Published: August 2010
Disorders of sodium concentration result from a perturbation in water balance. Water is the most abundant body fluid. In lean individuals, water accounts for 60% of total body weight, with approximately two thirds residing intracellularly and one third in the extracellular space. Of the water in the extracellular space, approximately 75% is in the interstitium and 25% in the intravascular space. Because fat contains less water than lean muscle, water accounts for a lower percentage of total body weight in women, older adults, and obese persons. Additionally, water can move between these compartments, resulting in changes in plasma sodium concentration. Water movement between body fluid compartments is regulated by the effective osmolality of the solutes within each compartment. Sodium is the main determinant of plasma osmolality, and water moves toward body compartments with higher osmolality and away from those with lower osmolality.
Plasma water is regulated by an interaction between sensory organs (e.g., carotid body and hypothalamus), antidiuretic hormone (ADH or vasopressin), and the kidney. Although the gastrointestinal tract, skin, and bronchial tree are capable of sodium and water loss, the kidney is the only organ able to conserve or excrete sodium and water under tight regulatory control.
Alterations in arterial blood pressure and plasma osmolality are the main physiologic signals regulating ADH secretion. As plasma water decreases, increases in plasma sodium concentration and osmolality are sensed by nuclei in the hypothalamus, with a resultant increase in production of ADH by the supraoptic and paraventricular nuclei. ADH acts to increase renal free water reabsorption in the collecting tubule to restore plasma water, resulting in a correction of plasma sodium concentration back toward the normal range. The antidiuretic effect of ADH is mediated by binding to the vasopressin type 2 (V2) receptor in the basolateral membrane of the collecting tubule. Binding of ADH leads to an increase in intracellular cyclic adenosine monophosphate (cAMP) and ultimately to the insertion of a water channel (aquaporin 2) into the luminal membrane and an increase in the aquaporin 2 mRNA level. Alternatively, as plasma water increases, plasma sodium concentration, osmolality, and ADH secretion decrease and the collecting tubule becomes impermeable to water, resulting in excretion of free water and restoration of the plasma sodium concentration.
Decreased arterial blood pressure can also act as a potent stimulus to ADH secretion, probably mediated by angiotensin II and neural inputs, even in the presence of hypo-osmolality. Decreased arterial pressure is sensed via baroreceptors in the aorta and carotid arteries. This can occur acutely during hypovolemia (e.g., blood loss) or chronically in disorders associated with decreased arterial perfusion (effective arterial blood volume), such as cirrhosis and heart failure.1
Disorders of water metabolism result from loss or gain of plasma water, often caused by or in association with altered conservation or release of water by the kidneys. Most of these disorders are caused by dysfunctional release or renal response to ADH.
Hyponatremia is defined as a serum sodium concentration lower than 136 mmol/L.2 It can result from a particular laboratory technique or from improper blood collection, excessively high water intake, or, most commonly, an inability of the kidneys to excrete free water (see later, “Pathophysiology and Natural History”).3
Hyponatremia is one of the most common electrolyte abnormalities. Indeed, approximately 15% of hospitalized patients have a plasma sodium concentration lower than 134 mmol/L. Patients with underlying severe dysfunction of the heart, liver, or kidneys are at greatest risk of developing hyponatremia. In addition, older women being treated with thiazide diuretics and premenstrual girls and women in the postoperative period, if given hypotonic fluids, are at higher risk for developing hyponatremia. Acute hyponatremia has also been reported in marathon runners and in those who ingest 3,4-methylenedioxymethylamphetamine (ecstasy).
Hyponatremia can result from improper collection of a blood sample from a vein that is being infused with hypotonic medications. Additionally, if older techniques (e.g., flame photometry using whole plasma) for sodium measurement are being used, high levels of protein or triglyceride in the sample can cause the sodium concentration to be falsely low (pseudohyponatremia).4 Hyperglycemia can also cause hyponatremia, via osmotically induced water movement from cells into the blood (translocational hyponatremia), resulting in a relative decrease in serum sodium concentration in the absence of hypo-osmolality. The sodium concentration should be increased by approximately 1.6 to 2 mmol/L for each 100-mg/dL increase in glucose concentration above 100 mg/dL.4
Excess water intake is a rare cause of hyponatremia. In persons with preserved renal function, any extra water intake above obligatory water loss is usually excreted in a dilute urine, hyponatremia does not develop. However, in psychogenic polydipsia, ingesting large volumes (>15-20 L/day) of water can result in hyponatremia, despite preserved renal function and diluting ability.
