does not cause acidemia
    3. Hypercalcemia: LR contains a small amount of calcium. Expert opinion remains mixed on whether to avoid any calcium in hypercalcemia, or whether just like in hyperkalemia, this calcium is a drop in the bucket compared to total body calcium

Pearl 4. Colloid

  1. What is oncotic pressure? How is it different from tonicity?
    1. Tonicity is used for salts and describes effective osmoles between extracellular and intracellular spaces.
    2. Oncotic pressure (or Colloid osmotic pressure) is used instead for large molecules like proteins. Oncotic pressure determines water flow within that extracellular space, i.e. between the intravascular and interstitial spaces. 
    3. Proteins, like albumin, remain in the intravascular space and can draw water from the interstitium back into blood vessels
  2. Are colloids, like albumin, better for volume resuscitation?
    1. Because of its ability to draw water into the intravascular space, 25g of albumin expands intravascular space by 450cc!
      • Compare this to only 250cc of intravascular fluid for 1L of LR or NS
    2. However, studies have repeatedly shown that colloids like albumin are no better than isotonic fluids in sepsis or in the ICU.
      • SAFE trial: Multicenter randomized trial in ICU patients of 4% albumin vs NS showed no difference in mortality
      • CRISTAL trial: Multicenter randomized trial in ICU patients of colloid (including 4% and 20% albumin) vs crystalloid resuscitation showed no difference in mortality or renal outcomes
      • ALBIOS trial: Multicenter randomized trial is severe sepsis patients to receive 20% albumin with a goal serum albumin of 3g/dL vs crystalloid alone showed no difference in mortality
    3. Likely due to short half-life of the true profound intravascular expansion.
      • One study:
        • Half life of infused albumin is only 12-16 hours
        • Half-life of its volume expansion is only 2-3 hours
      • Inflammation further reduces this effect by increasing vascular permeability and reducing benefit of albumin
    4. Cirrhosis: Albumin has clear indications for improving renal outcomes and mortality in cirrhotic patients, including post-large volume paracentesis, spontaneous bacterial peritonitis, and hepatorenal syndrome. It’s use as a volume expander generally in decompensated cirrhosis is controversial, with multiple conflicting studies.

Pearl 5. Blood

  1. Blood as an intravascular expander
    1. One unit of pRBC contains about ~300cc, but that all stays in the intravascular space (compared to only 250cc for 1L of LR or NS)
    2. Unlike albumin, blood is not an oncotic force and does not draw more fluid into the vasculature. 
      • Oncotic pressure is related to the number of particles. 
      • In normal plasma, the number of albumin molecules per liter is on the order of 10^20, versus the number of red blood cells on the order of 10^12, a 100 million-fold difference.
      • pRBC alone is actually hypo-oncotic compared to plasma.

Transcript

S: This is the Core IM, 5 Pearls podcast bringing you high yield, evidence based pearl.  I’m Shreya Trivedi, an internist at BIDMC. 

Z: And I’m Zach Avigan, a 2nd year Internal Medicine resident at BIDMC

S: And today, we’ll be talking about fluids, the forgotten drug of Internal Medicine

Dr. Farouk: And so I think one of our take homes here is that when you’re thinking about prescribing IV fluids to really think about them, like you would any other medication, which one, how much, how long, and when do you think you can stop?

Z: That’s Dr. Samira Farouk, a nephrologist at Mt. Sinai… and to better gauge which fluid, how much, how long, and when to stop, we have to understand what makes up the fluid and where in our body that fluid goes.

S: Yes! I cannot wait! This is an episode I wish I had heard like 10-15 years ago! So let’s get into those pearls we’ll be covering in the episode. Test yourself by pausing after each of the 5 questions. Remember, the more you test yourself, the deeper your learning gains.

Z: Pearl 1: Where does fluid go?

  • S: How much of 1L of isotonic saline actually contributes to intravascular volume? Compared to 1L of D5W?

Z: Pearl 2–Hypotonic fluids 

  • S: How much sugar is actually in D5W? Does D5 contribute to volume overload? How much ½ normal saline ends of in our blood vessels?

