Sodium measurement—when the method matters

Amy Carpenter Aquino

October 2022—William E. Winter, MD, D(ABCC), is blunt about whether to report a corrected sodium: He would worry if his name were on such a report.

“I think you have to be careful about formulas,” he said in his “hot topic” talk at the AACC meeting in July. “Whenever you’re doing an estimate, there are errors.”

He “kind of flinches,” he said, “when discussing calculations that are not well documented.”

In the case of sodium and diabetic ketoacidosis (DKA), the concept behind the formula is to reveal what the sodium would be if the patient were not hyperglycemic. “I don’t have a problem with the clinician doing that,” he says of the formula to calculate the serum or plasma sodium in DKA patients to determine the sodium deficit. “But I would be very worried if my name was on the report for a corrected sodium. I don’t believe that laboratories should be in the business of providing such tentative extrapolations.”

How to report and interpret sodium measurement isn’t always well understood, Dr. Winter, professor of pathology and pediatrics, University of Florida College of Medicine, tells CAP TODAY. “And if you don’t interpret the sodium correctly and don’t understand its ramifications, it could lead to misdiagnosis or mismanagement.” It’s also one of the most commonly measured analytes, “so we’d better do it right,” he said.

The sodium reference interval for adults 18 and over is 135 to 145 mEq/L. Abnormalities of sodium—hyponatremia (<135 mEq/L) or hypernatremia (>145 mEq/L)—are common, especially in hospitalizations. “They’re more common than abnormalities of potassium,” said Dr. Winter, who is also medical director of clinical laboratory support services (phlebotomy) and point-of-care testing.

Sodium measurements are also commonly performed in outpatients, he said. In one study of community subjects from the population-based Rotterdam Study, 15 percent of patients over age 75 had sodium abnormalities. For those 55 to 64, the prevalence was 9.8 percent, and for ages 65 to 74, nine percent (Liamis G, et al. Am J Med. 2013;126[3]:256–263).

Sodium abnormalities are associated with increased morbidity and mortality in cardiac ICU patients. In a retrospective study of 9,676 adult patients admitted to the Mayo Clinic cardiac ICU between 2007 and 2015, the authors found that hyponatremia was associated with an elevated risk of in-hospital mortality, but hypernatremia was not, whereas both were associated with a higher risk of post-discharge mortality (Breen T, et al. J Am Heart Assoc. 2020;9[2]:e014140).

Dr. Winter presented the session’s attendees with a challenge: A patient with hypoalbuminemia, massive proteinuria, massive hyperlipidemia, and pitting edema has a sodium concentration of 126 mEq/L. The physician asks if the patient is truly hyponatremic. “How should you respond?”

The answer depends on how the sodium concentration was measured, he said, noting that the case is one of nephrotic syndrome. In nephrotic syndrome, massive proteinuria causes hypoalbuminemia, which can cause a hyperlipidemia and low oncotic pressure (from the hypoalbuminemia) in which water moves from the vasculature into the interstitium, causing the pitting edema. “But the patient’s hyponatremic,” he said.

Sodium concentration in the blood is measured most commonly by direct or indirect ion-selective electrode methods. For the direct method, there’s no dilution of the sample, and the typical analyzer is a whole blood analyzer. “What we do most commonly is measure sodium on the automated analyzer”—an indirect method in which the sample of serum or plasma is diluted before analysis.

When the test is performed on whole blood, there is no physical separation of plasma from the cells. “It measures the true sodium activity in the aqueous fraction of plasma,” Dr. Winter said, “and this will exclude lipids and proteins.” The direct sodium measurements are corrected using a fixed (ion-specific) multiplier to report a concentration that agrees with that of indirect methods “and because flame emission spectrophotometry, an indirect method, is a reference method,” he said. The “uncorrected” direct method for sodium measurement is about five percent higher than the indirect method measurement.

“Does the method matter?” he asks. Usually not, but “under special circumstances there are major differences between the direct and indirect methods that could have clinical implications.”

With the indirect ISE method, serum or plasma is separated from the blood cells by centrifugation, he said. “If it’s serum, you have allowed that sample to clot.” This measures the sodium activity in an aqueous solution of diluted plasma or serum (mmol/kg H₂O). Normally, the solution is about 93 percent water plus the dissolved electrolytes, and about seven percent solids, which are the proteins. “If you take that sample and dilute it, the results are corrected to report a concentration to agree with flame photometry.”

In this case of the hyponatremic patient with nephrotic syndrome, would it matter if the sodium was measured by an indirect ISE method? “If you have a normal proportion of solids to water in plasma—whether the solids are lipids or proteins—you’re going to get a clinically appropriate value,” Dr. Winter said.

However, if there is massive hyperlipidemia or massive proteinuria or both, the indirect method will measure a lower sodium, he explained, because hyperlipidemia, a characteristic of nephrotic syndrome, reduces the proportion of plasma that is water, thereby reducing the measured sodium concentration. “This is the dilutional error,” also referred to as electrolyte exclusion effect or volume displacement effect, he said. The consequence is a sodium measurement error: “The sodium measured by the indirect ISE is falsely low,” Dr. Winter said (Koch CD, et al. Clin Chim Acta. 2021;520:63–66).

“This is pseudohyponatremia because of the hyperlipidemia,” he said.

Other analytes can be affected, he said, but it’s usually not a clinically significant difference compared with the effect on the sodium measurement because the sodium reference interval is so narrow. “Your reference interval for potassium could be 3.5 to 5.2 [mEq/L], so a little bit of an error there is not going to have the same magnitude of the effect as an error would for sodium.”

If the range of sodium is 10 mEq/L, for example, and it’s divided by the mean of the reference interval (140 mEq/L), the variation between high and low is only 7.1 percent. For potassium (RI: 3.5–5.2 mEq/L), the percent range of reference interval is 39 percent [percent range = (1.7 mEq/L ÷ 4.35 mEq/L) × 100]. So it’s easier to “hit” the target (“normal range”), per se, for potassium than for sodium when measured by an indirect method, he said.

If pseudohyponatremia is suspected, the only way to find the true sodium measurement is to measure sodium directly, “so you’d ask that a whole blood specimen be sent. In our institution, we’d send it for a blood gas.”