Hyponatremia

Etiology

The etiology of hyponatremia can be classified based on the volume status of the extracellular fluid. As mentioned earlier, sodium is the major solute of extracellular fluid (ECF). Based on the volume of ECF, a patient can be classified into hypovolemic, euvolemic, or hypervolemic.[3]

Physiological stimuli that cause vasopressin release in adjunct with increased fluid intake can cause hyponatremia. Hypothyroidism and adrenal insufficiency may contribute to an increased release of vasopressin. Physiological stimuli for vasopressin release include loss of intravascular volume (hypovolemic hyponatremia) and the loss of effective intravascular volume (hypervolemic hyponatremia).

Causes of Hypovolemic Hyponatremia (TBW decreases less than a decrease in total body sodium)[4]

• Gastrointestinal fluid loss (diarrhea or vomiting)
• The third spacing of fluids (pancreatitis, hypoalbuminemia, small bowel obstruction)
• Diuretics
• Osmotic diuresis (glucose, mannitol)
• Salt-wasting nephropathies
• Cerebral salt-wasting syndrome (urinary salt wasting, possibly caused by increased brain natriuretic peptide)
• Mineralocorticoid deficiency

Causes of Hypervolemic Hyponatremia (TBW increases greater than an increase in total body sodium)[5]

• Renal causes (acute renal failure, chronic renal failure, nephrotic syndrome)
• Extrarenal causes (congestive heart failure, cirrhosis)
• Iatrogenic

Causes of Euvolemic Hyponatremia (TBW increase with stable total body sodium)

Nonosmotic, pathologic vasopressin release may occur in the setting of normal volume status, as with euvolemic hyponatremia.

Causes of euvolemic hyponatremia include:

• Drugs, as mentioned below.
• Syndrome of inappropriate antidiuretic hormone (SIADH)
• Addison's disease
• Hypothyroidism
• High fluid intake in conditions like primary polydipsia; or potomania, caused by a low intake of solutes with relatively high fluid intake
• Medical testing related to excessive fluids, such as a colonoscopy or cardiac catheterization[6][7][8]
• Iatrogenic

Many drugs cause hyponatremia, and the most common include:

• Vasopressin analogs such as desmopressin and oxytocin
• Medications that stimulate vasopressin release or potentiate the effects of vasopressin, such as selective serotonin-reuptake inhibitors and other antidepressants, morphine, and other opioids
• Medications that impair urinary dilution, such as thiazide diuretics
• Medications that cause hyponatremia, such as carbamazepine or its analogs, vincristine, nicotine, antipsychotics, chlorpropamide, cyclophosphamide, nonsteroidal anti-inflammatory drugs
• Illicit drugs such as methylenedioxymethamphetamine (MDMA or ecstasy).[6]

Epidemiology

Hyponatremia is the most common electrolyte disorder, with a prevalence of 20% to 35% among hospitalized patients. The incidence of hyponatremia is high among critical patients in the intensive care unit (ICU) and also in postoperative patients. This is more common in elderly patients due to multiple comorbidities, multiple medications, and a lack of access to food and drinks.[9]

Pathophysiology

Thirst stimulation, antidiuretic hormone (ADH) secretion, and handling of filtered sodium by kidneys maintain serum sodium and osmolality. Normal plasma osmolality is around 275 mOsm/kg to 290 mOsm/kg. To maintain normal osmolality, water intake should be equal to water excretion. The imbalance of water intake and excretion causes hyponatremia or hypernatremia. Water intake is regulated by the thirst mechanism, where osmoreceptors in the hypothalamus trigger thirst when body osmolality reaches 295 mOsm/kg. Water excretion is tightly regulated by antidiuretic hormone (ADH), synthesized in the hypothalamus, and stored in the posterior pituitary gland. Changes in tonicity lead to either enhancement or suppression of ADH secretion. Increased ADH secretion causes reabsorption of water in the kidney, and suppression causes the opposite effect. Baroreceptors in the carotid sinus can also stimulate ADH secretion, but it is less sensitive than the osmoreceptors. Baroreceptors trigger ADH secretion due to decreased effective circulating volume, nausea, pain, stress, and drugs.[10]

