# Isoosmolar hyponatremia

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This is a pseudohyponatremia, caused by a measurement artefact. In actual fact the sodium concentration is normal. The college has explored pseudohyponatremia in two previous SAQs:

• Question 20.4 from the second paper of 2015 (the patient has hyponatremia, and pancreatitis presumably due to high triglycerides; the question sadistically asked "what blood test would you now order?")
• Question 21 from the second paper of 2009 (all about TURP syndrome)

The best article to reference for a discussion of such pseudohyponatremia would have to be the 2011 article by Fortgens and Pillay, who treat the problem with lucid explanations.

## Causes of error in "formal" sodium measurement

The plasma sample is taken to the biochem lab, and is diluted to 1/10th. Then, this diluted result is run through either a flame emission spectrophotometer (i.e. it gets burned and the emission spectra measured), or run through an indirect ion-sensitive electrode. Either way, the whole plasma is used, not just the water fraction. The amount of sodium found in this way is then “diluted” by calculation, with the assumption that it comes from a sample which originally consisted of 93% water.

Obviously, if you has 20% protein in that sample (eg. in multiple myeloma) then this assumption is false. So, anything that causes there to be less water in your sample than the assumed 93%, will cause the test to show a falsely decreased sodium.

## Causes of iso-osmolar hyponatremia

### High triglycerides (most common)

High triglycerides have been observed to increase the-non-water volume of plasma. This was the topic of Question 20.4 from the second paper of 2015. It has also been observed personally by the author. For instant, here is a photograph of a colleague's hand, holding a sampling tube with some blood and supernatant.

The triglyceride level there was about 45g/L, probably the highest level seen in this fat-loving corner of an especially BBQ-obsessed country, and thoroughly beating the Guinness record.   We even had to get the pharmacy to make up a batch of special "fatless" parenteral nutrition mixture for this guy, and he narrowly avoided plasma exchange (it was viewed as useless, given that much of the pancreas was already necrotic). With this horrific lipaemia, the serum sodium level was only modestly depressed, down to 130mmol/L (when tested in the ABG machine's ion-sensitive electrode, the level was 135mmol/L).

Historical anecdotes of this abound. Ladenson et al (1981) reported on a similar situation, where serum sodium was measured low as an artifact of flame photometry. The authors made a strong case for the increased use of potentiometric sodium measurement, in an era when blood gas machines were probably absurdly expensive and impractically large.

A more specific example can be found in the 1985 article by Howard et al, where six cases of hyperlipaemic pancreatitis are presented. The authors offer a scenario which explains the importance of recognising this possible measurement error. Of the six patient presented in their study, one was mistakenly resuscitated with hypertonic saline, with intracerebrally disastrous consequences.

What if one has no access to a direct sodium-sensing electrode a'la ABG machine? One may be able to correct the erroneous serum sodium measurement if the triglyceride level is known. For instance, Fortgens and Pillay offer the following equation to correct sodium:

$$"Correct" Na^+ = {"incorrect" Na^+ \times 0.93 \over [99.1 - (0.001 \times [lipid, mg/dL) - (0.7 \times protein, g/dL)] \div 100 }$$

Thus, if one's "formal" sodium is 130 mmol/L and the protein level is 60g/L, the equation gives 133.8 mmol/L as the corrected sodium, which is not far from the actual ABG result in the real-life example offered above. This is startling; for every 10g/L increase in triglyceride levels, the sodium is only depressed by about 0.85mmol/L. Thus, a 10mmol/L decrease in sodium would require a 85g/L serum triglyceride level, which is preposterously high and represents a lipaemia where 8.5% of blood volume is replaced by blobs of fat.

### High paraprotein (eg. multiple myeloma)

Elevated levels of paraprotein have been observed to increase the non-water volume of plasma. Using the same equation as above (and assuming a reasonably normal lipid concentration) one can estimate that for every 10g/L elevation in protein (from zero), the "formal" serum sodium will be depressed by about 0.53 mmol/L. Thus, a patient with multiple myeloma who has a measured sodium of 130mmol/L and a ridiculous serum protein level of 190g/L  would have a corrected sodium level of 139mmol/L. Again, vast elevations of protein would be required to generate modest decreases in sodium. Yu et al (2005) report a case of multiple myeloma where the serum protein was about 99g/L, causing the sodium to drop by about 5mmol/L when compared to ABG values.

