The Fluid Debate: Balanced or Unbalanced

DEK: Considering the benefits of shifting away from normal saline.

Introduction

We prescribe and administer intravenous fluids (IVF) every shift for rehydration, resuscitation and treatment. The usual options include normal saline (0.9% saline) or balanced fluids (Lactated Ringer’s and Plasma-Lyte.) If you are like most emergency physicians, your default IVF is normal saline, which may not be the best physiologic choice for all of your patients. Based solely on the latest evidence it is hard to strongly argue for an immediate practice change from NS to a balanced fluid. But, when you combine the interpretation of the evidence with the physiological advantages of balanced fluids, we advocate for the expanded use and consideration of balanced fluids in your patients.

Understanding Fluid Composition and Effects

Before we talk about specific fluids, let’s review some common terms that are frequently used to describe fluids that can be confusing: osmolarity, osmolality and tonicity. Osmolarity is the concentration of a solute per volume and osmolality is concentration of a solute per unit mass. These are very similar in this context because one liter of water has a mass of one kilogram. Similarly, when measuring concentrations of sodium and chloride, a milliequivalant (mEq) is equal to a millimole (mmol) because sodium and chloride are monovalent cations and anions. Tonicity is the effect of the solute concentration differences between two compartments, typically intra and extracellular compartments. Tonicity, is only influenced by solutes that cannot cross the membrane. For example, dextrose 5% (D5W) is an isosmolar solution, but when infused the sugar passes into the cells and the remaining water is a hypotonic solution.(¹⁾

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Normal Saline

NS is an unbuffered solution that contains 154 mEq/L of sodium and 154 mEq/L of chloride (see Table 1 for comparison of fluids.) The chloride content in NS is supraphysiologic compared to normal plasma chloride concentration of 94-111 mEq/L.(²⁾ Resuscitating patients with a fluid that has a supraphysiologic chloride content may result in adverse physiologic changes to your patient including metabolic acidosis and decreased renal perfusion.

The increased chloride load in normal saline leads to a non-anion gap hyperchloremic metabolic acidosis, with the acidosis increasing as the volume of NS increases.(³⁾ The ultimate effects of IV fluids on pH and electrolyte composition is determined by the fluid’s interaction with the serum plasma. Two theories that address why NS causes an acidosis are the strong ion difference and a bicarbonate dilution effect.(^4-7) While these effects are not something we think about on a shift, we can see the development of a metabolic acidosis increase with large volume NS infusions (typically multiple liters.) The magnitude and effects of the acidosis depend on the individual patient and the underlying disease.

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In addition to an acidosis, hyperchloremia alone has been implicated in renal injury. Chloride reduces renal blood flow, causes renal vasoconstriction and reduces the glomerular filtration rate (GFR).(^4,8) Although other mechanisms may exist, most studies that suggest harm with chloride rich fluids (including the recent NEJM articles) are related to worse renal outcomes.(^9-11) It is true that many patients have received NS without observed harm, but effects of worsening acidosis and decreased renal perfusion may be additive in your sick patient in the ED. For these reasons, we recommend reconsidering NS as the primary resuscitation fluid for ED patients who require multiple liters of volume resuscitation.

When to use normal saline

Normal saline offers advantages for patients at risk for cerebral edema and those with a chloride-responsive metabolic alkalosis. In traumatic brain injury (TBI) the osmolarity and tonicity of the plasma and the fluids administered are important. Normal saline has a theoretical osmolarity of 308 mOsmol/L versus the osmolarity of LR 273 mOsmol/L. Plasma has a calculated osmolarity of about 291 mOsmol/L.(¹²⁾

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In the case of TBI, the hypo-osmolarity of LR could potentially increase the risk of cerebral edema. Keep this concern in mind when treating patients with, or at risk for, cerebral edema, and choose NS instead.(¹³⁾ Similarly, DKA causes plasma hyperosmolarity and a rapid decrease in plasma osmolarity could place a patient at risk for cerebral edema. This would favor NS, rather than a hypo-osmolar and hypotonic fluid, as the initial fluid for volume replacement in DKA.(¹⁴⁾ NS is a good resuscitation fluid choice in patients who have developed hypovolemia and a chloride responsive metabolic alkalosis (i.e. from vomiting).(¹⁵⁾ Normal saline is also advantageous when administering blood or certain medications because it does not contain calcium. NS has better compatibility than LR with medications (e.g. ceftriaxone) and blood products.(¹²⁾

