Labs and Lytes 014
Author: Adam Drenzla
Reviewer: Chris Nickson
“You are the salt of the earth. But if the salt loses its saltiness, how can it be made salty again?“
— Jesus, Matthew 5:13, New International Version
A 79 year-old lady presented to the ED with one week of lethargy, nausea and decreased food intake. She was started on trimethoprim for a urinary tract infection 3 days prior to presentation. Since then she has had ongoing nausea, worsening confusion and unsteadiness on her feet. A near fall prompted a neighbour to bring her to hospital.
Past medical history is remarkable for:
- previous thyroidectomy for autoimmune thyroid disease, for which she is on replacement thyroxine
- hypertension treated with a b-blocker
- mild chronic airways disease
On examination:
- she is a small, thin lady
- She appears euvolaemic and is haemodynamicaly unremarkable
- She is disoriented but alert
- Nothing else of note!
Relevant investigations:
- Na 114 mmol/L
- K 3.5 mmol/L
- albumin 28g/L
- glucose 5 mmol/L
- a morning cortisol and TFTs pending
- Renal function is normal
- Serum osmolality is 240 mOsm/kg
- Urine osmolality is 450 mOsm/kg
- Urine Na 110 mmol/L
- CTB is unremarkable
- CXR shows mild interstitial changes
A 1L fluid restriction for possible SIADH was imposed and she was admitted to ICU/HDU for electrolyte monitoring. On arrival an arterial line was inserted and a blood gas sent but before the line could be secured she had a short self-limiting seizure during which her arterial line and peripheral IV cannula were dislodged.
- The arterial blood gas shows a sodium of 103 mmol/L
A wide bore peripheral cannula was immediately inserted in her cubital fossa and an infusion of 3% NaCl was commenced promptly after a full set of bloods was sent to the lab and a VBG was performed.
- The venous sodium reported by the lab is 118 mmol/L
- The VBG sodium is 112 mmol/L
Q1. How does the method of laboratory measurement affect the measured value of plasma sodium?
Depending on the method used, and the clinical situation, the sodium may be artificially high or low!
- Most hospitals now measure plasma sodium with ion-selective electrodes (ISE)
- There are two main methods – indirect ISE (used by most central lab analyzers) and direct ISE (used by point of care blood gas analyzers)(Burtis et al, 2012)
Differences in reported plasma sodium values between the two methods arise from two sources: To put these differences in perspective:
‘Pseudohypo’ effect
Some reviews suggest that the rare but well known phenomenon of pseudohyponatremia has largely been eliminated by the replacement of flame spectrophotometry with ion selective electrodes, however the indirect ISE is prone to similar errors (Spasovski et al, 2014).
- this is due to the ‘electrolyte exclusion effect’ that describes the exclusion of electrolytes from the fraction of total plasma volume that is occupied by solids, normally 7%. i.e. The main electrolytes are confined to the water phase, normally 93% (Burtis et al, 2012)
- Methods such as flame photometry and indirect ISE that require dilution of a small sample of plasma with fixed volume of diluent assume that the water phase is a fixed 93% and thereby the degree of dilution is constant.
- As the water phase decreases (as occurs in conditions such as hyperlipidemia), the same amount of diluent causes a relatively greater degree of dilution.
- The assumption that the water phase is fixed therefore leads to a relative underestimation of the true plasma sodium concentration.
- This “pseudohypo” effect is the basis for pseudohyponatremia or pseudonormonatremia and can lead to an underestimation of any degree of hypernatremia.
‘Pseudohyper’ effect
Less well known is that an increase in the water phase can also occur, leading to a relatively smaller degree of dilution by the fixed volume of diluent.
- This is more common clinically, particularly in the ICU, due to conditions such as hypoproteinemia and hypoalbuminemia (Story et al, 2007).
- The assumption that the water phase is fixed in this circumstance leads to overestimation of the true plasma sodium.
- This overestimation or “pseudohyper” effect can cause pseudohypernatremia or pseudonormonatremia and of course can underestimate any degree of hyponatremia (Lang et al, 2002).
Dilution may not be the solution…
These methods for measuring sodium levels which rely on a dilution step calculate the concentration in total volume of plasma not the more physiologically and physicochemically relevant plasma water volume.
- Normal plasma water sodium concentration is in fact 140/0.93 or about 150 mmol/L — which is why normal saline has the sodium concentration it does, it is in fact isotonic to normal plasma water.
- This negative “error” in plasma electrolyte analysis has been recognised for years . However, it was assumed that the volume fraction of water in plasma was constant enough to allow electrolyte reference intervals to be reported in total plasma concentrations rather than the more physiologic plasma water volume values (Burtis et al, 2012).
To make direct ISE sodium concentration comparable to these historic reference intervals most blood gas machines operate in “flame mode”.
- This multiplies the directly measured concentration, which is proportional to plasma water phase ion activity in direct ISE, by 0.93. Therefore, although the plasma water volume fraction may vary widely from 93%, as long as the ion is not bound by protein the value is independent of the relative proportions of water and solid.
- While reducing variability due to fluctuations of water phase size it does mean that as plasma water proportion increases in low protein states the value derived by flame mode becomes further removed from the true value in plasma water. Although this absolute value can easily be determined by dividing the concentration given in flame mode by 0.93 it is rarely done in clinical practice (and its clinical utility is not established) (Story et al, 2007).
Q2. How does the site of blood sampling affect the measured value of plasma sodium?
Sampling site can be important! From the little literature available it appears there are at least four ways different sampling sites can have clinically significant effects on the measurement of sodium concentration Explanations: Unfortunately there has been little well conducted systematic research into these effects, particularly in clinically relevant settings.The extent and operation of these effects in combination and the possibility of as yet undiscovered effects and their influence is still unclear. For the severely hyponatremic patient in particular there is even less data.
Q3. What implications do these measurement differences have for patient management?
The discrepancies in serum sodium values between direct and indirect ISE are large enough to be clinically meaningful. These effects will be particularly important in conditions of high and (more commonly) low solid phase states, and perhaps more so with greater derangements in sodium concentration. Laboratories have different protocols for confirming indirect ISE determined sodium levels with direct ISE methods. These can vary depending on lipid, protein and sodium level and it might be worth knowing these triggers in your lab. It is prudent to monitor sodium levels and their response to therapy with one method, and many experts agree that direct ISE is the method of choice. There are also circumstances in which differences between arterial and venous sodium levels might be clinically significant (see Q4 and Q5). Awareness of these may at the least avoid management decisions based on misleading values.
Q4. Is oral fluid intake immediately prior to sodium measurement clinically important?
Yes, it can be… This “input physiology” is frequently neglected but can have potentially important clinical implications. If significant hypotonic fluid intake into the GIT cannot be excluded before hospital arrival it is prudent to assume that such intake has occurred and be aware that hypotonia may worsen substantially before it gets better. Fluid restriction cannot account or ameliorate for fluid that has already been ingested but not yet absorbed!
Q5. How should venous plasma sodium concentrations measured immediately after a seizure be interpreted?
Blood tests, particularly venous blood samples, taken shortly after a convulsive seizure could be misleading (as described in Q2).
- Consider repeating venous plasma sodium measurements 5-10 mins after seizure termination, to allow time for the water absorbed by skeletal muscle to reinfuse into the circulation as cellular metabolism normalises.
References and Links
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- Burtis CA, Ashwood ER, Bruns DE. Chapter 28.Electrolytes and Blood Gases, in, Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 5th ed 2012. Elsevier
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