However, most cases of hyponatremia are caused by decreased renal excretion of water, secondary to persistent action of ADH or the use of medications that interfere with urinary dilution (e.g., thiazide diuretics and nonsteroidal anti-inflammatory drugs [NSAIDs]). Most of these clinical disorders (e.g., congestive heart failure, nephrotic syndrome, cirrhosis) share a reduction in effective arterial blood volume, resulting in persistent ADH activity despite hypo-osmolar plasma. In addition, acute or chronic renal failure results in reduced functional nephron mass, decreased glomerular filtration rate, and therefore decreased capacity for water excretion.
The drugs most commonly associated with the development of hyponatremia are thiazide diuretics and NSAIDs. The mechanism of diuretic-induced hyponatremia is complex and includes interference with urinary dilution by the thick ascending loop of Henle and the distal convoluted tubule, as well as volume contraction–induced increase in ADH secretion. Hyponatremia occurs almost exclusively with thiazide diuretics because of preservation in medullary osmolality and urine-concentrating ability. NSAIDs can lead to hyponatremia via a decrease in prostaglandin-mediated suppression of ADH. Many other drugs can be associated with hyponatremia via the augmentation of ADH release or action (Box 1).
|Box 1 Drugs Associated With Increased Antidiuretic Hormone Release or Action|
Hyponatremia can also be seen in hypovolemic disorders where solute and water losses (e.g., diarrhea) result in hemodynamically mediated ADH release. Importantly, hyponatremia results only if these losses are replaced with a source of free water (e.g., hypotonic fluids).
Other, less-common causes of hyponatremia include a reset osmostat, adrenal insufficiency, hypothyroidism, low dietary solute intake, beer drinker’s potomania, and salt-wasting nephropathy. Although the mechanisms of hyponatremia associated with adrenal or thyroid dysfunction are complex and not entirely clear, replacement of the deficient hormone usually leads to resolution of the hyponatremia, barring any other concomitant cause.
Most symptoms of hyponatremia are caused by cerebral edema from transcellular shifts of plasma water into cells of the central nervous system (CNS). Symptoms and signs usually do not manifest until the sodium concentration is lower than 125 mmol/L. These can include nausea, emesis, headache, seizures, lethargy, development of focal neurologic deficits, respiratory depression, and coma. Serious neurologic changes such as seizure and coma are usually not seen until the sodium concentration is lower than 110 to 115 mmol/L. Patients with rapidly developing severe hyponatremia (<120 mmol/L over 24-48 hours) are at highest risk for developing serious, life-threatening CNS disturbances.
After sampling error, hyperglycemia, and pseudohyponatremia have been ruled out, the diagnosis of hyponatremia begins with careful examination of the patient’s extracellular fluid (ECF) volume status (Box 2). Patients are classified as hypovolemic, euvolemic, or hypervolemic according to features of the history (e.g., emesis, diarrhea) and physical examination findings (e.g., flat or distended neck veins, dry or moist skin or mucosa, heart rate, blood pressure, orthostatic vital signs, presence of edema or ascites).
|Box 2 Causes of Hyponatremia Based on Extracellular Fluid Volume Status|
|Gastrointestinal solute loss (diarrhea, emesis)|
|Third-spacing (ileus, pancreatitis)|
|Syndrome of inappropriate antidiuretic hormone (SIADH)|
|Beer drinker's potomania, psychogenic polydipsia|
|Hypervolemia with Decreased Effective Circulating Blood Volume|
|Decompensated heart failure|
|Advanced liver cirrhosis|
|Renal failure with or without nephrosis|
Patients with edema or ascites are, by definition, hypervolemic. Patients with hypotension, flat neck veins, dry mucosa, and no edema are hypovolemic. Other patients may be euvolemic or might have clinically undetectable forms of hypovolemia. Additional testing using determination of spot urine sodium, blood urea nitrogen (BUN), and serum uric acid levels and response to isotonic intravenous fluids may be helpful in this patient subgroup.