Z: Pearl 3–Isotonic fluids

  • S: What are the differences between normal saline or balanced solutions? And does it really matter?

Z: Pearl 4–Albumin

  • S: How does albumin compare to other fluids in terms of volume resuscitation?

Z: Pearl 5– pRBCs

  • S: How much of a blood transfusion ends up in the intravascular space? Does it pull in water like colloids?

Pearl 1

S: Zach, we are often in the business of either trying to take off volume or trying to buff up someone’s effective blood volume – but what was a big knowledge gap for me before this episode was how much that 1L of fluid that we are giving through the blood vessels actually stay in the blood vessel?

Z: Shreya…what if I told you that when you give a liter of normal saline, only a quarter of it actually stays in the blood vessels?

S: Whoa

Z: Ya, that was my reaction too. I definitely did not understand that before working on this episode, but we’ll go through it step by step. I think to really understand this concept, we first need to remind ourselves about all places that fluid can go in the body. To keep things simple, we really have 3 main categories: there are fluids that distribute to all the water in the body, fluids that go just to the extracellular space, and some fluids that just stay completely in the blood vessels.

S: So how do we know which fluids go all over the body or which fluids the ones that just stay in the extracellular space?

Z: That’s where we need to think about osmolality and tonicity. So the way I think about it, all the “stuff” in a fluid makes up the osmolality, but only some of that stuff are “effective” osmoles. What makes them effective osmoles is that they don’t easily cross the membrane, so they can can pull fluid from one space to another.

Dr. Farouk: Tonicity is essentially the effective osmolality. And so an example of an effective osmole would be something like sodium, glucose, potassium. Whereas an ineffective osmole, would be something like urea that can kind of move freely across a semi-permeable membrane. 

S: So I think the biggest take away here is that when you are choosing the fluid, you need to know what actually makes up that fluid – and I think people can easily make the mistake of just thinking well whats the osmolality of the fluid but really what need to know what those osmoles, do they have tonicity and can they effectively pull fluid out of the cells.

Z: Right exactly! Those effective osmoles are what keep that fluid in the extracellular space. So fluids with more tonicity are better at staying extracellular.

S: So lets put that into context. How about we start with isotonic fluids – the fluids with the same tonicity as your plasma, like normal saline or Lactated ringers.

Z: Right, what makes them isotonic is that they have plenty of effective osmoles, like Na and Cl, that normally live outside the cells and hold onto fluid in that extracellular space. 

S: Ok, so salts help that whole liter of NS and LR stay in the extracellular space, but what percentage of that gets into the intravascular space — thats the part we care about – intravascular space is the plasma, the stuff that’s inside peoples blood vessels.  

Dr. Farouk: What is important is that when you give someone an isotonic fluid, say one liter of a normal saline or or plasma light, then only about 25% of that is going into the intravascular space. And so we should think about giving 1L isotonic fluid as expanding the intravascular volume by 250 milliliters.

Z: And if you want to get nerdy about it, we gotta think way back to that page in First Aid that had body compartments. Of the extracellular space, only 25% of that real estate is the intravascular space

S: Oh okay that makes a lot of sense because NS and LR are isotonic and has the same toncity as our plasma, the isotonic fluid will distribute equally in the extracellular space so 25% of it goes in the intravascular space and 75% in the interstitium.

Dr. Farouk: Contrasting that to a hypotonic or zero tonicity, essentially fluid like dextrose five and free water that is going to really distribute within all of the total body water. And so you’re only going to have about, you know, 8% of that that’s going to end up in the intravascular space so much, much smaller. 

S: So the teaching point here is that free water has no effective osmoles, no tonicity, to hold onto the fluid. So the water just goes everywhere.

S: Right, so D5W distributes all across the total body. Let’s break down and get nerdy how we get to just 8% staying in the blood vessels. Again my vague recollection of that that 1 page in the First Aid, I remember that for total body water, ⅔ is inside our cells  and only ⅓ of that is extracellular.

