Intravenous Fluid Lecture: Citations

I have been missing for a few weeks as I am putting the finishing touches on my lectures that are due on the 15th of this month. The amount of time and effort necessary to write a CME lecture is insane. I've written 7 of them in this last year. Voluntarily, of course. I'm not complaining. For my intravenous fluid lecture, I have cited 43 different articles listed below. I have attempted to cite these articles as well as I know how to but there will be some inevitable errors. If you plan on creating an IVF lecture of your own, this is my gift to you. My only request is that you credit me in some way, shape, or form. Ultimately, I did not write any of these articles. I have to tip my hat to everyone who contributed to the writing of all of these articles. They are the ones who did the leg work and I am ultimately piggybacking on their efforts. 

This lecture discusses the three fluids we use for resuscitation in critically ill patients: 0.9% NaCl, Lactated Ringers, and Plasma-Lyte. I go over the history of the three fluids, and also break down the contents of these fluids, based on the data on how they affect our patients and our organs, then present the relevant data on how these data changes outcomes in our critically ill patients. The reason why this is a controversial topic is because most clinicians use saline because they really do not understand what is in it, nor the effects of it. As I mention in one of my slides, if the FDA had to approve 0.9% NaCl today, chances are that it would not be approved. 

I am sorting out how to provide you all with this lecture, youtube or some other medium. The issue is that youtube has a thing for demonetizing my videos the moment I say the words "mortality", "death" and others. I do earn some income from you all visiting my website, eddyjoemd.com to check out the links and download the articles I share. Thank you all for your support! 

-EJ

Citations:

Lobo DN, Stanga Z, Aloysius MM, et al. Effect of volume loading with 1 liter intravenous infusions of 0.9% saline, 4% succinylated gelatine (Gelofusine) and 6% hydroxyethyl starch (Voluven) on blood volume and endocrine responses: a randomized, three-way crossover study in healthy volunteers. Crit Care Med. 2010;38(2):464–470. doi:10.1097/CCM.0b013e3181bc80f1

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Ragaller MJ, Theilen H, Koch T. Volume replacement in critically ill patients with acute renal failure. J Am Soc Nephrol. 2001;12 Suppl 17:S33–S39.

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Bark BP, Persson J, Grände PO. Importance of the infusion rate for the plasma expanding effect of 5% albumin, 6% HES 130/0.4, 4% gelatin, and 0.9% NaCl in the septic rat. Crit Care Med. 2013;41(3):857–866. doi:10.1097/CCM.0b013e318274157e

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Lobo DN, Dube MG, Neal KR, Simpson J, Rowlands BJ, Allison SP. Problems with solutions: drowning in the brine of an inadequate knowledge base. Clin Nutr. 2001;20(2):125–130. doi:10.1054/clnu.2000.0154

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Awad S, Allison SP, Lobo DN. The history of 0.9% saline. Clin Nutr. 2008;27(2):179–188. doi:10.1016/j.clnu.2008.01.008

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Lewins, Robert. Injection of Saline Solutions into the Veins. (1832). The Boston Medical and Surgical Journal, 6(24), 373–375.

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Hartmann AF, Senn MJ. STUDIES IN THE METABOLISM OF SODIUM r-LACTATE. II. RESPONSE OF HUMAN SUBJECTS WITH ACIDOSIS TO THE INTRAVENOUS INJECTION OF SODIUM r-LACTATE. J Clin Invest. 1932;11(2):337–344. doi:10.1172/JCI100415

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Weinberg L, Collins N, Van Mourik K, Tan C, Bellomo R. Plasma-Lyte 148: A clinical review. World J Crit Care Med. 2016;5(4):235–250. Published 2016 Nov 4. doi:10.5492/wjccm.v5.i4.235

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Rizoli S. PlasmaLyte. J Trauma. 2011;70(5 Suppl):S17–S18. doi:10.1097/TA.0b013e31821a4d89

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Brown RM, Wang L, Coston TD, et al. Balanced Crystalloids versus Saline in Sepsis. A Secondary Analysis of the SMART Clinical Trial. Am J Respir Crit Care Med. 2019;200(12):1487–1495. doi:10.1164/rccm.201903-0557OC