The presence of low urinary spot sodium (<10 mmol/L), normal or elevated serum uric acid, and elevated BUN levels suggest hypovolemia, whereas levels of urinary spot sodium higher than 10 to 20 mmol/L, low serum uric acid, and normal BUN imply that the ECF volume is not decreased. Additionally, the response of the serum sodium concentration to volume replacement may be helpful. In patients with hypovolemia, the serum sodium level should increase following administration of 1 to 2 L of normal saline. In patients with euvolemia, the serum sodium level will decrease further (e.g., syndrome of inappropriate antidiuretic hormone, SIADH) as water is reclaimed by the nephron, or the level will remain unchanged.
Urine osmolality is inappropriately high (>100 mOsm/kg)) in almost every patient with hyponatremia. It should be checked to confirm inappropriate urinary dilution, but it does not help delineate the cause of hyponatremia, except in patients found to have dilute urine (psychogenic polydipsia and reset osmostat).3 Plasma osmolality (Posm) is almost always low (<270 mOsm/kg) in patients with hyponatremia, because serum sodium is the major determinant of Posm. If measured Posm is more than 10 mOsm/kg higher than calculated osmolality ([2Na + BUN/2.8] + [glucose/18]), there is an effective osmole in the plasma other than sodium or glucose (e.g., mannitol, glycine, or sorbitol), or high levels of plasma protein or lipid causing pseudohyponatremia.
In euvolemic patients, or those with clinical suspicion of endocrine disorders, measures of thyroid function (thyroid-stimulating hormone [TSH] and free thyroid hormone level determination) and adrenal function (cosyntropin [Cortrosyn] stimulation test) can be assessed. Euvolemic patients with normal thyroid, adrenal, and renal function might have SIADH. This syndrome is associated with various drugs (see Box 1) and clinical disorders including pulmonary infections, ectopic production by certain cancers (particularly small cell lung carcinoma), various CNS disorders, and pain.
Appropriate treatment of any patient with truly hypo-osmolar hyponatremia, regardless of its cause or the patient’s ECF volume status, begins with a thorough clinical assessment that aims to answer the following questions5:
Hyponatremia is considered to be of acute onset if it develops in less than 48 hours. Patients who develop hyponatremia acutely almost always do so during hospitalization, and often during the postoperative period. Chronic hyponatremia is defined as that developing over a time course longer than 48 hours. In patients for whom the time frame is unknown, it should be assumed that they developed hyponatremia chronically. Alternatively, an imaging study assessing for cerebral edema can be performed.
The distinction between acute and chronic hyponatremia is made to alert the clinician to the clinical consequences associated with the timing of the cerebral response to hyponatremia. As water enters the brain cells during acute hyponatremia, there is a loss of intracellular sodium and potassium in an attempt to prevent further water entry. Over the next several days, additional osmolytes are lost from the brain (e.g., inositol). If hyponatremia is corrected too rapidly, regardless of the method of correction, excess water can be lost from the cells, resulting in cellular dehydration and central pontine myelinosis (CPM).2 CPM is characterized by demyelination of neurons and the development of neurologic dysfunction, including seizures, dysphagia, dysarthria, paresis, and even death. Thus, the patient with chronic hyponatremia is at greater risk of developing CPM if the hyponatremia is corrected too rapidly.
All patients with symptomatic hyponatremia should be treated with hypertonic (3%) saline at 1 to 2 mEq/L/hour along with intravenous furosemide if there is evidence of hypervolemia.5 The saline is used to increase free water excretion via interference with urinary-concentrating ability and to avoid worsening of hypervolemia from the intravenous sodium load. The serum sodium level should be followed closely and should not be corrected to normal with hypertonic saline. The goal of hypertonic saline is to bring sodium up to a safer level—usually approximately 125 mEq/L—while ameliorating neurologic signs and symptoms.6
Although the exact rate of correction is a matter of debate, acute hyponatremia should not be corrected by more than 2 mEq/L/hour. Chronic hyponatremia or hyponatremia of unknown duration should be corrected by no more than 0.5 mEq/L/hour or no more than 10 to 12 mEq/day. If the patient with chronic hyponatremia presents with severe symptoms, a more rapid initial rate of correction, 1 to 2 mEq/L/hour over the first few hours, is advisable to ameliorate neurologic morbidity. However, the sodium level should not be raised more than 12 mEq/L during the first day of treatment.
