Treatment Guidelines for Hyponatremia: Stay the Course.

International guidelines designed to minimize the risk of complications that can occur when correcting severe hyponatremia have been widely accepted for a decade. On the basis of the results of a recent large retrospective study of patients hospitalized with hyponatremia, it has been suggested that hyponatremia guidelines have gone too far in limiting the rate of rise of the serum sodium concentration; the need for therapeutic caution and frequent monitoring of the serum sodium concentration has been questioned. These assertions are reminiscent of a controversy that began many years ago. After reviewing the history of that controversy, the evidence supporting the guidelines, and the validity of data challenging them, we conclude that current safeguards should not be abandoned. To do so would be akin to discarding your umbrella because you remained dry in a rainstorm. The authors of this review, who represent 20 medical centers in nine countries, have all contributed significantly to the literature on the subject. We urge clinicians to continue to treat severe hyponatremia cautiously and to wait for better evidence before adopting less stringent therapeutic limits.

Morbidity Associated with Chronic Hyponatremia.

This article will discuss the consequences of chronic hyponatremia. In conditions such as cancer, heart failure, liver cirrhosis, or chronic kidney disease, the presence and magnitude of hypotonic hyponatremia are considered to reflect the severity of the underlying disease and are associated with increased morbidity as well as mortality. Hyponatremia can be acute (<48 h) or chronic (>2-3 days). Chronic hyponatremia is associated with attention deficit, dizziness, tiredness, gait disturbance, falls, sarcopenia, bone fractures, osteoporosis, hypercalciuria (in the syndrome of inappropriate antidiuresis-SIADH), and kidney stones. In vitro studies have shown that cells grown in a low concentration of extracellular sodium have a greater proliferation rate and motility. Patients with chronic hyponatremia are more likely to develop cancer. We will not review the clinical consequences of respiratory arrest and osmotic demyelination syndrome (ODS) of the too-late or excessive treatment of hyponatremia.

Normonatremic Transient Renal Salt Wasting (TRSW) Is Not Rare in a Department of Internal Medicine.

Background: We previously reported that for around 5% of patients hospitalized with hyponatremia, it was related to what is called "transient renal salt wasting" (TRSW). In the present study we ask whether TRSW can also be observed in patients without hyponatremia. Methods: In this observational retrospective study we analyze the urine solute excretion of 200 consecutive normonatremic patients with normal kidney function and admitted in our department over one year. Patients were selected for analyses of FE.K, UCa/UCr and FE.PO4 if FE.Na was higher than 2% (N < 1.6%) before any treatment, and only if they were not taking diuretics. Result: Eleven normonatremic patients presented with transient high FE.Na > 2% on admission (2.9 ± 0.6% with a high FE.K of 28 ± 6.4%; a high UCa/UCr of 0.37 ± 0.13 and a high FE.PO4 of 23.2 ± 9.6%). All of these patients were elderly. Seven were female and four were male. Neurological disorders were observed in six patients (three strokes, one transient ischemic attack, one syncope and one epileptic attack). Heart problems were observed in three patients (all angina pectoris, two of which also had HBP). One patient presented with rectal bleeding with HBP, and another presented COPD with a pneumothorax. One patient with angina pectoris showed a transient relapse after four days of hospitalization (FE.Na 3.6%). The urine electrolyte excretion in these patients are similar to those observed after furosemide intake. Conclusion: Normonatremic TRSW is not a rare observation, particularly in patients with neurological or cardiac problems.

The Urine Calcium/Creatinine Ratio and Uricemia during Hyponatremia of Different Origins: Clinical Implications.

