Review
Electrolytes: The Salts of the Earth
Wendy Arneson, MS, MASCP, MLS(ASCP)CM 1*
What do you need to know as medical laboratory scientists
when performing plasma electrolyte analysis? What new
information should you consider regarding best laboratory
practice in electrolyte analysis? This review article will answer some of these questions.
Background
In human physiology it is best to refer to electrolytes, the
main component in bodily fluids, in the context of extracellular fluid (ECF) volume and total water (H2O) content in
the body. Electrolytes are also best referenced collectively
rather than individually because they are part of an integrated physiological mechanism of H2O and ionic balance.
Thirst, renal function, and hormonal response help to
maintain homeostasis of electrolytes.1
These entities play a role in general functions of metabolic pathways, enzyme activation, acid-base balance,
muscular-function regulation, and nervous-tissue contractions. Control of electrolyte levels is based on H2O and pH
DOI: 10.1309/LM24GWIUEXOKN7AP
Abbreviations
ECF, extracellular fluid; H2O, water; Na, sodium; K, potassium; ATPase,
adenosine triphosphatase; Cl, chloride; HCO3 –, bicarbonate; SIADH,
syndrome of inappropriate antidiuretic hormone secretion; CO2, carbon
dioxide; ISEs, ion-selective electrodes; TAT, turnaround time; POC,
point-of-care; tCO2, total plasma CO2; NADP+,nicotinamide adenine
dinucleotide phosphate; CSF, cerebrospinal fluid; EDTA, ethylenediaminetetraacetic acid
Keywords: electrolytes, ion-selective electrodes, ionic balance, renal
function
Center for Global Health, ASCP, Chicago
1
*To whom correspondence should be addressed.
E-mail: [email protected]
www.labmedicine.com
balance and is enacted by the renal glands through processes such as active transport in the proximal convoluted
tubules, osmosis, and passive diffusion. At a cellular level,
sodium (NA) and potassium (K) levels are maintained by
the Na-K–adenosine triphosphatase (ATPase) pump.1 The
endocrine system influences the distal convoluted tubules
via the renin-aldosterone system and the circulating levels
of vasopressin and natriuretic peptides in bodily fluids.
Clinical Significance
Potassium maintains cardiac rhythm and contributes to
neuromuscular conduction. Imbalances in K level, as indicated by hyperkalemia or hypokalemia, will cause cardiac
arrhythmias and neuromuscular weakness. Chloride (Cl)
helps to maintain electrical neutrality with Na. Cl also
contributes to the maintenance of acid-base balance by
participating in the isohydric shift to buffer H+ and the Cl
shift to maintain electrical neutrality with movement of
bicarbonate (HCO3– ) ions. Renal and endocrine disorders
often are characterized by electrolyte imbalances that
can be reflected in plasma electrolyte levels. Changes in
electrolyte levels, compared with total H2O content in the
body, are associated with pathological consequences and
increased mortality.2,3,4
Hypernatremia is caused by renal and nonrenal disorders;
it is closely tied to total H2O levels in the body. A common
nonrenal cause for hypernatremia is hypotonic dehydration
resulting from severe diarrhea, extensive burns, or excessive sweating without proper fluid replacement. Infants,
elderly individuals, and other patients will also experience
hypernatremia due to dehydration if they are deprived of
sufficient amounts of H2O or are not properly hydrated.
