Hyponatremia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Saeedeh Kowsarnia M.D.[2]

The hyponatrmeia registry gives a quantitative overview of the diagnosis and treatment of hyponatremia^[1].

In 1858, Claude Bernard, French physiologist first proposed a direct relationship between the central nervous system and renal excretion of osmotically active solutes. In 1913, Jungmann and Meyer in Germany induced polyuria and increased urinary salt excretion in animals through medullary lesion. In 1950, Peters, Welt, and co-workers described few patients with encephalitis, hypertensive intracranial hemorrhage, and bulbar poliomyelitis who presented with severe dehydration and hyponatremia.

Hyponatremia (serum sodium less than 135 mEq/L) may be classified based upon serum ADH level, duration of hyponatremia, serum osmolality and volume status. The various classification systems enable accurate identification of the cause of hyponatremia and hence translate into optimal management based on the condition of the patient.

Hyponatremia is defined as serum sodium less than 135 mEq/L (mmol/L). Sodium is the major electrolyte which determines serum osmolality. Hyponatremia is a water balance disorder in which the ratio between sodium and water is disturbed. Water homeostasis is regulated mainly by two organs: hypothalamus by ADH secretion and thirst, kidney by water reabsorption or excretion. ADH is secreted due to alteration in serum osmolality or intravascular volume. Mechanisms in which different disorders cause hyponatremia involve ADH (secretion or action) and kidney function ( absorption or excretion). ADH secretion is increased by increased osmolality of serum or decreased effective intravascular volume.

Hyponatremia is caused by either increase ADH action/ secretion or kidney function impairment. SIAD is the most common cause of euvolemic hyponatremia. After SIAD, polydipsia, drugs and clinical disorders are the most encountered etiologies in clinical practice.

Different disorders which cause hyponatremia are differentiated based on volume status, clinical presentation, serum and urine osmolality.

Hyponatremia is the most common electrolyte disorder. Its frequency is higher in females, elderly, and the patients who are hospitalized. The incidence of hyponatremia depends largely on the patient population which is a dependent on the underlying cause. A hospital incidence of 15–30% is common. Age over 30, female gender and lower body weights are risk factors for developing complications associated with hyponatremia.

Hyponatremia, the most common electrolyte abnormality, is more common in patients with chronic underlying diseases. Certain drugs, low body weight and previous history of hyponatremia are the most prominent risk factors for developing hyponatremia.

Hyponatremia is the most common electrolyte disturbances which are common with certain medical conditions and drugs. Screening the hyponatremia is necessary for preventing further decrease in serum sodium and complications of treatment.

Brain adaptive mechanisms to hyponatremia are developed over hours. Shifting of water to brain cells causes brain edema and increased intracranial pressure. Excretion of osmole from brain cells decreases osmotic gradient and brain edema. Impairment of adaptive mechanisms and acute onset of hyponatremia cause encephalopathy and brain herniation. Rapid treatment of hyponatremia will not allow adaptive mechanisms to develop and may cause in osmotic demyelination syndrome, also called central pontine demyelination.

Best diagnostic test to measure hyponatremia, serum sodium < 135 mEq/L, is direction-specific electrode potentiometry. Other tests are associated with false results in certain conditions. Different etiologies of hyponatremia are differentiated based on serum osmolality, urine osmolality, and urine sodium.

Symptoms associated with hyponatremia are caused mostly by impairment of brain function. There is a spectrum of signs from no detectable presentation to death. To evaluate the causes of hyponatremia, careful history has to be taken. Drug history and past medical history can lead to the most common causes of hyponatremia.

Hyponatremia by itself has the signs of CNS function impairment and the other signs which can be detected in the physical exam are caused by the etiologies of hyponatremia. Depending on the severity of hyponatremia, signs vary from subtle cognitive impairment to brain death. Patients who present with hyponatremia, depending on the underlying causes, may present with different signs in clinical evaluation.

