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Mirjam Christ-Crain @ChristCrain

Mirjam Christ-Crain is Full Professor and Deputy Chief of Endocrinology at the University Hospital of Basel, Switzerland. Her main research interest is on vasopressin-dependent disorders of fluid homeostasis, i.e. vasopressin deficiency and hyponatremia. She authored and co-authored more than 300 publications and received several honors and awards for her research.

Competitors for the Hyponatremia Correction Region

Team 1: Rapid Correction vs Team 2: Slow Correction

Image generated by Evan Zeitler using Image Creator from Microsoft Designer, accessed via https://www.bing.com/images/create, January, 2024. After using the tool to generate the image, Zeitler and the NephMadness Executive Team reviewed and take full responsibility for the final graphic image.

For the most common electrolyte disorder, hyponatremia is brimming with controversy concerning diagnosis, and especially treatment. It frazzles not only internal medicine residents, but also nephrologists and endocrinologists who all think that they know best about water balance and extracellular volume physiology.

The most feared complication of hyponatremia treatment is Osmotic Demyelination Syndrome (ODS), a symptom complex associated with overly rapid sodium correction. This has led to international guidelines with strict speed limits stratified by risk. ODS is a potentially devastating complication, and this is why the winner of Hyponatremia Region in my opinion should be team Slow Correction!

What do we know about ODS? The exact pathophysiology of demyelination is incompletely understood, but we know that the combined insult of crenation with influx of intracellular cations (sodium, potassium) to compensate for the absence of organic osmolytes leads to protein aggregation and DNA fragmentation, prompting apoptosis. There is strong preclinical evidence that osmotic stress of rapid serum sodium correction can damage the protective neural myelin sheath, with severe, potentially fatal, consequences. As often is the case, it is difficult to transfer preclinical evidence to patients, since causality is much more challenging to prove in clinical trials.

Two recent large observational studies have now challenged the recommended correction rates and the existing preclinical evidence, at least in the opinion of team Rapid Correction. But is there really enough evidence to challenge the established speed limits?

Both studies reported a very low prevalence of ODS; however, it was already known that this is (fortunately!) a rare condition. In addition, underreporting is highly likely, knowing that the delay of symptoms (up to 7 days) and radiological findings (up to 3 weeks) makes for a difficult diagnosis. Especially in the first study from MacMillan et al, nearly 90% of the patients had sodium levels >120mmol/L, a population in which ODS is known to be extremely rare. In patients with sodium <110 mmol/L ODS was seen in 2.6%, which is too common to ignore.

Looking at the study from Seethapathy et al, it is true that the group of patients with a correction rate >10 mmol/L/day had a better outcome than those with a correction rate of <6 mmol/L/day or those in the reference group with a correction rate of 6-10 mmol/L/day. However, it is well known that hyponatremia is an indicator of disease severity (i.e., in pneumonia, stroke, sepsis etc.) Generally, the lower the sodium, the worse the prognosis and outcome, and the higher the mortality. Every doctor knows from experience that correction of hyponatremia becomes extremely difficult in severely ill patients with many comorbidities. Not all underlying disease factors can be corrected for by multivariable analysis. So how can we conclude from these observational retrospective data whether association means causation?

The only way to obtain enough data to challenge the correction limits or transfer the preclinical evidence of causality to human studies is to conduct a prospective randomized intervention trial. Patients should be randomized into a “standard of care per guidelines” group versus “rapid correction of >10-12mmoL/L/day” group. This study should ideally be performed in a multicenter multinational setting. Before having such data, in dubio we should stick to the current guidelines and correct slowly. Preventing the devastating ODS cases should be more important than decreasing length of stay and hospital free days to reduce hospital costs!

Lastly, team Rapid Correction states that we need to tailor our treatment to the patient at hand, knowing that most will be at low risk for ODS, reserving caution for patients with a history of alcohol abuse disorder, malnutrition, or hypokalemia. I couldn’t agree more! But this is not contradicting the guidelines! It is not the guidelines’ fault when they are misinterpreted and indiscriminately applied to all patients.

So, in conclusion, until waiting for robust RCT evidence, the winner for me is the Slow Correction team, with the recommendation to be especially cautious with patients at high risk for ODS while applying common sense to those at low or moderate risk.

Let’s keep in mind our Hippocratic Oath and its famous maxim: primum non nocere!

Copyright: DarSzach/Shutterstock

– Guest Post written by Mirjam Christ-Crain @ChristCrain

As with all content on the AJKD Blog, the opinions expressed are those of the author of each post and are not necessarily shared or endorsed by the AJKD Blog, AJKD, the National Kidney Foundation, Elsevier, or any other entity unless explicitly stated.

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