Hypernatremia can also be caused by renal loss of H2O,
such as from nephrogenic diabetes insipidus. Serum osmolality and urinary Na levels can help to differentiate the
cause of hypernatremia, be it renal loss of H2O or nonrenal
in nature.5
Winter 2014 | Volume 45, Number 1 Lab Medicine
e11
Review
Hyponatremia, also of renal and nonrenal origins, is classified based on extracellular fluid (ECF) levels. However,
clinical assessment of hyponatremia and ECF volume
status is difficult without measuring the concentration of
Na in a spot urine sample.6 In situations in which there is
increased ECF volume, there may be an actual increase
in total Na levels in the body but a dilutional effect of
plasma Na levels due to ascites, nephrotic syndrome,
or congestive heart failure.7 Urine Na levels are usually
normal or decreased in hyponatremia due to edema. Decreased total Na levels in the body, even in the context
of decreased ECF levels, are found in salt-losing renal
nephritis, renal tubular acidosis, and treatment with certain types of diuretics or in the syndrome of inappropriate antidiuretic hormone secretion (SIADH) with resulting
renal loss of Na. These causes of hyponatremia may be
evaluated by testing for the presence of excess urinary
Na levels.5 This illustrates the value of measuring urine Na
levels along with serum Na levels.6
Because of the high concentration of Na in extracellular fluid, such as plasma H2O, Na plays a major role in
maintaining osmotic pressure. Extremely high or low Na
concentrations in plasma will cause severe osmotic pressure changes that can induce serious consequences to
several organs. The most immediate effect is swelling on
the brain and potential coma.5
Hyperkalemia may be caused by decreased renal excretion in acute or chronic renal failure, treatment with
certain diuretics, or hormonal imbalances such as hypoaldosteronism or hypocortisolism. Hyperkalemia may also
be caused by ionic shift, as may be observed in cases
of diabetic ketoacidosis or other metabolic acidosis; hyperkalemia is also associated with leukemia, excessive
muscle activity, and hemolysis. Finally, hyperkalemia is
associated with iatrogenic causes of excessive K administered intravenously or orally. Maintaining serum K levels
in the normal reference range in patients with cardiac
conditions may decrease life-threatening complications
because abnormal serum K levels are associated with
increased mortality.4
Hypokalemia is caused by renal loss such as renal tubular acidosis, hyperaldosteronism, hypercortisolism, and
treatment of patients using certain diuretics. Potassium
levels can also be low due to gastrointestinal dietary
deficit or loss from severe vomiting, diarrhea, nasogastric
suctioning, laxatives, and/or malabsorption. Transcellular
ionic shifts that take place during insulin overdose and in
metabolic alkalosis can also cause hypokalemia.8
e12
Lab Medicine Winter 2014 | Volume 45, Number 1
Chloride is the major extracellular anion that balances with
Na to maintain electrical neutrality. Chloride levels outside
of reference ranges, even when considered by themselves,
usually indicate a more serious underlying metabolic disorder, such as metabolic acidosis or alkalosis. Testing for Cl
levels is diagnostically important and should be evaluated
in a wide variety of clinical situations, especially those dependent on total H2O levels in the body.9 Thus, hyperchloremia, like hypernatremia, occurs most commonly due to
dehydration.
Hypochloremia may occur due to loss of Cl from the ECF
or excess extracellular fluid levels, such as in edema or
similar causes including hyponatremia. Cl loss can occur
in the gastrointestinal tract, in compensation for respiratory
acidosis, or in primary metabolic alkalosis.10 The typical
close inverse relationship between serum Cl and HCO3–
concentrations is often less correlated when patients also
exhibit significant changes in H2O balances and concurrent
acidosis with anion gap disturbances.11
HCO3 –, the metabolic component of the plasma buffer
system, is the major component of the extracellular buffer system; renal tubular cells and erythrocytes serve as
its reservoirs. Changes in plasma tCO2 and HCO3 – levels
indicate the presence of an acid-base disturbance but
must be evaluated in the context of clinical information and
several sequential electrolyte and anion gap results. Decreased plasma levels of total CO2 or HCO3 – usually result
from primary metabolic acidosis or as part of compensation for respiratory alkalosis. Extremely low levels of HCO3 –
in plasma almost always point to metabolic acidosis, such
as in ketosis, renal failure, or other metabolic causes that
limit compensation for respiratory alkalosis.
