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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)

English title 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)
Applicant Christ-Crain Mirjam
Number 192979
Funding scheme Investigator Initiated Clinical Trials (IICT)
Research institution Abteilung Endokrinologie, Diabetologie und Metabolismus Universitätsspital Basel
Institution of higher education University of Basel - BS
Main discipline Internal Medicine
Start/End 01.11.2020 - 30.04.2025
Approved amount 2'979'892.00
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All Disciplines (3)

Discipline
Internal Medicine
Clinical Cardiovascular Research
Clinical Endocrinology

Keywords (4)

Hyponatremia; Mortality; targeted correction; Re-Hospitalization

Lay Summary (German)

Lead
Gezielte Behandlung der Hyponatriämie bei hospitalisierten Patienten - eine randomisierte, kontrollierte Studie - Die Hyponatriämie Interventionsstudie (HIT)
Lay summary

Ein zu tiefer Natrium-Spiegel im Blut (= Hyponaträmie) ist die häufigste Elektrolytstörung bei hospitalisierten Patienten, sie kann verschiedene Ursachen mit entsprechend unterschiedlicher Behandlung je nach Auslöser haben. Verschiedene Untersuchungen haben gezeigt, dass eine Hyponaträmie mit vermehrten klinischen Komplikationen, Spitalaufenthalten sowie erhöhter Sterblichkeit einhergeht. Trotz dieser Ergebnisse ist bis heute nicht klar, ob eine gezielte Behandlung der Hyponaträmie zu weniger Komplikationen sowie tieferer Sterblichkeit führt.
Das Ziel dieser Studie ist folglich zu untersuchen, ob eine gezielte Anhebung des Natrium-Spiegels im Blut im Vergleich zur bisherigen Standardbehandlung zu weniger Komplikationen und erneuten Hospitalisationen sowie tieferer Sterblichkeit führt. 

Insgesamt werden 2278 Patienten eingeschlossen. Die Patienten werden gemäss dem Zufallsprinzip in zwei Gruppen unterteilt (Gruppe A oder B).
? In der Gruppe A kontrolliert und behandelt ein auf Hyponaträmie-spezialisiertes Behandlungsteam täglich den Natriumspiegel mit dem Ziel, diesen baldmöglichst zu normalisieren.
? In der Gruppe B erhalten die Patienten die bisher übliche Standardbehandlung durch die Stationsärzte.
Die Behandlung wird bis zur Entlassung aus dem Spital fortgeführt. 30 Tage sowie 1 Jahr nach Einschluss in die Studie werden die Patienten erneut durch das Studienteam kontaktiert um mögliche Komplikationen oder erneute Hospitalisationen zu erfragen.

Diese Studie wird das zukünftige Management der Hyponatriämie, unabhängig vom Outcome der Studie, beeinflussen: Falls die Intervention eine reduzierte Sterblichkeit und Hospitalisationsrate aufzeigt, wird die Hyponatriämie in Zukunft substantiell anders und strenger behandelt werden. Falls die Intervention keinen Effekt aufzeigt, wird die Hyponatriämie in Zukunft mehr als Marker für den Schweregrad einer Krankheit, und weniger als Ursache zur Kenntnis genommen werden. 

Direct link to Lay Summary Last update: 05.10.2020

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Publications

Publication
Hyponatremia Intervention Trial (HIT): Study Protocol of a Randomized, Controlled, Parallel-Group Trial With Blinded Outcome Assessment
Refardt Julie, Pelouto Anissa, Potasso Laura, Hoorn Ewout J., Christ-Crain Mirjam (2021), Hyponatremia Intervention Trial (HIT): Study Protocol of a Randomized, Controlled, Parallel-Group Trial With Blinded Outcome Assessment, in Frontiers in Medicine, 8, n/a-n/a.

Abstract

Background and Rationale: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.
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