Hospital Practice: Volume 38: No.1

Evaluation and Management

Robert D. Zenenberg, DO; Alessia L. Carluccio, BS; And Mark A. Merlin, DO, EMT-P, FACEP

Abstract: Hyponatremia is one of the most common electrolyte disorders encountered in clinical practice. The pathophysiology is complex, but its understanding is vital to the disorder’s evaluation and treatment. The clinical manifestations of hyponatremia include headache, dizziness, nausea/vomiting, seizures, obtundation, and death. Undercorrection must be avoided, but overly aggressive treatment can also be detrimental. We review normal water physiology, including central osmosensory mechanisms, that are now becoming better understood. We will then review the classification and causes of hyponatremia and the clinical evaluation and workup of the disorder. Treatment options will be briefly reviewed. Evaluation of hyponatremia begins with a detailed history and physical examination. Appropriate urine and serum studies can contribute to the evaluation and classification of the disorder. Treatment decisions are based on the underlying cause and severity of symptoms. We present an extensive review of the physiology, pathophysiology, clinical evaluation, and management of hyponatremia.

Keywords: hyponatremia; antidiurectic hormone; SIADH; saline

Hyponatremia is defined as a serum sodium concentration < 136 mmol/L. It is one of the most common electrolyte disorders encountered in clinical practice. Upadhyay et al¹ found that 42.6% of hospitalized patients had serum sodium levels < 136 meq/L. Treatment goals involve returning the patient’s serum sodium levels back to normal at an appropriate rate of correction while avoiding overly aggressive management. Hyponatremia may manifest as headache, nausea, vomiting, disorientation, muscle cramps, lethargy, restlessness, seizures, respiratory arrest, brain stem herniation, and death. These neurologic manifestations are due to the movement of water into the brain, which causes edema in the enclosed space of the cranium with resultant intracranial hypertension.² If, however, serum sodium levels are subsequently corrected too rapidly, patients may develop pontine and extrapontine cerebral myelinolysis, potentially resulting in brain injury. Once treatment is instituted, continuous clinical and laboratory monitoring are required to ensure achievement of appropriate correction goals.

The excretion of a water load begins with the formation of the initial glomerular filtrate (Figure 1). The filtrate undergoes a large percentage of reabsorption (~65%) in the proximal tubule. Next, the thick ascending limb of the loop of Henle begins the “diluting segment.” The diluting segment reabsorbs sodium chloride (Na⁺Cl⁻) from the glomerular filtrate without water. This allows the dilution of the filtrate and the reabsorbed Na⁺Cl⁻ contributes to the interstitial medullary osmotic gradient, which will draw water from the collecting tubule in the presence of vasopressin. In the collecting tubule, with vasopressin present, water is reabsorbed via aquaporin channels down a concentration gradient due to the medullary interstitial hypertonicity. In the absence of vasopressin, water is not reabsorbed and dilute fluid is excreted.^3–5

The amount of solute per liters of solution is referred to as osmolality and reflects the concentration of solutes in solution. Tonicity reflects the solutes in solution that can effect water movement across cell membranes. Normal serum tonicity is approximately 280 to 295 mOsm/kg. Small changes in tonicity can be detected by central osmoreceptors. These central osmoreceptors have been localized to regions of the brain identified as the organum vasculosum laminae terminalis, subfornical organ, and median preoptic nucleus. The mechanism by which these osmoreceptors sense tonicity and then translate that into vasopressin release or repression and thirst is not yet fully understood. It is likely that osmoreceptor neurons themselves undergo volume changes depending on water movement into or out of them, resulting in a cationic current and depolarization. In the setting of increased serum tonicity, the osmoreceptor cell shrinks and activates stretch-inhibitable cationic cation channels to depolarize the cell; this results in nerve transmission to the vasopressin-containing magnocellular neurons in the hypothalamus and stimulates thirst. These magnocellular neurons release preformed vasopressin into the bloodstream (Figure 2).^6-9