In hyponatremia, depending on the causes, different laboratory abnormalities can be found. Check for

Hyponatremia, serum sodium < 135 mEq/L, is the most common electrolyte disturbances in the clinical encounter. Treatment of hyponatremia based on the etiologies is the best approach because in most cases, hyponatremia resolves with the treatment of underlying causes. The rate of correction for hyponatremia is very important to prevent the syndrome of osmotic demyelination. Hyponatremia must be corrected slowly in order to lessen the chance of the development of Osmotic demyelination syndrome or central pontine myelinolysis (CPM), a severe neurological disease. In fact, overly rapid correction of hyponatremia is the most common cause of that potentially devastating disorder. During treatment of hyponatremia, the serum sodium should not be allowed to rise by more than 8  mmol/l over 24 hours (i.e. 0.33  mmol/l/h rate of rising). In practice, rapid correction of hyponatremia and then CPM is most likely to occur during the treatment of hypovolemic hyponatremia. In particular, once the hypovolemic state has been corrected, the signal for ADH release disappears. At that point, there will be an abrupt water diuresis (since there is no longer any ADH acting to retain the water). A rapid and profound rise in serum sodium can then occur. Should the rate of rising of serum sodium exceed 0.33  mmol/l/h over several hours, vasopressin may be administered to prevent ongoing rapid water diuresis.

In patients at risk of developing hyponatremia, preventing approaches has to be done to eliminate the aggravation of hyponatremia.

The rate of correction for hyponatremia is very crucial for preventing the complication of treatment like osmotic demyelination syndrome.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Saeedeh Kowsarnia M.D.[2]

In 1858, Claude Bernard, French physiologist first proposed a direct relationship between the central nervous system and renal excretion of osmotically active solutes. In 1913, Jungmann and Meyer in Germany induced polyuria and increased urinary salt excretion in animals through medullary lesion. In 1950, Peters, Welt, and co-workers described few patients with encephalitis, hypertensive intracranial hemorrhage, and bulbar poliomyelitis who presented with severe dehydration and hyponatremia.

The historical perspective of hypernatremia is as follows:^[1][2][3][4]

• In 1858, Claude Bernard, French physiologist first proposed a direct relationship between the central nervous system and renal excretion of osmotically active solutes.
• In 1913, Jungmann and Meyer in Germany induced polyuria and increased urinary salt excretion in animals through medullary lesion.
• In 1920, cerebral edema from water toxication was recognized.
• In 1936, first successful treatment of severe hyponatremia was published.
• in 1950, Peters, Welt, and co-workers described few patients with encephalitis, hypertensive intracranial hemorrhage, and bulbar poliomyelitis who presented with severe dehydration and hyponatremia.

• In 1952, Welt and colleagues presented patients with cerebral lesions (including trauma, tumor, and infection) and severe hyponatremia with clinical dehydration but no potassium retention.
• In 1967, Bartter and Schwartz introduced SIAD.
• In 1970s, the complications of rapid treatment of hyponatremia were first described.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Saeedeh Kowsarnia M.D.[2]

Hyponatremia (serum sodium less than 135 mEq/L) may be classified based upon serum ADH level, duration of hyponatremia, serum osmolality and volume status. The various classification systems enable accurate identification of the cause of hyponatremia and hence translate into optimal management based on the condition of the patient.

Hyponatremia is defined as serum sodium less than 135 mEq/L (mmol/L) ^[1] .There are different classifications for hyponatremia based on duration, severity, volume status, ADH level and serum osmolality.

Hyponatremia is classified based on serum sodium level into the following types ^[2] :

• Mild : Serum sodium 130– 135 mmol/L
• Moderate:  Serum sodium ≤125–129 mmol/L
• Severe: Serum sodium <124 mmol/L

Hyponatremia may be classified based on duration into the following types:^[3]

• Hyper acute ^[4]: Develops in a few hours, excess water intake, impaired water excretion, runners, users of the recreational drug (Ecstasy)

• Acute: Rapid onset <48 hours, surgeries, colonoscopy preparation, polydipsia, diuretics
• Chronic: Gradual onset >48 hours, caused by chronic disease ( including cardiac, renal, hepatic and other conditions)

( Etiologies cause hyperacute and acute hyponatremia are applicable to each category interchangeably depending on the onset of symptoms)