Background: Chronic hyponatremia is known to be associated with osteoporosis. It has been shown that chronic hyponatremia increases bone resorption in an attempt to release body stores of exchangeable sodium by different mechanisms. We wanted to know the calciuria of patients with hyponatremia of different origins. Material and Methods: We made a retrospective study of 114 consecutive patients with asymptomatic hyponatremia of different origins with the usual serum and urine chemistry. Result: In hyponatremia due to SIADH, we had a high urine calcium/creatinine ratio of 0.23 ± 0.096 while in patients with salt depletion the UCa/UCr ratio was low (0.056 ± 0.038), in patients with hyponatremia secondary to thiazide intake the value was also low (0.075 ± 0.047) as in hypervolemic patients (0.034 ± 0.01). In hyponatremia due to polydipsia, the value was high (0.205 ± 0.10). Correction of hyponatremia in the euvolemic patients was associated with a significant decrease in the UCa/UCr ratio. In patients with hyponatremia secondary to thiazide intake, we noted that in the patients with low uric acid levels (<4 mg/dL, suggesting euvolemia) we also observed a low UCa/UCr (<0.10). In nine patients with chronic SIADH (SNa 125.1 ± 3.6 mEq/L), the 24 h urine calcium excretion was 275 ± 112 mg and decreased to 122 ± 77 mg (p < 0.01) after at least 2 weeks of treatment. Conclusions: Patients with chronic hyponatremia due to SIADH usually have a high UCa/UCr ratio (>0.15). This is also observed in hyponatremia secondary to polydipsia. Patients with thiazide-induced hyponatremia usually have low UCa/UCr levels and this is the case even among those with a biochemistry similar to that in SIADH (uric acid < 4 mg/dL).

Low Creatininuria due to Hyponatremia Is Reversible in Many Patients.

BACKGROUND: Chronic hyponatremia has been reported to be associated with low solute intake and low creatinine excretion (reflecting likely sarcopenia). We wanted to study the effect, on the long term, of correction of hyponatremia on solute and creatinine excretion in chronic SIADH. METHODS: We made a retrospective review of clinical and biochemical data of patients with euvolemic hyponatremia. We analyzed 24-h urine solute and creatinine excretion in volunteers with hyponatremia induced by dDAVP over 4 days, in 12 patients with chronic SIADH (>1 month) before and after a few days of SNa correction and in 12 patients (6 women and 6 men) before and after 3 months of SNa correction by a vaptan or urea. RESULTS: We confirm a low urine creatinine and solute excretion only in patients with chronic hyponatremia (>1 month). Correction of SNa (from 127 ± 2.3 mEq/L to 139 ± 2.8 mEq/L) for >3 months, in the 12 patients (mean age 58 ± 18), was associated with an increase in 24-h creatinine excretion (from 986 ± 239 to 1,238 ± 220 mg; p < 0.02) and in patients treated with a vaptan (n = 5) solute excretion increased from 656 ± 207 mmol/24 h to 960 ± 193 mmol/24 h (p < 0.02). Sodium excretion increased also in the 12 patients (from 100 ± 53 mEq/24 h to 169 ± 38 mEq/24 h; p < 0.01). CONCLUSION: Chronic hyponatremia (>1 month) is associated with a decrease in solute output (or intake) and in creatinine excretion. In many patients, these abnormalities are reversible in the long term.

Variations in daily urine solute output in patients with NDI, CDI, SIADH, and NSIAD: Clinical implications.

INTRODUCTION: We aimed to study the effects of daily variation in solute intake on urine volume in patients with syndrome of inappropriate secretion of antidiuretic hormone secretion (SIADH), syndrome of nephrogenic antidiuresis (NSIAD), central diabetes insipidus (CDI), or nephrogenic diabetes insipidus (NDI). MATERIALS AND METHODS: In 6 patients with CDI, 7 patients with NDI, 7 patients with SIADH, and 2 patients with NSIAD we had the opportunity to have 24-hour urine collections during normal diet before any treatment. We had two 24-hour urine collections with a difference of at least 20% in solute output (measured by the formula urine osmolality × urine volume). In 1 patient with NDI taking a high protein diet we analyzed the effect of a normal protein intake on diuresis. With respect to patients with NDI and CDI we included only patients with a urine osmolality lower than 110 mOsm/kgH2O, and for SIADH/NSIAD we included only patients with a urine osmolality between 500 and 700 mOsm/kgH2O. RESULTS: When the data of the patients with CDI/NDI were pooled, a high correlation between urine volume and solute output was observed (R = 0.83; p < 0.001). In 1 patient with X-linked NDI, we decreased urine volume simply by decreasing protein intake. If we pooled the data concerning SIADH/NSIAD, a correlation was observed between urine volume and solute output (R = 0.94; p < 0.001). As expected, increasing solute intake is beneficial in SIADH/NSIAD, while decreasing it decreases diuresis in NDI. CONCLUSION: Daily variations in solute output affect urine volume in NDI/CDI/SIADH/NSIAD, this could affect serum sodium (SNa) despite no variation in fluid intake. In SIADH, if solute intake is lower than usual for a few days it may significantly influence the SNa level despite no variation in fluid intake.

