Hyponatremia is defined as a decrease in sodium (NA+) concentration below the normal range (135-145 mEq/L [or mmol/L in international units]), and is usually indicative of hypo-osmolality of body fluid due to excess of water relative to solute.1
While hyponatremia is possibly the most common electrolyte disturbance in a general hospital population (up to 22 percent in some settings) 4, the incidence by no means indicates that the condition is benign. Mortality rates as high as 17.9 percent have been quoted, but rates this extreme usually occur in the context of critically ill hospitalized patients.1 There in the U.S is equal between males and females. 3
Although most cases are mild, hyponatremia is important clinically because:
Because the treatment of hyponatremia differs according to the cause, a logical and efficient approach to the evaluation and management of patients with hyponatremia is imperative.
Most chronically hyponatremic patients are asymptomatic. Symptoms of hyponatremia are nonspecific, variable, and dependent on the degree of chronicity of the disturbance, usually not appearing unless levels drop below 120 mEq per liter.1 Symptoms of hyponatremia are:
In severe hyponatremia however, neurologic and gastrointestinal symptoms can be common, with the possibility of seizure and coma increasing as plasma NA+ decreases. Also, the rapidity with which plasma NA+ level decreases may precipitate symptoms above 120 mEq per liter. 1 In patients with severe acute hyponatremia, signs of brainstem herniation include3:
Inside fixed spaces (i.e. intracerebral space) the brain is capable of compensating for gradual NA+ loss by extruding solutes and fluid into the extracellular space, sometimes allowing NA+ levels as low as 110 mEq per L with minimal symptoms. When the loss is abrupt this compensatory mechanism is overwhelmed, cerebral edema results, and in severe cases progresses to brainstem herniation and death. Rhabdomyolysis is an occasional outcome of severe hyponatremia and should be considered in patients with severe muscle cramping or muscle tenderness. 3
The first step is prompt clinical assessment of the patient’s volume status, followed by measurement of:
Significantly elevated glucose, protein, and lipid serum levels may produce reduced NA+ levels. Referred to as factitious hyponatremia, this phenomenon occurs when increased percentages of large molecules are present in the serum compared to the NA+ concentration. Serum OSM (normal range 280-300mOsm/L [or mmol/L in international units] 6) can also be calculated at the bedside using the formula:
Serum OSM = 2 x (NA + K) + (BUN / 2.8) + (glucose / 1.8)
A high glucose level can produce one form of factitious hyponatremia. If serum OSM is greater than 300, the NA+ may need to be corrected depending upon the glucose level. This is accomplished for glucose by using the formula:
True Na+ = [(measured glucose – 100) /100] x 1.6 + measured Na+
For example, a patient is noted to have a NA+ level of 127, and serum glucose of 600. By correcting for glucose, the true NA+ level is found to be 135 and not hyponatremic at all. This is an example of redistributative or translational hyponatremia because no net change in total body water (TBW) has occurred. No specific therapy is indicated for the hyponatremia, because Na+ concentration will return to normal once the plasma glucose concentration is lowered. 2
The oncotic pressure of the serum glucose causes free water to move from the interstitial space to the intravascular space, giving the appearance of hyponatremia. As the hyperglycemic state is corrected (usually by administration of exogenous insulin), the NA+ also corrects accordingly.
If, however, NA+ level is 118, the K+ is 4.0, and the BUN is 18, the calculated serum OSM is 582, clearly above 300. By correcting for the elevated glucose of 600, the OSM is still above 300 and the NA+ level is now 121. Still low, but unless there are significant symptoms of hyponatremia, the coexisting fluid/electrolyte imbalance must be addressed before any attempt is made to correct the hyponatremia. Administration of both fluids for the corresponding dehydration and exogenous insulin, which will change the K+ level as well as the glucose level, will alter both the OSM and true NA+ level.