Vasopressin release and thirst can also be stimulated by baroreceptor-mediated afferent signals sent via cranial nerves IX and X to the brainstem, and then to the hypothalamic magnocellular neurons, in states of absolute (bleeding, diarrhea, diuretics) or “effective” (decreased cardiac output, cirrhosis) arterial underfilling.^3,10 These hemodynamic stimuli shift the sensitivity of vasopressin release to osmotic stimuli; thus, a given level of tonicity will cause a greater vasopressin response in hypovolemic conditions. At more severe degrees of volume depletion (~10% blood volume) direct vasopressin release may be stimulated.^3,4,6,11 Once secreted, vasopressin stimulates V2-receptors in the collecting tubules of the kidney and allows for expression of aquaporin-2 water channels in the apical membrane of the otherwise impermeable collecting tubules. This allows water to be reabsorbed from the tubular lumen down its concentration gradient. When the body’s tonicity has returned to normal, vasopressin secretion ceases, and the water channels are again downregulated from the collecting tubule membrane.^3,5,11

Hyponatremia is problematic because of its associated hypotonicity. In all forms of “true” hypotonic hyponatremia, serum tonicity is < 275 mOsm/kg. However, the serum osmolality may be ≥ 275 mOsm/kg in true hypotonic hyponatremia. This is evident when measured osmolality includes freely permeable osmoles, such as urea or alcohols, that do not contribute to tonicity. In azotemic patients, the correction for an elevated blood urea nitrogen (BUN) divides the BUN by 2.8, which is subtracted from the measured osmolality, giving the true tonicity.^22,11,12 There are 2 conditions in which hyponatremia is found in the labwork although the patient is not hypotonic. The treatment is directed at the underlying condition only, and no treatment for the hyponatremia itself is necessary. This occurs in translocational hyponatremia and pseudohyponatremia.

The presence of osmotically active extracellular solutes other than sodium, such as glucose, mannitol, or radiocontrast agents, can cause an osmotic shift of free water from the intracellular to the intravascular space. This causes a dilution of serum sodium and, thus, causes a translocational hyponatremia with normal serum tonicity or even hypertonicity. While total body water and sodium content remain unchanged, the resultant increase in intravascular fluid causes a dilution in sodium concentration. For glucose, one can calculate the corrected sodium depending on the glucose concentration (add 2.4 meq/L to the measured sodium concentration per 100 mg/dL glucose > 100).^2,11-14

The aqueous part of plasma normally comprises 93% of the total volume. This is where the sodium and other electrolytes are contained. The other 7% of plasma is comprised of the nonaqueous components, such as protein and lipid. The sodium concentration in the aqueous part of plasma is 154 meq/L (explaining why normal saline is 154 meq/L and not 140 meq/L). Patients with conditions such as severe hypertriglyceridemia or elevated total protein levels have a larger percentage within the nonaqueous portion of the serum sample. This can lower the serum sodium concentration in the total sample even though the sodium content of the aqueous compartment has not been altered, and thus the overall tonicity is normal. This is known as pseudohyponatremia. For each mg/dL of lipid, the serum sodium decreases by 0.002 meq/L, and for each gram of protein > 8 g/dL, the sodium decreases by 0.25 meq/L.^13,14 These patients have a normal serum osmolarity. Pseudohyponatremia should not be of issue with the current use of ion-selective electrodes, which measure only the aqueous portion of the blood sample, but results are occasionally inaccurate due to specimen dilution. When one dilutes the serum specimens, a dilution error can be introduced into the specimen and cause a spuriously low sodium. Use of equipment that does direct measurements of only the aqueous phase of the specimen using direct potentiometry, like that used in blood gas or portable rapid electrolyte monitors, avoids this dilutional error.^13,14 In addition, when hyperproteinemia is caused by an accumulation of cationic gamma globulins (Immunoglobulin G myeloma), this causes additional lowering of the measured sodium due to the large amounts of unmeasured cationic charges.¹⁴

