Does this patient have hyponatremia?

The patient has hyponatremia if the plasma sodium concentration (PNa) is < 135 meq/L.

What is PNa a reflection of?

PNa reflects body fluid tonicity. Metabolic processes within cells can only occur under constant conditions of the extracellular fluid (ECF) such as pH or potassium concentration. The kidneys maintain the constancy of the ECF in a process called homeostasis. Tonicity is one of these biological constants that must be kept at a certain strict range because changes in ECF tonicity can cause net water movement between body fluid compartments altering cell volume significantly, and therefore cell function. Under normal conditions, all the body fluid compartments have the same tonicity: intracellular fluid (ICF) tonicity = ECF tonicity = interstitial fluid tonicity = intravascular fluid or plasma tonicity, and these are all equal to the total body fluid tonicity.

What is the difference between plasma tonicity and plasma osmolality?

The main osmoles in plasma are sodium (Na), glucose (Glu) and urea (BUN) as expressed in the equation to calculate plasma osmolality.

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  • Plasma osmolality = 2 x Na (mEq/L) + Glu (mg/dl)/18 + BUN (mg/dl)/2.8

Plasma osmolality simply refers to the concentrations of all the particles dissolved in plasma. Normal plasma osmolality ranges between 280 to 295 mOsm/kg. On the other side, plasma tonicity refers to the concentration of only those dissolved particles in plasma that exert an osmotic effect, i.e. “effective” osmoles. Urea is an “ineffective” osmole as it quickly enters cells reaching equilibrium within 1 hour, and it should not be considered when calculating plasma tonicity. Normal plasma tonicity ranges between 270 to 285 mOsm/kg. Furthermore, normal plasma glucose concentration (i.e. 90 mg/dl) only contributes to about 5 mOsm/kg of the plasma tonicity. Therefore, PNa is the main determinant of plasma tonicity.

In general, plasma osmolality may be used as a surrogate for plasma tonicity where low plasma osmolality corresponds to low plasma tonicity. Normal plasma osmolality usually corresponds to normal plasma tonicity but under certain circumstances, it can also be associated with low plasma tonicity. For instance, patient with end-stage renal disease with hypotonic hyponatremia due to increase free water intake in the setting of low GFR might have a normal plasma osmolality due to the effects of an elevated BUN level. High plasma osmolality usually corresponds to high plasma tonicity, but under certain circumstances, it can be associated with normal plasma tonicity (e.g., patient with hypotonic hyponatremia of any etiology and concomitant hyperglycemia) or low plasma tonicity (e.g., patient with hypotonic hyponatremia of any etiology and concomitant acute ethanol intoxication). Therefore, the interpretation of plasma osmolality should be done considering the clinical context.

What are the main determinants of PNa?

In 1958, Edelman empirically demonstrated that PNa is determined by the ratio between total body cations (i.e. sodium and potassium) and total body water as expressed in the following equation called the simplified Edelman equation:

PNa = Total body sodium + Total body potassium

Total body water

The contributions of total body sodium and total body water to PNa are relatively obvious, however, the contribution of total body potassium is less intuitive. While sodium is the main cation in the ECF compartment, potassium is the main cation in the ICF compartment. Changes in total body potassium can result in net water shifts. For instance, hypokalemia due to total body potassium depletion can result in hyponatremia. On the other hand, potassium replacement without administration of sodium containing solutions in patients with both hypokalemia and hyponatremia can not only increase PNa but also cause overcorrection of hyponatremia.

How is hyponatremia classified?

Hyponatremia is traditionally classified as hypertonic (high plasma tonicity), isotonic (normal plasma tonicity) or hypotonic (low plasma tonicity) based on plasma osmolality. Hyponatremia is most often associated with hypotonicity. However, it can occur with normal or even high plasma tonicity as in pseudohyponatremia and translocational hyponatremia. Measure plasma osmolality to establish if the patient has hypotonic hyponatremia with the caveat that osmolality and tonicity are not synonyms.

What are pseudohyponatremia and translocational hyponatremia?

