What do nephrologists think the standard of care is?

Dr. Ayus: Well, nobody would disagree that the standard of care is to give hypertonic saline. But many people believe you need to use formulas to calculate how much fluid you’re going to give to these patients. We do not believe that the formulas currently in the literature are useful, because they don’t take into consideration that the patient is excreting urine. 

Those formulas would be useful in a closed system, but when you have a system that is open—because the patient is urinating—you can underestimate the correction and end up with higher serum sodium than you’re expecting.

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At what level is hyponatremia diagnosed?

Dr. Ayus: The diagnosis of hyponatremia is made at a sodium level of 135 mEq/L or lower. In the past we believed that if sodium was 130 or 128, no big deal. But, not any longer, because those people with this mild degree of hyponatremia, especially the elderly, can have gait abnormalities, and these are the people at high risk of falling and breaking their hip and having significant problems. (Nephrol Dial Transplant 2012;27:3725-3731)

Is hyponatremia ever directly fatal?

Dr. Ayus: In 1992 we published a seminal article in the Annals of Internal Medicine, “Postoperative Hyponatremic Encephalopathy in Menstruant Women” [1992;117:891-897]. That paper revolutionized the concept because at that time, everybody was saying that the risk for death in hyponatremia was related to the level of the sodium: the lower it was, the higher the chance of death, depending on how quickly the hyponatremia developed.

However, we found that the people who developed the most complications were young, menstruant females. And our study showed conclusively for the first time that if a premenopausal women and a man both undergo surgery and both develop hyponatremia, and the woman’s sodium level is 126 and the man’s is 100, the woman has a risk of death approximately 28 times higher than the man’s, even though her sodium level is higher. Being a young female was a significant risk factor for death from hyponatremia.

But the most impressive evidence is an editorial we just had published in Nephrology Dialysis Transplantation [2013;28:2206-2209] on the recreational drug Ecstasy. We were asked to comment on a study in the Netherlands that showed women were more prone to develop hyponatremia as a result of Ecstasy use. Our editorial explains clearly that there are a series of factors that make females more susceptible to both developing hyponatremia and developing neurologic symptoms of hyponatremia. 

When hyponatremia develops in a female, there is an impaired ability for the brain to adjust to that increased water volume compared to a males. Estrogen has an effect on the mechanism that regulates sodium contained in the brain, so there’s a molecular basis for this.

How does this knowledge help advance diagnosis or treatment of hyponatremia?

Dr. Ayus: Now we have identified that young females are at significant risk for developing this complication. And now we need to go back to the most important part, which is prevention. The single most important factor in preventing postoperative hyponatremic encephalopathy is the way the IV fluid is administered during and after surgery.

If you use hypotonic fluid—a concentration of less than 154 mEq/L—the chance for the patient to develop hyponatremia increases significantly, because at the same time you’re giving the solution, surgery pain and anesthesia increase vasopressin secretion, which is telling the kidney to retain water. That combination makes the person susceptible to hyponatremia. There’s a high risk for complications in a female who develops hyponatremia.

In 2003, we proposed [in the journal Pediatrics 2003;111:227-230] that the only parenteral fluid should be normal saline (0.9% sodium chloride). We proposed this for children, but now everybody agrees that this should also be the case for other patients.