Increased plasma levels of total CO2 result from primary
metabolic alkalosis or compensation for acute respiratory
acidosis, such as in emphysema or respiratory failure.12
Mixed metabolic and respiratory acidosis due to respiratory failure, in combination with hyponatremia or hypochloremia due to fluid imbalances such as edema, can yield
serious complications and require prolonged treatment.13
Methods of Analysis
The reference method for these electrolytes, other thanHCO3 –, is flame emission photometry. However, ionselective electrodes (ISEs) are the most commonly used
instruments of electrolyte analysis in clinical laboratories.14
www.labmedicine.com
Review
Only the free unbound ion is measured by the ISE; conditions that affect binding and ionization can affect the accuracy of measurements. ISEs consist of or are covered by
a unique material that is more selective for a certain ion in
solution than for other ions. When the selected ion comes
in contact with the electrode, a change in the potential can
be observed, compared with the reference electrode; this
is measured as a voltage change, due to the ionic activity.15
Turnaround time (TAT) for urgent electrolyte-level testing
orders is a consideration when choosing methodology platforms. It is common to set the completion time for urgent
electrolyte-test requests at 15 minutes, although health care
professionals would prefer a TAT of 5 minutes.16 This is possible with use of point-of-care (POC) devices to achieve this
TAT. However, laboratorians must consider various technical
aspects, such as issues of the reliability of results, before instituting this option. POC devices can produce unreliable results due to variable levels of experience among testing staff,
less care taken by certain testing-staff members, the effects
of sample integrity, and the general assumption that simpler
testing equates error-proof results. Given less control over
the testing process, tracking and managing errors generated
by POC electrolyte devices may be more difficult than doing
so in the centralized laboratory testing environment.17
Principles
The ISEs for Na and K are similar; they only possess differences in the composition of the membrane that provides
for selectivity of the unique ion. For Na, the ISE membrane
is often made of a lithium aluminum silicate or other composite silicon dioxide glass compound that selects for Na+
more readily than K+ or H+. The ISE for K typically uses a
selective membrane containing valinomycin.
Chloride can be measured by an ISE consisting of a silver
chloride (AgCl)–membrane solid-state electrode. When the
ion comes in contact with the electrode, a change occurs
in the potential compared with the reference electrode; this
change can be measured as a voltage change due to the
ionic activity. Chloride can also be measured via coulometric-amperometric titration, with silver (Ag) ions released
at a constant rate and forming insoluble AgCl. The time of
titration is proportional to the Cl activity in the sample. This
method is commonly used for sweat Cl analysis.15
The total plasma CO2 (tCO2) gas cell/electrode contains
an acid to convert HCO3– to gas, which diffuses through
www.labmedicine.com
a silicone membrane and reacts with an HCO3 –/carbonic
acid buffer to produce H+ in proportion to the amount of
tCO2 in the plasma. The H+ molecules are detected by
an ISE made of silicon dioxide/lithium and calcium oxide
glass that selects for Na+ over H+ and registers a change
in potential versus the AgCl reference electrode. Total CO2
can be measured via ISE or by an enzymatic/photometric
method. A spectrophotometric/enzymatic methodology for
total CO2 measurement uses urea amidolyase. The enzyme
catalyzes the reaction of HCO3 – with urea to form several
products, including ammonium. Ammonium is then measured using glutamate dehydrogenase (after first assessing
the endogenous ammonium ion concentration) to produce
nicotinamide adenine dinucleotide phosphate (NADP+),
which produces change in absorbance at 340 nm.18
The Specimen
Venous serum, lithium heparinized whole blood or plasma,
or heparinized arterial whole blood should be collected
using a method that does not trigger hemolysis, release
from muscle activity, or leakage from erythrocytes. Heparinized plasma is the specimen of choice; it contains less
K, namely, 0.3 to 0.7 mmol per L, than serum due to platelet release during coagulation. Laboratorians may also
analyze electrolytes in bodily fluids such as urine, sweat,
cerebrospinal fluid (CSF) and gastric fluids; specimens of
these fluids are stable if maintained in closed containers
and analyzed promptly.15 The specimen type may be the
cause of a consistent difference between direct and indirect ISE methods, especially when POC devices are used.
This difference may occur due to the differing ratios of the
volume of anticoagulant to patient specimen used in central laboratory testing versus capillary whole blood that is
tested in POC devices.14
Interferences
Several preanalytical variables affect electrolyte results,
including type of anticoagulant, storage conditions, and
hemolysis. Hemolysis of blood causes a false increase
in plasma K results by releasing intracellular K; however,
grossly hemolyzed specimens will affect the analyses of
Na and Cl levels due to a dilutional effect. The presence
of excess anticoagulant when small volumes of blood are
collected will similarly cause a dilutional effect and falsely
decreased plasma levels of Na and Cl.14,19 Refrigeration of
Winter 2014 | Volume 45, Number 1 Lab Medicine
e13
Review
unseparated whole blood may actually enhance the intracellular release of K from erythrocytes.20
Some anticoagulants, such as trisodium citrate (Na3C6H5O7)
or ethylenediaminetetraacetic acid (EDTA), chelate cations and should be avoided to prevent a false decrease in
plasma results. Ammonium or sodium heparin may falsely
add electrolytes to results. Therefore, lithium heparin is the
only recommended anticoagulant for plasma electrolyte
analysis.21
Analytical variables may also cause limitations. Flame
emission and ISE systems that dilute the sample before
analysis with the electrode are termed indirect methods.
