SAN DIEGO — Use of targeted plasma sodium correction did not reduce 30-day mortality and readmission rates in hospitalized patients with hyponatremia despite often achieving normonatremia, results of a large, prospective, randomized trial showed.

The findings suggest that “hyponatremia in hospitalized patients is more a marker of a worse outcome than a cause of it,” said first study author Julie Refardt, MD, PhD, University Hospital Basel, Basel, Switzerland. Medscape Medical News.

With a wide range of potential causes of hyponatremia, sometimes overlapping, diagnosis as well as appropriate treatment can be challenging. Findings from a hyponatremia registry showed that up to 25% of hospitalized patients with mild to moderate hyponatremia never received treatment, and most patients who had hyponatremia in the hospital were discharged while still hyponatremic.

The implications can be serious, with chronic hyponatremia associated with problems such as neurocognitive impairment, gait instability, and falls, as well as an increased rate of readmissions and adverse outcomes, including death.

However, data are lacking on how — or even if — appropriate treatment of hyponatremia can prevent these disorders, said Refardt, who presented the results here at Kidney Week 2024: Annual Meeting of the American Society of Nephrology.

To investigate, she and her colleagues conducted a randomized, international, multicenter Hyponatremia Intervention Trial (HIT), enrolling 2174 patients hospitalized at nine centers in Europe with hyponatremia, defined for the study as serum sodium concentrations < 130 mmol/ IT. Patients were recruited between August 2018 and April 2024.

Study participants were randomized to either undergo targeted correction of plasma sodium levels based on the European Hyponatremia and Cardiology and Hepatology guidelines (n = 1079) or to a control group that received correction of hyponatremia based on standard practice (n = 1095). Standard practice often involved either no treatment or only fluid restriction, Refardt explained.

The mean age of all participants was approximately 72.5 years, and approximately 48% were male. About 53.8% had euvolemia, 30.8% had hypovolemia, and 15.4% had hypervolemia, with approximately equal proportions in both groups.

Patients were excluded if they had severe symptomatic hyponatremia requiring hypertonic saline or if they had end-stage renal disease or active liver failure or were receiving end-of-life care.

Overall, 641 (60.4%) patients in the intervention group achieved normonatremia compared with 493 (46.2%) patients in the control group.

For the coprimary endpoints, death occurred within 30 days in almost identical proportions of patients in the intervention and control groups (8.6% and 8.5%, respectively), while hospitalization within 30 days also occurred in almost the same percentages (13.0% versus 14.0%, respectively).

Combined, the overall event rate was not significantly different, occurring in 21.0% of patients in the intervention group and 22.2% of patients in the control group (p = .50).

At discharge, 55.9% of the intervention group and 36.9% of the control group had normonatremia, while 41.5% and 41.3% of the intervention and control groups, respectively, developed hyponatremia within 30 days.

Those who achieved normonatremia at discharge were 25% less likely to experience the primary outcome; however, the association was independent of whether the patients received the intervention or not, noted Refardt.

Results were consistent in a subgroup analysis that included severity of hyponatremia, etiology, treatment, sex, and age.

Rates of sodium overcorrection were low, occurring in 2.4% of the intervention group and 1.5% of the control group (p = .143), and there were also no significant differences in adverse events due to sodium overcorrection (1.2% vs 0.8%, respectively; p = .372) or cases of severely symptomatic hyponatremia (0.5% and 0.1%; p = .0983).

Refardt noted that key caveats include that the results only reflect outcomes involving hospitalized patients. In addition, most patients had mild to moderate hyponatremia.

However, she said, the results were a surprise to the authors.

“Having been researching hyponatremia for some time and knowing all the adverse outcomes associated with it, we expected a positive result,” she said. Medscape Medical News.

“However, the results are compelling and also robust in subgroup analyses.”

Refardt also noted that the rate of only 60% of patients in the intervention group achieving normonatremia was disappointingly low. We concluded that “in some patients with hyponatremia, you just can’t (get better) with the guideline treatment that we have right now because they’re too sick,” she told the presentation audience.

That said, she emphasized that “an important message is that our results deliver not we suggest you should not treat hyponatremia because the control group received the standard of care.”

It further removes overcorrection concerns

Commenting on the study, discussant Carol Pollock, clinical professor of medicine at the University of Sydney, Sydney, Australia, said caveats include questions such as how chronic versus acute hyponatremia was determined in the study, which might alter treatment and by what proportion. of patients had comorbidities, such as malnutrition or alcoholism, which dictate how quickly sodium should be corrected.

She noted the concern that doctors had around the potential for over-correcting the hyponatremia that leads to the rare but potentially devastating osmotic demyelination syndrome (ODS).

Recent studies, however, incl a 2023 study who analyzed more than 22,000 hospitalizations, showed only a very small fraction of patients (0.05%) developing ODS in the context of rapid correction of hyponatremia.

Pollock said the results of the new study make her “more comfortable about trying to improve hyponatremia more quickly in patients with moderate levels of hyponatremia with the goal of early discharge.”

“How this is done is not yet clear and depends on the cause,” she said, with “options including fluid restriction or rehydration, depending on volume status; K replenishment; loop diuretics; oral urea; AVP antagonists; sodium-glucose cotransporter-2 inhibitors; and 3% sodium chloride.”

HIT was funded by a clinical trial grant from the Swiss National Science Foundation. Refardt had no disclosures to report. Pollock revealed that he is an advisor to Otsuka.