Hyponatremia may be classified into the following types based on ADH levels:

• ↑ ADH: Volume depletion (GI loss, Renal loss) , decreased perfusion ( CHF, Cirrhosis), increased ADH secretion, reset osmostat

• ↓ ADH: Primary polydipsia, ↓ dietary solute intake, advanced renal failure

Hyponatremia may be classified into the following types based on serum osmolality:^[5]

• Hypertonic hyponatremia: Serum osmolality >295 mOsm/kg
• Hypotonic hyponatremia: Serum osmolality < 275 mOsm/kg
• Normotonic hyponatremia: Serum osmolality 275–295 mOsm/kg

Hyponatremia may be classified into the following types according to volume status :

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Saeedeh Kowsarnia M.D.[2]

Hyponatremia is defined as serum sodium less than 135 mEq/L (mmol/L). Sodium is the major electrolyte which determines serum osmolality. Hyponatremia is a water balance disorder in which the ratio between sodium and water is disturbed. Water homeostasis is regulated mainly by two organs: hypothalamus by ADH secretion or thirst, kidney by water reabsorption or excretion. ADH is secreted due to alteration in serum osmolality or intravascular volume. Mechanisms in which different disorders cause hyponatremia involve ADH (secretion or action) and kidney function ( absorption or excretion). ADH secretion is increased by increased osmolality of serum or decreased effective intravascular volume.

Sodium is the main cation in the extracellular fluid, thus the plasma concentration of sodium is the determinant of tonicity and serum osmolality.

The osmotic gradient of solutes that do not cross cell membranes constitutes serum Tonicity which determines the distribution of water in the body.^[1]

Plasma tonicity = (Extracellular solute + Intracellular solute) / TBW

Serum or plasma osmolality measures different solutes in plasma. It helps to evaluate the etiology of hyponatremia and screen other solutes in the serum.

Serum Osmolality = (2 x (Na + K)) + (BUN (mg/dL) / 2.8) + (glucose (mg/dL) / 18) + (Ethanol (mg/dL) /3.7) ^[2]

Normal Range= 275–295 mosm /kg (mmol /kg) ^[3]

‡ Mmol and Meq are the same for univalent ions like sodium, potassium

† mOsmol /kg = n x mmol /L, for Na⁺, Cl^–, Ca²⁺, urea, and glucose, 1 mmol /L equals 1 mOsmol /kg because n=1 , for NaCl n=2

Plasma water is regulated by sensory organs (baroreceptors and hypothalamus osmoreceptors), antidiuretic hormone ( ADH or vasopressin, AVP), and the kidney.

Osmoreceptors in the hypothalamus are sensitive to the increased or decreased tonicity of serum ( magnocellular neurons). The primary brain osmoreceptors are located outside the blood-brain barrier in the lamina terminalis. Primary osmoreceptors are connected to brain areas responsible for ADH secretion and thirst by neuronal projections. Osmoreceptors can both stimulate and inhibit ADH secretion and thirst in response to hyper-and hypotonicity of serum, respectively.^[5]

ADH secretion from hypothalamus through posterior pituitary is increased by:^[6][7]

• ↑ Angiotensin II ( through activation of Renin-Angiotensin-Activation System)
• ↑ Sympathetic stimulation
• ↑ Effective osmoles ( Hypertonicity)
• ↓ Baroreceptor firing ( ↓ effective intravascular volume)
• ↓ Right atrium stretching

Baroreceptors are in carotid sinus, Juxtaglomerular cell, atrial pressure receptors, hepatic volume receptors, cerebrospinal fluid volume receptors.

ADH increases renal free water reabsorption from the collecting tubules which results in correction of plasma sodium toward the normal range. The vasopressin type 2 (V₂) receptor in the basolateral membrane of the collecting tubule acts as the antidiuretic effect of ADH.

Binding of ADH to V2 receptor intensifies the action of intracellular cyclic adenosine monophosphate ( cAMP) which results in insertion of water channel ( aquaporin 2) into the luminal membrane and increasing the numbers of aquaporin-2 mRNA level.^[8][9][10]

As plasma water increases, plasma sodium concentration, osmolality, and ADH secretion decrease and the collecting tubule becomes impermeable to water.

