Inappropriate therapy of euvolemic hyponatremia, the most frequent type of hyponatremia in SARS-CoV-2 infection, is associated with increased mortality in COVID-19 patients.

Introduction: Admission hyponatremia, frequent in patients hospitalized for COVID-19, has been associated with increased mortality. However, although euvolemic hyponatremia secondary to the Syndrome of Inappropriate Antidiuresis (SIAD) is the single most common cause of hyponatremia in community-acquired pneumonia (CAP), a thorough and rigorous assessment of the volemia of hyponatremic COVID-19 subjects has yet to be described. We sought to identify factors contributing to mortality and hospital length-of-stay (LOS) in hospitalized COVID-19 patients admitted with hyponatremia, taking volemia into account. Method: Retrospective study of 247 patients admitted with COVID-19 to a tertiary hospital in Madrid, Spain from March 1st through March 30th, 2020, with a glycemia-corrected serum sodium level (SNa) < 135 mmol/L. Variables were collected at admission, at 2nd-3rd day of hospitalization, and ensuing days when hyponatremia persisted. Admission volemia (based on both physical and analytical parameters), therapy, and its adequacy as a function of volemia, were determined. Results: Age: 68 years [56-81]; 39.9% were female. Median admission SNa was 133 mmol/L [131- 134]. Hyponatremia was mild (SNa 131-134 mmol/L) in 188/247 (76%). Volemia was available in 208/247 patients; 57.2% were euvolemic and the rest (42.8%) hypovolemic. Hyponatremia was left untreated in 154/247 (62.3%) patients. Admission therapy was not concordant with volemia in 43/84 (51.2%). In fact, the majority of treated euvolemic patients received incorrect therapy with isotonic saline (37/41, 90.2%), whereas hypovolemics did not (p=0.001). The latter showed higher mortality rates than those receiving adequate or no therapy (36.7% vs. 19% respectively, p=0.023). The administration of isotonic saline to euvolemic hyponatremic subjects was independently associated with an elevation of in-hospital mortality (Odds Ratio: 3.877, 95%; Confidence Interval: 1.25-12.03). Conclusion: Hyponatremia in COVID-19 is predominantly euvolemic. Isotonic saline infusion therapy in euvolemic hyponatremic COVID-19 patients can lead to an increased mortality rate. Thus, an exhaustive and precise volemic assessment of the hyponatremic patient with CAP, particularly when due to COVID-19, is mandatory before instauration of therapy, even when hyponatremia is mild.

Aetiological diagnosis of hyponatraemia in non-critical patients on total parenteral nutrition: A prospective multicentre study.

BACKGROUND: In patients receiving total parenteral nutrition (TPN), the frequency of hyponatraemia is high. However, the causes of hyponatraemia in TPN have not been elucidated, although diagnosis is required for appropriate therapy. The aim of this study is to describe the aetiology of hyponatraemia in non-critical hospitalised patients receiving TPN. METHODS: Prospective multicentre study in 19 Spanish hospitals. Non-critically hyponatraemic patients receiving TPN and presenting hyponatraemia over a 9-month period were studied. Data collected included sex, age, previous comorbidities, and serum sodium levels (SNa) before and following TPN initiation. Parameters for study of hyponatraemia were also included: clinical volaemia, the presence of pain, nausea, gastrointestinal losses, diuretic use, oedema, renal function, plasma and urine osmolality, urinary electrolytes, cortisolaemia, and thyroid stimulating hormone. RESULTS: 162 patients were included, 53.7% males, age 66.4 (SD13.8) years. Volume status was evaluated in 142 (88%): 21 (14.8%) were hypovolaemic, 96 (67.6%) euvolaemic and 25 (17.6%) hypervolaemic. In 111/142 patients the analytical assessment of hyponatraemia was completed. Hypovolaemic hyponatraemia was secondary to GI losses in 10/111 (9%), and to diuretics in 3/111 (2.7%). Euvolaemic hyponatraemia was due to Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH) in 47/111 (42.4%), and to physiological stimuli of Arginine Vasopressin (AVP) secretion in 28/111 (25.2%). Hypervolaemic hyponatraemia was induced by heart failure in 19/111 (17.1%), cirrhosis of the liver in 4/111 (3.6%). CONCLUSIONS: SIADH was the most frequent cause of hyponatraemia in patients receiving TPN. The second most frequent cause was physiological stimuli of AVP secretion induced by pain/nausea.

Aetiological diagnosis of hyponatraemia in non-critical patients on total parenteral nutrition: A prospective multicentre study.