The clinician should be aware that the risk of hyponatremia-induced cerebral edema is increased in certain patient groups and characteristics, including hypoxemia, older women on thiazide diuretics, postoperative menstruating girls and women, children, and patients with psychogenic polydipsia.5 Additionally, patients at higher risk for developing CPM include alcoholics, older women on thiazide diuretics, burn victims, and patients with malnutrition or severe concomitant potassium depletion.5 Patients at higher risk for CPM should be monitored closely and undergo slower rates of correction.
Patients with asymptomatic chronic hyponatremia do not need immediate correction. The clinician should focus on determining the cause of the hyponatremia (see earlier, “Diagnosis”) and assessing the ECF volume status. The ECF volume status directs the initial therapeutic approach.
In patients with hypovolemia, volume should be restored with normal saline to reduce the nonosmotic stimulus to ADH secretion.
Patients with clinical evidence of hypervolemia should undergo sodium and water restriction. Furosemide should be used to control volume and promote free water excretion. If possible, the underlying illness should be treated (e.g., angiotensin-converting enzyme [ACE] inhibitor for heart failure). This is often difficult, because hyponatremia is usually a manifestation of severe underlying disease (e.g., severe decompensated heart failure or cirrhosis). Data from clinical trials indicate that V2 receptor antagonists (e.g., tolvaptan) promote solute-free water loss and thus may be effective therapies for hypervolemic hyponatremia.7
In patients who are euvolemic, there are three methods to raise the serum sodium level: fluid restriction, increased solute intake (salt tablets or oral urea) plus furosemide to increase obligate water excretion, and pharmacologic inhibition of ADH action with lithium, V2 receptor antagonists, or demeclocycline. Pharmacologic inhibition of ADH is generally reserved for patients who are unresponsive to or cannot tolerate fluid restriction or increased solute intake plus furosemide. Lithium use has declined secondary to the frequent development of adverse effects. Demeclocycline is usually started at a dose of 300 mg twice daily and the dosage titrated to up to 1200 mg/day in divided doses. Vasopressin antagonists have been reported to be efficacious in treating the hyponatremia associated with SIADH.7
Pharmacologic antagonists of the V2 receptor exert their aquaretic effect via a decrease in transcription and insertion of aquaporin-2 channels into the apical collecting duct membrane, resulting in decreased water permeability even in the presence of circulating vasopressin. Vasopressin action (agonism) occurs via interactions with various receptor subtypes including V1a (vasoconstriction, platelet aggregation, ionotropic stimulation, myocardial protein synthesis), V1b (ACTH secretion) and V2 (water reabsorption, von Willebrand factor and factor VIII release).
Conivaptan is a combined V1a/V2 antagonist that has been FDA approved for the treatment of euvolemic and hypervolemic hyponatremia.8 As a result of concerns regarding drug interactions due to its inhibition of the cytochrome P-450 (CYP) 3A4 system, use of conivaptan has been limited to the hospital setting using the intravenous formulation for up to 4 days. Dosing recommendations are for an initial 20-mg infusion over 30 minutes, followed by daily continuous infusions of 20 to 40 mg/day. Dosing adjustments in renal and hepatic impairment have not been well defined. Conivaptan should not be used in patients with hypovolemic hyponatremia due to concerns with V1a blockade causing hypotension or V2 blockade producing water excretion and a worsening of the volume-depleted state. Further studies are needed in patients with cirrhosis, because V1a antagonism may be expected to cause a decrease in systemic blood pressure or even a worsening of portal hypertension via splanchnic vasodilation. Alternatively, patients with heart failure and hyponatremia theoretically might benefit from V1a antagonism-induced vasodilatation, but further studies are needed to clarify this issue.
