Targeted correction of plasma sodium levels in hospitalized patients with hyponatremia: a randomized, controlled, parallel-group trial with blinded outcome-assessment - The Hyponatremia Intervention Trial (HIT trial)

Hyponatremia is the most common electrolyte disorder with a prevalence of up to 30% in hospitalized patients. It can be caused by the underlying disease, prescribed drugs, or aspecific stimuli such as nausea and pain. Hyponatremia may be life-threatening if it develops acutely and causes cerebral edema with neurological symptoms. The treatment of acute symptomatic hyponatremia is therefore straight forward and implies the administration of hypertonic saline to treat cerebral edema. In contrast, the rationale for treatment of chronic hyponatremia - the most prevalent subtype - is less evident. There are no intervention studies to show that correcting chronic hyponatremia improves outcomes.Importantly, there is increasing data showing an association between chronic hyponatremia and complications such as falls or attention deficit, as well as increased risk of fractures and osteoporosis. It has also been reported that hyponatremia is associated with a poorer prognosis of cardiac, hepatic, kidney and pulmonary diseases as well as the overall outcome of ICU patients resulting in a significant association with an increased mortality and readmission risk. However, it is unclear whether these are merely associations or indicate causality: despite several retrospective analyses showing improvement of readmission and mortality rates, as well as some small uncontrolled studies reporting reduction of adverse events with plasma sodium correction, there is a complete lack of randomized clinical trials investigating whether correction of hyponatremia counteracts the increased risk of readmission and mortality. Thus, there is clinical equipoise on whether chronic hyponatremia should be treated or not. Therefore, the aim of this intervention study is to determine the benefits and harms of a targeted correction of plasma sodium concentration on the combined endpoint 30-day mortality and rehospitalization rate. Patients will be randomly assigned to targeted correction of plasma sodium concentration or standard care alone. Study Design: Pragmatic randomized (1:1 ratio) controlled, superiority, parallel-group international multi-center study with blinded outcome assessment.Patients: Hospitalized patients with chronic hypotonic hyponatremia <130mmol/l. Patients requiring acute treatment with 3% saline infusion due to severe symptomatic hyponatremia, patients on dialysis, patients with acute liver failure, encephalopathic complications of liver failure or hepatorenal syndrome will be excluded. Intervention: Targeted correction of plasma sodium concentrationComparison: Current standard careOutcome measures: The primary objective is to investigate whether targeted correction of hyponatremia compared to standard care alone reduces the combined risk of death or rehospitalization within 30 days. Secondary objectives will include: Short- (30 days) and longterm (1 year) risk of death and rehospitalization; other clinical outcomes (neurocognition, quality of life, falls, fractures, length of hospital stay); Safety of the intervention; Exploratory analysis of biomarkers for hyponatremia. Main statistical hypothesis and sample size calculation:The intervention is superior to standard care by reducing the patients risk of death or re-hospitalization within 30 days from 23% to 18%. 2050 patients are required to detect an effect that is relevant for patients, clinicians and policy makers, i.e. an absolute reduction of 5% of the primary outcome (combined mortality and rehospitalization rate) with a statistical power of 80% (two-sided significance level 5%). With an assumed drop-out rate of 10 %, 2278 patients should be recruited.Importance: This study will influence future hyponatremia management on a national and international level regardless of its outcome:If the intervention results in a significant reduction of mortality and rehospitalization rate, hyponatremia awareness and its consecutive treatment during hospitalization will change substantially.If the intervention shows no effect on mortality and rehospitalization rate, hyponatremia will be recognized more as a marker of severity of the disease and not as its cause. Current treatment guidelines will be adapted.