Hyponatremia is defined as serum sodium less than 135 mEq/L (mmol/L). Hyponatremia is a water balance disorder which represents an imbalance in a ratio where total body water is more than total body solutes ( total body sodium and total body potassium).

Pathogenesis

Hyponatremia occurs when the release of ADH ( AVP) is increased either physiologically appropriate due to decreased effective circulating volume, or inappropriately due to no physiologic reason. In response to the release of ADH, urine volume decreases and hyponatremia will develop especially when water intake exceeds urinary and insensible losses of water. Patients are typically classified based on their total body sodium as hypovolemic, euvolemic, and hypervolemia.

Hypovolemic hyponatremia

• Volume loss: GI loss, bleeding and insensible loss cause solute and water loss simultaneously which leads to the rise in ADH secretion. A considerable reduction in effective arterial blood volume increase release of ADH by baroreceptors rather than osmoreceptors. There is a marked release in ADH secretion by acute hypovolemia compared to the response that is caused by hypertonicity.^[11] ADH increases free water reabsorption from collecting tubules by V2 receptors and vascular resistance by V1 receptors. Replacement of losses with hypotonic fluid may cause further hyponatremia in addition to ADH effect. Hypovolemia caused by diarrhea induces sodium absorption from urine, results in low urine sodium. Vomiting caused hyponatremic hypovolemia which results in high urine sodium and low urine chloride due to bicarbonaturia and metabolic alkalosis.

• Third spacing of fluid: Causes decreased intravascular volume which increases ADH secretion and water reabsorption. Decreased vascular volume induces the activity of the renin-angiotensin-aldosterone system. Aldosterone increases water and sodium absorption by the kidney. As a net result of ADH and aldosterone actions, water is absorbed more than sodium which causes hyponatremia.

• Diuretics: Thiazides increase water reabsorption and water permeability of medullary part of collecting tubules which is independent of ADH action. Excretion of sodium and potassium to the urine causes further hyponatremia.^[12] In contrast, loop diuretics decrease the action of ADH on medullary part of collecting tubules by impairing medullary gradient.^[13]
• Renal loss: Inappropriately loss of sodium in urine causes hypovolemia and ADH secretion.
  • Salt-wasting nephropathy: Renal tubular dysfunction causes hyponatremia especially when sodium intake is reduced. The causes include Interstitial nephropathies, reflux nephropathies, recovery phase of ATN, medullary cystic disease and post-obstructive uropathies.
  • Bicarbonaturia: Renal tubular acidosis and metabolic alkalosis cause loss of bicarbonate and sodium in urine to balance charges in urine.
  • Cerebral salt-wasting syndrome: Subarachnoid hemorrhage, ischemic stroke, spontaneous intracerebral hemorrhage (ICH), craniotomy, encephalitis, meningitis and head trauma are considered the most common etiologies. The pathophysiology of CSW syndrome is not completely understood. Decreased sympathetic activity to the kidneys and Increased brain natriuretic peptide are the most accepted hypothesis. Renin-aldosterone is decreased due to reduced sympathetic stimulation.^[14] Increased natriuretic peptides causes sodium loss by kidney (natriuresis ) through increasing GFR and preventing sodium reabsorption in the collecting duct.^[15] Natriuretic peptides inhibit aldosterone and ADH action. Reducing sympathetic outflow by natriuretic peptides decreases aldosterone secretion which lowers sodium level further.^[16]
  • Osmotic diuresis: Urinary excretion of osmotically active solutes causes volume depletion and hyponatremia. Glucosuria and ketonuria in DKA and HHS obligate sodium and water loss even in the presence of hypovolemia.
  • Mineralocorticoid deficiency: Adrenal insufficiency ( primary, aldosterone deficiency) leads to renal sodium loss and volume depletion, causing the release of ADH due to hypovolemia. Patients typically present with hypovolemia, hyponatremia, hyperkalemia, decreased bicarbonate and increased urine sodium and inappropriate renal response in the setting of volume depletion.

