Clinical trial NCT04402190: Hypotonic Hyponatremia: Criteria for the Correct Classification of Its Etiology and of Patient Volume Status
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
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Hyponatremia
Hyponatremia With Extracellular Fluid Depletion
Hyponatremia With Normal Extracellular Fluid Volume
Hyponatremia With Excess Extracellular Fluid Volume
Keywords: Hyponatremia
Hyponatremia with Extracellular Fluid Depletion
Hyponatremia with Normal Extracellular Fluid Volume
Hyponatremia with Excess Extracellular Fluid Volume
Hypotonic Hyponatremia
Volume Status
Intravascular Volume Status
Extracellular Fluid Volume Status
Copeptin
Lead sponsor: A.O.U. Città della Salute e della Scienza
Sponsor class: OTHER
First posted: 2020-05-26
Enrollment: 123
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: 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).

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Subtype classification of hypotonic hyponatremia according to the overall judgment of the clinical case by the point-of-care clinician
timeFrame: At ED admission
measure: Subtype classification of hypotonic hyponatremia according to the overall judgment of the clinical case by the point-of-care clinician
timeFrame: At hospital ward admission
measure: Physical Examination (PE) as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
timeFrame: At ED admission
measure: Physical Examination (PE) as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
timeFrame: At hospital ward admission
measure: Inferior Vena Cava (IVC) ultrasound evaluation as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
timeFrame: At ED admission
measure: Inferior Vena Cava (IVC) ultrasound evaluation as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
timeFrame: At hospital ward admission
measure: Serum creatinine as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
timeFrame: At ED admission
measure: Serum urea as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
timeFrame: At ED admission
measure: Serum urea / serum creatinine ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
timeFrame: At ED admission
measure: Urine sodium as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
timeFrame: At ED admission
measure: Urine sodium / urine osmolality ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
timeFrame: At ED admission
measure: Urine sodium / plasma osmolality ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
timeFrame: At ED admission
measure: Serum NT-proBNP as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
timeFrame: At ED admission
measure: Serum NT-proBNP / urine sodium ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
timeFrame: At ED admission
measure: Serum creatinine as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
timeFrame: At hospital ward admission
measure: Serum urea as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
timeFrame: At hospital ward admission
measure: Serum urea / serum creatinine ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
timeFrame: At hospital ward admission
measure: Urine sodium as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
timeFrame: At hospital ward admission
measure: Urine sodium / urine osmolality ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
timeFrame: At hospital ward admission
measure: Urine sodium / plasma osmolality ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
timeFrame: At hospital ward admission
measure: Plasma renin activity (PRA) as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
timeFrame: At hospital ward admission
measure: Uric acid as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
timeFrame: At hospital ward admission
Secondary outcomes:
measure: Plasma copeptin as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
timeFrame: At ED admission
measure: Plasma copeptin / urine sodium ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
timeFrame: At ED admission
measure: Plasma copeptin as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
timeFrame: At hospital ward admission
measure: Plasma copeptin / urine sodium ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
timeFrame: At hospital ward admission
Other outcomes:
measure: Length of hospitalization
timeFrame: Up to 6 months after ED admission
measure: Overall mortality
timeFrame: Up to 6 months after ED admission
Locations:
city: Torino
country: Italy
facility: AOU Città della Salute e della Scienza
state: Piemonte
Study officials:
affiliation: AOU Città della Salute e della Scienza, Torino
name: Ezio Ghigo, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
citation: 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.
citation: 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.
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.
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.
citation: 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.
citation: 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.
citation: Kumar S, Berl T. Sodium. Lancet. 1998 Jul 18;352(9123):220-8. doi: 10.1016/S0140-6736(97)12169-9.