Two thirds of US clinical laboratories still use indirect ion selective electrode (indirect ISE) technique on a diluted blood sample to measure PNa on a routine basis. Plasma is composed of a water and non-aqueous fractions (i.e. proteins and lipids) which constitutes 93% and 7% of plasma volume respectively. Pseudohyponatremia is a laboratory artifact that occurs when the water fraction is altered by the presence of increased protein and lipid and the dilution step resulting in a falsely low PNa. Pseudohyponatremia is associated with isotonicity. Only direct ISE methods (e.g., blood gas analyzer) with an undiluted sample can accurately measure PNa.

Translocational hyponatremia refers to the translocation of water from the ICF compartment to the ECF compartment usually in the setting of hypertonicity, which dilutes the PNa. This most commonly occurs with hyperglycemia but can also occur with mannitol, glycine, and maltose. To correct for the translocational effect of glucose, the plasma sodium concentration is increased by approximately 1.6 mEq/L for every 100 mg/dl of plasma glucose above 100 mg/dl.

How does hypotonic hyponatremia occur?

Based on the Edelman equation, hypotonic hyponatremia develops when there is an excess of total body water relative to total body sodium and potassium, i.e. excess free water (Figure 1).

Figure 1.

Based on the Edelman equation, hypotonic hyponatremia develops when there is an excess of total body water relative to total body sodium and potassium.

Excess free water occurs due to either:

  • Increased free water intake (i.e. water intoxication), or

  • Decreased renal free water excretion

The kidneys have an extraordinary, but not limitless capacity to excrete water. In this scenario, hypotonic hyponatremia occurs when the amount of free water input overwhelms the kidneys maximal capacity to excrete free water.

Urine volume is a surrogate for renal free water excretion. The maximum urine volume can be calculated using the urine osmolality (UOsm) formula. UOsm can be conceptualized as the ratio between the daily urine solute load (USL) and the daily urine volume (V) expressed as:

UOsm = USL/V … (1)

Moving the terms of equation (1) we now have:

V = USL/UOsm … (2)

To understand how USL affects V then we should make three assumptions:

  • In order for V to be the maximum possible, USL must be the highest, and UOsm must be the lowest.

  • Under solute balance conditions, USL is equal to the daily solute intake. The average daily solute intake is 600 to 900 mOsm. Salt and protein are considered solutes. Carbohydrates do not produce any meaningful solutes, as they are not excreted under normal conditions.

  • The lowest UOsm kidneys can generate is 50 mOsm/L.

Applying the three above assumptions in equation (2) then we have:

V = 900 mOsm/day / 50 mOsm/L = 18 L/day … (3)

This means that ingesting over 18 L of water per day (i.e. > 750 mL/h) will overwhelm the maximal renal water excretory capacity resulting in water retention and hypotonic hyponatremia.

Hypotonic hyponatremia can also be due to decreased renal free water excretion and this can occur by three mechanisms:

  • Increased vasopressin activity

  • Decreased solute intake

  • Decreased glomerular filtration rate

Vasopressin binds to the V2 receptor located in the basolateral membrane of principal cells in the collecting duct, which signals through cyclic-AMP and regulates the insertion of the water channel (aquaporin-2) into the luminal membrane thereby rendering this epithelium water permeable. The presence of vasopressin and the activation of this pathway in conjunction with persistent water intake underlies the mechanism of hyponatremia.

Increase vasopressin activity occurs by three different mechanisms:

  • Reduced effective arterial blood volume

  • Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

  • Cortisol deficiency

When the effective arterial blood volume (EABV) decreases by more than 15%, there is a non-osmotic release of vasopressin. EABV is conceptualized as the volume of arterial blood that perfuses tissues. EABV depends not only on volume but also on the function of the heart pump and the vascular tone. Therefore, decreased EABV can be caused by hypovolemia, heart failure, or systemic vasodilation.

