The Pseudohyponatremia Debacle

Measurement of electrolytes in a sample of plasma is probably one of the most common tests that is performed. Every patient who gets blood drawn will also get a Chem 7 or CP13 which will include an analysis of electrolytes. There are two different technological approaches to measuring electrolytes, depending on what kind of chemistry analyzer is employed. Some use an indirect ISE and some are centered on direct ISE.

When a whole blood sample is used it is typically centrifuged beforehand to separate the sample into its plasma and red cell layers. Measurement of the electrolytes will involve using the plasma portion of the sample. Plasma consists of 93% water and approximately 7% of solid constituents, mainly proteins and lipids. The electrolytes being measured are somewhere in the water portion the plasma.

The two different methods; indirect and direct ISE differ in that direct ISE is able to respond to the electrolyte concentration within the plasma water while the indirect measures the electrolyte concentration by volume of total plasma. Total plasma including the 93% water content and 7% protein and lipid portion. That is an important distinction because the distribution of the water and protein content of plasma is important. The ratio of water/protein content is not always going to be 93/7. Depending on the patient that ratio can be skewed and inaccurate results can be reported.

So lets recap, the direct ISE measures the electrolytes using the water content of plasma, while the indirect ISE measures the electrolytes using the ratio of water/protein in whole plasma.

Indirect ISE

Indirect ISE measures electrolytes using a total plasma sample that has been diluted with diluent. This requires that the whole blood sample has been centrifuged and separated. The method measures the mean concentration in the entire plasma; water and protein content of plasma. The concentration is then multiplied by the dilution factor.


Variation of the content of proteins and lipids from a normal with cause an error in the reported electrolyte results when using an indirect ISE. In particular, when measuring sodium (Na+). Dilution, as needed in the indirect ISE involves taking a pre-determined volume of the “total” sample, not only the water content of the plasma, and adding to a diluent. The total number of measurable ions in the sample is expressed as the average concentration in the total volume of the original sample, because of this the reported values depend on the protein and lipid content of the samples. A patient with hyperlipidemia will skew the 93/7 ratio which will cause falsely decreased levels of electrolytes, most often sodium. If the low sodium level is due to lipids, its possible to centrifuge to clarify the sample to get a more accurate result. Sometime the best thing to do is to rerun the sample using direct ISE. If its possible to get a whole blood sample then use point-of-care analyzers, like an i-STAT, or some blood gas analyzers (ABG) which can give a more accurate result.

Direct ISE

Direct ISE measures electrolytes using non-diluted whole blood or a plasma sample. The actual measurement that is gained is based on the water content of the plasma. It measures the electrolyte activity in the plasma water. The electrochemical activity of the ions in the water is converted to the readout concentration by a fixed multiplier that is ion-specific. The use of the fixed factor reflects the actual, clinically significant result, irrespective of the level of proteins or lipids within the solid phase of plasma.