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NCT Number: NCT04402190

Hypotonic Hyponatremia: Criteria for the Correct Classification of Its Etiology and of Patient Volume Status

Hyponatremia is the most frequent electrolyte disorder encountered in clinical practice. The patient approach, however, is still problematic, above all because hyponatremia is a manifestation correlated to various pathological conditions, with complex etiopathogenesis.

Even though some algorithms have been proposed to correctly assess hyponatremia subtype classification and patient volume status, there is no single parameter that has proven to be able alone to perfectly achieve this result.

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Key information

Conditions

Hyponatremia Diabetes Insipidus Endocrine System Diseases Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Hyponatremia With Excess Extracellular Fluid Volume Hyponatremia With Extracellular Fluid Depletion Hyponatremia With Normal Extracellular Fluid Volume Kidney Diseases Male Urogenital Diseases Metabolic Diseases Nutritional and Metabolic Diseases Pituitary Diseases Urogenital Diseases Urologic Diseases Water-Electrolyte Imbalance

Age range

18 year and older

Sex eligibility

All sexes

Study type

Observational

Primary location

AOU Città della Salute e della Scienza

Turin, Piedmont, 10126, Italy

About this study

Hyponatremia is the most frequent electrolyte disorder encountered in clinical practice and is often associated with increased mortality, morbidity and risk of hospitalization. The patient approach, however, is still problematic, above all because hyponatremia is a manifestation correlated to various pathological conditions, with complex etiopathogenesis.

The most commonly used classification of hypotonic hyponatremia is, nowadays, the one described in a famous review by Kumar and Berl (see Bibliography). Probably the most crucial point in this classification is represented by the correct assessment of Extracellular Fluid Volume Status (i.e. hypovolemia, euvolemia, hypervolemia).

Even though some algorithms have been proposed to correctly assess hyponatremia subtype classification and patient volume status, there is no single parameter that has proven to be able alone to perfectly achieve this result.

In the current study, the reference test (gold standard) for the definitive assessment of hyponatremia subtype classification and patient volume status was a post-discharge re-evaluation of all the available evidence (with the exception of plasma copeptin levels) carried out by two independent neuroendocrinologists with specific expertise in sodium disorders. In case of disagreement, the experts proceeded to a discussion and comparison of their opinions, in order to produce a shared one.

Using this gold standard, the main aims of this observational prospective study were:

  • to estimate the diagnostic accuracy of the clinicians in identifying the subtype of hyponatremia at the first evaluation of the patients in the ED and then at the admission to the wards;
  • to evaluate the diagnostic accuracy of the most important methods suggested by the literature (clinical, imaging, biochemical) for the assessment of Extracellular Fluid Volume.

In addition to this, in recent years copeptin has been shown to be a promising parameter for the evaluation of sodium disorders and water imbalances, but its diagnostic role in the setting of hyponatremic patients is still largely unknown. Therefore, a secondary objective of the study was to specifically evaluate the utility of copeptin (whose values - as specified before - were hidden to the neuroendocrinologists in charge of defining the gold standard diagnoses for each patient) for the assessment of hyponatremia subtype classification and patient volume status.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Access to the emergency department (ED) of our hospital from Monday to Thursday, between 8 am and 6 pm (time constraint needed so that all the necessary laboratory analyzes could be correctly completed)
  • Detection at the time of ED access of moderate-severe hyponatremia, defined as serum sodium < 130 mmol/L at blood gas analysis (BGA)
  • Need for hospitalization

Exclusion criteria

  • Programmed hospitalization that did not include access through the ED

Treatment and study plan

Primary outcomes

  1. Subtype classification of hypotonic hyponatremia according to the overall judgment of the clinical case by the point-of-care clinician

    Time frame: At ED admission

    The point-of-care clinician was asked to provide a subtype classification of hypotonic hyponatremia according to his/her overall judgment of the clinical case (using Kumar and Berl classification classes as a reference frame). This will be compared to the gold standard reference (as defined in the "Study Description" Section). The strength of agreement (by Cohen's kappa) and the accuracy will thus be evaluated.

  2. Subtype classification of hypotonic hyponatremia according to the overall judgment of the clinical case by the point-of-care clinician

    Time frame: At hospital ward admission

    The point-of-care clinician was asked to provide a subtype classification of hypotonic hyponatremia according to his/her overall judgment of the clinical case (using Kumar and Berl classification classes as a reference frame). This will be compared to the gold standard reference (as defined in the "Study Description" Section). The strength of agreement (by Cohen's kappa) and the accuracy will thus be evaluated.

  3. Physical Examination (PE) as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status

    Time frame: At ED admission

    Elements of PE relevant for ECF Volume Status assessment were recorded (blood pressure, heart rate, pulmonary crepitations/rales, jugular vein distension, peripheral edema, dry mucous membranes). The overall evaluation of ECF Volume Status based on PE alone will be compared to the gold standard reference (as defined in the "Study Description" Section).