Another form of factitious hyponatremia, pseudohyponatremia results from significantly elevated protein and lipid serum levels (usually triglycerides >1500mg/dL or protein >10g/dL 5) giving the appearance of reduced serum sodium levels. This phenomenon occurs when flame emission spectrophotometry or indirect potentiometry (used in approximately 60 percent of U.S. laboratories 3), rather than direct potentiometry technique is used to assay serum sodium levels. These large molecules do not actually affect the serum osmolality, and therefore the serum remains isotonic causing a relative decrease in serum sodium without changing osmolality. Hyperlipidemia that is severe enough to produce pseudohyponatremia is almost always accompanied by a lipemic appearance of the serum sample (fat globules in suspension or a lipid layer at the top of the sample), and hyperproteinemia of sufficient magnitude to induce pseudohyponatremia is commonly due to underlying multiple myeloma. 3
When serum OSM has been measured and found to indeed be less than 280, the clinical volume status of the patient becomes more significant. Hypotonic hyponatremia can be classified as:
Edema associated with hypervolemic hyponatremia indicates that the total body water is proportionally greater than the total NA+ and is usually accompanied by pulmonary crackles, indicating the presence of pulmonary as well as peripheral edema. Peripheral edema with or without pulmonary edema may be caused by congestive heart failure, cirrhosis, Syndrome of Inappropriate Anti Diuretic Hormone secretion (SIADH), recent significant beer intake “beer potomania,” MDMA (ecstasy) use, hypothyroidism, and renal disease, including renal failure and nephrotic syndrome. Measurement of urine OSM can help to differentiate between SIADH and other causes of hypervolemic hyponatremia. 3 Typically, patients with SIADH have inappropriately concentrated urine, often with osmolarities in excess of 300mOsm/Kg (normal range can vary considerably, from 200-1200 mOsm/Kg), 7 depending on the corresponding serum osmolarity.
Although SIADH is classically attributed to sustained antidiuretic hormone (ADH) release, several abnormal patterns of ADH release have been identified by ADH radioimmunoassay. In some patients, ADH secretion is erratic and apparently independent of osmotic control. In another large subset, ADH levels vary appropriately with plasma OSM, but the osmotic threshold for ADH release is abnormally low (a reset osmostat). Small subsets of patients appear to have a constant low-level release of ADH within the normal range of plasma OSM. ADH release is appropriate, but when the plasma becomes hypo-osmotic, ADH release is not suppressed. Another small subset of patients is unable to maximally dilute the urine or excrete a water load, but have normal ADH release. These patients have a syndrome of inappropriate antidiuresis rather than SIADH and may be distinguished only by assay of plasma ADH levels. 2
Appropriate laboratory studies can prove or disprove cirrhosis, hypothyroidism, CHF, and renal disease. Use of MDMA or excessive beer intake can be determined from the history, either from the patient or the patient’s friends/family if the patient is unconscious.
Differentiating clinically between euvolemia and hypovolemia can be more difficult, often requiring additional laboratory analysis, especially if the usual consequences of hypovolemia, including hypotension and tachycardia, are absent or masked. Generally speaking, the consequences of volume depletion are fairly easy to recognize, and include:
Most common causes of hypovolemic hypotonic hyponatremia are renal salt loss, extrarenal salt loss (i.e. excessive sweating or diarrhea), adrenal insufficiency, and third space sequestration (severe malnutrition, pancreatitis, peritonitis, or severe burns).
Once it has been determined that outside influences (especially drugs, i.e. beta-blockers) are not masking or responsible for signs suggestive of hypovolemia, it is reasonable to conclude that the patient is experiencing euvolemic hypotonic hyponatremia. The most common causes are:
Primary or psychogenic polydipsia can cause hyponatremia only when water intake overwhelms the kidneys' ability to excrete water. Since normal kidneys can excrete up to 25 L urine/day, hyponatremia due solely to polydipsia results only from the ingestion of large amounts of water or from defects in renal diluting ability. This usually occurs only in psychosis or in patients with more modest degrees of polydipsia and renal insufficiency. 2
It should also be noted that many medications may also cause hyponatremia, including3:
angiotensin II receptor blockers
angiotensin-converting enzyme inhibitors
proton pump inhibitors
selective serotonin reuptake inhibitors
Thiazide diuretics, in particular, affect the kidneys' diluting ability while increasing NA+ excretion. Once volume depletion occurs, the nonosmotic release of ADH can cause water retention and worsen hyponatremia. Concomitant hypokalemia shifts NA+ intracellularly and enhances ADH release, thereby worsening hyponatremia. This effect of thiazides may last for up to two weeks after cessation of therapy; however, the hyponatremia usually responds to replacement of K+ and volume deficits along with judicious restriction of water intake until the drug effect dissipates. 2
First, any life-threatening conditions should be addressed, and supportive care initiated. If possible, IV access should be established and oxygen administered via nonrebreather or venturi mask in patients with altered mental status.3 Blood glucose should be checked as soon as possible, and corrected if necessary.
