A Randomized Trial of Targeted Hyponatremia Correction in Hospitalized Patients

Abstract Background: Chronic hyponatremia is associated with adverse outcomes, including falls, neurocognitive disorders, and mortality, but whether hyponatremia itself increases morbidity and mortality, or is simply an indicator of underlying disease severity, remains unclear. We aimed to evaluate the effects of targeted hyponatremia correction versus routine care on mortality and rehospitalization rates. Methods: We conducted a randomized, controlled, parallel-group, multicenter trial across nine European centers. Hospitalized participants with plasma sodium lower than 130 mmol/l were assigned to undergo either a multifaceted targeted correction of hyponatremia (intervention) or routine care for hyponatremia (control). The primary outcome was the combined risk of death or rehospitalization within 30 days of trial inclusion. Results: A total of 2173 patients were randomly assigned to intervention (n=1079) or control (n=1094). The median age was 73 years (interquartile range, 63 to 81) and 48% were male. The median baseline sodium levels were 127 mmol/l (interquartile range, 124 to 128) in both groups. The mean (± standard deviation) maximum absolute change in sodium levels during the treatment period was 10.0 mmol/l (±5.6) in the intervention group, compared with 8.7 mmol/l (±5.6) in the control group, resulting in normal sodium levels (defined as 135-145 mmol/l) in 641 (60.4%) and 492 (46.2%) patients in the intervention and control groups, respectively. Within 30 days after inclusion, the primary outcome occurred in 20.5% (218 of 1065 patients) in the intervention group and 21.8% (234 of 1073 patients) in the control group (estimated absolute difference, -1.3 percentage points; 95% confidence interval, -4.9 to 2.2; P=0.45). Death occurred in 86 (8.0%) patients and rehospitalization in 141 (13.2%) patients in the intervention group compared with 88 (8.0%) patients and 151 (14.1%) patients in the control group. Overcorrection occurred in 25 (2.3%) patients in the intervention group and 16 (1.4%) patients in the control group; no cases of osmotic demyelination syndrome were observed. Conclusions: In hospitalized patients with chronic hyponatremia, a targeted correction intervention resulted in higher normonatremia rates but did not reduce a composite outcome of 30-day mortality and rehospitalization. (Funded by the Swiss National Science Foundation [grant number, 33 IC30_192979]; ClinicalTrials.gov number, NCT03557957.).