Z: Then we can do some quick multiplication – we said we had ⅓ of the water is extracellular, and of that extracellular volume, ¼ is intravascular. ⅓ times ¼ is 1/12, so just about 8% of your total body water is intravascular.

S: Thats a good nugget – that only 8% of the total body water is intravascular. So if give a 1L of D5W and it disperses to the whole body, only 83 mL, or about 8%, will stay in the blood vessels.

Dr. Sparks: Another point to make about this is assuming everything is perfect. Okay. And in the hospital, that’s just not the case. You have sepsis, liver failure, kidney failure. Like these are estimates. It’s sort of like 250 mLs of normal saline stays in the intravascular space, but like yeah, in a patient who’s septic, you’re–that’d probably be great if you could get that and achieve that. And maybe it’s because they just don’t, you don’t have a good oncotic pressure. You have endothelial capillary beds that are sort of sloughed off from sepsis. And so you have leaky capillaries. So there’s a lot of things that can perturb this and, and cause issues. 

S: That was Dr. Matt Sparks, a nephrologist at Duke and what a great caveat. So putting it together and recap, in the real world, especially in any inflammatory state, how much fluid stays in the intravascular space is probably a bit less, but good starting points are for 1L of isotonic fluid, 250cc stays in intravascular space, but for a liter of free water, only ~80cc stays inside the vessels.

Z: And we just want to point out–what we don’t want you to take away from this is that fluids are actually less volume than we think, or that a liter of saline has secretly been just 250ccs this whole time. You know from your clinical experience what it means to give someone a liter of isotonic fluid. But we do think, especially when you’re comparing different types of fluid like saline and D5W, it’s actually helpful to be explicit and really understand where each fluid goes and how they compare to each other, to help use them appropriately.

Pearl 2: Hypotonic Fluids

Z: Ok, so now that we have the basics of body compartments, let’s start with the most basic fluid we’ve got–water. 

S: Or in our case, D5W.  And as headsup, we will be using D5W and free water changeably here.

Z: The main reason we give free water is for hypernatremia–you can think of it as giving a lot of water to help dilute the sodium and bring down that hypernatremia. 

S: Right and D5W is made up of just water and sugar; there’s no sodium.  Zach, just how much sugar is there in D5W? 

Z: So D5W is 5% dextrose in water. So in a 100cc, 5% is 5g and in 1L, 5% if 50g of dextrose.

S: Hah 50g of dextrose in a liter – one thing I didn’t know before this episode was why do we add all that sugar in the water.  I remember when I was a med student I’d heard a surgeon telling a patient that this fluid was giving nutrition to the patient but now I know that’s the not the case.

Dr. Sparks: So I’d like to think of D5W as isotonic asterisk. Okay. It’s basically there to serve a purpose so that you don’t lyse all your red cells. Like if you just gave sterile water, you cannot give that into someone’s vein because it will lyse all the red cells because it’s so hypotonic, it’s no tonicity, zero. So the dextrose is put in there to basically give it isotonicity, when you put it in, but it rapidly is metabolized and goes away.

S: Fascinating, it all comes back to that tonicity, and sugar is basically a temporary effective osmole– like a temporary wingwoman or wingman to get the water inside and keep red cells from bursting. 

Z: Ya, and I think it’s good to remember that the important part of D5W is the water, not the D5. You know, if we’re trying to fix hypernatremia sometimes on rounds we’ll talk in shorthand and just say to “start them on a D5 drip.” But just make sure you’re ordering D5W. If you order something else like D5NS, that’s just saline with some added sugar — there’s no free water. 

S: But how much sugar is 50g of dextrose really? Half of my list on any given day has diabetes so help me put into context.

Dr. Sparks: D5W, it is 50 grams of glucose mixed in, um, or dextrose into one liter. So how, how many grams does a Snickers candy bar have of sugar? 20 grams. So, I mean, this is more than a candy bar. Okay. Um, one pint of Ben and Jerry’s ice cream, um, is about, uh, six and a half liters of D5W, the whole pint. I mean, that’s, it, that’s an entire binge on Netflix.