  4. Physical Examination (PE) as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status

    Time frame: At hospital ward admission

    Elements of PE relevant for ECF Volume Status assessment were recorded (blood pressure, heart rate, pulmonary crepitations/rales, jugular vein distension, peripheral edema, dry mucous membranes). The overall evaluation of ECF Volume Status based on PE alone will be compared to the gold standard reference (as defined in the "Study Description" Section).

  5. Inferior Vena Cava (IVC) ultrasound evaluation as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status

    Time frame: At ED admission

    IVC diameter and collapsibility were recorded. The overall evaluation of ECF Volume Status based on IVC ultrasound evaluation alone will be compared to the gold standard reference (as defined in the "Study Description" Section).

  6. Inferior Vena Cava (IVC) ultrasound evaluation as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status

    Time frame: At hospital ward admission

    IVC diameter and collapsibility were recorded. The overall evaluation of ECF Volume Status based on IVC ultrasound evaluation alone will be compared to the gold standard reference (as defined in the "Study Description" Section).

  7. Serum creatinine as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status

    Time frame: At ED admission

    Serum creatinine (mg/dl) will be used to estimate GFR (ml/min) according to CKD-EPI formula. eGFR will then be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.

  8. Serum urea as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status

    Time frame: At ED admission

    Serum urea (mg/dl) will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.

  9. Serum urea / serum creatinine ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status

    Time frame: At ED admission

    Serum urea / serum creatinine ratio will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.

  10. Urine sodium as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status

    Time frame: At ED admission

    Urine sodium (mmol/L), evaluated on a spot sample, will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.

  11. Urine sodium / urine osmolality ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status

    Time frame: At ED admission

    Urine sodium / urine osmolality ratio will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.

  12. Urine sodium / plasma osmolality ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status

    Time frame: At ED admission

    Urine sodium / plasma osmolality ratio will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.

  13. Serum NT-proBNP as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status

    Time frame: At ED admission

    Serum NT-proBNP (pg/ml) will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.

  14. Serum NT-proBNP / urine sodium ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status

    Time frame: At ED admission

    Serum NT-proBNP / urine sodium ratio will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.

  15. Serum creatinine as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status

    Time frame: At hospital ward admission

    Serum creatinine (mg/dl) will be used to estimate GFR (ml/min) according to CKD-EPI formula. eGFR will then be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.

  16. Serum urea as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status

    Time frame: At hospital ward admission

    Serum urea (mg/dl) will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.

  17. Serum urea / serum creatinine ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status

    Time frame: At hospital ward admission

    Serum urea / serum creatinine ratio will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.

  18. Urine sodium as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status

    Time frame: At hospital ward admission

    Urine sodium (mmol/L), evaluated on a spot sample, will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.

  19. Urine sodium / urine osmolality ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status

    Time frame: At hospital ward admission

    Urine sodium / urine osmolality ratio will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.

  20. Urine sodium / plasma osmolality ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status

    Time frame: At hospital ward admission

    Urine sodium / plasma osmolality ratio will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.

  21. Plasma renin activity (PRA) as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status

    Time frame: At hospital ward admission

    PRA (ng/ml/h) will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.

  22. Uric acid as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status

    Time frame: At hospital ward admission

    Uric acid (mg/dl) will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.

Secondary outcomes

  1. Plasma copeptin as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status

    Time frame: At ED admission

    Plasma copeptin (pmol/L) will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.

  2. Plasma copeptin / urine sodium ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status

    Time frame: At ED admission

    Plasma copeptin / urine sodium ratio will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.

  3. Plasma copeptin as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status

    Time frame: At hospital ward admission

    Plasma copeptin (pmol/L) will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.

  4. Plasma copeptin / urine sodium ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status

    Time frame: At hospital ward admission

    Plasma copeptin / urine sodium ratio will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.

Other outcomes

  1. Length of hospitalization

    Time frame: Up to 6 months after ED admission

    The length of hospitalization will be compared across subgroups according to hyponatremia subtype classification. As already previously described, these subgroups will be identified by the gold standard reference defined in the "Study Description" Section.

  2. Overall mortality

    Time frame: Up to 6 months after ED admission

    All deaths occurring during hospitalization and/or within 6 months after hospital discharge will be registered. The overall mortality will be compared across subgroups (using a survival analysis model) according to hyponatremia subtype classification. As already previously described, these subgroups will be identified by the gold standard reference defined in the "Study Description" Section.

Sponsors and collaborators

Lead sponsor

A.O.U. Città della Salute e della Scienza

Other

Registry information

Official study title

Hypotonic Hyponatremia: Criteria for the Correct Classification of Its Etiology and of Patient Volume Status at the Access in the Emergency Department and at the Subsequent Re-evaluation in Hospital Wards

Important dates

Study start
2018
Primary completion
2019
Study completion
2020
First posted
May 26, 2020
Registry last updated
May 26, 2020

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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