Hyponatremia Intervention Trial (HIT): Study Protocol of a Randomized, Controlled, Parallel-Group Trial With Blinded Outcome Assessment

Abstract

Background: Hyponatremia is the most common electrolyte disorder with a prevalence of up to 30% in hospitalized patients. In contrast to acute hyponatremia where the need for immediate treatment is well-recognized, chronic hyponatremia is often considered not clinically relevant. This is illustrated by reports showing that appropriate laboratory tests are ordered in <50% of patients and that up to 75% are still hyponatremic at discharge. At the same time, emerging evidence suggests an association between hyponatremia and adverse events including increased risk of mortality and rehospitalization.Methods: This is a randomized (1:1 ratio) controlled, superiority, parallel-group international multi-center trial with blinded outcome assessment. In total 2,278 participants will be enrolled. Participants will be randomly assigned to undergo either targeted correction of plasma sodium levels or standard of care during hospitalization. The primary outcome is the combined risk of death or re-hospitalization within 30 days.Discussion: All data on hyponatremia and mortality are derived from observational studies and often lack methodologic robustness. Consequently, the direct impact of hyponatremia on mortality and rehospitalization risk is still debated, resulting in a clinical equipoise whether in-hospital chronic hyponatremia should be treated or not. Therefore, a randomized controlled trial is required to study whether targeted plasma sodium correction reduces the risk of mortality and rehospitalization associated with hyponatremia.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT03557957.

Hyponatremia is associated with unfavorable outcomes after reperfusion treatment in acute ischemic stroke

“…Hyponatremia is commonly associated with higher mortality in hospitalized patients [23]. It remains, however, unclear whether hyponatremia by itself can contribute directly to mortality or is a marker for the severity of the underlying disease [24]. Although our study is unable to address causality, it is conceivable that hyponatremia—at least in part—contributes to morbidity and mortality by negatively affecting the disease course in acute ischemic stroke.…”

Diagnostic Workup and Outcome in Patients with Profound Hyponatremia

“…Adult, hospitalised patients from all disciplines were included in the study (general medicine, geriatric medicine and surgical departments). The chosen time period was five years after the 2014 hyponatremia clinical practice guidelines and before the initiation of the "Hyponatremia Intervention Trial" (HIT) [37]. The HIT is an international, randomised, controlled, multicentre trial to study the effects of targeted correction of plasma sodium versus standard of care, which started at KSBL in April 2021 and could have been a bias to our audit.…”

Hyponatremia Correction Rates and Mortality: Causality or Epiphenomenon?

“…However, surprisingly, several studies have shown that once sodium levels drop below 120 mmol/L, there is no increase in mortality despite the worsening hyponatremia; instead mortality actually decreases. 10 One possible explanation for this observation is that patients who survive with very low PNa (<110 mmol/L) are usually hospitalized due to drug-induced hyponatremia rather than severe illness. On the other hand, hyponatremia of mild to moderate severity (≥120 mmol/L) tends to occur more frequently among patients admitted for life-threatening conditions, such as heart failure or cirrhosis.…”

“…We eagerly await the results of the Targeted Correction of Plasma Sodium Levels in Hospitalized Patients with Hyponatremia (HIT) trial, an international multicenter randomized, controlled trial aiming to enroll 2278 hospitalized adult patients with PNa <130 mmol/L. 10 This study will compare mortality and 30-day rehospitalization in patients randomized to standard of care or targeted correction of hyponatremia following correction goals and limits recommended by the European clinical practice guidelines. However, the HIT trial may not be large enough to completely resolve the fast/slow correction debate.…”