SIADH is a condition where vasopressin is released in the absence of a physiological stimulus (autonomous vasopressin release). However, hyponatremia in SIADH is not purely dilutional, as there is also a component of negative sodium balance. Following initial water retention (which causes mild ECF volume expansion); there is a compensatory natriuresis that serves to regulate ECF volume towards normal. Mild volume expansion in SIADH is undetected by bedside examination (patients with SIADH are clinically euvolemic).

Cortisol exerts an inhibitory effect in vasopressin gene synthesis effectively inhibiting vasopressin release. Cortisol also increases the sensitivity of vascular smooth muscle to the actions of catecholamines. Cortisol deficiency therefore causes the opposite effects: decrease negative feedback inhibition of vasopressin synthesis and vasodilation, both of which will stimulate vasopressin release causing hypotonic hyponatremia.

Low dietary solute intake can also result in decreased renal free water excretion. If we change the values of equation (3) by changing the USL to 800 mOsm/day and maintaining a maximally diluted urine with a UOsm of 50 mOsm/L, then the maximal urine volume the kidneys can generate will be reduced to 16 L/day. If we decrease the USL even further to 600 mOsm/day, then the maximal urine volume now decreases to 12 L. From this, we can infer that USL determines the maximal urine volume, and therefore the maximal renal water excretory capacity. Patients on a low solute diet have a limited ability to excrete free water.

Finally, the first step in renal water excretion is glomerular filtration. In conditions associated with reduced glomerular filtration rate (GFR), renal water excretion will be compromised. Given their limited renal water excretory capacity, patients with severely reduced GFR (< 10 mL/min) can become hyponatremic by drinking a relatively normal volume of water.

Once hypotonic hyponatremia has been confirmed, what is the next step?

After confirmation that the patient has hypotonic hyponatremia, the next step is to measure the UOsm which can be done on a spot urine collection.

How do I interpret the UOsm?

UOsm (Figure 2) assesses whether the patient is capable of diluting the urine. If UOsm is less than plasma osmolality, the kidneys are appropriately diluting the urine and this is suggestive of a vasopressin-independent hypotonic hyponatremia which can occur in primary polydipsia, low solute intake (beer potomania, “tea and toast” diet), and renal insufficiency. Patients with primary polydipsia and low solute intake usually can maximally dilute their urine to a UOsm < 100 mOsm/kg.

Figure 2.

Determining the etiology of vasopressin-dependent hypotonic hyponatremia.

If UOsm is greater than plasma osmolality (usually > 100 – 300 mOsm/kg), a diluting defect is present and this is almost always mediated by vasopressin (i.e. vasopressin-dependent hypotonic hyponatremia). Vasopressin limits the diluting ability of the kidney thereby limiting renal water excretion.

What is the next step in determining the etiology of vasopressin-dependent hypotonic hyponatremia?

Obtain a spot urine sodium concentration (UNa) to determine if vasopressin-dependent hypotonic hyponatremia is appropriate or inappropriate (Figure 2).

How do I interpret the UNa?

UNa ≤ 30 mEq/L is suggestive of appropriate vasopressin secretion from decreased EABV. Low UNa in this setting results from renal sodium retention due to renin-angiotensin-aldosterone system (RAAS) activation.

UNa > 30 mEq/L is suggestive of inappropriate vasopressin secretion. (i.e. SIADH).

A caveat to this is that hypotonic hyponatremia due to renal sodium loss (e.g., primary adrenal insufficiency, diuretics, and salt wasting nephropathies) is associated with hypovolemia and decrease EABV despite having a UNa > 30 mEq/L.

What is the next step in the evaluation of vasopressin-dependent hypotonic hyponatremia from appropriate vasopressin secretion?

The next step is to assess the ECF volume status:

ECF volume contraction:

  • Hypovolemia from extrarenal sodium losses (e.g., vomiting, diarrhea, third spacing)

ECF volume expansion:

  • Heart failure

  • Cirrhosis (i.e. vasodilation)

What is hypovolemic hyponatremia and why does it occur?

Hypovolemic hyponatremia is a result of hypovolemia causing decreased EABV that stimulates the non-osmotic release of vasopressin. This leads to free water reabsorption in the kidney and hyponatremia.