Hypertonic saline, isotonic saline, water restriction, long loops diuretics, urea or vaptans to treat hyponatremia.

Introduction: Hyponatremia is the most common fluid and electrolyte abnormality. It is associated with much higher morbidity and mortality rates than found in non hyponatremic patients.Areas covered: When the physician is faced to a hyponatremic patient he first has to confirm that hyponatremia is associated with hypoosmolality. Then he must answer to a series of questions: What is its origin? Is it acute or chronic? Which treatment is the most appropriate? We will discuss the various options for the treatment of hypotonic hyponatremia. For a better comprehensive approach of the treatment we will also discuss some pathophysiological data. The use of urea in euvolemic and hypervolemic hyponatremia will be particularly discussed. Literature was reviewed from Jan 1970 to Dec 2019.Expert opinion: Prospective studies showing the benefit in decreasing morbidity by increasing SNa in patients with chronic hyponatremia should be done. These studies should also compare the efficacy and side effects of urea therapy compare to vaptans.

Estimated Daily Urine Volume and Solute Excretion from Spot Urine Samples to Guide the Therapy of Hyponatremia in SIADH.

Background: In hyponatremia, due to the inappropriate secretion of antidiuretic hormone (SIADH), a high versus low solute intake will affect the urine volume (UV) and, hence, the SNa level. The clinical implication of the fractional solute excretion is presented. Methods: In 35 normal controls and 24 patients with SIADH and urine osmolality higher than serum osmolality, we compared exact solute intake obtained from 24 h urine collection, with the estimated value obtained on a urine morning spot sample by the formula: eGFR (L/min) × Sosm × 1440 × FE.Osm (%) = mmol/24 h. The exact UV was compared with the estimated value given by the formula: eGFR × 1440 × S.Creat/U.Creat (for eGFR the MDRD was used). In 65 patients with chronic SIADH, from which a morning spot urine sample was available, we determined the estimated fluid and solute intake. Results: A good correlation was observed between the measured solute output or urine volume and the estimated values obtained from the controls (r = 0.86) as well as in SIADH (r = 0.91). Conclusion: Patients with low solute intake (FE.Osm <1.4%) and low diuresis (V/eCcr <0.8%) should increase their intake by taking oral urea, for example. Patients with high solute intake (FE.Osm >2.5%) and high diuresis (V/eCcr >1.5%) could usually be treated by mild water restriction (<1.5-21/24 h).

Hyponatremia secondary to transient renal salt wasting (TRSW): A not so uncommon observation in the elderly
.