Z: So just two snickers bars — that’s not much sugar! 

S: It’s interesting we sometimes give D5W when patients are NPO to add some “nutrition,” but it’s really just a couple candy bars a day. 

Z: That reminds me of another pain point we run into: how do we weigh giving D5W to someone who is hypernatremic but also has diabetes? Here is Dr. Jeff William, a nephrologist at BIDMC with his thoughts

Dr. William: You know, if you’re trying to correct somebody’s hypernatremia and you have no other way of doing it, right… they’re not taking PO they don’t have any sort of enteral access, then what choice do you have? You know, they’re losing more water, they’re going to become, you know, increasingly obtunded they’ll lose their thirst. They won’t be able to correct it at all. And, you know, we can fix hyperglycemia. We’re good at that. Right. We have insulin. Um, you can’t fix somebody’s water deficit without water.

Dr. Sparks: And I’ll tell you, hypernatremia is miserable. You are so thirsty. It is the only thing your brain is going to think is you got to drink. And so if you have a patient in the ICU, who’s not sedated, who’s hypernatremic, this is something that, you know, you just think about how that would feel. Uh, and so we need to correct that. 

Z: Ok so if a patient is hypernatremic and we have to give D5W, just give it, and we can always manage the hyperglycemia.

S: Great I think the other thing we worry with any fluid is contributing volume overload, especially when a good handful of our patients have has end stage renal disease or systolic dysfunction and can’t handle as much fluids.

Z: That’s definitely something we struggle with all the time. Going back to Pearl 1, we said for every liter of free water, 83cc stays intravascularly. So how much does 83 cc really impact volume overload?

Dr. William: So how much does it contribute to volume overload? A very, very, very small amount. Does it contribute at all? Yes. Is it a significant clinical amount or clinically significant amount? No, it is not. Unless you’re giving liter after liter after liter of it…

Dr. Sparks: So when you calculate a water deficit, you give a lot of D5W you do not have to worry about this causing pulmonary edema. 

S: I really appreciate hearing that with D5W, we don’t have to worry about pulmonary edema. But for the pathophys nerds out there, why is that?  

Z: Ya this was new to me, but basically, the lungs are built a bit differently from the rest of your tissues with a few safety factors built in to try to prevent fluid from distributing into the interstitium. We’ll leave some more details in the show notes, but what we really need to know is that in general, pulmonary edema is driven almost exclusively by increased hydrostatic pressure in the pulmonary vasculature, or specifically just more intravascular volume. 

S: That makes sense because if we remember from pearl 1, only 8% of D5W stays in the intravascular space and that’s really the only space that can really contribute to pulmonary edema.

Z: Ya totally. And I will say, one interesting takeaway for me has really been changing the way that I look at an “ins and outs” chart for a patient. Right, like when you look at the intake, if you just look at the number, all that volume is treated the same, whether it’s isotonic fluid or free water. But really, if you think about how much it affects the blood volume, it takes 3L of D5W to have the same effect as 1L of saline on the intravascular volume. 

S: I think a good learning point is to look change the way I look a patient’s intake – instead of looking as much at the absolute volume, see what types of fluids was given and how much will that type  really affect blood volume.

Z: Before we finish, we should talk about another hypotonic fluid, half normal saline.

S: Ugh yes because I think most of us scratch their heads with half normal saline.

Dr. Farouk: Half normal saline, for example, a part of that will go into the, into the intracellular space because you’re, you can think of half normal saline, uh, liter of that as half a liter of water, plus half a liter of normal saline. So that half a liter that will behave like the isotonic fluid and that half a liter of water is going to distribute throughout both intra and extracellular compartments. 

S: Ok, so say we have a liter of half normal saline. So, how much of that stays in the intravascular space? And to put it into context more, how does half normal saline compare it L of good old normal saline and D5W?

Dr. Farouk: And so just to kind of break down the numbers, a liter of normal saline, 250 mLs will go into the intravascular space, a liter of half normal saline, 167 mLs will go into the intravascular space and a liter of a D5 water, 83 mLs only will go into the intravascular space.