Medical history should point to volume depletion such as:

  • Gastrointestinal losses: vomiting, nasogastric suctioning, diarrhea

  • Renal losses: primary adrenal insufficiency, thiazide diuretics, salt wasting nephropathies

  • Skin losses: excessive sweating, burns

  • Hemorrhage

What are the physical exam findings of a patient with hypovolemic hyponatremia?

The classical physical exam findings of hypovolemia are weight loss, dry mucous membranes, sunken eyes, poor skin turgor, dry axilla, orthostatic hypotension, orthostatic tachycardia, frank hypotension, frank tachycardia, and oliguria. However, multiple studies have shown that the sensitivity and specificity of the clinical evaluation of volume status in the setting of hyponatremia are very poor.

What are other causes of hypotonic hyponatremia due to appropriate vasopressin secretion, and why do they develop?

Heart failure and cirrhosis. Early in the disease process, reduced EABV from heart failure and splanchnic vasodilation from cirrhosis lead to activation of neurohormonal pathways including the sympathetic nervous system and RAAS which lead to sodium retention and ECF volume expansion. Late in the course of these conditions, the EABV decreases even further, and now non-osmotic release of vasopressin occurs causing also water retention and the development of hyponatremia. Hyponatremia in heart failure and cirrhosis reflects the severity of the disease and its onset is associated with increased mortality.

What are the physical exam findings in hypotonic hyponatremia associated with ECF volume expansion?

Lower extremity edema, ascites, pulmonary edema, pleural effusions, or elevated jugular venous pressure. Patients with decompensated heart failure or cirrhosis may have hypotension in the setting of hypervolemia due to poor cardiac output and splanchnic vasodilatation, respectively.

What is the next step in the evaluation of vasopressin-dependent hypotonic hyponatremia from inappropriate vasopressin secretion?

The next step is to assess the ECF volume status:

Normal ECF volume:


  • Secondary and tertiary adrenal insufficiency

ECF volume contraction (again the caveat here is that this is an appropriate vasopressin secretion from reduced EABV but associated with a high UNa):

  • Hypovolemia from renal sodium losses (e.g., primary adrenal insufficiency, diuretics, salt wasting nephropathies)

What is and what causes vasopressin-dependent hypotonic hyponatremia from inappropriate vasopressin secretion?

The main causes are SIADH and adrenal insufficiency.

SIADH is a condition characterized by inappropriate vasopressin secretion in the absence of a physiologic stimulus for its release. SIADH is a diagnosis of exclusion. Diagnostic criteria for SIADH include:

  • Hypotonic hyponatremia.

  • Clinical euvolemia. Patients with SIADH are actually mildly volume expanded from water retention but this is not perceived at the bedside.

  • Inappropriately high UOsm (> 100 mOsm/kg).

  • High UNa (> 30 mEq/L). This is caused by compensatory natriuresis caused by inactivation of the RAAS system from mild volume expansion. In fact, hyponatremia in SIADH is not just dilutional but also due to sodium loss. In patients with SIADH, the excretion of sodium reflects dietary intake.

  • Normal thyroid, kidney and adrenal function. Hypothyroidism only causes hyponatremia when severe (TSH > 50-100 IU/L). Normal kidney function is suggested by normal BUN and serum creatinine. Adrenal function can be assessed with an 8AM random cortisol and if indeterminate (< 18 g/dL) then ACTH stimulation test needs to be performed.

  • Although not part of the diagnostic criteria, low plasma uric acid (< 4 mg/dl) is also suggestive of SIADH. Mild volume expansion in SIADH decreases the proximal tubular reabsorption of uric acid increasing the fractional excretion of uric acid and decreasing the plasma uric acid concentration.

The most common causes of SIADH are:

  • Malignancies: small cell lung cancer is the prototype but other malignancies can also cause it.

  • Pulmonary disorders: pneumonia, pleural effusion, pneumothorax, etc. Increased intrathoracic pressure caused by pulmonary problems activate the baroreceptor causing non-osmotic release of vasopressin.