AIMS: We attempted to classify 115 consecutive nonedematous hyponatremic patients according to their history and saline responsiveness. We hereby describe 6 out of them presenting a transient renal salt wasting (TRSW) state of unknown origin. MATERIALS AND METHODS: Six patients with an initial SNa of 126 ± 3 mEq/L were included in the study. They were treated with 2 L isotonic saline infusion over 24 hours. The evolution of the biochemical data of 5 patients were compared to 6 patients with syndrome of inappropriate antidiuretic hormone (ADH) secretion (SIADH), 6 hyponatremias following the use of thiazides, and to 5 salt-depleted hyponatremic patients of similar age and body weight, treated in the same way. RESULTS: The mean values of FEurea and FEuric acid in the 6 described patients, together with a clearly inappropriate natriuresis suggested SIADH. However, the high mean fractional potassium excretion (FEK = 34 ± 15%) was not observed in SIADH (13 ± 3%) (p < 0.01). Plasma sodium levels improved quickly after saline infusion in most of these patients, while fractional solute excretions and diuresis decreased. Calciuria is increased in patients with renal salt waisting (RSW), while low calciuria values are observed in the thiazide group. Four of the 6 hyponatremic patients were admitted for syncopal malaise or fall. CONCLUSION: We observed in 6 out of 115 consecutive hyponatremic patients a TRSW. RSW as a diagnosis has to be considered when in hyponatremia with excessive natriuresis, high FEK and an intake of diuretics is ruled out. This hyponatremia is saline-responsive, but relapse can be frequently observed.

Severe Solute Depletion in Patients with Hyponatremia Due to Diuretics Despite Biochemical Pictures Similar Than Those Observed in the Syndrome of Inappropriate Secretion of Antidiuretic Hormone.

BACKGROUND/AIMS: Hyponatremia secondary to distal diuretics intake could have a biochemical picture similar to the one observed in the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). In these patients, water retention is considered to be the main causal factor and solute depletion a secondary one. METHODS: We compared the level of cation (Na + K) depletion and water balance in patients with high or low uric acid levels (< 4 mg/dL or 238 µmol/L) or with high or low (< 30 mg/dL or 5 mmol/L) urea levels. Data were collected from 15 consecutive patients treated in a similar way by a daily infusion of 2 L isotonic saline with potassium chloride until SNa reached at least 132 mmol/L. The same procedure was performed in 6 patients with hyponatremia due to salt depletion not related to diuretic intake. RESULTS: Hyponatremia, associated with low or high uric acid level is mainly due to severe cation depletion (around 600 mmol) and not due to water retention, since body weight did not change significantly (SNa 122 ± 2.0 mEq/L). If patients were classified according to serum urea levels those with higher urea levels (≥30 mg/dL) presented with a mild increase in BW (0.84 ± 0.37 kg). In patients with salt depletion and hyponatremia not related to diuretic intake, we observe as expected an increase in BW (1.5 ± 0.3 kg) and similar cation retention with the treatment. CONCLUSION: We therefore suggest that diuretic induced hyponatremia with an SIADH-like biochemical profile, should be treated mainly by solute -repletion.

Hyponatremia and the Brain.

Hyponatremia is defined by low serum sodium concentration and is the most common electrolyte disorder encountered in clinical practice. Serum sodium is the main determinant of plasma osmolality, which, in turn, affects cell volume. In the presence of low extracellular osmolality, cells will swell if the adaptation mechanisms involved in the cell volume maintenance are inadequate. The most dramatic effects of hyponatremia on the brain are seen when serum sodium concentration decreases in a short period, allowing little or no adaptation. The brain is constrained inside a nonextensible envelope; thus, brain swelling carries a significant morbidity because of the compression of brain parenchyma over the rigid skull. Serum sodium concentration is an important determinant of several biological pathways in the nervous system, and recent studies have suggested that hyponatremia carries a significant risk of neurological impairment even in the absence of brain edema. The brain can also be affected by the treatment of hyponatremia, which, if not undertaken cautiously, could lead to osmotic demyelination syndrome, a rare demyelinating brain disorder that occurs after rapid correction of severe hyponatremia. This review summarizes the pathophysiology of brain complications of hyponatremia and its treatment.