Hypertonic Hyponatremia (Serum osmolality of greater than 290 mOsm/kg)

• Hyperglycemia
• Mannitol

Isotonic Hyponatremia (Serum osmolality between 275 mOsm/kg and 290 mOsm/kg)

• Pseudo-hyponatremia is a laboratory artifact. It is usually caused by hypertriglyceridemia, cholestasis (lipoprotein X), and hyperproteinemia (monoclonal gammopathy, intravenous immunoglobulin [IVIG]). Two-thirds of clinical labs in use still use indirect ion-selective electrode technology, and therefore this problem is still present.
• Nonconductive irrigant solutions: these solutions contain mannitol, glycine, or sorbitol and are used in urological and gynecological procedures such as transurethral resection of the prostate (TURP).[11]

Hypotonic Hyponatremia (Serum osmolality of less than 275 mOsm/kg)

Hypotonic hyponatremia represents an excess of free water. This excess free water can be caused by two mechanisms:

• Increased free water intake: The patient drinks a large volume of free water (greater than 18 L/day or greater than 750 mL/h) that overwhelms the kidney's capacity to excrete free water. Examples of this are psychogenic polydipsia, marathon runners, water drinking competitions, and ecstasy.
• Decreased free water excretion: Patients drink a normal volume of free water, but the kidneys cannot excrete the water for some reason.

There are three mechanisms involved in the inability of kidneys to excrete water:

1. High ADH activity: Three different mechanisms can cause high ADH:

• Decreased effective arterial blood volume (EABV): antidiuretic hormone (ADH) is released when there is a reduction of 15% or more of the EABV. This occurs with hypovolemia (e.g., vomiting, diarrhea), decreased cardiac output (e.g., heart failure), or vasodilation (e.g., cirrhosis).

• SIADH: ADH is secreted autonomously. Four general causes of this are brain disorders, lung disorders, drugs (e.g., SSRI), and miscellanea (e.g., nausea and pain).

• Cortisol deficiency: Cortisol exerts an inhibitory effect on ADH release. When cortisol is decreased, ADH is released in large amounts. Adrenal insufficiency is the cause of this mechanism.[12]

2. Low glomerular filtration rate (GFR): a low glomerular filtration rate would impair the kidney's ability to get rid of water. Typical examples are acute kidney injury (AKI), chronic kidney disease (CKD), and end-stage renal disease (ESRD).

3. Low solute intake: Patients on a regular diet consume 600 mOsm to 900 mOsm of solute per day. Solutes are defined as substances that are freely filtered by the glomeruli but have relative or absolute difficulty in being reabsorbed by the tubules in relationship to water. The main solutes are urea (which comes from the metabolism of proteins) and electrolytes (e.g., salt). Carbohydrates do not contribute to solute load. In steady-state conditions, solute intake is equal to urine solute load. Therefore, it is expected that these patients also excrete 600 mOsm to 900 mOsm of solute in the urine. Urine volume, and hence water excretion, is dependent on the urine solute load. The more solute one needs to excrete, the larger the urine volume one needs to produce. The less solute one needs to excrete, the smaller the urine volume one needs to produce. Patients who eat a low amount of solute per day (eg., 200 mOsm/day) on steady-state conditions will also excrete a low amount of solute in the urine, and therefore they will do it in a smaller volume of urine. This decreased urine volume will limit the capacity of the kidneys to excrete water. Typical examples of this are beer potomania and the tea-and-toast diet.

