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Balanced versus unbalanced salt solutions: What difference does it make?

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Background

The infusion of crystalloid solutions is a fundamental part of the management of critically ill patients. These solutions are used to maintain the balance of water and essential electrolytes and replace losses when patients have limited gastrointestinal intake. They also act as carriers for intravenous infusion of medication and red cells. The most commonly used solution, 0.9% saline, has equal concentrations of Na+ and Cl even though the plasma concentration of Na+ normally is 40 meq/L higher than that of Cl. The use of this fluid thus can produce a hyperchloremic acidosis in a dose-dependent manner, but it is not known whether this has clinical significance.

Approach

The first part of this article deals with the significance of Na+ and Cl in normal physiology. This begins with examination of their roles in the regulation of osmolality, acid–base balance, and generation of electrochemical gradients and why the concentration of Cl normally is considerably lower than that of Na+. The next part deals with how their concentrations are regulated by the gastrointestinal tract and kidney. Based on the physiology, it would seem that solutions in which the concentration of Na+ is “balanced” by a substance other than Cl would be advantageous. The final part examines the evidence to support that point.

Conclusions

There are strong observational data that support the notion that avoiding an elevated Cl concentration or using fluids that reduce the rise in Cl reduces renal dysfunction, infections, and possibly even mortality. However, observational studies only can indicate an association and cannot indicate causality. Unfortunately, randomized trials to date are far too limited to address this crucial issue. What is clear is that appropriate randomized trials will require very large populations. It also is not known whether the important variable is the concentration of Cl, the difference in concentrations of Na+ and Cl, or the total body mass of Cl.

Introduction

Single-atom electrolytes such as sodium, potassium, and chloride play a unique role in biology [1], [2], [3], [4]. Because they are not metabolized, their quantity in the body must be regulated through intake and excretion. They are primarily dissolved in water although there are exceptions, such as the formation of boney structures by calcium and the interaction of calcium ion with the many calcium-binding proteins. Sodium ion (Na+), too, can be sequestered by glycosaminoglycans in the skin in a process that is tightly regulated by monocyte phagocytic cells and vascular endothelial growth factor C (VEGF-C) [5], [6]. However, these bound ions do not contribute to the osmotic activity of solutions. Electrolytes in solutions play three crucial biological roles. They are major determinants of the osmolality of the extracellular and intracellular compartments, which is essential for the maintenance of constant cell volume relative to the external environment [4]. Second, gradients in strong electrolytes across cell membranes create a transmembrane potential energy that can be used to move charged substances across the walls of cells and to regulate intracellular processes [4]. Third, strong electrolytes are important regulators of hydrogen ion (H+) concentration, that is, pH [7]. I will first review the physiological significance of electrolytes in general and chloride (Cl) in particular and then discuss the empiric evidence for the clinical use of intravenous solutions in which the concentration of Cl is less than that of Na+. Some of these issues have been well discussed in two recent reviews, one especially focused on specific issues related to Cl [8] and the other on the nature of substitutes for Cl [9].

Section snippets

Osmolality

Water is the essential solvent of living organisms and the volume of water in cells needs to be regulated to maintain normal cell function. Water does not flow freely, but rather follows along concentration gradients. Accordingly, water volume is regulated by regulating the concentrations of solutes. Since single-atom electrolytes are not metabolized, they provide ideal substances for regulating water distribution.

Life evolved out of the sea in which the two most common elements (not including

Transmembrane potential

For a cell to be able to regulate its interior volume independently from the surrounding environment, it is most efficient to have an intracellular cation that is not Na+. K+ serves this purpose. It is the sixth most common element in water. Potassium sits below sodium in the periodic table and thus K+ can be expected to behave similar to Na+. By having Na+ dominate cations outside the cell and K+ dominate cations inside the cell, it became possible to independently regulate the relative

Acid–base considerations

The dominant negative ion in the extracellular space is Cl, but it is only 70% of the concentration of Na+. Why is there a difference as Cl has a higher concentration than Na+ in seawater? One factor is that there are other important negative ions (www.seafriends.org.nz/oceano/seawater.htm). Carbon dioxide (CO2), and consequently its dissociation into bicarbonate and H+, is an end product of aerobic metabolism and thus an essential element in any aerobic species. Bicarbonate is the major

Terminology

The title of this article refers to balanced and unbalanced salt solutions. Other terms often used are physiologically buffered salt solutions and low-chloride solutions. A buffer is a substance that decreases the rate of increase in [H+] during titration with a strong acid. Albumin and carbonic acid are weak acids and when added to the solution they create a range in which the pH is much lower than what it would be in a solution with only strong ions, but the rate of change in [H+] for change

Regulation of the concentration difference between [Na+] and [Cl]

As the quantity of electrolytes in the body is dependent upon their intake and output, mechanisms must be in place in the gastrointestinal tract and kidney, and to a minor extent in the skin, to maintain the normal difference between [Na+] and [Cl] of ∼40 mmol/L. Both the gastrointestinal tract and kidney secrete and then reabsorb large amounts of fluid. The human gastrointestinal tract normally takes in ∼1.5–2 L/day of water per day and secretes approximately 8–10 L/day but reabsorbs most of

Clinical significance of excess [Cl]

A simple but easily correctable consequence of hyperchloremia is that clinicians may not appreciate that an elevated base excess measurement and acidemia are due to the elevated [Cl] and waste time and effort looking for other causes to explain it rather than trying to deal with the factors increasing [Cl] which primarily the fluid being infused.

Despite the clear physiological challenge to the organism with a high [Cl], the presence of a direct clinical impact requires empiric data which is

Observational studies

In general, randomized trials are much more useful than observational studies because they directly address causality rather than just association, but the current lack of appropriate randomized trials leaves us dependent upon observational studies. Although not definitive, they can present important evidence for future large randomized trials. They also make it economically feasible to study large populations and to include subjects who are excluded from randomized trials such as emergency

Synthesis

From an evolutionary and physiological perspective, there is little doubt that serum chloride concentrations much above 100 are abnormal. The question remains, do they have a significant impact? Animal studies indicate harm under septic conditions but it is less clear that there is a problem in non-septic animals *[42], *[43], [44]. Three large observational studies indicate greater morbidity and even mortality in one study, but this only indicates an association and not causality.

Conflict of interest

The author has no conflicts of interest to report related to this manuscript. There were no outside funding sources or sponsor.

Practice points

  • When administering electrolyte solutions, consideration should be given to total body accumulation and not just concentration.

  • Solutions with a high chloride concentration add a stress to excretory systems.

  • Solutions with high chloride should be expected to produce a metabolic acidosis and increase base excess; one must be careful not to overreact to this

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