Balanced Fluids

Though there are many on the market, the balanced fluids most studied and used are Lactated Ringer’s and Plasma-Lyte. They are “balanced” because they are buffered with precursors of bicarbonate and more closely mimic plasma electrolyte composition, particularly in regards to chloride content. See Table 1 for fluid comparisons. A major advantage of balanced fluids over NS is the buffering effect. Sodium lactate and acetate are metabolized into bicarbonate, which alkalinizes plasma.(^12,16,17) This could be beneficial to your patient with a metabolic acidosis. While LR and Plasma-Lyte do not have the same electrolyte composition as human plasma, they do not cause hyperchloremia or the acidosis seen with NS. Currently in our ED, an academic center in New England, there is not a significant cost difference between NS and balanced fluids as each cost about $1 to $5.

Special Considerations with Balanced Fluids

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Lactate

Lactate is predominantly metabolized by the liver and whether LR significantly elevates lactate in patients with liver failure and sepsis induced organ dysfunction is unclear. In a study of healthy patients LR did not cause a rise in serum lactate.(¹⁸⁾ One main difference is that the lactate in LR is sodium lactate and not lactic acid.¹⁶ If serum lactate is elevated because of the sodium lactate in LR it would be elevated from the decreased ability of a dysfunctional liver to metabolize lactate rather than the concerning cause of hyperlactatemia — anaerobic metabolism caused by hypoperfusion.

Hyperkalemia

It is probably safe to give hyperkalemic patient balanced fluids and may be preferable. LR and Plasma-Lyte do contain potassium, but studies of diabetic ketoacidosis, rhabdomyolysis and post renal transplant suggest the serum potassium is unchanged or higher with NS as compared to balanced fluids.(^19-21) This may be because of extracellular shifts of potassium related to the hyperchloremic metabolic acidosis caused by NS.(²⁰⁾ Additionally, the potassium content is low in LR and the infused volume dilutes plasma potassium simultaneously to the level of the crystalloid (i.e. 4 mEq/L in LR). Notably the SALT-ED and SMART trials did not show significant difference in potassium between groups.(^9,10) This data suggests that for most patients the effect of the potassium in balanced solutions is minimal.

Balanced Fluids in Large Volume Resuscitation

Disorders like sepsis, burns and pancreatitis require large fluid volumes and increase the exposure to the possible negative effects of normal saline. In our opinion, most septic patients should not receive several liters of normal saline for resuscitation. While there is no conclusive study for septic patients, multiple studies show a trend in favor of balanced fluids. A retrospective cohort study of adult patients with sepsis suggests an association between normal saline and increased mortality as compared to those who were resuscitated with balanced fluids.(²²⁾ In the subgroup analysis of septic patients in the supplement of the SMART trial there is a trend towards improved outcome (composite outcome and mortality) with balanced fluids.(¹⁰⁾ In burn victims, balanced fluids are favored over NS.(²³⁾ Similarly LR is favored in treatment guidelines for acute pancreatitis for both better electrolyte balance and a study showing less patients developing systemic inflammation as compared to those receiving NS.(²⁴⁾

Review of the Recent Literature

Our aim is to summarize the recent literature and not perform the same level of analysis and critiques that happen at journal clubs and blogs.

In 2014, Raghunathan et al. performed a large retrospective cohort observational trial that compared balanced and unbalanced fluids across 360 U.S. hospitals for adult patients with sepsis admitted to an ICU by hospital day two. They showed that administering balanced fluids in critically ill adults with sepsis was associated with lower in hospital mortality (but no significant difference in acute kidney injury).(²²⁾ In 2015 the SPLIT trial, a randomized controlled trial of critically ill adults in four ICUs in New Zealand, compared the incidence of AKI with NS and Plasma-Lyte.(²⁵⁾ The study population was largely surgical patients who received a median of 2 liters of fluid. There was no difference in the incidence of AKI between the NS and Plasma-Lyte group.