If the patient is experiencing seizures, standard anticonvulsant therapy should be administered. Response will probably be suboptimal, but administration may help to stabilize the patient until a definitive diagnosis can be established.3 At this point, intubation and ventilation should be strongly considered, especially in patients exhibiting signs of brainstem herniation (obtundation; fixed, dilated, unilateral pupil; and/or decorticate or decerebrate posture). Hypotonic (0.45 %) IV fluids should be avoided if hyponatremia is suspected, as it may exacerbate cerebral edema.3
Treatment in the Emergency Department is two-fold; first an attempt to establish the chronicity should be undertaken; and second, the underlying cause should be determined if possible to facilitate appropriate treatment. 3 Acute hyponatremia is less common than chronic hyponatremia, and is usually due to sudden water overload in, for instance, acute psychogenic polydipsia; drug ingestion, including large amounts of beer (“beer potomania”); excessive use of irrigation fluids in post-operative patients (usually post transurethral prostate resection or hysteroscopy, known as post-TURP and post-hysteroscopy syndromes, respectively), where irrigation fluids can be absorbed directly by exposed vasculature; infants given inappropriate amounts of tap water; etc. 3
The danger for these patients is intercerebral edema and subsequent brainstem herniation when NA+ levels fall below 120mEq/L, often resulting in death or severe disability. First, the source of free water must be identified and eliminated. In patients with normal renal function and mild to moderate symptoms, this may be all that is required to correct the imbalance. The therapeutic goal is to correct the NA+ deficit by 4-6mEq/L over one to two hours. Patients with seizures, severe confusion, coma, or symptoms of brainstem herniation, should be given only enough hypertonic (3%) solution to arrest the progression of symptoms and begin to correct the NA+ imbalance. 3
In contrast, patients with mild to no symptoms and NA+ levels below 125mEq/L, or no history of free water loading, almost exclusively have chronic hyponatremia, and must be managed with extreme caution. 3 If the history is not consistent with known causes of hyponatremia, labs should be redrawn before any treatment is initiated. A rapid increase in NA+ once compensatory mechanisms are in place can lead to cerebral pontine myelinolysis (CPM), an often irreversible condition characterized by:
The risk of CPM is minimal in patients with chronic hyponatremia whose deficit is corrected at less than 0.5mEq/L/hour or 12mEq/L/day. There are anecdotal reports suggesting that therapeutic relowering of NA+ using hypotonic saline and desmopressin (DDAVP) may help avert neurologic sequelae in patients whose chronic hyponatremia is inadvertently corrected too quickly. 3
The presence of hyponatremia, hyperkalemia, and hypotension should suggest acute adrenal insufficiency and may require IV glucocorticoid administration (100 to 200 mg hydrocortisone in 1 L of 5% dextrose and 0.9% saline given over four hours) for treatment.
When adrenal function is normal, but hyponatremia is associated with extra cellular fluid (ECF) volume depletion and hypotension, administration of 0.9 % saline usually corrects both the hyponatremia and hypotension. If the underlying disorder responds slowly or hyponatremia is marked (i.e. plasma Na < 120 mEq/L), restriction of water ingestion to not more than 500 to 1000 mL/24 h is highly effective. 2
Patients with symptoms of severe hyponatremia (coma, recurrent seizures, and signs of brainstem involvement) should be managed in a medical intensive care unit. Medications known to precipitate hyponatremia should be discontinued. Thiazide diuretics, which are commonly associated with hyponatremia in the elderly, should be discontinued on all patients with hyponatremia. Patients with known or suspected hyponatremia secondary to free water ingestion should be admitted to a unit where free water access can be restricted and monitored. 3
Most patients in whom dilutional hyponatremia is associated with ECF volume expansion due to renal NA+ retention (e.g. heart failure, cirrhosis, or nephrotic syndrome) experience few symptoms associated with hyponatremia. In these patients, water restriction combined with treatment of the underlying disorder is often successful. Captopril, or any of the ACE inhibitors, in conjunction with a loop diuretic, can be used to correct refractory hyponatremia in patients with heart failure. Captopril and other ACE inhibitors may also be effective in other ECF volume-expanded states characterized by increased activity of the renin-angiotensin-aldosterone axis, especially nephrotic syndrome. If SIADH is present, severe water restriction of 25 to 50% of maintenance is required. Lasting correction depends on successful treatment of the underlying disease process. 2
Hypertonic saline is the drug of choice for patients with severe symptoms of hyponatremia. The volume administered depends upon current and desired NA+ levels and patient's weight. In general, an increase of 4-6 mEq/L in NA+ is sufficient to arrest progression of symptoms in severe hyponatremia. 3 Further rapid increase in NA+ is not indicated.