SIADH (Syndrome of inappropriate antidiuretic hormone secretion)[13]

This is a condition where inappropriate secretion of ADH despite normal or increased plasma volume causes impaired water excretion by the kidney leading to hyponatremia. SIADH is a diagnosis of exclusion, as there is no single test to confirm the diagnosis. Patients are hyponatremic and euvolemic.[14]

Causes of SIADH include

• Any central nervous system (CNS) disorder,
• Ectopic production of ADH (most commonly small cell carcinoma of the lung),
• Drugs (carbamazepine, oxcarbazepine, chlorpropamide, and multiple other drugs),
• HIV,
• Pulmonary diseases (pneumonia, tuberculosis),
• Postoperative patients (pain medicated)

Treatment includes fluid restriction and the use of vasopressin 2 receptor inhibitors.[12][15][12][15][12]

History and Physical

Symptoms depend upon the degree and chronicity of hyponatremia. Patients with mild-to-moderate hyponatremia (greater than 120 mEq/L) or a gradual decrease in sodium (greater than 48 hours) have minimal symptoms. Patients with severe hyponatremia (less than 120 mEq/L) or rapid decrease in sodium levels have multiple varied symptoms.[16]

Symptoms can range from anorexia, nausea and vomiting, fatigue, headache, and muscle cramps to altered mental status, agitation, seizures, and even coma.[17]

Apart from symptoms, a detailed history taking to include a history of pulmonary and CNS disorders, all home medications, and social history (increased beer intake or use of MDM or ecstasy) is very important.

Physical examination includes assessing volume status and neurological status. 

Patients with neurological symptoms and signs need to be treated promptly to prevent permanent neurological damage.[18]

Evaluation

The following steps may be performed while evaluating a patient with suspected hyponatremia[19]:

Step 1: Plasma Osmolality (275 mOsm to 290 mOsm/kg)

• It can help differentiate between hypertonic, isotonic, and hypotonic hyponatremia.
• True hyponatremic patients are hypotonic.
• If the patient is hypotonic, then go to step 2.

Step 2: Urine Osmolality

• Urine osmolality less than 100 mOsm/kg indicates primary polydipsia or reset osmostat.
• Urine osmolality greater than 100 mOsm/kg usually indicates a high ADH state; go to step 3.

Step 3: Volume Status (ECF status)

• Hypovolemic vs euvolemic vs hypervolemic.
• If the patient is hypovolemic, then proceed to step 4.

Step 4: Urine Sodium Concentration

• Urine sodium less than 10 mmol/L indicates extrarenal loss of fluid (remote diuretic use and remote vomiting).
• Urine sodium greater than 20 mmol/L suggests renal loss of urine (diuretics, vomiting, cortisol deficiency, and salt-wasting nephropathies).

Other tests that might help in differentiating the causes include

• Serum thyroid-stimulating hormone (TSH)
• Serum adrenocorticotropic hormone (ACTH)
• Serum urea
• Liver function tests
• Chest X-ray or computed tomography (CT) scan of the chest
• CT scan of the head

Treatment / Management

Treatment of hyponatremia depends upon the degree of hyponatremia, duration of hyponatremia, severity of symptoms, and volume status.

Acute Symptomatic Hyponatremia

• Severely symptomatic hyponatremia: Administer 3% sodium chloride; 100 mL intravenous (IV) bolus (repeat up to twice if symptoms persist).
• Mild to moderately symptomatic hyponatremia: 3% Sodium chloride, slow infusion (use sodium deficit formula to calculate the rate of infusion but recalculate rate with frequent sodium monitoring).

Chronic Asymptomatic Hyponatremia

• Hypovolemic hyponatremia: Isotonic fluids administration and holding of any diuretics.
• Hypervolemic hyponatremia: Treat underlying condition, restrict salt and fluids, and administer loop diuretics.
• Euvolemic hyponatremia: Fluid restriction to less than 1 liter per day.