The results are compromised by hyperlipidemia or hyperproteinemia because the large lipid or protein molecules
that occur in unusually high amounts in those conditions
displace some of the volume of the plasma within the dilution. For example, if triglycerides or total protein are significantly elevated, the laboratorian may begin to experience
interference.14 The effect of hyperlipidemia or hyperproteinemia is to falsely lower the measured Na levels and sometimes the Cl levels in plasma due to this dilutional effect.
Direct systems do not dilute the sample before analysis.
Even with normal plasma H2O concentration, a slight difference in ionic activity would be measured via direct and
indirect ISE systems. Direct ISE systems generally have a
conversion factor that yields results in concentration terms
that are comparable to the reference method (flame photometry) for specimens with normal plasma H2O levels.14
Analytical limitations may be more pronounced in some
methodologies than others. For example, a study22 of a POC
device that measures blood gases and electrolytes reported
significantly different Na levels than a bench-top analyzer in
paired sample tests. The researchers recommend that critical decisions could safely be made based on POC K values
but that Na results might not be as reliable.22
Variation will also occur in the spectrophotometric method
for determining the total CO2 level, due to the presence of
interfering chemicals that are absorbed at wavelengths
that overlap with the wavelengths established for the test
analysis. The enzymatic/photometric method for total CO2
may yield a false decrease in the results due to turbidity
production, which alters the reaction kinetics of the enzymatic assay and causes an initial increase in absorbance
and a falsely low total CO2 value. Turbidity may have resulted from precipitation of paraproteinsor an endogenous
antibody that binds with an animal protein included in the
assay reagents.23
e14
Lab Medicine Winter 2014 | Volume 45, Number 1
Reference ranges vary with populations, geographical locations, methods, and other conditions. A study24 suggests
the need for separate reference intervals for neonates versus infants. The historical reference ranges for electrolytes
used by the National Institute of Health are as follows: Na,
135 to 144 mmol/L; K, 3.3 to 5.1 mmol/L; Cl, 99 to 107
mmol/L; and total CO2, 21 to 31 mmol/L.25 Developing specific standardized reference ranges and critical values can
be useful in making clinical decisions.
Accurate electrolyte analysis and valid results are vital for
patient outcomes. It is important to use a well-maintained
and well-calibrated instrument; to pay critical attention
to standard operating procedures; to refer to information
provided by the manufacturers of analyzers; and to test
methodologies to minimize preanalytical, analytical and
postanalytical errors. In conclusion, standardization of
methods of specimen handling, analysis, and reporting, as
well as following best practices in confirmation by crosschecking results, is essential in the quest to eliminate errors
in the laboratory. LM
References
1. Ackerman GL. Serum Sodium. In: Walker HK, Hall WD, Hurst JW,
editors. Clinical Methods: The History, Physical, and Laboratory
Examinations. 3rd edn. Boston: Butterworths; 1990. Chapter 194.
2. Stelfox HT, AhmedSB, Khandwala F, Zygun D, Shahpori R, Laupland
K.The epidemiology of intensive care unit-acquired hyponatraemia
and hypernatraemia in medical-surgical intensive care units.Crit Care.
2008;12:R162.doi:10.1186/cc7162.
3. Alderman, M, Piller, L, Ford, C, et al. Clinical significance of incident
hypokalemia and hyperkalemia in treated hypertensive patients in the
antihypertensive and lipid-lowering treatment to prevent heart attack
trial. Hypertension. 2012;59:926-933.
4. Goyal A,Spertus JA,Gosch K.Serum potassium levels and mortality
in acute myocardial infarction.JAMA. 2012;307(2):157-164.
5. Kumar S, Tomas B. Sodium. Lancet. 1998;352:220-228.
6. Chung H-M, Kluge R,Schrier RW, Anderson RJ.Clinical
assessment of extracellular fluid volume in hyponatremia.Am J
Med.1987;83(5):905-908.
7. Sigal SH.Hyponatremia in cirrhosis.J Hosp Med. 2012;7Suppl 4:S1417.
8. Gennari FJ. Hypokalemia. New Engl J Med.1998;339(7):451-458.
9. BerendK, van Hulsteijn LH, Gans ROB.Chloride: The queen of
electrolytes?EurJ Intern Med.2012;23(3):203–211.