Most recently, two articles in the New England Journal of Medicine tried to address the question of NS or balanced solution in a general ED population and a critical care population. In 2018, the SMART trial compared NS and a balanced solution (Plasma-Lyte or LR) in critically ill adults at single tertiary center.(¹⁰⁾ Their primary composite outcome was major adverse kidney events at 30 days (MAKE-30) consisting of mortality, needing renal replacement therapy, or persistent renal dysfunction at 30 days. Each group received a surprisingly small, median volume of 1L of fluid over the 30 days. They favored using balanced solutions over NS to decrease the composite outcome with a number needed to treat of 94. Also in 2018, the SALT-EM trial was performed in a single tertiary care center emergency department asked whether balanced solutions versus NS led to a decrease in hospital free days in adults who were admitted to a non-ICU hospital ward. There was no difference in the primary outcome, hospital free days, but there was a reduction in the same MAKE-30 composite end point favoring the balanced crystalloid solution with a number needed to treat of 111.(⁹⁾

The choice to use a composite outcome in the New England Journal studies and whether the studies individually or collectively should change practice is debated in the NEJM editorials, local journal clubs, multiple emergency medicine blogs and FOAM.(^26-29) It should be noted that in the composite end point death was equivalent to an elevated creatinine. While we await more conclusive trials to help guide future management, we cannot make a strong recommendation solely on the findings in these trials. While there may continue to be arguments about composite outcomes, generalizability and effect size, we did not see an increased harm from balanced fluids. There may be a 1% improvement with balanced fluids in the outcomes as presented above.  We also do not have data for patients receiving large volume fluid resuscitation (greater than two liters.)

Recommendations

Consider using balanced fluids in your ED unless you are treating a patient at risk for cerebral edema, or a patient with a chloride responsive metabolic alkalosis, e.g. from gastric losses. Although the superiority of balanced fluids to NS is still debated, balanced solutions have many physiologic advantages. The commonly used balanced fluids, LR and Plasma-Lyte, do not contain supraphysiologic chloride and are buffered by precursors to bicarbonate.

Normal saline can eventually lead to acid base disturbances and potentially renal dysfunction. The evidence above is not definitive in our ED patient population, but suggests a benefit with balanced fluids over NS. In practice, this supports the use of balanced fluids in anyone receiving substantial volumes of crystalloid — the choice of fluid in those receiving a one-time bolus is unlikely to matter. Depending on your department, formulary and EHR, this research and the physiological effects of IVF could prompt EPs to favor balanced fluids in order sets or in practice.

Take Home Points

• Consider a switch to balanced fluids. Although it is debated, recent studies suggest balanced fluids (LR, Plasma-Lyte, etc.) may be better than normal saline for patients who require large volumes of fluid.
• Balanced fluids are more similar to plasma and contain precursors to bicarbonate, but LR contains calcium that limits compatibility with blood and medication. Although balanced fluids contain potassium, they are unlikely to cause or worsen hyperkalemia.
• Normal saline causes a hyperchloremic metabolic acidosis and potentially worsens renal function.
• Normal saline should still be prescribed for those at risk for cerebral edema (TBI, stroke, DKA), those receiving blood products or ceftiaxone, or those with a chloride responsive metabolic alkalosis.