The issue is complicated by the fact that multiple myeloma paraproteins are strongly cationic, and can give rise to "true" hyponatremia by participating in the balance of electroneutrality (Bloth et al, 1978) In this manner, the presence of cationic paraproteins can give rise to a falsely depressed anion gap (either by "faking" a low sodium or producing a genuinely low sodium). All the various ways in which paraproteins can affect lab results are discussed with great attention to detail in the excellent 2010 article by King and Florkowski.

## "TURP syndrome"

Following a TURP using glycine as an non-conducting irrigation fluid, one can fall prey to the so-called "TURP syndrome". This bizarre complication can occur in as many as 5-10 TURP cases. It is due to absorption of irrigant solution through the distended urethra.

In the course of a trans-urethral prostatectomy, small prostatic veins are cut. To keep the view clear, the irrigant solution needs to pump at pressure higher than venous pressure. This solution is iso-osmolar, but it can't be conductive, or the monopolar diathermy won't work. The solution is made iso-osmolar by addition of glycine or sorbitol. As much as 6 litres of this crap gets infused into the periprostatic veins as the TURP is conducted. The bloodstream is thus inundated with glycine or sorbitol; these act in the same way as high lipids and high paraprotein, confusing the indirect ion-sensing electrode. Additionally, the sorbitol or glycine can act as osmotic agents, expanding the ECF volume.

This is a thing of the past: nowadays, progressive urologists use normal saline to irrigate, and a bipolar diathermy probe which doesn't care how conductive your irrigant is. However, the topic is still dear to the College of Intensive Care Medicine. Question 21 from the second paper of 2009 asked a horrendous amount of detail about TURP syndrome, extending all the way to the metabolytes of glycine and its influence on the metabolism of ammonia. In addition, in Oh's Manual Delaney and Finfer spend about as much ink on TURP syndrome as they did on SIADH and CSW combined, so it must seem important to them in some way. In proportion to this interest from figures of authority, some extra space will be devoted here to TURP syndrome.

Thus:

### What the hell is glycine and what is it for?

Glycine is the smallest possible amino acid, consisting only of two carbon atoms, some hydrogen and the NH2 / COOH groups. According to Wikipedia, it is sweet-tasting. A 1.5% glycine solution (220 mmol/L) is usually the culprit behind TURP syndrome.  Risk factors for TURP syndrome include prolonged operation time (over 1 hour), resection of over 60g of prostate tissue, a perforation of the prostate or bladder, and hight irrigation fluid bag pressure (i.e. hanging higher than 70cm above the patient). TURPs are not the only situations where this can happen; irrigation fluid of the same type has also been used in hysteroscopy.

### Clinical features of TURP syndrome

Glycine itself has a well-known toxicity syndrome. The specific constellation of features includes haemodynamic instability, a decreased level of consciousness (with or without seizures) and hyponatremia which is usually iso-osmolar. On top of that, the  metabolism of glycine by oxidative deamination can result in a massive excess of ammonia, with its own delirium-generating effects. Traditionally, glycine toxicity causes blindness,  but stupour and coma are also common. A good article on this topic has a table (Table 1) which lists other unpleasant CNS manifestations, including dilated unreactive pupils, seziures and paralysis. The table is so good that it is reproduced below with minimal alteration (mainly, I just removed "coma" and "death" from the bottom of each category).

 Respiratory Respiratory  distress Cyanosis Cardiovascular Hypertension Bradycardia Dysrhythmia Hypotension Shock Haemolysis Acute  renal  failure Hyperammonaemia Neurological Nausea/vomiting Confusion/restlessness Blindness Twitches/seizures Lethargy/paralysis Dilated/nonreactive  pupils Encephalopathy

The abnormalities can develop immediately, or be delayed by up to 24 hours. Other irrigant solutions (eg. sorbitol and mannitol) can also do this, but only glycine causes blindness and hyperammonaemia. It is an inhibitory neurotransmitter in the spinal cord (where its famous antagonist is strychnine) and the retina, and it passes freely into the intracellular compartment. Likely, most of the problems from TURP syndrome are due to this molecule.