The required volume of hypertonic saline = (desired change in NA+) (TBW) / (NA+ in IV fluid - current NA+), where TBW = body weight x 0.6.
For example, a 60-kg woman with NA+ of 113 mEq/L would require 360 mL of hypertonic saline. 3 In general, 300-500 mL of 3% NaCl is a reasonable dose in most adult patients with severe symptomatic hyponatremia, given IV over first one to two hours until resolution of seizures. 3 Hypertonic saline may be administered to children as in adults, but is considered category “C” in pregnancy (safety has not been established).
Because of the possibility of precipitating additional neurologic sequelae, hypertonic saline should be used with great caution in the setting of hyponatremia.1 Experts agree that overcorrection of hyponatremia is dangerous; hypernatremia and even normonatremia should be avoided. Many experts recommend that plasma NA+ be raised no faster than 1 mEq/L/h and that the absolute rise should be no more than 10 mEq/L/24 hour. The following is a reasonable compromise: 250 mL of hypertonic saline should be slowly infused IV, and then NA+ checked 10 hours later. If values remain too low, the amount may be repeated, maintaining the rise in NA+ within 10 mEq/L/24 hours. 2
The most important neurologic sequela following too-rapid correction of hyponatremia is central pontine myelinolysis. This is demyelinization of the central basal pons. Demyelinization may also affect other areas of the brain. Quadriparesis and weakness of the lower face and tongue can evolve over a few days or weeks. The lesion may extend dorsally to involve sensory tracts and leave the patient with a locked-in syndrome. Locked-in syndrome is an awake and sentient state in which the patient has generalized motor paralysis and cannot communicate, except possibly by coded eye movements. Damage often is permanent and systemic complications may develop. If NA+ is replaced too rapidly (e.g. when large volumes of normal saline are given to a burn patient), inducing hyponatremia with hypotonic fluid can sometimes mitigate the development of central pontine myelinolysis. 2
In general, the prognosis in hyponatremia depends to a great extent on the underlying etiology, the speed of development and severity of symptoms, and availability of appropriate monitoring and treatment. In all patients with hyponatremia, the cause should be identified and treated if possible. Some causes, such as congestive heart failure or diuretic use, are obvious. Other causes, such as SIADH and endocrine deficiencies, usually require further evaluation before appropriate treatment can be initiated. In patients with hypervolemic hyponatremia, fluid and NA+ restriction is the preferred treatment. Loop diuretics can be used in severe cases, with hemodialysis an alternative in patients with renal impairment.1 Hyponatremia in volume depleted patients is usually due to loop diuretics, and treatment is to hold the medication and possibly the gradual replacement of isotonic (0.9%) normal saline. The U.S. Food and Drug Administration (FDA) has approved VAPRISOL(R) (generic name: conivaptan hydrochloride injection), an arginine vasopressin (AVP) antagonist for the intravenous treatment of euvolemic hyponatremia in hospitalized patients.
1. Kian Peng, Goh. (2004). Management of Hyponatremia. American Family Physician, 15 May 2004, vol. 69/No. 10.
2. Water and Sodiun Metabolism, Accessed 25 August 2005, at http://www.merck.com/mrkshared/mmanual/section2/chapter12/12b.jsp
1995-2005 Merck & Co., Inc., Whitehouse Station, NJ, USA.
3. Craig, Sandy E., Hyponatremia, Accessed 24 August 2005, at http://www.e-medicine.com
4. Verbalis, JG: (1998) Hyponatremia and Hypoosmolar Disorders. In: Greenberg, A (ed) Primer on Kidney Diseases, 2nd edition. Academic Press, San Diego, CA, pp 57-63, 1998
5. Zhongxin, Yu, MD; K. Michael Parker, PhD; Kenneth E. Blick, PhD, (2005). Markedly Decreased Serum Sodium Concentration in a patient with Multiple Myeloma. Lab Med. 2005; 36 (4): 224-226. American Society for Clinical Pathology, Accessed at http://www.medscape.com/viewarticle/502690_print
6. Ferri, Fred F., MD, Practical Guide to the Care of the Medical Patient, 2nd edition. Mosby Year Book, St. Louis, MO, pp 603, 1991
7. Moses, Arnold M; David H. P. Streeten, Disorders of the Neurohypophysis. In: Iselbacher, Kurt J., et al (ed) Harrison’s Principles of Internal Medicine, 13th edition. McGraw-Hill, inc. USA, pp 1928, 1994