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Li H, Sun SR, Yap JQ, Chen JH, Qian Q. 0.9% saline is neither normal nor physiological. J Zhejiang Univ Sci B. 2016;17(3):181–187. doi:10.1631/jzus.B1500201

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Wilcox CS. Regulation of renal blood flow by plasma chloride. J Clin Invest. 1983;71(3):726–735. doi:10.1172/jci110820

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Quilley CP, Lin YS, McGiff JC. Chloride anion concentration as a determinant of renal vascular responsiveness to vasoconstrictor agents. Br J Pharmacol. 1993;108(1):106–110. doi:10.1111/j.1476-5381.1993.tb13447.x

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Chowdhury AH, Cox EF, Francis ST, Lobo DN. A randomized, controlled, double-blind crossover study on the effects of 2-L infusions of 0.9% saline and plasma-lyte® 148 on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers [published correction appears in Ann Surg. 2013 Dec;258(6):1118]. Ann Surg. 2012;256(1):18–24. doi:10.1097/SLA.0b013e318256be72

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McCluskey SA, Karkouti K, Wijeysundera D, Minkovich L, Tait G, Beattie WS. Hyperchloremia after noncardiac surgery is independently associated with increased morbidity and mortality: a propensity-matched cohort study. Anesth Analg. 2013;117(2):412–421. doi:10.1213/ANE.0b013e318293d81e

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Myburgh JA, Mythen MG. Resuscitation fluids. N Engl J Med. 2013;369(13):1243–1251. doi:10.1056/NEJMra1208627

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Noritomi DT, Soriano FG, Kellum JA, et al. Metabolic acidosis in patients with severe sepsis and septic shock: a longitudinal quantitative study. Crit Care Med. 2009;37(10):2733–2739. doi:10.1097/ccm.0b013e3181a59165

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Neyra JA, Canepa-Escaro F, Li X, et al. Association of Hyperchloremia With Hospital Mortality in Critically Ill Septic Patients. Crit Care Med. 2015;43(9):1938–1944. doi:10.1097/CCM.0000000000001161

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Suetrong B, Pisitsak C, Boyd JH, Russell JA, Walley KR. Hyperchloremia and moderate increase in serum chloride are associated with acute kidney injury in severe sepsis and septic shock patients. Crit Care. 2016;20(1):315. Published 2016 Oct 6. doi:10.1186/s13054-016-1499-7

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Modi, MP. A comparative study of impact of infusion of Ringer's Lactate solution versus normal saline on acid-base balance and serum electrolytes during live related renal transplantation.Saudi J Kidney Dis Transpl. 2012 Jan;23(1):135-7.

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Khajavi MR, Etezadi F, Moharari RS, et al. Effects of normal saline vs. lactated ringer's during renal transplantation. Ren Fail. 2008;30(5):535–539. doi:10.1080/08860220802064770

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Piper GL, Kaplan LJ. Fluid and electrolyte management for the surgical patient. Surg Clin North Am. 2012;92(2):189–vii. doi:10.1016/j.suc.2012.01.004

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Andersen LW, Mackenhauer J, Roberts JC, Berg KM, Cocchi MN, Donnino MW. Etiology and therapeutic approach to elevated lactate levels. Mayo Clin Proc. 2013;88(10):1127–1140. doi:10.1016/j.mayocp.2013.06.012

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Ichai C, Orban JC, Fontaine E. Sodium lactate for fluid resuscitation: the preferred solution for the coming decades?. Crit Care. 2014;18(4):163. Published 2014 Jul 7. doi:10.1186/cc13973

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Farkas, Josh. “Three myths about Plasmalyte, Normosol, and LR” https://emcrit.org/pulmcrit/three-myths-about-plasmalyte-normosol-and-lr/\.1/26/15

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Nalos M, Leverve XM, Huang SJ, Weisbrodt L, Parkin R, Seppelt IM, Ting I, Mclean AS: Half-molar sodium lactate infusion improves cardiac performance in acute heart failure: a pilot randomized controlled clinical trial. Crit Care 2014, 18:R48.