True or hypotonic hyponatremia is classically characterized by the patient’s overall volume status. In hypovolemic hyponatremia, extracellular fluid volume is depleted as a result of renal (diuretics or mineralocorticoid deficiency) or extrarenal (gastrointestinal, third spacing of fluids) losses. This results in unloading/stimulation of arterial baroreceptors, which causes increased activation of the sympathetic nervous system, renin-angiotensin-aldosterone system, and vasopressin release. This results in a decreased glomerular filtration rate (GFR) and increased proximal reabsorption of filtrate, with decreased delivery of filtrate to the diluting segment, and increased collecting tubule reabsorption of water that makes it to this segment.³ These responses prevent excretion of a water load and results in hyponatremia in the setting of hypotonic fluid intake. A hypovolemic variety of hyponatremia is cerebral renal salt wasting. This debated entity classically occurs in patients with neurologic conditions, such as subarachnoid hemorrhage, but may occur in non-central nervous system conditions and is often misdiagnosed as syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH). The implications of misdiagnosis can be detrimental. This entity is caused by an apparent proximal tubular dysfunction that causes salt wasting. The salt wasting causes volume depletion and subsequent baroreceptor-mediated vasopressin release. These patients have high fractional excretion of uric acid and low serum uric acid levels during hyponatremia, and often have elevated urine sodium levels, similar to patients with SIADH and atypical of classic volume depletion. In addition, BUN/creatinine ratios are not typically elevated as they would be in volume depletion. This makes the differentiation of cerebral renal salt wasting from SIADH difficult. The etiology is unknown, but theories include elaboration of a natriuretic peptide or renal denervation as the cause of the salt wasting.^15,16

Hypervolemic hyponatremia is seen in states of poor cardiac output, liver cirrhosis, and, occasionally, nephrotic syndrome. The overall pathophysiology is essentially the same as hypovolemic hyponatremia. The patients are clinically volume overloaded, but because of poor cardiac output in patients with cardiac dysfunction and splanchnic vasodilation in cirrhosis, there is arterial underfilling despite total body volume overload with baroreceptor unloading, and subsequent activation of the sympathetic nervous system, renin-angiotensin-aldosterone system, and vasopressin release. The baroreceptors sense a state of poor perfusion. There is decreased GFR with avid proximal reabsorption of filtrate, and decreased delivery of filtrate to the diluting segment with increased reabsorption of water in the collecting duct.^{3,5,10,17–20} The kidneys respond the same way to states of poor “effective” circulating volume as they do to “true” or absolute hypovolemia.