Guía de práctica clínica sobre el diagnóstico y tratamiento de la hiponatremia / Hyponatraemia diagnosis and treatment clinical practice guidelines

La hiponatremia se define como una concentración sérica de sodio <135mmol/L y es el trastorno hidroelectrolítico más frecuente en la práctica clínica. La hiponatremia puede causar un amplio espectro de síntomas clínicos, desde sutiles hasta graves o incluso mortales, y se asocia con aumento de la morbimortalidad y prolongación de la estancia hospitalaria. A pesar de ello, el manejo de los pacientes con hiponatremia sigue siendo problemático. La prevalencia de hiponatremia en enfermedades muy diferentes y su manejo por muy diversos especialistas han fomentado la existencia de protocolos de diagnóstico y tratamiento muy diversos, que varían con la especialidad y la institución. La Sociedad Europea de Medicina Intensiva (ESICM), la Sociedad Europea de Endocrinología (ESE) y la Asociación Renal Europea-Asociación Europea de Diálisis y Trasplante (ERA-EDTA), representada por la European Renal Best Practices (ERBP), han desarrollado la guía de práctica clínica sobre el enfoque diagnóstico y tratamiento de la hiponatremia como una empresa conjunta de las 3 sociedades que representan a los especialistas con un interés natural en la hiponatremia, a fin de ofrecer una visión común y holística del abordaje del problema. Además de ofrecer un enfoque riguroso en la metodología y la evaluación de la evidencia, el documento está centrado en resultados importantes para el paciente y en facilitar una herramienta útil para los médicos en la práctica clínica cotidiana. Presentamos ahora una versión abreviada de las recomendaciones y sugerencias sobre el diagnóstico y el tratamiento de la hiponatremia recogidas en la guía complete (AU)

Hyponatremia, defined as a serum sodium concentration <135mmol/l, is the most common water-electrolyte imbalance encountered in clinical practice. It can lead to a wide spectrum of clinical symptoms, from mild to severe or even life threatening, and is associated with increased mortality, morbidity and length of hospital stay. Despite this, the management of hyponatremia patients remains problematic. The prevalence of hyponatremia in a wide variety of conditions and the fact that hyponatremia is managed by clinicians with a broad variety of backgrounds have fostered diverse institution- and specialty-based approaches to diagnosis and treatment. To obtain a common and holistic view, the European Society of Intensive Care Medicine (ESICM), the European Society of Endocrinology (ESE) and the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA), represented by European Renal Best Practice (ERBP), have developed clinical practice guidelines on the diagnostic approach and treatment of hyponatremia as a joint venture of 3 societies representing specialists with a natural interest in hyponatremia. In addition to a rigorous approach to the methodology and evaluation of the evidence, the document focuses on patient-positive outcomes and on providing a useful tool for clinicians involved in everyday practice. In this article, we present an abridged version of the recommendations and suggestions for the diagnosis and treatment of hyponatremia extracted from the full guide (AU)

Hyponatraemia diagnosis and treatment clinical practice guidelines. / Guía de práctica clínica sobre el diagnóstico y tratamiento de la hiponatremia.

Hyponatremia, defined as a serum sodium concentration <135mmol/l, is the most common water-electrolyte imbalance encountered in clinical practice. It can lead to a wide spectrum of clinical symptoms, from mild to severe or even life threatening, and is associated with increased mortality, morbidity and length of hospital stay. Despite this, the management of hyponatremia patients remains problematic. The prevalence of hyponatremia in a wide variety of conditions and the fact that hyponatremia is managed by clinicians with a broad variety of backgrounds have fostered diverse institution- and specialty-based approaches to diagnosis and treatment. To obtain a common and holistic view, the European Society of Intensive Care Medicine (ESICM), the European Society of Endocrinology (ESE) and the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA), represented by European Renal Best Practice (ERBP), have developed clinical practice guidelines on the diagnostic approach and treatment of hyponatremia as a joint venture of 3societies representing specialists with a natural interest in hyponatremia. In addition to a rigorous approach to the methodology and evaluation of the evidence, the document focuses on patient-positive outcomes and on providing a useful tool for clinicians involved in everyday practice. In this article, we present an abridged version of the recommendations and suggestions for the diagnosis and treatment of hyponatremia extracted from the full guide.