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Weinberg L, Collins N, Van Mourik K, Tan C, Bellomo R. Plasma-Lyte 148: A clinical review. World J Crit Care Med. 2016;5(4):235–250. Published 2016 Nov 4. doi:10.5492/wjccm.v5.i4.235

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Yartsev, Alex. Metabolic Fate of Lactate, Acetate, Citrate and Gluconate. http://www.derangedphysiology.com/main/core-topics-intensive-care/manipulation-fluids-and-electrolytes/Chapter%204.1.4/metabolic-fate-lactate-acetate-citrate-and-gluconate. Accessed 3.13.2020

Spriet I, Lagrou K, Maertens J, Willems L, Wilmer A, Wauters J. Plasmalyte: No Longer a Culprit in Causing False-Positive Galactomannan Test Results. J Clin Microbiol. 2016;54(3):795–797. doi:10.1128/JCM.02813-15

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Stocker RA. "Normal" Saline and Co: What Is Normal?. Crit Care Med. 2016;44(12):2282–2283. doi:10.1097/CCM.0000000000002030

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Zampieri FG, Ranzani OT, Azevedo LC, Martins ID, Kellum JA, Libório AB. Lactated Ringer Is Associated With Reduced Mortality and Less Acute Kidney Injury in Critically Ill Patients: A Retrospective Cohort Analysis. Crit Care Med. 2016;44(12):2163–2170. doi:10.1097/CCM.0000000000001948

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Shaw AD, Bagshaw SM, Goldstein SL, et al. Major complications, mortality, and resource utilization after open abdominal surgery: 0.9% saline compared to Plasma-Lyte. Ann Surg. 2012;255(5):821–829. doi:10.1097/SLA.0b013e31825074f5

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Gupta RG, Hartigan SM, Kashiouris MG, Sessler CN, Bearman GM. Early goal-directed resuscitation of patients with septic shock: current evidence and future directions. Crit Care. 2015;19(1):286. Published 2015 Aug 28. doi:10.1186/s13054-015-1011-9

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Ince C, Groeneveld AB. The case for 0.9% NaCl: is the undefendable, defensible?. Kidney Int. 2014;86(6):1087–1095. doi:10.1038/ki.2014.193

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Hammond NE, Taylor C, Saxena M, et al. Resuscitation fluid use in Australian and New Zealand Intensive Care Units between 2007 and 2013. Intensive Care Med. 2015;41(9):1611–1619. doi:10.1007/s00134-015-3878-y

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Mahler SA, Conrad SA, Wang H, Arnold TC. Resuscitation with balanced electrolyte solution prevents hyperchloremic metabolic acidosis in patients with diabetic ketoacidosis. Am J Emerg Med. 2011;29(6):670–674. doi:10.1016/j.ajem.2010.02.004

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McFarlane C, Lee A. A comparison of Plasmalyte 148 and 0.9% saline for intra-operative fluid replacement. Anaesthesia. 1994;49(9):779–781. doi:10.1111/j.1365-2044.1994.tb04450.x

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Young JB, Utter GH, Schermer CR, et al. Saline versus Plasma-Lyte A in initial resuscitation of trauma patients: a randomized trial. Ann Surg. 2014;259(2):255–262. doi:10.1097/SLA.0b013e318295feba

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Young P, Bailey M, Beasley R, et al. Effect of a Buffered Crystalloid Solution vs Saline on Acute Kidney Injury Among Patients in the Intensive Care Unit: The SPLIT Randomized Clinical Trial [published correction appears in JAMA. 2015 Dec 15;314(23):2570]. JAMA. 2015;314(16):1701–1710. doi:10.1001/jama.2015.12334

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Self WH, Semler MW, Wanderer JP, et al. Balanced Crystalloids versus Saline in Noncritically Ill Adults. N Engl J Med. 2018;378(9):819–828. doi:10.1056/NEJMoa1711586

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Semler MW, Self WH, Wanderer JP, et al. Balanced Crystalloids versus Saline in Critically Ill Adults. N Engl J Med. 2018;378(9):829–839. doi:10.1056/NEJMoa1711584

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Young PJ. Balanced Crystalloids or 0.9% Saline in Sepsis. Beyond Reasonable Doubt?. Am J Respir Crit Care Med. 2019;200(12):1456–1458. doi:10.1164/rccm.201908-1669ED

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Early Vasopressors in Septic Shock?