BACKGROUND: In patients receiving total parenteral nutrition (TPN), the frequency of hyponatraemia is high. However, the causes of hyponatraemia in TPN have not been elucidated, although diagnosis is required for appropriate therapy. The aim of this study is to describe the aetiology of hyponatraemia in non-critical hospitalised patients receiving TPN. METHODS: Prospective multicentre study in 19 Spanish hospitals. Non-critically hyponatraemic patients receiving TPN and presenting hyponatraemia over a 9-month period were studied. Data collected included sex, age, previous comorbidities, and serum sodium levels (SNa) before and following TPN initiation. Parameters for study of hyponatraemia were also included: clinical volaemia, the presence of pain, nausea, gastrointestinal losses, diuretic use, oedema, renal function, plasma and urine osmolality, urinary electrolytes, cortisolaemia, and thyroid stimulating hormone. RESULTS: 162 patients were included, 53.7% males, age 66.4 (SD13.8) years. Volume status was evaluated in 142 (88%): 21 (14.8%) were hypovolaemic, 96 (67.6%) euvolaemic and 25 (17.6%) hypervolaemic. In 111/142 patients the analytical assessment of hyponatraemia was completed. Hypovolaemic hyponatraemia was secondary to GI losses in 10/111 (9%), and to diuretics in 3/111 (2.7%). Euvolaemic hyponatraemia was due to Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH) in 47/111 (42.4%), and to physiological stimuli of Arginine Vasopressin (AVP) secretion in 28/111 (25.2%). Hypervolaemic hyponatraemia was induced by heart failure in 19/111 (17.1%), cirrhosis of the liver in 4/111 (3.6%). CONCLUSIONS: SIADH was the most frequent cause of hyponatraemia in patients receiving TPN. The second most frequent cause was physiological stimuli of AVP secretion induced by pain/nausea.

Real-World, Non-Interventional, Retrospective Study (SAMPLE) of Tolvaptan in Patients with Hyponatraemia Secondary to the Syndrome of Inappropriate Antidiuretic Hormone Secretion.

INTRODUCTION: The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most common cause of hyponatraemia in hospital inpatients. We present data on treatment setting, patient characteristics, and outcomes for patients treated with tolvaptan for SIADH across a range of real-world settings in Germany and Spain. METHODS: This was a non-interventional, observational, retrospective chart review study. Management was at the discretion of the treating physician, with tolvaptan prescribed according to local clinical practice. Hospital notes and/or medical charts were reviewed from treatment initiation for 6 weeks. Follow-up data were collected when patients were discharged early. Patients were eligible for inclusion if they were ≥ 18 years of age and had been treated with ≥ 2 doses of tolvaptan for one episode of hyponatraemia secondary to SIADH in 2014. RESULTS: The Full Analysis Set comprised 100 patients from 8 centres. The mean age of patients was 73.9 years. The primary endpoint of the mean increase in serum sodium level from baseline to hospital discharge, or to final available measurement, was 10.3 mmol/L (SD 6.4; 95% CI 9.0, 11.6), from 123.0 mmol/L (SD 6.0) to 133.3 mmol/L (SD 4.9). Seventy-seven patients (77.0%) achieved sodium normalisation within 6 weeks of tolvaptan initiation. Mean daily dose of tolvaptan was 12.7 mg (SD 9.2), and mean treatment duration 28.0 days (SD 16.5). Tolvaptan at off-label doses (< 15 mg/day) was prescribed to 72 patients at some point. A favourable safety and tolerability profile was reported. CONCLUSIONS: Tolvaptan was well tolerated and effectively corrected sodium levels in hospitalised adults with hyponatraemia secondary to SIADH in real-world settings. CLINICALTRIALS. GOV IDENTIFIER: NCT02545101.

The Diagnostic Approach to the Patient with Hyponatremia: Are the Correct Investigations Being Done?

Numerous observational studies have confirmed that inadequate investigation of hyponatremia leads to diagnostic errors and incorrect treatment. In fact, only one out of five patients diagnosed as having syndrome of inappropriate antidiuresis (SIAD) have had all the tests necessary to meet the diagnostic criteria. Diagnostic errors could help explain why a majority of patients presenting hyponatremia during hospitalization are discharged while still hyponatremic. The correct differentiation of hypovolemic from euvolemic patients is a clinical diagnostic challenge. Yet the value of the physical examination in the volemic classification of the patient with hyponatremia has been reinforced by ultrasound studies revalidating the utility of the measurement of internal jugular vein pulse height in the clinical evaluation of intravascular volume. In this chapter, we review the data available on current approaches to the diagnosis of hyponatremia, and suggest our recommended approach to the evaluation of patients with hyponatremia, and more specifically, patients with SIAD. In addition, we will explore how specialized input from multidisciplinary hospital "hyponatremia teams," supported by technologies such as automated electronic alert systems, and computerized physician-support systems can aid the diagnostic pathway and clinical care delivery for patients with hyponatremia.