S: Right, so half normal saline is in between free water and isotonic fluid, about 167mls goes in the intravascular space with a liter of 1/2NS. When might you reach for ½ NS?

Dr. Farouk: And so one example of that would be that you want to both expand the intravascular space, but maybe you also have a, um, indication for a hypotonic fluid say for example, like hypernatremia. And so you have kind of two things coexisting at the same time. And so you give a fluid that’s essentially in the middle. And so in my mind, I kind of think of, you know, half normal saline as is kind of in between when you have kind of competing interests.

Z: So to recap, our 3 big takeaways for free water are (1) D5W is just free water plus dextrose, and the dextrose is just there so the red cells don’t lyse. (2) There’s not that much sugar in D5W. And (3) since so little of D5W stays in the intravascular space, unless you are giving liter after liter, it rarely contributes to pulmonary edema.

S: So other hypotonic fluid is 1/2 NS – basically you can think of it as half isotonic fluid and half free water. It’s hypotonic so it dilutes your sodium but it still has some tonicity so it still holds onto some fluid in the extracellular space. So you might reach for it when your patient has hypernatremia AND needs volume resuscitation.

Pearl 3: Isotonic Fluids

Z: Alright, time to talk about isotonic fluids. I know there’s been a lot of debate between normal saline and balanced solutions–so let’s jump right into it.

S: First off, normal saline is made up of 154 mEq each of sodium and chloride. But 154 mEq of chloride seems like way more than our patient’s plasma – if I look at most patients BMPs in the clinic setting their Cl are usually low 100s or so

Dr. Farouk: And so that is not, you know, normal. And that is why, you know, you know, some of us call it abnormal saline.Um, if you want to get real nerdy.

S: Yep, abnormal indeed and that’s because of all that chloride. 

Z: What about balanced solutions?

Dr. William: The idea of balanced solutions, uh, was developed in sort of the surgical world. It was the idea of replacing plasma that was similar to plasma the idea that you should give somebody a fluid that is just sodium and chloride is kind of ridiculous. And then, this whole idea of creating sort of the ideal solution that was the most native, um, to what the human plasma would be. And how could you replace that?

Z: Alright, so let’s break down the two most common balanced solutions: Lactated Ringers and Plasma-Lyte.

S: Ya, the two solutions are a little different in the numbers but similar – Both LR and plasmalyte both contain 130-140 mEq of sodium, ~100mEq of chloride, and ~4-5 mEq of potassium. And just like our plasma has bicarb as a buffer, they both use a different buffer to act as a base.

Z: Right, that’s really the main difference between them, is that they use different buffers. Lactated Ringers uses sodium lactate, and Plasma-Lyte uses gluconate and acetate. 

S: But really, the buffer doesn’t matter too much, since all of those buffers are actually broken down by the body into good old bicarb.

Z: You know, balanced solutions are much more similar to plasma especially in terms of that chloride. That definitely seems in theory like a better idea than our friend Abnormal saline…but does that actually pan out? 

S: Let’s start with some of the biggest trials, the SMART and SALT-ED trials

Dr. Sparks: And so every, I think month or two, they would like block the entire thing to say, all right, we are all using saline… and then we are all using, um, LR and, and those were the two main things, but it was a lot of patients in the smart, which is in the ICU, 15,000, almost 16,000 patients. They basically uh, showed in the ICU that you had a lower composite outcome of death from any cause new, um, kidney replacement therapy or dialysis that would occur in the ICU, persistent AKI that was all favoring the use of balanced solutions.

S: Huh. That sounds pretty convincing that maybe we should just stick with balanced solutions. Seems like Lactated Ringers showed better mortality and was better for the kidneys.

Dr. Sparks: But that does lead us to BASICS, which is another randomized clinical trial from Brazil. Now, the difference is instead of using lactated ringers, they used plasma-lyte 148. So this really was a shock because we had all been living post smart and salted. And there was no difference in 90 days survival and really across the board, there was no difference.