This is a question that is often asked. Do we give fluids until the patient no longer "responds to fluids" or start vasopressors early?

Here's my bias: I dislike arbitrarily pounding patients with fluids. It causes harm. We know this.

I don't know what people who aren't doing advanced hemodynamic monitoring of some sort mean when they say "they respond to fluids". "I gave a liter of fluids and the BP got better" for 30 minutes is not a determinant of fluid responsiveness. Remember, I've cited here before that critically ill patients extravasate 80% of that liter of fluids within one hour. What did you really do outside of feeling like you did something? The authors used PPV, SVV, echo with VTI combined with PLR, end-expiratory occlusion maneuvers, and capillary refill time. Did I mention that these authors are legends in the field? Well, they are.

In my opinion, providing pressors early provides a safety net of sorts to the organs to make sure they're being perfused. You've seen it often in your ED and ICU. Patient comes in sick. They're hypotensive, they get their 30cc/kg and their BP gets "better". The cuff cycles again 15 minutes later and their BP is now 60/30. How long did those organs go under-perfused? Minutes matter. We NEED to get better at this. After all, we are supposed to be the biggest badasses in medicine, yet we often shrug our shoulders and react when it's ugly instead of preemptively fixing the issues.

Turns out that very early vasopressors were beneficial to the patients. The definitions of the two groups are defined on my slides. The outcomes are also defined there for the sake of not taking up too much space.

This could be practice changing data. I personally start vasopressors really early in my practice. Some may say, let's wait for a prospective randomized clinical trial before putting this into practice. To those people I say, there's no harm in this. Also, you can't blind the physicians so when that study comes out positive some will say "oh but the physicians weren't blinded". Research. Sigh.

A hat tip to the authors. This article was published yesterday. How's that for cutting edge?

-EJ

Ospina-Tascón, G.A., Hernandez, G., Alvarez, I. et al. Effects of very early start of norepinephrine in patients with septic shock: a propensity score-based analysis. Crit Care 24, 52 (2020).



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Elevated Lactate Does Not Equal More Fluids

There is a law of diminishing returns when resuscitating patients with bolus after bolus of IV fluids.

Yes, lactate decreased with additional boluses by 1.3% per every 7.5mg/kg increase in fluids making the numbers look pretty, but does that mean we're treating the source of the lactate or are we just diluting it? This study shows that mortality actually increases as we keep providing more fluids.

I’m not saying that patients who are in septic shock do not need fluids. On the contrary, they need judicious use of IV fluids and 30cc/kg initial resuscitation is okay with me in the vast majority of patients. I had to read many articles to finally fall in line with that. Of course there are several patient populations where I’m against it. For example, severe pulmonary hypertension patients with right hearts living on a tight rope. I digress. But tagging along with my prior post discussing giving fluid boluses reflexively, this study shows that fluids don’t really “clear” lactate in the way we all hope and want them to. The correlation of having an elevated lactate to mortality is there. The correlation with more fluids making lactate decrease isn’t. The pathophysiology behind where lactate comes from explains why not. And as we all should know, fluids are not benign. The more fluids we give patients the higher the mortality per the 9000 that were assessed in this study.
A 🎩 tip to the authors. .

Liu V, Morehouse JW, Soule J, Whippy A, Escobar GJ. Fluid volume, lactate values, and mortality in sepsis patients with intermediate lactate values. Ann Am Thorac Soc. 2013;10:466–73.

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Don't give fluids just because the lactate is elevated.

Lactate is elevated? (without assessing the patient) Give a fluid bolus.

Wait, WHAT?!?!? Whyyyy? 😫

This is something I routinely see today. I routinely saw it at the Ivory Tower where I trained in fellowship. I routinely did it myself when I was a young whipper snapper of a resident and didn't know any better. Now, I'm here to tell you that you can do better.

I don't blame you for doing this, though. You've seen other clinicians do it. You were likely trained this way. The nurses have been trained this way. When the lactate is elevated, page the doctor and expect an order for a fluid bolus. It makes one feel all warm and fuzzy inside like "I did something". Everyone pats themselves on the back. Well I'm here to tell you that from now on, every time you do that, you're more likely to be wrong in your management that right.