Hyponatremia in patients receiving parenteral nutrition: the importance of correcting serum sodium for total proteins. The role of the composition of parenteral nutrition in the development of hyponatremia.

BACKGROUND/OBJECTIVES: Hyponatremia is the most common electrolyte disorder, and is associated with high-morbimortality rates. The true prevalence of hyponatremia in patients on parenteral nutrition (PN) is unknown, and the relationship between PN composition and development of hyponatremia has yet to be studied. Hypoproteinemia, a common finding in patients receiving PN, induces an overestimation of serum sodium (SNa) levels, when using indirect electrolyte methodology. Thus, SNa should be corrected for serum total protein levels (TP). The objective was to accurately determine the prevalence of hyponatremia (indirect SNa corrected for PT) and evaluate the relationship between the composition of PN and the development of hyponatremia. SUBJECTS/METHODS: Medical records of 222 hospitalized patients receiving total PN during a 7-month period were reviewed. Composition of PN, indirect SNa-mmol/l-, and SNa corrected for TP (SNa-TP)-mmol/l-, both upon initiation and during PN administration, were analyzed. RESULTS: Hyponatremia (SNa < 135 mmol/l) was present in 81% of subjects when SNa was corrected for TP, vs. 43% without correction (p = 0.001). In total 64% of patients that were eunatremic upon initiation of PN developed hyponatremia during PN administration, as detected by SNa-TP, vs. 28% as detected by uncorrected SNa (p < 0.001). There were no significant differences in volume, osmolarity, sodium or total osmols administered in PN between patients who developed hyponatremia and those who remained eunatremic. CONCLUSIONS: A majority of patients receiving PN present hyponatremia, when indirect SNa levels are corrected for TP. The development of hyponatremia during PN is not related to the composition of the PN.

Prevalence of Hyponatremia and Its Associated Morbimortality in Hospitalized Patients Receiving Parenteral Nutrition.

BACKGROUND: The objective of the study was to determine the prevalence of hyponatremia (HN) and its associated morbimortality in hospitalized patients receiving parenteral nutrition (PN). METHODS: A retrospective study including 222 patients receiving total PN (parenteral nutrition group [PNG]) over a 7-month period in a tertiary hospital and 176 matched to 179 control subjects without PN (control subjects group [CSG]). Demographic data, Charlson Comorbidity Index (CCI), date of HN detection-(serum sodium or SNa <135 mmol/L)-intrahospital mortality, and hospital length-of-stay (LOS) were registered. In the PNG, body mass index (BMI) and SNa before, during, and after PN were recorded. RESULTS: HN was more prevalent in the PNG: 52.8 vs. 35.8% (p = 0.001), and independent of age, gender, or CCI (OR 1.8 [95% CI 1.1-2.8], p = 0.006). In patients on PN, sustained HN (75% of all intraindividual SNa <135 mmol/L) was associated with a higher mortality rate independent of age, gender, CCI, or BMI (OR 7.38 [95% CI 1.07-50.8], p = 0.042). The absence of HN in PN patients was associated with a shorter hospital LOS (<30 days) and was independent of other comorbidities (OR 3.89 [95% CI 2.11-7.18], p = 0.001). CONCLUSIONS: HN is more prevalent in patients on PN. Sustained HN is associated with a higher intrahospital mortality rate. Absence of HN is associated with a shorter hospital LOS.

Hiponatremia en una paciente hospitalizada por meningitis. Más allá del síndrome de secreción inadecuada de hormona antidiurética en la hiponatremia euvolémica / Hyponatremia in a patient admitted for meningitis: euvolemic hyponatremia not due to the Syndrome of Inappropriate Antidiuretic Hormone Secretion

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Respuesta al caso clínico publicado: tratamiento con urea como alternativa al tolvaptán en el síndrome de secreción inadecuada de la hormona antidiurética / Response to clinical case report: treatment with urea as an alternative to tolvaptan for the syndrome of inappropriate secretion of antidiuretic hormone

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[Current considerations in syndrome of inappropriate secretion of antidiuretic hormone/syndrome of inappropriate antidiuresis]. / Aspectos actuales del síndrome de secreción inadecuada de hormona antidiurética/síndrome de antidiuresis inadecuada.