10.Morrison G. Serum Chloride. In: Walker HK, Hall WD, Hurst JW,
eds. Clinical Methods: The History, Physical, and Laboratory
Examinations.3rd edn. Boston: Butterworths; 1990. Chapter 197.
11. Feldman M, Soni NJ, Dickson B.Use of sodium concentration and
anion gap to improve correlation between serum chloride and
bicarbonate concentrations.J Clin Lab Anal. 2006;20(4):154-159.
12.Centor RM. Serum total carbon dioxide. In: Walker HK, Hall
WD, Hurst JW, eds. Clinical Methods: The History, Physical, and
Laboratory Examinations.3rd edn. Boston: Butterworths; 1990.
Chapter 196.
www.labmedicine.com
Review
13.Terzano C, Di Stefano F, Conti V, et al. Mixed acid-base disorders,
hydroelectrolyte imbalance and lactate production in hypercapnic
respiratory failure: the role of noninvasive ventilation.PLoS
ONE.2012;7(4):e35245. doi:10.1371/journal.pone.0035245
14.Igbokwe AA. CAP Point of Care Testing Committee. The
measurement of electrolyte—sodium, potassium, chloride:
Comparison of Point of Care Testing (POCT) Methods and Central
Laboratory Methods for Key Electrolytes. Available at:www.cap.
org/apps/docs/newspath/0711/key_electrolytes.doc‎.Accessed
November 12, 2013.
15.Scott MG, LeGrys VA, Klutts JS. Electrolytes and blood gases. In:
Tietz Textbook of Clinical Chemistry and Molecular Diagnostics.
4thedn.Burtis DE, AshwoodER, and Bruns DE, eds. St. Louis: Elsevier
Saunders; 2006.
16.Cox CJ.Acute care testing: Blood gases and electrolytes at the point
of care. Clin Lab Med.2001;21(2):321-335.
17.College of American Pathologists: Point of Care Testing Committee.
Point of Care Testing Toolkit.http://www.cap.org/apps/cap.portal?_
nfpb=true&cntvwrPtlt_actionOverride=/portlets/contentViewer/
show&_windowLabel=cntvwrPtlt&cntvwrPtlt%7BactionForm.
contentReference%7D=committees/pointofcare/poct_toolkit.html.
Accessed November 12, 2013.
18.Kimura S, Yamanishi H, Iyama S, Yamaguchi Y, Kanakura Y.
Enzymatic assay for determination of bicarbonate ion in plasma using
urea amidolyase. ClinChimActa. 2003;328(1-2);179-184.
www.labmedicine.com
19.Yip PM, Chan MK, Zielinski N, Adeli K.Heparin interference in whole
blood sodium measurements in a pediatric setting.ClinBiochem.
2006;39(4):391-395.
20.Smellie WSA, Shaw N, Bowlees R, Taylor A, Howell-Jones R,
McNulty CAM. Best practice in primary care pathology: review 9.
J ClinPathol.2007; 60(9):966-974..
21.Clinical and Laboratory Standards Institute (CLSI; formerlyNCCLS).
Tubes and Additives for Venous Blood Specimen Collection—Fifth
Edition; Approved Standard, H1-A5, Vol. 23 No.33, 2003. Wayne,
PA: CLSI.
22.Jain A,Subhan I,Joshi M. Comparison of the point-of-care blood gas
analyzer versus the laboratory auto-analyzer for the measurement of
electrolytes.Int J Emerg Med. 2009;2(2):117-120.
23.Goldwasser P, Manjappa NG, Luhrs CA, Barth RH.
Pseudohypobicarbonatemia caused by an endogenous assay
interferent: a new entity.Am J Kidney Dis. 2011;58(4):617-620..
24.Melkie M,Yigeremu M,Nigussie P,TekaT,Kinde S.Establishing
reference intervals for electrolytes in newborns and infants using
direct ISE analyzer. BMC Res Notes. 2013;6:199-204.
25.National Institute of Health (NIH). Test guide—Historical reference
ranges.NIH Web site.http://cclnprod.cc.nih.gov/dlm/testguide.nsf/
Index/6CFB5DFC4DCDC8E285256C0F00645927?OpenDocument.
Accessed November 12, 2013.
Winter 2014 | Volume 45, Number 1 Lab Medicine
e15