This article which describes the "lacto-bolus reflex", i.e. to give a bolus of fluid for every elevated lactate. The authors are just as fed up about it as I am. IV fluid boluses are not benign. Fortunately, this article is completely free (I like finding you all full free articles) and it describes why the whole idea of patients developing a lactic acidosis due to cells not getting oxygen hypoperfusion is silly to the point where many of us need to be re-educated. I will admit, I had to be re-educated myself. I was not born knowing this stuff. I used to do it wrong. Now I'm trying to do it right.

The article is easy to read, for those of you who choose to dive further into it. Ultimately, they conclude that, although lactate levels are helpful for prognosis (plenty of data on that), and lactate not going away is helpful to know whether you have control of your patient or not, it ultimately does not help in any way, shape, or form, to guide fluid resuscitation. A 🎩 tip to the authors.

-EJ



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Spiegel R, Gordon D, Marik PE. The origins of the Lacto-Bolo reflex: the mythology of lactate in sepsis. J Thorac Dis 2020;12(Suppl 1):S48-S53.

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Incorporating Dynamic Assessment of Fluid Responsiveness Into Goal-Directed Therapy: A Systematic Review and Meta-Analysis.

Incorporating Dynamic Assessment of Fluid Responsiveness Into Goal-Directed Therapy: A Systematic Review and Meta-Analysis.

Let’s talk a little bit about resuscitation. I chose to go down this path to start off the weekend bc I frequently see patients receiving arbitrary fluid boluses for SBP less than x (we all know how o feel about using systolics on oscillometric machines), MAP less than 65, or decreased urine output. It makes us feel like we are doing something but we are actually causing harm. At the end of the day, giving fluid just to make the blood pressure pretty does not indicate fluid responsiveness. If I were to give you a liter of fluid, definitely not saline, your BP would go up. That doesn’t mean you’re fluid responsive. Using the technologies listed in this article from 2017 are a step in the right direction. If you read the validation studies for them you’ll learn that they leave much to be desired but they’re amongst the best tools we have today. I’m going to go much deeper down this rabbit hole in the upcoming months.

What do you use at your shop to measure fluid responsiveness?

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Bednarczyk JM, Fridfinnson JA, Kumar A, et al. Incorporating Dynamic Assessment of Fluid Responsiveness Into Goal-Directed Therapy: A Systematic Review and Meta-Analysis. Crit Care Med. 2017;45(9):1538–1545. doi:10.1097/CCM.0000000000002554

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IV Fluids Types: Do you know your -ish?

Problems with solutions: drowning in the brine of an inadequate knowledge base

More than 50% of residents do not know how much sodium is in 0.9% NaCl. I know you do, though... it's 154mmol/L. Far more than our "normal" of 140mmol/L.
Why do I nag so much with intravenous fluids and what's in them? Truth be told, I did not know my fluid composition as well as I should have even as an intern. I had an ICU attending, a mentor, now someone I'm fortunate to call a colleague, who would pimp the house staff on IV fluids and make us feel ashamed if we didn't know the answer. He was right. My embarrassment was deserved. After all, these are substances that we are mindlessly pouring into our patients. The vast majority of clinicians, I'm not even talking about nurses, I AM REFERRING TO US DOCTORS, do not know what's in these bags that are so easy to click in the EMR and order. We mindlessly just do it. I was embarrassed. I do not want you to feel the same way. I have been teaching fluids now for 4 years. It's one of my passions. I have a talk that is complete and can present at any time of the day. I know it well. But I am always reading and adding to it. The talk is going to be one of the lectures I will be presenting in Hawaii in May of 2020. It will also be presented to the Department of Anesthesia at my hospital on October 20th of this year. I am currently brushing up that talk, adding and subtracting some things, and I ran into this study from 2001 which asked preregistration house officers and senior house officers (I guess that means interns and residents) about the composition of fluids amongst other things. I won't go over the methodology but the training needs to start in medical school. Overall, 11.5% said their training in the matter was poor, 22% stated it was unsatisfactory. I have to agree with this 100%. I received ZERO training in med school regarding IVF. Since it's something so ubiquitous in our daily practice of medicine, it's something we need to do better. A lot better. If you are in medical school or residency, have you been trained in the composition of IV Fluids?