References

1. Boron, WF and Boulpaep EL. Medical Physiology: A Cellular and Molecular Approach. Saunder Elsevier. Second Edition. 2009
2. Self WH, Semler MW, Wanderer JP, et al. Saline versus balanced crystalloids for intravenous fluid therapy in the emergency department: study protocol for a cluster-randomized, multiple-crossover trial. Trials. 2017;18:178. doi:10.1186/s13063-017-1923-6.
3. McFarlane C, Lee A. A comparison of Plasmalyte 148 and 0.9% saline for intra-operative fluid replacement. Anaesthesia. 1994 Sep 49(9):779-81
4. Yunos, Met al. Bench-to-bedside review: Chloride in critical illness. Critical Care; 2010 14:226.
5. Scheingraber, S et al.. Rapid saline infusion produces hyperchloremic acidosis in patients undergoing gynecologic surgery. Anesthesiology. 1999; 90: 1265–1270
6. Stewart PA. Modern quantitative acid-base chemistry. Can J Physiol Pharmacol. 1983 Dec; 61(12):1444-61.
7. Kellum JA and Elbers P Stewart’s Textbook of Acid-Base. Lulu Enterprises. 2009
8. Chowdhury, A et al. 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. Ann Surg 2012;256:18–24
9. Self, W et al. Balanced Crystalloids versus Saline in Noncritically Ill Adults. N Engl J Med 2018; 378:819-828
10. Semler, M et al. Balanced Crystalloids versus Saline in Critically Ill Adults. N Engl J Med 2018;  378:829-839
11. Yunos, MN et al. Association Between a Chloride-Liberal vs Chloride-Restrictive Intravenous Fluid Administration Strategy and Kidney Injury in Critically Ill Adults. JAMA. 2012;308(15):1566-1572
12. Reddy et al. Crystalloid fluid therapy. Critical Care; 2016 20:59.
13. Haddad SH, Arabi YM. Critical care management of severe traumatic brain injury in adults. Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine. 2012;20:12.
14. Gosmanov AR, et.al Management of adult diabetic ketoacidosis. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2014;7:255-264.
15. Berend, K et al. Physiological Approach to Assessment of Acid-Base Disturbances. N Engl J Med 2014; 371:1434-1445
16. White, SA et al. Is Hartmann’s the solution? Anaesthesia 1997; 52:422–427
17. Yartsev, Alex. Deranged Physiology. Metabolic Fate of Lactate, Acetate, Citrate and Gluconate. June 25, 2015. http://www.derangedphysiology.com/main/core-topics-intensive-care/manipulation-fluids-and-electrolytes/Chapter%204.1.4/metabolic-fate-lactate-acetate-citrate-and-gluconate
18. Didwania, A. Effect of intravenous lactated Ringer’s solution infusion on the circulating lactate concentration: Part 3. Results of a prospective, randomized, double-blind, placebo-controlled trial. Crit Care Med 1997; 25:1851-1854
19. Young, SC. Comparison of lactated Ringer’s solution and 0.9% saline in the treatment of rhabdomyolysis induced by doxylamine intoxication. Emerg Med J 2007;24:276–280.
20. O’Malley et al. A Randomized, Double-Blind Comparison of Lactated Ringer’s Solution and 0.9% NaCl During Renal Transplantation Anesth Analg 2005;100:1518 –24
21. Chua, HR et al. Plasma-Lyte 148 vs 0.9% saline for fluid resuscitation in diabetic ketoacidosis. Journal of Critical Care 2012; 27:138–145
22. Raghunathan, K et al. Association Between the Choice of IV Crystalloid and In-Hospital Mortality Among Critically Ill Adults With Sepsis. Crit Care Med 2014; 42:1585-1591
23. Gillenwater, J. Acute Fluid Management of Large Burns: Pathophysiology, Monitoring and Resuscitation. Clin Plast Surg 2017 Jul; 44(3): 495-503
24. Tenner, S. American College of Gastroenterology Guideline: Management of Acute Pancreatitis. Am J Gastroenterol 2013; 108:1400-1415.
25. Young P 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. JAMA. 2015;314(16):1701–1710. doi:10.1001/jama.2015.12334
26. Myburgh, J. Patient-Centered Outcomes and Balanced Fluids. N Engl J Med 2018; 378:862-863
27. Rory Spiegel. EMCrit.org. CC Nerd-The Case of the Unbalanced Solution. March 1, 2018 https://emcrit.org/emnerd/cc-nerd-case-unbalanced-solution/
28. Salim Rezaie. R.E.B.E.L EM. Is the Great Debate Between Balanced vs Unbalanced Crystalloids Finally Over? Feb. 28, 2018 http://rebelem.com/great-debate-balanced-vs-unbalanced-crystalloids-finally/http://rebelem.com/great-debate-balanced-vs-unbalanced-crystalloids-finally/
29.  Magee, Fraser. The Bottom Line. Balanced crystalloids versus saline in non-critically ill adults. The   SALT-EM Study. March 2, 2018 http://www.thebottomline.org.uk/summaries/icm/salt-em/