  • Central nervous system disorders: meningitis, encephalitis, brain tumors, etc.

  • Drugs: SSRIs, antipsychotics, narcotics, tricyclic antidepressants, DDAVP.

  • Other: nausea, pain.

If SIADH is suspected, an extensive evaluation for the etiology is warranted and should include:

  • Complete review of medications

  • Age appropriate cancer screening

  • Chest x-ray and/or computed tomography (CT) scan depending on risk factors and clinical scenario

  • Imaging of the central nervous system with either a CT scan or magnetic resonance imaging (MRI)

Adrenal insufficiency can be classified as:

  • Primary adrenal insufficiency: adrenal gland problem

  • Secondary adrenal insufficiency: pituitary problem

  • Tertiary adrenal insufficiency: hypothalamic problem

In the case of secondary and tertiary adrenal insufficiency, hyponatremia is a result of selective cortisol deficiency. However, in primary adrenal insufficiency, there is both cortisol and aldosterone deficiency which are responsible for vasopressin release. Aldosterone deficiency is associated with renal sodium loss and hypovolemia.

What are the signs and symptoms of hyponatremia?

Symptoms of hyponatremia can be classified as asymptomatic, mild symptoms (i.e. nausea, headaches), moderate symptoms (i.e. disorientation, lethargy and confusion) and severe symptoms (i.e. seizures, coma). In general, patients with more severe symptoms will have greater degrees of cerebral edema. There is not a specific PNa level that is associated with onset of symptoms. Both the level of hyponatremia and the rate at which it develops (acute vs. chronic) are important determinants of symptoms. Recent evidence suggests that the so-called “asymptomatic” hyponatremia is not asymptomatic, and even at mild degrees of hyponatremia (PNa of 130 to 134 mEq/L) are associated with attention deficits, gait disturbances, falls, and osteoporosis and bone fractures.

How does the brain adapt to hyponatremia and its correction?

After a decrease in PNa, water moves into the brain along osmotic gradients, producing brain edema. Astrocytes are the most common nonneuronal cell type in the central nervous system and represent about 50% of the human brain volume. Astrocytes have an important role in brain water handling. Astrocytes selectively swell after hypotonic stress. Water moves into astrocytes likely via aquaporin 4 (AQP4). Immediate adaptation to brain swelling includes movement of fluid from the brain interstitial space into the CSF driven by a hydrostatic pressure gradient created by increased intracranial pressure from cerebral edema. This is a limited adaptive mechanism. However, the main way the brain fully adapts to swelling is by losing solutes to decrease ICF tonicity and stop water movement into astrocytes. Astrocyte adaptation occurs by a cellular process known as regulatory volume decrease (RVD). Initially, astrocytes lose electrolytes, mainly Na+, K+ and Cl. This process peaks at 3 hours after initial brain swelling and is completed after 6 or 7 hours. Astrocytes then employ in addition, organic osmolytes for osmoregulation. The main organic osmolytes lost during cell adaptation are glycerophosphorylcholine, phoscreatine, creatine, glutamate, glutamine, taurine, and myo-inositol. Full adaptation occurs by 48h.

What is the definition of acute hyponatremia and how does it present?

Acute hyponatremia is defined as the new onset of hyponatremia within 48 hours. In acute hyponatremia, the brain attempts to adapt to the rapid decrease in plasma tonicity, however, given its acute onset, complete adaptation does not occur and astrocytes swell causing significant brain edema associated with moderate to severe symptoms of hyponatremia.

What is the definition of chronic hyponatremia and how does it present?

Hyponatremia is considered chronic if it is present for more than 48 hours. If the duration is unknown, hyponatremia should be considered chronic. In this setting, the gradual onset of hyponatremia allows for more time for full adaptation consisting of loss of intracellular osmolytes. This decreases brain water content. Therefore, the risk of cerebral edema is markedly decreased and symptoms are often mild or absent.

How do I treat moderately or severely symptomatic hyponatremia?