-EJ



Link to the Abstract

Lobo, D.N., Dube, M.G., Neal, K.R., et al., 2001. Problems with solutions: drowning in the brine of an inadequate knowledge base. Clin. Nutr., 20(2):125-130.
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Normal Saline: A History Lesson for the Inappropriate Name

A little history lesson, my friends, regarding the origins of us calling 0.9% saline solution, aka 0.9% sodium chloride, "normal saline".

We are all disappointed in ourselves. You've been calling it normal saline, I've been calling it normal saline, we just can't stop ourselves! Of course you know I am referring to 0.9% sodium chloride solution used so commonly, and many times inappropriately, in our everyday practice. Why is it not normal? Well, I have covered this many times on my Instagram page and YouTube videos. First of all, the sodium concentration in serum is 140meq/L. The reference range in the labs are usually 135-145meq/L. What's the sodium concentration in "Normal Saline"? 154meq/L. How much chloride is in serum? 98-109meq/L. What about in "normal saline"? 154meq/L because it's equal parts sodium and chloride. We can continue talking about strong ion difference and all the adverse effects of the 0.9% saline but that will take me forever. It's Saturday and I have a birthday party to go to. Where in the world did the associate with "normal" come from? The inspiration for this post came from @anursingnote and her discussion with @med.life.crisis, two RN's who are trying to kick butt and get smarter every day. You go girl(s)!
This article is not free, unfortunately, but they do make a couple key points, all of which show that even though they used the word "normal", it's not in the appropriate way. You're never going to think about a Hamburger now without thinking about 0.9% saline solution. Sorry I ruined that for you.
Here's how all this went down in chronological order:
I credit the authors of this paper for doing much of this heavy lifting, by the way. I can't actually get my hands on many of these papers. I'm going to do my best to briefly summarize.
1888: Hamburger. This Dutch physiologic chemist performed in vitro studies (not in vivo, take a second to let that process) where he found that there was less hemolysis with 0.92% saline than other concentrations.
1888: Dr Churton. "he was ordered transfusion of ‘normal saline’ solution in order to replace the fluid thus lost". That fluid was nothing like the saline we know and are still trying to understand to this day. That particular fluid had 150meq/L of Na and 128meq/L of chloride. It also had some bicarb in it.
1892: Dr Spencer used the term "normal salt solution" but the composition of the fluid was not defined.
There are plenty more goodies in the article which I recommend you try to get your hands on. The article is going to definitely be included in my lecture regarding intravenous fluids that I will be giving to the anesthesia department in my shop next month and on various lectures I have scheduled nationally next year. It's that important. A great job by the authors!
All in all, can we really stop saying "normal saline"? I think it's too embedded in our vernacular and it'll be too challenging to fix. I am always trying to make a conscious effort to stop but it's challenging because I have been hearing it for over a decade now. I'm getting old.

-EJ





Link to Abstract


Citation:
Awad S, Allison SP, Lobo DN. The history of 0.9% saline. Clin Nutr Edinb Scotl. 2008;27:179–188.
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Balanced crystalloids versus normal saline for fluid resuscitation in critically ill patients

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Association Between the Choice of IV Crystalloid and In-Hospital Mortality Among Critically Ill Adults With Sepsis

https://www.ncbi.nlm.nih.gov/pubmed/24674927

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A Randomized, Controlled, Double-Blind Crossover Study on the Effects of 2-L Infusions of 0.9% Saline and Plasma-Lyte® 148 on Renal Blood Flow Velocity and Renal Cortical Tissue Perfusion in Healthy Volunteers

https://journals.lww.com/annalsofsurgery/Abstract/2012/07000/A_Randomized,_Controlled,_Double_Blind_Crossover.5.aspx

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Fluids given ≠ Fluids retained: Bibliography

https://www.ncbi.nlm.nih.gov/pubmed/19789444



https://jasn.asnjournals.org/content/12/suppl_1/S33.long



https://link.springer.com/article/10.1007%2Fs00134-004-2510-3

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