Hypervolemic hyponatremia

• Renal disease: Chronic or acute renal failure results in reduced functional nephron mass, decreased glomerular filtration rate (GFR) and therefore decreased capacity for water excretion. Nephrotic syndrome causes reduced effective circulatory volume due hypoproteinemia which results in increased ADH effect.

• Clinical disorders: In Congestive heart failure ( CHF) and cirrhosis, the reduction in effective arterial blood volume, resulting in persistent ADH activity despite hypoosmolar plasma. The ability to excrete water is also limited when the posterior pituitary continues to secrete ADH despite a low serum osmolality and plasma sodium concentration. Decreased effective arterial blood volume is sensed as hypovolemia which is the stronger stimulant of ADH secretion than osmolality of plasma. ADH is secreted without an osmotic stimulus if circulation is inadequate. Inpatients with cirrhosis decreased effective circulating volume is a result of arterial vasodilation of the splanchnic circulation, which is due to the increased endothelial release of nitric oxide. Moreover, large volume paracentesis in cases of refractory ascites can lead to more reduction of effective arterial volume, leading to postparacentesis circulatory dysfunction (PPCD) which worsens the renal failure and hyponatremia. ^[17]

Euvolemic hyponatremia

• Syndrome of inappropriate antidiuresis: The most common cause of hyponatremia (euvolemic) due to either an increased level of ADH or gain-of-function mutation of the V2 receptor of ADH. Inappropriate secretion or action of ADH in the absence of osmotic or hemodynamic stimulus is called SIAD ( syndrome of inappropriate diuresis). Nephrogenic SIAD has the same presentation but ADH level is normal. Nearly 10% of SIAD is nephrogenic. Recently, hyponatremia has been found associated with COVID-19 infection ^[18] . Interleukin-6 (IL-6), which has been showed to be involved in the pathophysiology of COVID-19 and is released by monocytes and macrophages plays an important role in development of hyponatremia; it induces the non-osmotic release of vasopressin ^[19]. This along with the cytokine cascade cause numerous renal pathological changes, such as acute kidney injury (AKI), tubular necrosis, dysfunction of the kidney proximal tubule, glomerulopathy and electrolyte abnormalities.Also, renal cells expressing the receptors of the virus (ACE2), may explain the damage to kidney and subsequent electrolyte imbalances. Approximately 60% of patients with COVID-19 and watery diarrhea have moderate hyponatremia as well. ^[18]

† Mmol and Meq are the same for univalent ions like sodium, potassium

‡ mg/dl = molecular weight (MW) x mmol/l, for example MW for glucose and uric acid is 180 and 168 respectively

• Excess water intake: In exercise-associated hyponatremia, increased level of ADH due to hypovolemia and excess free water intake cause hyponatremia. In primary polydipsia, there is an increase in thirst, especially in psychotic patients. The osmotic threshold for thirst is lower than the threshold for ADH release.
• Hormonal: Glucocorticoids have an inhibitory effect on ADH release by the posterior pituitary so cortisol deficiency induces ADH secretion. Thyroid hormone deficiency especially primary hypothyroidism causes hyponatremia and the mechanism is not well-understood. in patients who present with hypothyroidism, there is an elevation to ADH level and reduction in GFR which means decreased ability to excrete diluted urine.^[22][23] Secondary adrenal insufficiency (hypopituitarism), presents with features of SIAD ( euvolemic hyponatremia).

• Medications: Mechanisms in which medications can cause hyponatremia are; Interfering with urinary dilution (thiazide diuretics and nonsteroidal anti-inflammatory drugs (NSAIDs)), increasing ADH secretion, persisting ADH effect and reset osmostat.

To review the drugs click here.

• Reset osmostat: There is a downward resetting for ADH secretion by osmoreceptors, therefore, a lower level of plasma sodium concentration is required to completely suppress ADH release and water intake ( thirst). Pregnancy and drugs are the most common etiologies. In pregnancy, secretion of human chorionic gonadotropin is the main cause of resetting osmostat.