Z: And just to add, there was a similar trial, the PLUS trial, that also compared NS and Plasma-Lyte in ICU patients and again found no difference in mortality or kidney outcomes. 

S: But then again, this was stuff I learned from nephrologists on twitter, there was a big meta-analysis of over 35,000 patients and it did find a small mortality benefit of balanced solutions in ICU patients, but it didn’t quite reach significance.

Z: Ugh so close! So we have all these studies, but what do we make of all of the conflicting data clinically?

Dr. Sparks: I have no idea. I know people are blaming plasma-lyte. I think the big time balanced solution people are just wanna ignore it.

Z: Yeah its hard. I’ve definitely seen people who are permanently shifted to Lactated Ringers and haven’t really changed their practice.

S: Yeah it’s really hard to go back when there was some signal in some of the trials that there is more AKI and more people on dialysis who got NS for resuscitation. 

Dr. William: The knock on normal saline has been this idea that, um, giving too much of it can create this hyperchloremic metabolic acidosis basically the way to think about it is that an excess of chloride creates a state of a non-gap metabolic acidosis. And obviously any state of acidosis is not good for an ailing patient, especially a critically ill ailing patient. And we’ve all seen it, right? We’ve all seen giving a large amount of normal saline to a patient and inevitably they end up with a chloride and like the high one hundreds low one teens and their bicarb drops into like the 15, 16 range.

S: Yep have seen that in too many basic metabolic panels! 

Z: Ya, I think another thing to point out is that the kidney really regulates GFR based on flow. So if the kidney is seeing really high flow, it’ll turn down GFR. If the kidney sees low flow, it’ll try to turn up the GFR. And what’s interesting is that the way the kidney actually senses flow, funny enough, is by chloride delivery. So if the kidney is seeing a lot of chloride, it thinks the flow is really high, and it will turn down the GFR. Just think about that for a second. If you think about a septic patient whose kidney is already at risk, that really high chloride basically tricks the kidney into dropping its own GFR, and in a vulnerable kidney that could be enough to push it into AKI.

Dr. Sparks: And so one of the mechanisms that is called tubuloglomerular feedback, and so in the macula densa, whenever you have increasing levels of chloride, it then turns to the glomerulus and shuts down and clamps the afferent arteriole, so you do not make any more, your GFR goes down to zero.

S: So ironic that the electrolyte that we forgot about the most is the one that that kidney cares about the most to regulate flow. 

Z: I will say, just to push back a little bit on that chloride theory–if you really look at those trials comparing normal saline and LR, the serum chlorides in the normal saline group were only like 1-2 points higher. So even though that tubuloglomerular feedback mechanism sounds really cool, I definitely won’t fault you for saying it may be a little bit far-fetched for 1-2 points of chloride to explain a mortality difference.

S: Either way, whatever the mechanism, I think the takeaway is that most of us are reaching for LR unless there is a compelling reason not to.

Z: Every now and then I hear a few myths creep up about LR. The first one is hyperkalemia.

Dr. William: The reason it’s a myth  because I think it’s best described as a drop in the bucket. I mean, let’s just say you’re giving a liter of lactated ringers and, um, it has about 4 meq per liter. Okay. So you’re giving literally four milliequivalents of potassium into, into somebody’s body. Okay. And remember, it’s a fluid that’s going to redistribute in the extracellular space, right. In the extracellular fluid. So we’re talking about 4meq that are diluted in one third of the body’s total body water.

Z: And what’s crazy is that there’s even some data that NS may raise the potassium more than LR because of the non-anion gap acidosis it causes.

S: Hmm interesting. What about the lactate myth in LR?

Dr Sparks: There is an issue that when you measure lactate in the lab, you know, you’re not measuring lactic acid, it’s lactate. And so if you give someone lactated ringers, you will make the lactate go up just a little bit. And that’s something to note when you’re measuring serial measurements, but it does not affect the pH. This is not lactic acid.

S: The last myth is thinking about calcium. We said LR is more like plasma, so it also has a little bit of calcium. So is there an issue with LR in patients with hypercalcemia?