Drugs: Selective vasopressin 2 receptor antagonists are being used recently. They increase the excretion of water in the kidneys without affecting sodium, thereby increasing serum sodium levels. These medications are used in patients with euvolemic and hypervolemic conditions (except liver failure) if the above measure does not help.[20][21]

The goal of correction: Correct sodium by no more than 10 mEq/L to 12 mEq/L in any 24-hour period.

Risk factors for osmotic demyelination syndrome (ODS): Hypokalemia, liver disease, malnutrition, and alcohol use.

Limits of Correction

• High-risk for ODS: less than 8 mEq/L in any 24-hour period
• Average risk for ODS: less than 10 mEq/L in any 24-hour period

In the absence of false laboratory hyponatremia, pseudo hyponatremia, and a lack of hypovolemic state, including postural hypotension, the next step is to measure urine sodium and osmolarity. In the low urinary sodium of less than 100 mOsm/kg and absence of rapid water consumption, the potential for a high fluid, low protein diet, including beer potomania, should be examined. In patients with severe hyponatremia of less than 120 mEq/L, the chronicity of the hyponatremia should be considered. Accordingly, in severe, chronic hyponatremia, intravenous 3 percent saline at a rate of 15 to 30 mL/hour should be initiated. In some patients, desmopressin (dDAVP) should also be administered to prevent overly rapid correction.

Three percent saline can be safely infused via a peripheral vein, and so far, vascular thrombosis and extravasation injuries have not been reported. However, some centers have policies against the peripheral infusion of hypertonic saline. In these circumstances, central vein infusions or infusions of a lower concentration with higher infusion rates are required.  Tolvaptan is indicated in hyponatremia associated with high anti-diuretic hormone (ADH) activity.

Fluid restriction is adequate for patients who have normovolemic hypotonic hyponatremia. Some patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) who are malnourished may need a high protein intake, which increases the solute load for renal excretion, resulting in more free water removal. Laboratory findings in patients with SIADH reveal hyponatremia (plasma sodium level of less than 135 mEq/L) and low serum osmolality (less than 280 mOsm/kg). Moreover, patients with SIADH have increased urinary sodium levels (greater than 20 mMol/L) and urine osmolality (generally above 100 mOsm/L).[22](A1)

Differential Diagnosis

True hyponatremia is associated with hypo osmolality. Conditions causing hyperosmolar hyponatremia and iso-osmolar hyponatremia (pseudo-hyponatremia) should be differentiated first.[23]

• Hyperglycemia
• Mannitol overdose
• Hyperlipidemia
• Hyperproteinemia

Differential Diagnosis for Hypo-Osmolar Hyponatremia

• Gastroenteritis
• Diuretic use
• Congestive heart failure
• Liver failure
• Psychogenic polydipsia
• Renal causes
• SIADH
• Adrenal crisis
• Hypothyroidism

Prognosis

The prognosis in patients with hyponatremia depends on the severity of hyponatremia and the underlying condition causing it. The prognosis is poor in patients with severe hyponatremia, acute hyponatremia, and older patients.[24]

Complications

If left untreated or inadequately treated, patients with hyponatremia can develop rhabdomyolysis, altered mental status, seizures, and even coma.

Rapid correction of chronic hyponatremia (greater than 10 mEq/L to 12 mEq/L of sodium in 24 hrs) can lead to osmotic demyelination syndrome.

Osmotic demyelination syndrome, formerly known as central pontine myelinolysis, is a complication of rapid correction of sodium in patients with chronic hyponatremia.[25] In patients with hyponatremia, the brain adapts to a fall in serum sodium level, without developing cerebral edema, in about 48 hours. As a result, patients with chronic hyponatremia are mostly asymptomatic. Once the brain adapts to low serum sodium, the rapid correction of sodium leads to osmotic demyelination syndrome. Clinical manifestations are typically delayed by a few days and comprise several irreversible neurological symptoms, including seizures, disorientation, and even coma. "Locked-in" syndrome occurs in severely affected patients. These patients are awake but unable to move or can communicate with the help of their eyes only.[26]