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.

Adaptation of the Brain to Hyponatremia and Its Clinical Implications.

Hyponatremia is the most common electrolyte disorder, occurring in up to 25% of hospitalized patients. Hypo-osmotic hyponatremia when severe and left untreated invariably results in cell swelling, which can lead to fatal consequences, especially in the central nervous system. The brain is particularly vulnerable to the consequences of decreased extracellular osmolarity; because of being encased in the rigid skull, it cannot withstand persistent swelling.

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

: 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.: When the physician is faced to a hyponatremic patient he first has to confirm that hyponatremia is associated with hypoosmolality.

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.

Regional oligodendrocytopathy and astrocytopathy precede myelin loss and blood-brain barrier disruption in a murine model of osmotic demyelination syndrome.

The osmotic demyelination syndrome (ODS) is a non-primary inflammatory disorder of the central nervous system myelin that is often associated with a precipitous rise of serum sodium concentration. To investigate the physiopathology of ODS in vivo, we generated a novel murine model based on the abrupt correction of chronic hyponatremia. Accordingly, ODS mice developed impairments in brainstem auditory evoked potentials and in grip strength.

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.

Physiopathology, clinical diagnosis, and treatment of hyponatremia.

Hyponatremia is the commonest electrolyte disorder encountered in clinical practice. It develops when the mechanisms regulating water and electrolyte handling are impaired, which in many instances occur in the setting of concurrent diseases such as heart failure, liver failure, renal failure etc… Hyponatremia as an electrolyte disorder has several specificities: when profound it can be quickly fatal and when moderate it carries a high risk of mortality and morbidity, but at the same time incorrect treatment of profound hyponatremia can lead to debilitating neurological disease and it remains unclear if treatment of moderate hyponatremia is associated with a decrease in mortality and morbidity. A proper diagnosis is the keystone for an adequate treatment for hyponatremia and in the last few years many diagnosis algorithms have been developed to aid in the evaluation of the hyponatremic patient.

Urea minimizes brain complications following rapid correction of chronic hyponatremia compared with vasopressin antagonist or hypertonic saline.

Hyponatremia is a common electrolyte disorder that carries significant morbidity and mortality. However, severe chronic hyponatremia should not be corrected rapidly to avoid brain demyelination. Vasopressin receptor antagonists (vaptans) are now being widely used for the treatment of hyponatremia along with other alternatives like hypertonic saline.

Actual Therapeutic Indication of an Old Drug: Urea for Treatment of Severely Symptomatic and Mild Chronic Hyponatremia Related to SIADH.

Oral urea has been used in the past to treat various diseases like gastric ulcers, liver metastases, sickle cell disease, heart failure, brain oedema, glaucoma, Meniere disease, etc. We have demonstrated for years, the efficacy of urea to treat euvolemic (SIADH) or hypervolemic hyponatremia. We briefly describe the indications of urea use in symptomatic and paucisymptomatic hyponatremic patients.

Mild hyponatremia is associated with an increased risk of death in an ambulatory setting.

Hyponatremia is a common disorder associated with higher mortality in hospitalized patients, but its impact in an ambulatory setting remains unclear. Here we used data from the Dallas Heart Study, a prospective multiethnic cohort study that included ambulatory individuals, to determine the prevalence and determinants of hyponatremia (serum sodium <135 mEq/l), and its impact on mortality. The analysis included 3551 individuals with a median age of 43 years followed up over a median of 8.

Efficacy and tolerance of urea compared with vaptans for long-term treatment of patients with SIADH.

Background And Objectives: Vaptans (vasopressin V(2)-receptor antagonists) are a new approach for the treatment of hyponatremia. However, their indications remain to be determined, and their benefit compared with that of the usual treatments for the syndrome of inappropriate antidiuretic hormone secretion (SIADH) have not been evaluated. This prospective, long-term study compared the efficacy, tolerability, and safety of two oral vaptans with those of oral urea in patients with SIADH.

Astrocytes are an early target in osmotic demyelination syndrome.

Abrupt osmotic changes during rapid correction of chronic hyponatremia result in demyelinative brain lesions, but the sequence of events linking rapid osmotic changes to myelin loss is not yet understood. Here, in a rat model of osmotic demyelination syndrome, we found that massive astrocyte death occurred after rapid correction of hyponatremia, delineating the regions of future myelin loss. Astrocyte death caused a disruption of the astrocyte-oligodendrocyte network, rapidly upregulated inflammatory cytokines genes, and increased serum S100B, which predicted clinical manifestations and outcome of osmotic demyelination.

Minocycline protects against neurologic complications of rapid correction of hyponatremia.

Osmotic demyelination syndrome is a devastating neurologic condition that occurs after rapid correction of serum sodium in patients with hyponatremia. Pathologic features of this injury include a well-demarcated region of myelin loss, a breakdown of the blood-brain barrier, and infiltration of microglia. The semisynthetic tetracycline minocycline is protective in some animal models of central nervous system injury, including demyelination, suggesting that it may also protect against demyelination resulting from rapid correction of chronic hyponatremia.

Treatment of euvolemic hyponatremia in the intensive care unit by urea.

Introduction: Hyponatremia in the intensive care unit (ICU) is most commonly related to inappropriate secretion of antidiuretic hormone (SIADH). Fluid restriction is difficult to apply in these patients. We wanted to report the treatment of hyponatremia with urea in these patients.

In vivo morphological changes in animal models of amyotrophic lateral sclerosis and Alzheimer's-like disease: MRI approach.

Magnetic resonance imaging (MRI) is the only noninvasive technique that provides structural information on both cell loss and metabolic changes. After reviewing all the results obtained in clinical studies, reliable biomarkers in neurological diseases are still lacking. Diffusional MRI, MR spectroscopy, and the assessment of regional atrophy are promising approaches, but they cannot be simultaneously used on a single patient.

Re-induction of hyponatremia after rapid overcorrection of hyponatremia reduces mortality in rats.

Osmotic demyelination syndrome is a devastating neurologic disorder often seen after the rapid correction of chronic hyponatremia. The permeability of the blood-brain barrier is increased in experimental osmotic demyelination, and some have suggested that corticosteroids protect against this disorder by keeping the permeability of the blood-brain barrier low. We previously reported that re-lowering of the serum sodium after rapid correction of chronic hyponatremia was beneficial if performed early in the course (12 to 24 h).