Osmotic Stress-Induced Defective Glial Proteostasis Contributes to Brain Demyelination after Hyponatremia Treatment.

Adequate protein folding is necessary for normal cell function and a tightly regulated process that requires proper intracellular ionic strength. In many cell types, imbalance between protein synthesis and degradation can induce endoplasmic reticulum (ER) stress, which if sustained, can in turn lead to cell death. In nematodes, osmotic stress induces massive protein aggregation coupled with unfolded protein response and ER stress. In clinical practice, patients sustaining rapid correction of chronic hyponatremia are at risk of osmotic demyelination syndrome. The intense osmotic stress sustained by brain cells is believed to be the major risk factor for demyelination resulting from astrocyte death, which leads to microglial activation, blood-brain barrier opening, and later, myelin damage. Here, using a rat model of osmotic demyelination, we showed that rapid correction of chronic hyponatremia induces severe alterations in proteostasis characterized by diffuse protein aggregation and ubiquitination. Abrupt correction of hyponatremia resulted in vigorous activation of both the unfolded protein response and ER stress accompanied by increased autophagic activity and apoptosis. Immunofluorescence revealed that most of these processes occurred in astrocytes within regions previously shown to be demyelinated in later stages of this syndrome. These results identify osmotic stress as a potent protein aggregation stimuli in mammalian brain and further suggest that osmotic demyelination might be a consequence of proteostasis failure on severe osmotic stress.

Impact of hyponatremia on nerve conduction and muscle strength.

BACKGROUND: Hyponatremia is associated with unstable gait and propensity to falls. The potential contribution of peripheral nervous system dysfunction induced by hyponatremia has not yet been addressed by prospective studies. DESIGN: In the first part of this prospective study, we performed two tests evaluating muscle strength (grip test and quadriceps isometric contraction test) together with a timed up and go (TUG) test in 11 patients with chronic mild-to-moderate hyponatremia before and after the normalization of natremia. In the second part, we measured nerve conduction velocities and F-wave latencies in nine patients with profound hyponatremia (< 125 mmol/L) before and after the normalization of natremia. RESULTS: No significant change in muscle strength was observed when natremia was corrected from 127·7 ± 2·5 to 136·1 ± 1·8 mmol/L, contrary to a significant improvement in TUG from 14·9 ± 5·1 to 12·5 ± 4·7 s (P = 0·006). Nerve conduction velocities and F-wave latencies showed significant improvement in most of the studied nerves when natremia was corrected from 121·9 ± 2·4 to 135·5 ± 3·4 mmol/L (e.g. mean increase of 14·3% for motor nerve conduction and mean decrease of 21·6% for F-wave latency of left peroneal nerve). CONCLUSION: Whereas chronic mild-to-moderate hyponatremia has no impact on muscle strength, we demonstrate for the first time an impact of profound hyponatremia on nerve conduction studies. Further studies are needed to ascertain the contribution of these latter results on gait disturbances, propensity to falls and attention deficits associated with hyponatremia.

Acute Cardiac Tamponade in a 77-year-old Italian Woman with Erdheim-Chester Disease.

Erdheim-Chester disease (ECD) is a non-Langerhans' histiocytosisand a veryrare multisystemic disease of unknown aetiology, with skeletal involvement of the long bones and in more than 50% of cases with extraskeletal involvement. The disease was described in 1930 by the anatomopathologist Jakob Erdheim and his student William Chester. More than 500 cases have since been reported. We report the case of a 77-year-old Italian woman with ECD who was admitted to hospital for acute cardiac tamponade. The patient presented with simultaneous cutaneous, retro-orbital, skeletal, cerebral and cardiovascular manifestations and was successfully treated with corticosteroids followed by interferon. LEARNING POINTS: Erdheim-Chester disease (ECD) is a non-Langerhans' histiocytosisand a very rare multisystemic disease that is thought to be associated with cytokine disturbances.ECD has a variable prognosis but is poorer in those with heart involvement.First-line treatment involves the administration of interferon alpha.