Symptomatic hyponatremia is a medical emergency and therapy (Figure 3) should be immediately initiated. The initial goal is to reverse potentially life threatening cerebral edema and herniation.

Figure 3.

Treatment of moderately or severely symptomatic hyponatremia.

  • If severe symptoms are present: administer NaCl 3% (Sodium concentration of 513 mEq/L) 100 mL IV bolus and repeat twice more if symptoms persist.

  • If moderate symptoms are present: administer NaCl 3% slow infusion. Initial rate of hypertonic saline can be calculated using Adrogue-Madias or Na deficit formulas. PNa should be checked every 1-2h. Rate of correction should be adjusted based on subsequent PNa checks.

  • Attend to any hypoxemia.

  • Once the life-threatening symptoms have resolved, further management will depend on the underlying pathophysiology of hyponatremia.

How do I treat apparently asymptomatic or mildly symptomatic hyponatremia?

Since these are not medical emergencies, the main therapeutic goal is to correct the underlying pathophysiological mechanism responsible for hyponatremia when possible (e.g., stop the drug causing SIADH). However, the latter is not possible in a great majority of cases (i.e. splanchnic vasodilation in cirrhosis). Therefore, the goal would be to achieve a state of negative water balance. This can be accomplished by decreasing free water intake (i.e. fluid restriction) and increasing renal free water excretion:

  • Primary polydipsia: fluid restriction

  • Hypovolemia: volume expansion with isotonic fluids (e.g., NaCl 0.9%) to turn off vasopressin release.

  • Heart failure: fluid restriction with loop diuretics, or urea, or vasopressin receptor antagonists (VRAs)

  • Cirrhosis: fluid restriction with loop diuretics.

  • SIADH: fluid restriction with or without a drug (e.g., loop diuretics/salt tablets, urea, or VRAs)

  • Cortisol deficiency: glucocorticoid replacement

  • Low solute intake: increase in solute intake

  • Renal insufficiency: fluid restriction

How do I treat acute and chronic hyponatremia?

Acute hyponatremia is a medical emergency and is treated in a similar fashion as severely symptomatic hyponatremia. Chronic hyponatremia is treated based on the severity of symptoms as above.

What are the different therapies available for various types of hyponatremia?
  • Fluid restriction: If a patient excretes more free water than is consumed (either intravenously or orally) the PNa should increase. Fluid restriction includes not just water restriction but all different types of fluids consumed (i.e. juice, soup). In SIADH, to determine if this is a reasonable option, it is helpful to assess whether the patient is excreting free water. Free water is excreted if the ratio of (urine Na + urine K)/PNa or U/P ratio < 1 or if urine osmolality is equal or less than 500 mOsm/kg. Such a patient may respond to fluid restriction if severe enough and if he/she is compliant with this difficult regimen. If the U/P ratio is ≥ 1 or if urine osmolality is greater than 500 mOsm/kg then fluid restriction alone is unlikely to be effective and a drug may need to be added to the regimen (see below).

  • Loop diuretics with or without salt tablets: Loop diuretics result in excretion of electrolyte free water by decreasing medullary gradient for water reabsorption with an electrolyte clearance approximating half normal saline.

    In the setting of SIADH, continued use of a loop diuretic will result in hypovolemia due to urinary sodium losses. This decrease in total body sodium and potassium will also alter the numerator of the Edelman equation impeding the correction of PNa. Therefore, patients will need sodium and potassium supplementation.

    In the setting of heart failure and cirrhosis characterized by increased in total body sodium, loop diuretics alone will lead to both sodium and water excretion which is appropriate.

  • Urea: Urea works in hyponatremia by causing osmotic diuresis and hence increasing renal free water excretion. Urea has been used in Europe (Belgium) since the early 1980s but was not available in the US until recently. One of the main limitations for its use has been its bitter taste. The US formulation of urea comes in a sachet powder which should be dissolved in a small volume of water for oral ingestion and it has a sweet citrus flavor that increases palatability. The FDA considers urea as a medical food and therefore does not require a prescription.