The syndrome of inappropriate secretion of antidiuretic hormone (SIADH)/syndrome of inappropriate antidiuresis is characterized by a hypotonic hyponatremia, with an insufficiently diluted urine given the plasmatic hypoosmolality, in the absence of hypovolemia (with or without a third space), hypotension, renal or heart failure, cirrhosis of the liver, hypothyroidism, adrenal insufficiency, vomiting, or other non-osmotic stimuli of ADH secretion. The response of ADH to the infusion of hypertonic saline divides SIADH into 4 different types. In type D, there is no alteration in ADH secretion. Rather, the defect is the maintained permeability of kidney aquaporin-2 channels to water. Activating mutations of the V2 receptor have been identified. The most frequent cause of SIADH is the use of drugs that induce secretion of the hormone. Old age is per se a risk factor for its development. SIADH is underdiagnosed, and hospitalization often worsens the clinical situation, due to an iatrogenic excess in the use of oral and i.v. liquids, often hypotonic, together with a reduction in salt intake. Treatment is directed towards normalization of natremia when possible, together with the avoidance of both hyponatremic encephalopathy as well as the osmotic demyelinization syndrome. Cases of "appropriate" secretion of ADH with normovolemic hyponatremia and high mortality rates should be treated with the same urgency as SIADH--such is the case of post-surgical hyponatremia.

Aspectos actuales del síndrome de secreción inadecuada de hormona antidiurética/síndrome de antidiuresis inadecuada / Current considerations in syndrome of inappropriate secretion of antidiuretic hormone/syndrome of inappropriate antidiuresis

El síndrome de secreción inadecuada de hormona antidiurética (SIADH)/síndrome de antidiuresis inadecuada se caracteriza por una hiponatremia hipotónica con una insuficiente dilución urinaria para la hipoosmolalidad plasmática existente, en ausencia de un descenso del volumen circulante eficaz (con o sin tercer espacio), hipotensión, insuficiencia renal, insuficiencia adrenal, hipotiroidismo, vómitos prolongados, u otros estímulos fisiológicos no osmóticos de la ADH. Hay 4 tipos, en función de la respuesta de la ADH a la perfusión de salino hipertónico, de las cuales el tipo D no presenta alteración de la secreción de ADH, sino que se caracteriza por una apertura renal mantenida de los canales de aquaporina 2, en algunos casos por una mutación activadora del gen del receptor V2, y se denomina síndrome nefrogénico de antidiuresis inadecuada. La causa más frecuente de la SIADH es la provocada por fármacos y la edad avanzada es un factor de riesgo para el desarrollo del cuadro. Se infradiagnostica y el ingreso hospitalario con frecuencia agrava el cuadro por aporte iatrogénico de un exceso de líquido, con frecuencia hipotónico, junto a una disminución en el aporte de sal. Los objetivos de su tratamiento son la normalización de la natremia, cuando es posible, además de evitar tanto la encefalopatía hiponatrémica como el síndrome de desmielinización osmótica. Deberán ser tratados con la misma agresividad cuadros de secreción “adecuada” de la ADH con hiponatremia normovolémica y elevada morbimortalidad, como la hiponatremia posquirúrgica (AU)

The syndrome of inappropriate secretion of antidiuretic hormone (SIADH)/syndrome of inappropriate antidiuresis is characterized by a hypotonic hyponatremia, with an insufficiently diluted urine given the plasmatic hypoosmolality, in the absence of hypovolemia (with or without a third space), hypotension, renal or heart failure, cirrhosis of the liver, hypothyroidism, adrenal insufficiency, vomiting, or other non-osmotic stimuli of ADH secretion. The response of ADH to the infusion of hypertonic saline divides SIADH into 4 different types. In type D, there is no alteration in ADH secretion. Rather, the defect is the maintained permeability of kidney aquaporin-2 channels to water. Activating mutations of the V2 receptor have been identified. The most frequent cause of SIADH is the use of drugs that induce secretion of the hormone. Old age is per se a risk factor for its development. SIADH is underdiagnosed, and hospitalization often worsens the clinical situation, due to a yatrogenic excess in the use of oral and iv liquids, often hypotonic, together with a reduction in salt intake. Treatment is directed towards normalization of natremia when possible, together with the avoidance of both hyponatremic encephalopathy as well as the osmotic demyelinization syndrome. Cases of “appropriate” secretion of ADH with normovolemic hyponatremia and high mortality rates should be treated with the same urgency as SIADH - such is the case of post-surgical hyponatremia (AU)