Puedohyponatremia

• Hyperlipidemia, hyperproteinemia: Considerable elevations of either lipids or proteins in serum causes serum sodium to be measured lower than the actual total amount. Plasma osmolality is normal because the total number of solutes are the same but since the larger portion of plasma is occupied by excess lipids or protein, the measured serum sodium is lower especially with older techniques like flame photometry. Obstructive jaundice causes elevation of total serum cholesterol and high levels of lipoprotein X which causes the artefactual lower measurement of serum sodium concentration.

• Blood sampling: Phlebotomy from a vein which is being infused with hypotonic medications cause serum sodium to be measured lower than the actual amount.

• Hyperglycemia: Elevation of serum glucose causes hyponatremia by osmotic water movement from cells into the blood, which results in a relative decrease in serum sodium concentration. Calculation of serum osmolality and corrected serum sodium in hyperglycemia help to determine the actual cause of hyponatremia. For each 100-mg/dL increase in glucose concentration above 100 mg/dL, the sodium concentration should be increased by approximately 1.6 to 2 mmol/L. If the corrected serum sodium is within the normal range, hyponatremia can be explained by hyperglycemia. Lower or higher level of corrected serum sodium means hypotonic hyponatremia or hypernatremia, respectively.
  

• Administration of mannitol or hypertonic radiocontrast can also result in nonhypotonic hyponatremia. ^[24]

Hyponatremia represents an excess of water relative to total body sodium, resulting from impaired water excretion by the kidneys or the depletion of sodium in excess of water.

Hypotonic (dilutional) hyponatremia is classified by the extracellular volume status into hypo-, eu- and hyper-volemic hyponatremia.

• Nephrogenic SIAD (syndrome of inappropriate antidiuresis):^[28] Gain-of-function mutations of the V2 vasopressin receptor gene (AVPR2) causes hyponatremia.
• Pseudohypoaldosteronism
• Aldosterone Biosynthetic Defects
• Gittleman syndrome
• Bartter syndrome

• Fanconi syndrome
• Renal tubular acidosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Saeedeh Kowsarnia M.D.[2]

Hyponatremia is caused by either increase ADH action/ secretion or kidney function impairment. SIAD is the most common cause of euvolemic hyponatremia. After SIAD, polydipsia, drugs and clinical disorders are the most encountered etiologies in clinical practice.

To review the mechanisms of developing hyponatremia, click here.

( Etiologies that cause hyperacute and acute hyponatremia are applicable to each category interchangeably depending on the onset of symptoms)

‡ Hyperglycemia causes osmotic diuresis results in a rise in serum sodium concentration, on the other hand it leads to extracellular shift of water due to osmotic gradient which causes relative hyponatremia , depends on which effect is stronger, there would be hypertonicity or hypotonicity^[1].   

† Altered sensitivity to serum osmolality by the hypothalamic osmoreceptors

‡ Altered sensitivity to serum osmolality by the hypothalamic osmoreceptors

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Iqra Qamar M.D.[2], Saeedeh Kowsarnia M.D.[3]

Different disorders which cause hyponatremia are differentiated based on volume status, clinical presentation, serum and urine osmolality.

Differentiation between SIADH and Cerebral-salt wasting syndrome:

Biochemical evaluation for finding the etiologies of hyponatremia ^[26][27][28]:

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Saeedeh Kowsarnia M.D.[2]

Hyponatremia is the most common electrolyte disorder. Its frequency is higher in females, elderly, and the patients who are hospitalized. The incidence of hyponatremia depends largely on the patient population which is a dependent of the underlying cause. A hospital incidence of 15–30% is common. Age over 30, female gender and lower body weights are risk factors for developing complications associated with hyponatremia.

• Hyponatremia is the most common electrolyte disturbances in clinical practice, occurring in 15%-30% of hospitalized patients ( acutely or chronically) ^[1], 1-2% of this patients present with severe hyponatremia (serum sodium < 125 mEq/L) .
• Post-operative hyponatremia develops in 4.4% of patients within 1st week of surgery ^[2] .