    SIADH is the classical indication for urea use. Initial urea doses in this setting depend on UOsm: 15 g daily (UOsm < 300 mOsm/kg), 15 g BID (UOsm 300 to 500 mOsm/kg) and 30 g BID (UOsm > 500 mOsm/kg).

    BUN is expected to increase with urea use.

    Urea can be used in heart failure but its use in cirrhosis is relatively contraindicated as it can precipitate hepatic encephalopathy.

    Patients on urea should be maintained on 1-1.5 L/day fluid restriction.

Urea has a relatively low cost. Animal studies suggest that urea protects against ODS by increasing rates of osmolyte reuptake during RVD and by facilitating protein folding during osmotic stress.

  • VRAs: Conivaptan and tolvaptan are U.S. Food and Drug Administration approved VRAs for use in euvolemic and hypervolemic hyponatremia. These drugs increase free water excretion and raise serum sodium concentrations. VRAs are the only class of hyponatremia drug supported by randomized controlled trial data.

    Conivaptan is an intravenous V1/V2 receptor antagonist and Tolvaptan is an orally active selective V2 receptor antagonist. Patients with SIADH and congestive heart failure have similar rates of correction of PNa while those with cirrhosis have a more modest response.

    VRAs must be initiated and reinitiated in the hospital setting with frequent PNa monitoring and fluid restriction should be avoided in the first 24h of therapy.

    Trials of VRAs excluded patients with PNa < 125 mEq/L and patients with severe symptoms, therefore these agents should not be used under those conditions.

    Limitation for the use of VRAs include increased risk of liver injury when used at high doses (use is contraindicated in cirrhosis or for a period greater than 30 days), risk of overcorrection of PNa, and high cost.

What are the goals and limits of correction of hyponatremia?

The traditional increase in PNa of 10 or 12 mEq/L in any 24h is not a goal; instead, this is a threshold above which the risk for having complications significantly increases. There aren’t too many therapies in medicine where we set our goal at the toxic range. It is never wise to seek a PNa correction of 10 mEq/L in any 24h period because people just barely exceeding those limits sometimes develop complications (i.e. patients at high risk for ODS). There is no evidence that correcting PNa by more than 4-6 mEq/L per day offers any advantage in either acute or chronic hyponatremia. As a matter of fact, the best evidence suggests that increasing PNa by 6 mEq/L is enough correction to treat the most serious complications of acute symptomatic hyponatremia.

Goals of correction:

  • Increase in PNa by 4-6 mEq/L in any 24h period

Limits of correction:

  • For patients at average risk of ODS: Increase in PNa by no more than 10 mEq/L in any 24h period

  • For patients at high risk of ODS: Increase in PNa by no more than 8 mEq/L in any 24h period

There is little evidence that exceeding the traditional rates of correction of 1 mEq/L/h in acute hyponatremia or 0.5 mEq/L/h in chronic hyponatremia, are associated with ODS. Instead, exceeding the absolute magnitude of correction of 8 or 10 mEq/L in a 24h period does constitute an important risk factor for the development of ODS.

What is overcorrection of hyponatremia and how does it occur?

Overcorrection of hyponatremia is defined as the correction of PNa that exceeds the limit of correction in any 24h period. Overcorrection is usually preceded by the onset of a large water diuresis manifested clinically as an increase in urine output and a reduction in UOsm (i.e. diluted urine).

Risk factors for overcorrection of hyponatremia:

  • Volume expansion in hypovolemia

  • Administration of glucocorticoids in cortisol deficiency

  • Discontinuation of drugs causing transient SIADH (e.g., SSRI, carbamazepine, DDAVP)

  • Discontinuation of thiazide diuretics

  • Administration of vasopressin receptor antagonist for hyponatremia

What do I do to prevent overcorrection of hyponatremia?

Once PNa reaches the goal of six mEq/L in 24h then urine output should be matched with D5W mL per mL to prevent further elevation of PNa.

How do I deal with established overcorrection of hyponatremia?

If the PNa increases over the limits of correction before the 24h mark, re-lowering the PNa is indicated.