### Biochemical abnormalities in TURP syndrome

Glycine toxicity is associated with the following biochemical changes:

• Hyponatremia (by dilution)
• Hypoosmolarity (if an excess of water is absorbed; otherwise things stay isoosmolar)
• Hyperglycinaemia (glycine level can be up to 20mmol/L, according to Oh's Manual)
• Hyperserinaemia (serine is a major metabolite of glycine)
• Hyperammonaemia (ammonia is generated by by the deamination of glycine and serine)
• Hyperoxalaemia
• Hypocalcemia (due to chelation of calcium by the oxalate and glyoxylic acid)
• Metabolic acidosis: NAGMA due to absorption of fluid with a low strong ion difference, and HAGMA due to excess of oxalate and serine.

## References

Lai MY, Lin CC, Chung SL, Wu CH, Yang WC, Tseng YT. Milky plasma, diabetes, and severe hyponatremia. Kidney Int. 2009 May;75(9):996.

Vaswani SK, Sprague R. Pseudohyponatremia in multiple myeloma. South Med J. 1993 Feb;86(2):251-2.

Rhymer JC, Bell TJ, Perry KC, Ward JP. Hyponatraemia following transurethral resection of the prostate. Br J Urol. 1985 Aug;57(4):450-2.

LADENSON, JACK H., FRED S. APPLE, and DAVID D. KOCH. "Misleading hyponatremia due to hyperlipemia: a method-dependent error." Annals of internal medicine 95.6 (1981): 707-708.

Howard, John M., and Jordan Reed. "Pseudohyponatremia in Acute Hyperlipemic Pancreatitis: A Potential Pitfall in Therapy." Archives of Surgery 120.9 (1985): 1053-1055.

Fortgens, Philip, and Tahir S. Pillay. "Pseudohyponatremia revisited: a modern-day pitfall." Archives of pathology & laboratory medicine 135.4 (2011): 516-519.

Yu, Zhongxin, K. Michael Parker, and Kenneth E. Blick. "Markedly decreased serum sodium concentration in a patient with multiple myeloma." Laboratory Medicine 36.4 (2005): 224-226.

Bloth, B., T. Christensson, and H. Mellstedt. "Extreme hyponatremia in patients with myelomatosis." Acta medica Scandinavica 203.1‐6 (1978): 273-275.

King, Richard I., and Christopher M. Florkowski. "How paraproteins can affect laboratory assays: spurious results and biological effects." Pathology 42.5 (2010): 397-401.

Rhymer JC, Bell TJ, Perry KC, Ward JP. Hyponatraemia following transurethral resection of the prostate. Br J Urol. 1985 Aug;57(4):450-2.

Hahn, R. G. "Serum amino acid patterns and toxicity symptoms following the absorption of irrigant containing glycine in transurethral prostatic surgery." Acta anaesthesiologica scandinavica 32.6 (1988): 493-501.

Roesch, Ryland P., et al. "Ammonia toxicity resulting from glycine absorption during a transurethral resection of the prostate." Anesthesiology 58.6 (1983): 577-578.

Glycine Toxicity page from The Anesthesia Practice Manual for Spectrum by Tom VerLee.

Gravenstein, Dietrich. "Transurethral resection of the prostate (TURP) syndrome: a review of the pathophysiology and management." Anesthesia & Analgesia 84.2 (1997): 438-446.

Hahn, R. G., and M. Rundgren. "Vasopressin and amino acid concentrations in serum following absorption of irrigating fluid containing glycine and ethanol."British journal of anaesthesia 63.3 (1989): 337-339.

Stewart, PA Hamilton, and I. M. Barlow. "Metabolic effects of prostatectomy."Journal of the Royal Society of Medicine 82.12 (1989): 725-728.

Beal, J. L., et al. "Consequences of fluid absorption during transurethral resection of the prostate using distilled water or glycine 1.5 per cent." Canadian Journal of Anaesthesia 36.3 (1989): 278-282.

Fitzpatrick, J. M., G. P. Kasidas, and G. Alan Rose. "Hyperoxaluria following glycine irrigation for transurethral prostatectomy." British journal of urology 53.3 (1981): 250-252.