Hyponatremia can also occur in euvolemic states. The differential diagnosis of euvolemic hyponatremia is SIADH, glucocorticoid deficiency, severe hypothyroidism, exercise-associated hyponatremia, low solute intake states, and the nephrogenic syndrome of inappropriate antidiuresis (NSIAD). Patients with SIADH secrete the vasopressin hormone inappropriately, thereby promoting the constant presence of aquaporin-2 water channels in the collecting tubule, apical membrane, and reabsorption of water. The mild volume expansion caused by the water reabsorption leads to natiuresis, which contributes to the hyponatremia. The initial water reabsorption is attenuated after a few days by “vasopressin escape,” which is likely mediated by downregulation of aquaporin-2 and decreased vasopressin receptor expression.^3,5 The release of vasopressin in SIADH has been divided into 4 subtypes based on the patterns of release. Type A is characterized by unregulated and erratic secretion of vasopressin; Type B is characterized by an elevated basal secretion of vasopressin; Type C is a “reset osmostat” or normal regulation of vasopressin release, but at a lower osmotic set point; and Type D shows no detectable vasopressin on assay.^3,12 The causes of SIADH are usually related to tumors, severe pain, nausea, pulmonary disease, central nervous system conditions, and many medications (Table 1). Glucocorticoid deficiency stimulates the release of corticotropin-releasing factor and vasopressin from parvocellular neurons in the paraventricular nucleus of the hypothalmus. These neurons are stimulated to release vasopressin as a mechanism to assist corticotropin-releasing factor synergistically in causing adrenocorticotrophic hormone release. Other mechanisms that do not involve vasopressin may contribute to the hyponatremia in glucocorticoid deficiency, including increasing aquaporin-2 expression on the collecting tubule membrane and hemodynamic mechanisms.¹⁹ Severe hypothyroidism causes nonosmotic antidiuretic hormone release via hemodynamic mechanisms by decreasing cardiac output.^19,20 Psychogenic water drinking and the related low solute intake disorders of crash diets, “tea-and-toast” syndrome, and beer potomania also cause euvolemic hyponatremia. Pure psychogenic water drinking is caused by significant fluid intake, overwhelming one’s urinary diluting capacity. Many patients with underlying psychiatric illnesses are on medications (including nicotine), which may contribute to their impairment in diluting ability.²⁰ The “tea-and-toast” syndrome, crash diets, and beer potomania are syndromes of hyponatremia caused largely by poor osmolar intake, with a normal ability to dilute urine.^21,22 With maximally suppressed vasopressin, the urine osmolarity can be diluted to as low as 60 mOsm/kg. With an osmolar intake of 900 mOsm/day and maximally diluted urine, the patient would have to drink > 15 L/day in order to “outdrink” the urinary diluting capacity. If the osmolar intake is much less (~300 mOsm/day), then a decreased amount of water is required to “outdrink” the diluting capacity with maximally dilute urine.²¹

Another type of euvolemic hyponatremia is exercise-associated hyponatremia. This condition occurs during endurance events, such as marathons and triathlons, and may have a larger prevalence than previously appreciated. The most important risk factor for the development of this disorder is excessive fluid intake and weight gain during the endurance event. Additional factors are extremes of body size, duration of exercise, and potentially nonsteroidal anti-inflammatory drugs. The underlying pathophysiology involves increased hypotonic fluid intake and decreased renal diluting capacity due to avid proximal renal tubular reabsorption with decreased delivery of filtrate to the distal diluting segments. Additionally, increased vasopressin release contributes to the mechanism due to pain and stress or even possible cytokine Interleukin-6-mediated direct vasopressin release. Other potential reported mechanisms have included decreased exchangeable sodium in some athletes and even glycogen metabolism-mediated endogenous water release.²² 3^,22 4

The nephrogenic syndrome of inappropriate antidiuresis is a recently described cause of euvolemic hyponatremia.²⁵ It is an X-linked (Xq28) genetic defect that was initially described in 2 male infants. It results from an activating mutation of the V2-receptor, causing constitutive water reabsorption and hyponatremia in the setting of undetectable vasopressin concentrations. Nephrogenic syndrome of inappropriate antidiuresis may develop in adults and go unnoticed for years until a defect in solute or fluid intake uncovers the abnormality.²⁶

Plasma hypotonicity causes water to move from the intravascular space into the relatively hypertonic intracellular compartments. This becomes a problem in the brain because of the enclosed space the brain occupies. The brain gets rid of the intracellular electrolytes and organic osmolytes to decrease or reverse this intracellular water movement and, thus, avoid cerebral edema. The cerebral adaptation to hypotonicity begins immediately with the increased interstitial pressure, causing bulk flow of solute and water from the interstitial compartment into the cerebral spinal fluid and subsequently into the systemic circulation. Next, intracellular Na⁺, Cl⁻, and potassium are extruded via activation of channels and transporters; this is followed by the extrusion of organic osmolytes from the brain cells.^6,27 This cerebral adaptation is completed in approximately 48 hours. The end result is a greatly attenuated total increase in brain water. Reverse adaptation occurs as the sodium is corrected (hypertonic saline administration). As the serum tonicity increases, the brain cells reuptake electrolytes and organic osmolytes. If the correction occurs too rapidly, before the brain can re-adapt, there is a risk of pontine and extrapontine myelinolysis (osmotic demyelination). The mechanism of this cerebral myelinolysis during correction is theorized to occur due to the dehydration of cerebral vascular endothelial cells. This is followed by the loss of blood-brain barrier integrity, allowing access of complement components, cytokines, and other mediators, damaging the oligodendrocytes. Another potential mechanism is apoptosis of oligodendrocytes, induced by the tonicity changes and intracellular depletion of organic osmolytes. Research has suggested that this osmotic demyelination can be prevented by re-lowering the serum sodium, early administration of dexamethasone, or even myo-inositol infusion during the rapid correction.^22,22,22