This can be accomplished by ceasing further renal free water excretion with DDAVP (desmopressin) at a dose of 2-4 mcg IV Q6h. The administration of D5W IV at a rate of 3 mL/kg/h IV is also necessary to relower PNa. At this rate of D5W, PNa is expected to decrease by 1 mEq/L/h. In patients who are treated with a VRA, DDAVP may fail to abrogate free water losses.

What is osmotic demyelination syndrome (ODS)?

In chronic hyponatremia, intracellular osmolytes leave astrocytes in response to a fall in the plasma tonicity. Rapid correction of PNa then leads to astrocyte dehydration as water moves out of these cells. One of the current hypothesis proposes that acute brain shrinking causes astrocyte death and loss of cell-to-cell interactions between astrocytes and oligodendrocytes (myelin producing cells). Dying astrocytes are suggested to promote demyelination by enhancing the release of cytokines and other inflammatory mediators, and recruitment of T cells, microglia and macrophages. This can result in demyelination, classically in the central basis pontis (i.e. central pontine myelinolysis), but can also occur in extrapontine sites (i.e. extrapontine myelinolysis).

Risk factors for the development of ODS:

  • Overcorrection of chronic hyponatremia

  • PNa < 105 mEq/L

  • Alcoholism

  • Malnutrition

  • Hypokalemia

  • Liver disease

Symptoms include altered mental status, lethargy, obtundation, seizures, coma, and motor abnormalities such as quadriplegia, respiratory paralysis, and pseudobulbar palsy.

Neurologic symptoms from hyponatremia may initially improve but then rapidly deteriorate due to the development of ODS, which typically develops 2-6 days after the hyponatremia has been corrected but it could be longer.

ODS can be confirmed with brain magnetic resonance imaging (MRI) showing demyelination in in a typical distribution. However, MRI can be normal up to 1 month after of symptoms onset and therefore a normal MRI does not exclude the diagnosis.

The prognosis of ODS has been historically poor with increased mortality and disability rates but more recent case series suggest that neurological sequelae from ODS can significantly improve.

There is no treatment for ODS therefore prevention with careful and slow correction of the PNa is crucial.

How should a patient receiving treatment for hyponatremia be monitored?

Patients with symptomatic hyponatremia or a PNa < 120 mEq/L should be monitored in the intensive care unit where they can undergo frequent lab testing with PNa measured every 1-2 hours and close monitoring of their urine output and UOsm looking for ominous signs of overcorrection.

Once the stimulus for vasopressin released is removed (e.g., volume expansion in hypovolemic hyponatremia), a free water diuresis will ensue. These patients may require hypotonic fluids to prevent or treat overcorrection of PNa.

Neurologic status should be assessed every few hours to evaluate for improvement in symptoms.

How to utilize team care?

Nephrologists should be consulted for the use of hypertonic saline, the use of vasopressin antagonists, or any time the primary medical team feels uncomfortable managing the hyponatremia.

Nurses should be educated as to the importance of notifying the primary team if a patient’s urine output significantly increases. In addition, they can monitor fluid intake and fluid restrictions.

Pharmacists can assist in concentrating intravenous medications if indicated and ensuring that the amount of free water the patient is receiving with medications is minimized.

Dieticians can counsel patients about what a fluid restriction entails. A fluid restriction includes not only water but other liquids (juice, tea, etc.) and foods with a high water content, such as fruits.

Are there ongoing clinical trials of therapeutic significance?

An ongoing randomized crossover trial in Switzerland is investigating the efficacy of Empagliflozin in hyponatremia of SIADH. Empagliflozin is a sodium glucose co-transporter 2 (SGLT2)-inhibitor, which is a well-tolerated treatment option for type 2 diabetes mellitus. The inhibition of SGLT2 in the proximal tubule leads to renal excretion of glucose with subsequent osmotic diuresis. This mechanism could result in a therapeutic effect in patients with chronic SIADH, as it resembles the mechanism of action of urea in hyponatremia.

Other considerations


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