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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.
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:
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.
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| Measure | Description | Time Frame |
|---|---|---|
| Subtype classification of hypotonic hyponatremia according to the overall judgment of the clinical case by the point-of-care clinician | 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. | At ED admission |
| Subtype classification of hypotonic hyponatremia according to the overall judgment of the clinical case by the point-of-care clinician | 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. | At hospital ward admission |
| Physical Examination (PE) as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status | 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). | At ED admission |
| Physical Examination (PE) as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status | 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). |
| Measure | Description | Time Frame |
|---|---|---|
| Plasma copeptin as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status | 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. | At ED admission |
| Measure | Description | Time Frame |
|---|---|---|
| Length of hospitalization | 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. | Up to 6 months after ED admission |
Inclusion Criteria:
Exclusion Criteria:
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All consecutive patients admitted at the emergency department (ED) of our hospital in the time frames specified in the inclusion criteria with a detection, at the time of ED access, of moderate-severe hyponatremia (defined as serum sodium < 130 mmol/L at blood gas analysis).
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| Name | Affiliation | Role |
|---|---|---|
| Ezio Ghigo, MD | AOU Città della Salute e della Scienza Torino | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| AOU Città della Salute e della Scienza | Turin | Piedmont | 10126 | Italy |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24569125 | Background | Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, Decaux G, Fenske W, Hoorn EJ, Ichai C, Joannidis M, Soupart A, Zietse R, Haller M, van der Veer S, Van Biesen W, Nagler E; Hyponatraemia Guideline Development Group. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Eur J Endocrinol. 2014 Feb 25;170(3):G1-47. doi: 10.1530/EJE-13-1020. Print 2014 Mar. | |
| 20609688 |
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| At hospital ward admission |
| Inferior Vena Cava (IVC) ultrasound evaluation as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status | 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). | At ED admission |
| Inferior Vena Cava (IVC) ultrasound evaluation as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status | 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). | At hospital ward admission |
| Serum creatinine as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status | 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. | At ED admission |
| Serum urea as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status | 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. | At ED admission |
| Serum urea / serum creatinine ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status | 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. | At ED admission |
| Urine sodium as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status | 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. | At ED admission |
| Urine sodium / urine osmolality ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status | 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. | At ED admission |
| Urine sodium / plasma osmolality ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status | 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. | At ED admission |
| Serum NT-proBNP as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status | 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. | At ED admission |
| Serum NT-proBNP / urine sodium ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status | 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. | At ED admission |
| Serum creatinine as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status | 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. | At hospital ward admission |
| Serum urea as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status | 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. | At hospital ward admission |
| Serum urea / serum creatinine ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status | 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. | At hospital ward admission |
| Urine sodium as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status | 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. | At hospital ward admission |
| Urine sodium / urine osmolality ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status | 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. | At hospital ward admission |
| Urine sodium / plasma osmolality ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status | 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. | At hospital ward admission |
| Plasma renin activity (PRA) as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status | 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. | At hospital ward admission |
| Uric acid as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status | 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. | At hospital ward admission |
| Plasma copeptin / urine sodium ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status | 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. | At ED admission |
| Plasma copeptin as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status | 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. | At hospital ward admission |
| Plasma copeptin / urine sodium ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status | 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. | At hospital ward admission |
| Overall mortality |
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. |
| Up to 6 months after ED admission |
| Background |
| Fenske W, Maier SK, Blechschmidt A, Allolio B, Stork S. Utility and limitations of the traditional diagnostic approach to hyponatremia: a diagnostic study. Am J Med. 2010 Jul;123(7):652-7. doi: 10.1016/j.amjmed.2010.01.013. |
| 18984663 | Background | Fenske W, Stork S, Blechschmidt A, Maier SG, Morgenthaler NG, Allolio B. Copeptin in the differential diagnosis of hyponatremia. J Clin Endocrinol Metab. 2009 Jan;94(1):123-9. doi: 10.1210/jc.2008-1426. Epub 2008 Nov 4. |
| 27156761 | Background | Christ-Crain M, Morgenthaler NG, Fenske W. Copeptin as a biomarker and a diagnostic tool in the evaluation of patients with polyuria-polydipsia and hyponatremia. Best Pract Res Clin Endocrinol Metab. 2016 Mar;30(2):235-47. doi: 10.1016/j.beem.2016.02.003. Epub 2016 Feb 16. |
| 28556237 | Background | Sailer CO, Winzeler B, Nigro N, Suter-Widmer I, Arici B, Bally M, Schuetz P, Mueller B, Christ-Crain M. Characteristics and outcomes of patients with profound hyponatraemia due to primary polydipsia. Clin Endocrinol (Oxf). 2017 Nov;87(5):492-499. doi: 10.1111/cen.13384. Epub 2017 Jul 7. |
| 25828045 | Background | Boursier G, Almeras M, Buthiau D, Jugant S, Daubin D, Kuster N, Dupuy AM, Ribstein J, Klouche K, Cristol JP. CT-pro-AVP as a tool for assessment of intravascular volume depletion in severe hyponatremia. Clin Biochem. 2015 Jul;48(10-11):640-5. doi: 10.1016/j.clinbiochem.2015.03.013. Epub 2015 Mar 28. |
| 27658031 | Background | Nigro N, Winzeler B, Suter-Widmer I, Schuetz P, Arici B, Bally M, Blum CA, Nickel CH, Bingisser R, Bock A, Huber A, Muller B, Christ-Crain M. Evaluation of copeptin and commonly used laboratory parameters for the differential diagnosis of profound hyponatraemia in hospitalized patients: 'The Co-MED Study'. Clin Endocrinol (Oxf). 2017 Mar;86(3):456-462. doi: 10.1111/cen.13243. Epub 2016 Oct 7. |
| 9683227 | Background | Kumar S, Berl T. Sodium. Lancet. 1998 Jul 18;352(9123):220-8. doi: 10.1016/S0140-6736(97)12169-9. |
| ID | Term |
|---|---|
| D007010 | Hyponatremia |
| D003919 | Diabetes Insipidus |
| ID | Term |
|---|---|
| D014883 | Water-Electrolyte Imbalance |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D010900 | Pituitary Diseases |
| D004700 | Endocrine System Diseases |
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