Initial approach to the patient with hyponatremia must begin with a complete history and physical examination. Subtle differences in volume status, such as euvolemia versus mild volume depletion, may be difficult to distinguish via physical examination.²⁹ The confirmation of true hypotonic hyponatremia should be determined by measurement of the serum osmolarity with correction for any substance that may contribute to the osmolarity without contributing to tonicity. In euvolemic hyponatremia, disorders such as glucocorticoid deficiency or severe hypothyroidism must be eliminated from the differential diagnosis.

Laboratory values may be of assistance in cases where the clinical volume status is not obvious (Table 2). Because urine sodium is reabsorbed avidly in states of absolute (and “effective”) volume depletion due to the body’s attempt to conserve volume, concentrations < 30 meq/L tend to support volume depletion on a non–sodium-restricted diet. Urine sodium concentrations > 30 meq/L in the absence of diuretics or renal disorders with salt wasting, glycosuria, or mineralocorticoid deficiency suggest euvolemia or “lack of saline responsiveness.” In some situations, urine sodium levels as high as 50 to 60 meq/L can be found in states of volume depletion. This can be seen in situations where rapid adaptation to evolving volume depletion is poor, such as in the elderly. In these situations, a fractional excretion (FE) Na⁺ < 0.5% is a more reliable predictor of volume depletion.¹⁴ In states of hypovolemia, the proximal tubular reabsorption of BUN and uric acid increases. In euvolemic states or the mildly volume-expanded state of SIADH, the proximal tubular reabsoption of both uric acid and BUN diminishes and there is an increased fractional excretion of these substances. Therefore, in volume depletion, serum uric acid tends to be elevated (> 4) as does BUN, whereas in euvolemia and SIADH, serum uric acid levels and BUN tend to be low. It has been proposed to use a combination of FENa⁺ > 0.5% and FEUrea > 55% as a predictor of “saline unresponsiveness” or lack of volume depletion.^22,30 No laboratory value can be used to definitively diagnose the underlying etiology of hyponatremia. The entire clinical and laboratory picture must be considered when trying to determine the volume status. It is reasonable to give an empiric trial of isotonic fluids, particularly when distinguishing between euvolemic (SIADH) and mild volume depletion with borderline results on urinary and serum indices. When giving an isotonic fluid trial, euvolemic patients have no significant improvement in their serum sodium and their urine sodium will rapidly increase. In hypovolemia, when giving the isotonic fluid challenge, serum sodium will be improved with little increase in patients’ urine sodium.^12,28

Symptomatic hyponatremic patients may complain of headaches, nausea, vomiting, lethargy, confusion, and weakness. The mechanism of these symptoms is largely related to the cerebral edema that results from the hypotonicity of the plasma compartment relative to the intracellular brain compartment. This plasma hypotonicity causes water to move into the brain cells, which results in cerebral edema. Symptoms of hyponatremia may vary depending not only on the severity of the hyponatremia, but also on how rapid the sodium (tonicity) changes occur. Patients who become hyponatremic within ≤ 48 hours have more severe symptoms than patients who have a slow and chronic decrease in serum sodium levels.