• Prevalence of hyponatremia is 1720 per 100,000 in the U.S. population ^[3] .
• Nearly 7.7 % of patients who are visited in outpatients clinics are hyponatremic.
• Hyponatremia is seen in up to 27% of patients with heart failure (HF) ^[4] .
• Approximately 50% of patients with cirrhosis and ascites are found to be hyponatremic ^[5] .
• Hyponatremia has been reported in up to 30% of elderly patients in nursing homes and is also present in approximately 30% of depressed patients on selective serotonin reuptake inhibitors ^[6] .

• Over the period of 1999-2006, mortality rate was 11% and 4% for hyponatremic and normonatremia subjects, respectively ^[7] .
• There is an increased risk of mortality in patients with congestive heart failure, renal failure and cirrhosis.
• Hyponatremia is associated with worse clinical outcome, inpatients or outpatients.
• The underlying illness that is associated with hyponatremia has more correlation with mortality rate rather than severity of hyponatremia ^[8].

• Age over 30 is related to increased overall incident of hyponatremia especially hospital acquired hyponatremia. The association is stronger even with increasing severity of hyponatremia ^[9] .
• In elderly patients, lower body weight is associated with increased risk of drug-induced hyponatremia ^[10] .

• Female sex is considered a risk factor for psychotropic and diuretic-induced hyponatremia ^[11] .
• Severe hyponatremia occurs more frequently in women because of lower body weight.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Saeedeh Kowsarnia M.D.[2]

Hyponatremia, the most common electrolyte abnormality, is more common in patients with chronic underlying diseases. Certain drugs, low body weight and previous history of hyponatremia are the most prominent risk factors for developing hyponatremia.

• Strenuous exercises like the marathon and triathlon runner ^[1]
• Institutionalize schizophrenic patients
• Excess intake of water with no protein intake (↓ urea excretion causes ↓water excretion) like potomania, tea and toast diet
• Diuretics especially thiazides ( older age, female gender, low body weight, the tendency to increased water intake, decreased diluting ability of kidney, and hypokalemia increase the risk for thiazide associated hyponatremia) ^[2]
• Severe hyponatremia with using benzodiazepine and diuretics simultaneously
• Drugs with different mechanisms
• Chronic diseases like cirrhosis, congestive heart failure, hypertension, diabetes and severe kidney disease ^[3]
• Low body weight
• Hospitalized patients those with pneumonia, persons admitted to Intensive care unit, post surgery, patients with central nervous system disorder and patients receiving hypotonic fluid ^[4]
• Elderly patients, those who had previous episodes of hyponatremia ^[5]   

• Trans sphenoidal surgery (TSS) for pituitary adenomas may stretch the pituitary stalk and impair neurohypophyseal function (the risk of hyponatremia increased with increased DS (Diaphragma sellae) sinking depth, a larger pituitary stalk deviation angle difference, and a longer postoperative “measurable pituitary stalk” by MRI. ^[6]

• Cases of acute hyponatremia following religious fast have been recorded. Reproductive-age women are uniquely susceptible to hyponatremia and dangerous sequelae therein. Fasting individuals, particularly lactating women, due to reduced milk supply after fasting may consume water alone, which can lead to dangerous hyponatremia. ^[7]

• More recently, COVID 19 patients have been found to have an increased risk of developing hyponatremia. Nearly one- third of coronavirus disease patients were found to develop hyponatremia.^[8]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Saeedeh Kowsarnia M.D.[2]

Hyponatremia is the most common electrolyte disturbances which are common with certain medical conditions and drugs. Screening the hyponatremia is necessary for preventing further decrease in serum sodium and complications of treatment.

Plasma sodium should be check in

• 1–2 weeks after initiation of thiazide, SNRI, and SSRI therapy, especially in patients at high risk for hyponatremia ^[1][2]
• All hospitalized patients on admission

• Check plasma level daily in all patients with hyponatremia
• Check plasma level in all patients with risk of hyponatremia

To see the risk factors for developing hyponatremia, click here.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Saeedeh Kowsarnia M.D.[2]

Brain adaptive mechanisms to hyponatremia are developed over hours. Shifting of water to brain cells causes brain edema and increased intracranial pressure. Excretion of osmole from brain cells decreases osmotic gradient and brain edema. Impairment of adaptive mechanisms and acute onset of hyponatremia cause encephalopathy and brain herniation. Rapid treatment of hyponatremia will not allow adaptive mechanisms to develop and may cause in osmotic demyelination syndrome, also called central pontine demyelination.