Dr; Farouk: I guess it would be no. I mean, it’s kind of the same idea, very, very small volume compared to the total body water and how it’s distributed.

Dr. Sparks: I’ll tell you, um, in nephrology we get some tough hypercalcemia cases. And the last thing I want to do is be fooling around with more calcium going in … it’s probably similar to the issue lactated ringer or the, the potassium issue. But, um, I think if someone has hypercalcemia probably would stray away from LR. 

Dr. William: So I think theoretically, it makes sense, right? Someone has hypercalcemia, you’re giving a fluid that has calcium. Why would you do that? Just use another fluid. I don’t disagree with that. Um, but I think the argument’s the same as potassium that relatively speaking, when you’re putting a liter, um, with this certain amount of calcium into a much larger volume that you’re going to get a pretty big dilution. It’s not going to have much of an effect.

Z: So to sum up, balanced solutions like Lactated Ringers are at least as good if not better than normal saline for kidney outcomes and mortality. The problem child may be all that extra chloride, which can lead to acidosis and trick your kidney into reducing your GFR by tubuloglomerular feedback.

S: And LR is totally fine to use with hyperkalemia or elevated lactate, though the jury’s still out for hypercalcemia.

Pearl 4: Colloid 

S: Alright, we’ve talked a bunch about crystalloids. But now we wanted to shifts gears to something else we are putting in our patients BV colloids and proteins.

Z: To talk about colloids, we’re gonna introduce a new term, oncotic pressure. So whereas for small molecules like salts we talked about tonicity, for large molecules like proteins we instead talk about oncotic pressure. 

Dr. William: So oncotic pressure, the particles are, are big, right? There’s actually fewer of them, but they’re really big, so they don’t cross membranes, so that’s right. They kind of just stay there and they exert an oncotic pressure, which pulls water to it. 

S: The teaching point here is that proteins like albumin stay specifically in the intravascular space, and it can even pull interstitial fluid into the blood vessels. 

Z: So for our hypotensive patients, if our main goal is to expand that intravascular space, I would think that a colloid like albumin would be the best way to do it. 

Dr. Farouk: Giving one gram of albumin can attract 18 milliliters of water. And so then they kind of extrapolate that out to say that 100 milliliters of 25 grams of albumin can expand the intravascular compartment by 450 milliliters. And so the equivalent of almost two liters of isotonic saline. In theory it is a very potent expander of the intravascular space.

S: So in theory 25g of albumin can draw in enough fluid to expand the intravascular space by 450cc. Compared that to only 250cc for a liter of isotonic fluid. I just want to let that sink in… 450cc compared to 250cc.

Z: Ya, that’s a huge difference. I know this has been studied a lot, so why aren’t we using albumin all the time?

Dr. William: You can think of so many examples of this in medicine where it seems like such a great idea, and then it gets studied and there is no difference. And then people are like, that’s crazy. Like let’s, you know, study it again. And then–same thing. Like there’s no difference. And then people are like, that’s still crazy. Let’s study it again. And then somebody finds a difference and like, see, and then someone repeats and they can’t find a difference. So, so I think that, you know, albumin has, has been that sort of story where it seems too good not to work and that we have something like this. 

S: Right. So trials over and over have compared isotonic fluid and albumin for resuscitation, and found no difference in mortality or renal outcomes much to my dismay — I was always rooting for albumen.

Z: Yeah it’s confusing–you would really like to think from the physiology that colloid would be better. Any ideas for why albumin just isn’t as good as we’d expect?

Dr. William: The question is how long does it last?  And is it really more effective than pumping in a, you know an isotonic fluid that’s going to kind of just equilibrate in between both spaces and you’re giving plenty of it. 

S: Ok, so it seems like the big downfall of albumin is its half-life. In theory, it should draw in a bunch of intravascular fluid, but for whatever reason that effect is just too short lived to make it any better than good old saline.

Z: Not to mention the cost difference – it’s like hundred dollars for albumin compared to 2 cents for saline. 

