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

Hyponatremia Clinical Trial

Official 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04402190
• Other study ID #: IPSO-URG
• Status: Completed
• Start date: June 1, 2018
• Est. completion date: February 28, 2020

Study information

• Verified date: May 2020
• Source: Azienda Ospedaliera Città della Salute e della Scienza di Torino
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

Description:

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:

1. 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;

2. 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 123
• Est. completion date: February 28, 2020
• Est. primary completion date: August 31, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Hyponatremia
• Hyponatremia With Excess Extracellular Fluid Volume
• Hyponatremia With Extracellular Fluid Depletion
• Hyponatremia With Normal Extracellular Fluid Volume
• Hypovolemia

Locations

Country	Name	City	State
Italy	AOU Città della Salute e della Scienza	Torino	Piemonte

Sponsors (1)

Lead Sponsor	Collaborator
Azienda Ospedaliera Città della Salute e della Scienza di Torino

Country where clinical trial is conducted

Italy, 

References & Publications (8)

Boursier G, Alméras 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. — View Citation

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. Review. — View Citation

Fenske W, Maier SK, Blechschmidt A, Allolio B, Störk 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. Erratum in: Am J Med. 2011 Oct;124(10):e9. — View Citation

Fenske W, Störk 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. — View Citation

Kumar S, Berl T. Sodium. Lancet. 1998 Jul 18;352(9123):220-8. Review. — View Citation

Nigro N, Winzeler B, Suter-Widmer I, Schuetz P, Arici B, Bally M, Blum CA, Nickel CH, Bingisser R, Bock A, Huber A, Müller 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. — View Citation

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. — View Citation

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. Erratum in: Eur J Endocrinol. 2014 Jul;171(1):X1. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Primary	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
Primary	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
Primary	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
Primary	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 hospital ward admission
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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