Treating hypovolemic and hypervolemic hyponatremia involves identifying and correcting the underlying cause. If a patient has “absolute” volume depletion, isotonic volume replacement and identification and control of the underlying problem is the treatment. The volume replacement will reverse the decrease in GFR, increase filtrate delivery to the diluting segment, and shut off the baroreceptor stimulus for vasopressin release, thereby allowing excretion of the retained water and correction of the hyponatremia.

In the setting of “effective” volume-depleted states, such as congestive heart failure or cirrhosis, fluid restriction and reversal of the underlying cause should be started if possible. In congestive heart failure, one must attempt to first optimize the cardiac output and increase diuretics. Konstam et al³¹ reported that the use of vasopressin antagonists in congestive heart failure may not improve survival or heart failure-related morbidity but noted an improvement in serum sodium levels, dyspnea, edema, and body weight.

When the cause of SIADH is not readily reversible, treatment consists of the potential use of vasopressin receptor antagonists. Prior to the recent availability of V2-receptor antagonism, the use of demeclocycline, salt tablets, and diuretics were the only available modalities in the treatment armamentarium.

Urgent correction of hyponatremia should be undertaken in the setting of symptoms such as severe nausea, vomiting, altered mental status, seizures, coma, and obtundation. The initial treatment of symptomatic hyponatremia is 3% hypertonic saline. Hypertonic saline use, guided by correction formulas such as Adrogue– Madias, can sometimes be helpful and reasonably accurate; however, inadvertent overcorrection when using hypertonic (3%) saline is not uncommon, and sole reliance on them should be avoided. These formulas do not take into account the ongoing renal and extrarenal excretion of free water during correction and the effect that exchangeable potassium has on correction of hyponatremia in potassium-depleted patients.²² 2^,33 Bolus therapy with 3% hypertonic saline can be initiated using 100 mL of 3% hypertonic saline administered every 10 minutes; up to 3 doses can be administered if there is no clinical improvement in the severe symptoms. Usually a 4 to 6 mmol/L correction in Na⁺ concentration is enough to acutely avoid life-threatening complications. The overall correction should not exceed > 6 to 8 mmol/L for the first 24 hours; no more than 12 to 14 mmol/L over 48 hours; and no more than 14 to 16 mmol/L over 72 hours. Slower correction is warranted in patients with advanced liver disease or malnutrition to prevent pontine and extrapontine osmotic demyelination.³⁴ Potential long-term effects of this include paralysis, neurological deficits, coma, respiratory difficulties, and death.^28,35 When the stimulus that is causing water retention is corrected, the patient will begin to excrete the retained free water. This can sometimes occur quite rapidly with too rapid a correction in serum sodium. The administration of desmopressin acetate is very effective in controlling this rapid correction and regaining control of the sodium increase.³⁶ Frequent laboratory monitoring, up to every 2 hours, is essential in managing hyponatremic patients.

The V2-receptor antagonists tolvaptan and conivaptan allow excretion of electrolyte free water and are effective in increasing serum sodium in euvolemic and hypervolemic hyponatremia.³⁷

Regarding chronic hyponatremia, in the past, it was acceptable to allow mild and stable levels of hyponatremia to persist (ie, > 125 meq/L) in what was considered an apparently asymptomatic patient. Patients with even mild degrees of hyponatremia (mean Na⁺ 128 ± 3 meq/L) have been shown to have an increased incidence of falls, and therefore even these mild levels of hyponatremia may not be acceptable.^38,39

Any patient with serum sodium levels < 135 meq/L should be closely evaluated. Treatment goals involve returning the patient’s serum sodium levels back to normal. One must avoid undertreatment of hyponatremia, while simultaneously being careful to not provide overly aggressive treatment. All physicians need to be familiar with the differential diagnosis, causes, and management of hyponatremia. Careful treatment can improve outcome and prevent worsening symptomatology. Vasopressin receptor antagonists are now available and will be integral in the management of hypervolemic or euvolemic hyponatremic patients.

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