S: So to summarize our big takeaways from this section: Colloids, like albumin, are big molecules that stay specifically in the intravascular space, unlike crystalloids. On top of that, albumin exerts oncotic pressure that draws fluid from the interstitium back into the intravascular space. 

Z: But, unfortunately, even though that sounds like it would be the best volume expander, except for patients with cirrhosis, it doesn’t seem to work any better than LR for volume resuscitation.

S: Womp womp! But, it does seem like there’s ongoing work in studying uses of albumin, especially in dialysis patients, so stay tuned!

Pearl 5: Blood

S: Zach what about pRBCs? I know it’s a bit controversial to put in a fluids episode but we often give it for resuscitation. I think some people think of it like a colloid, so I think its worth diving into. 

Z: I’m glad we looked into it, and it was definitely really eye-opening to pick Dr. William’s brain about

S: Just some background- a unit of packed red blood cells is ~300 cc volume. That’s what’s hanging up on the IV pole when a patient is getting a unit. Just like we started with every other fluid–where does that 300cc of blood go?

Dr. William: The volume that you give with the packed red blood cell, like the bag is probably going to stay in the intravascular space. If you’re giving a packed a bag of packed red blood cells straight to the intravascular space, then that 300 ccs that you give is likely to stay there.

S: It’s all red blood cells, so that makes sense that it all stays in the blood vessels. Which basically means that whole 300ccs stays intravascularly. Compare that to 1L of LR, where 250cc stays in the blood vessels. 

Z: Ya, I don’t know if you felt this way, but I’m just gonna go right back to my soap box about ins and outs charts. I think one really important takeaway for me was also changing the way I look at ins and outs charts for blood transfusions. For intake, a blood transfusion is only gonna show up as 300ccs, which really doesn’t sound like much. But functionally, giving a unit of blood expands the intravascular space just as much or even a little more than giving a whole liter of LR. 

S: Ya, that’s wild.

Z: I think it’s important to recognize, because clinically, most of the time we’re giving isotonic fluid, so our brains are like wired to think about volume in terms of isotonic fluids. So in a way, the volume from a blood transfusion is way more than your brain has trained you to think it is. 

S: Or how much the I/Os make you believe.

Z: Right exactly. Just like what we said earlier, that in a way volume of D5W is way less than your brain has trained you to think it is.

S: Preach! I definitely had to shifted the way I look at i/o’s from this episode – speaking more of transfusionsI’ve also heard people talk about blood as a colloid. Does blood also draw in any extra fluid from the interstitium the way colloids do?

Dr. William: I think that the question then is will the packed red blood cell infusion actually attract more water into the intravascular space. And I don’t think that necessarily is true. But the reality is that in comparison to the sort of oncotic pressure overall the effect of packed red blood cells is actually relatively small because of the amount of particles.

Z: So this was definitely a learning point for me. I always assumed that red blood cells also acted as a colloid and had oncotic pressure to draw in more fluid.  

S: Another way to put it, proteins like albumin exert oncotic pressure, but cells don’t pull water.

Z: So to summarize this quick pearl, red blood cell transfusions can be great for resuscitation because they stay completely in the intravascular space. The whole 300ccs from a unit of blood stays intravascularly vs about 250cc from 1L of LR. 

S: But when we compare red cells to a protein like albumin, blood cells actually don’t really exert any oncotic pressure, so they can’t draw in any additional fluid from the interstitium. And that’s a wrap for today’s episode. If you found this episode helpful, please share with your team and colleagues and give it a rating on Apple podcasts or whatever podcast app you use! It really does help people find us! 

 If you want to add any of your own tips or share challenges, tweet us and leave a comment on our website page, on instagram or facebook page. Thank you to our peer reviewer Dr. Swapnil Hiremath and Dr. Helbert Rondon for peer reviewing this episode. 

Thank you to Daksh Bhatia for the audio editing and the soon to be Dr Preeyal Patel for the accompanying graphics. As always we love hearing feedback, email us at hello@coreimpodcast.com. Opinions expressed are our own and do not represent the opinions of any affiliated institutions.

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