Serum sodium concentration is the main determinant of serum osmolality. Maintaining constant serum sodium and osmolality is essential for keeping cell volume stable. This maintenance is very crucial for brain cells and volume. In acute hyponatremia, an osmotic gradient between brain cells and serum, causing water to enter brain cells and increased brain volume, edema, intracranial pressure and risk of herniation.In chronic hyponatremia, brain cells have time to lose osmoles (amino acids, polyols) to re-equilibrate the osmolar gradient and cell volume ^[1].

• Hyponatremic Encephalopathy : Clinical presentation of hyponatremic encephalopathy are associated with the degree of increased intracranial pressure and brain edema. These manifestations are ranged from nausea and vomiting which are the most common symptoms to cardiac arrest, permanent brain damage, and death ^[2].Pulmonary edema in hyponatremic encephalopathy named Ayus-Arieff syndrome, is a noncardiogenic edema results from increased vasoconstriction and protein permeability of pulmonary vessels. Pulmonary edema by hyponatremic encephalopathy is more common with exercise associated hyponatremia and postoperative. The treatment is to correct the underlying causes of hyponatremia and reversible. Hyponatremic encephalopathy can occur without any evidence of brain edema in CT scan. Female sex (peripubertal and pre-menopausal phase) and hypoxia increased the risk of developing severe hyponatremic encephalopathy.

• Brain herniation :In acute hyponatremia, if the brain adaptation to hyponatremia is impaired especially solute excretion of brain cells to achieve osmotic equilibrium, it causes brain cells swelling, increased intracranial pressure, cerebral edema, and eventual tentorial herniation ^[3].

• Osmotic Demyelination syndrome (Central Pontine Demyelination) :Hyponatremia, serum sodium < 135 mEq/L, causes brain edema due to shift of water from extracellular in to the brain cells. In the next 24 to 48 hours, brain starts to compensate by excreting solutes and water. If serum sodium is corrected too rapidly, brain cells do not have time to replace the solutes which results in dehydration of the brain cells named osmotic demyelination syndrome ^[4].

Risk of developing Osmotic Demyelination Syndrome is increased with:

• Serum sodium concentration ≤105 mmol/L
• Hypokalemia
• Alcoholism
• Malnutrition
• Advanced liver disease

Patients with congestive heart failure present with higher rate of ventricular premature beats which are correlated to the severity of hyponatremia. there are evidence that acute severe hyponatremia may cause second-degree or complete atrioventricular (AV) block ^[5].

• Asymptomatic hyponatremia in adults is associated with attention and gait deficit, falls and fractures, osteoporosis ^[6], calcium forming kidney stones ^[6] and increased mortality in patients with pneumonia, heart failure and liver disease ^[7]. Hyponatremia at hospital discharge after normal admission Na levels suggest poorer prognosis in heart failure patients admitted for decompensated heart failure. ^[8]

• Preterm neonates is associated with poor development and growth, cerebral palsy, sensorineural hearing loss, and intracranial hemorrhage, increased perinatal mortality in neonates who suffered perinatal asphyxia and increased sodium intake in later life ^{[9] [10][11]}
• Presence of hyponatremia in any clinical settings is associated with increased mortality as an independent risk ^[12]. Hyponatremia might predict adverse outcomes of patients under dialysis. ^[13]
• More recently, in COVID 19 patients, hyponatremia was found an independent predictor of in-hospital mortality, and was associated with increased risk of encephalopathy and mechanical ventilation. ^[14] Hyponatremia also increased length of hospital stay in COVID 19 patients. ^[15]

• Patients with Diabetes Insipidus admitted with COVID-19 have a high risk of mortality due to volume depletion. However, IV fluid replacement should be administered with caution in severe cases of COVID-19 because of the risk of pulmonary edema.

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