Tolvaptan is an oral selective V2 receptor antagonist that is effective at raising serum sodium in patients with hypervolemic and euvolemic hyponatremia. Data indicate that this agent might improve symptoms and result in enhanced weight loss in patients with decompensated heart failure.9 However, long-term end points including mortality and rehospitalization rate were not significantly improved.
Although there have been some cases of excessive increase in serum sodium during therapy with vasopressin antagonists, available data suggest that these agents are safe, with no reported case of CPM in any of the clinical trials. An increase in thirst has been described in some of these studies, highlighting the need to continue with water restriction and careful monitoring of serum sodium levels when these agents are made available for use in clinical practice. No data are available regarding the use of vasopressin antagonists in the treatment of hyponatremia in the presence of severe neurologic symptoms. Hypertonic saline should be considered the treatment of choice in this population.
Hypernatremia is defined as a serum sodium concentration greater than 145 mmol/L.10 It is most commonly caused by the loss of water via the skin, urine, or gastrointestinal (GI) tract. In all cases, loss of access to water or impaired thirst sensation is required to maintain the hypernatremic state (see later, “Pathophysiology and Natural History”).
Hypernatremia can develop in outpatient and inpatient settings. When it develops in the outpatient setting, it is most commonly seen in patients at the extremes of age. In the hospital, hypernatremia develops across a more general age distribution. In both settings, patients at highest risk are those who depend on others to adequately assess and provide water intake, such as breast-feeding infants, older nursing home residents, and the critically ill. Although estimates in large populations are not available, one observational study has suggested that approximately 1% of hospitalized patients have a serum sodium level higher than 150 mmol/L.11
An increase in serum sodium concentration is almost always a reflection of water loss rather than sodium gain. Water loss results in the development of plasma hyperosmolality; via hypothalamic sensors, this acts as a stimulant to thirst and production of ADH. Ultimately, free water is ingested and reclaimed via the kidneys, and sodium concentration and osmolality are restored to normal. Thus, the maintenance of hypernatremia requires diminished thirst sensation or decreased access to water. Even in states of impaired ADH release or reduced ADH function at the level of the kidneys (e.g., central or nephrogenic diabetes insipidus), hypernatremia is avoided if thirst is intact and access to free water is maintained in adequate amounts to compensate for renal losses.
Hypernatremia is not always associated with pure water loss. It can be associated with concomitant loss of sodium via hypotonic fluids (e.g., diarrheal fluid) or the addition of hypertonic fluids (e.g., excessive sodium from parenteral nutrition or sodium bicarbonate infusion).
Hypernatremia causes a loss of intracellular water into the ECF space and can be associated with cellular shrinkage. In the CNS, this can be catastrophic, with ensuing cell death or rupture of blood vessels. To protect against cell shrinkage, electrolytes enter into the ICF, usually in the first few hours. When hypernatremia persists beyond 2 or 3 days, the cells begin to generate intracellular osmolytes to maintain intracellular fluid (ICF) osmolarity further and avoid water loss into the ECF.
Most signs and symptoms relate to the underlying illness that is driving water loss (e.g., diarrhea, nausea, emesis, insensible loss from fever) and the condition causing decreased intake of water (e.g., delirium, dementia). Hypernatremia should cause an increase in thirst in the absence of altered sensorium or a new neurologic lesion involving the hypothalamus. The presence of polyuria (>3 L urine/day) should be noted, because this indicates renal loss of water via a solute diuresis (e.g., mannitol, urea, glucose) or pure water diuresis (e.g., diabetes insipidus). As noted, hypernatremia causes cellular dehydration, leading to a myriad of findings, including muscle cramps, seizures, headache, intracranial hemorrhage, lethargy, coma, and death. Patients might also have signs and symptoms of volume depletion if sodium has been lost along with water (e.g., hypotonic losses with diarrhea).
Figure 1 illustrates important causes of hypernatremia correlating with the bedside determination of the ECF volume status. Patients with euvolemia usually have had a pure water loss. Patients with evidence of reduced ECF volume and hypernatremia have predominantly developed a water loss; however, they have also had some loss of sodium from the ECF to account for the clinical signs of hypovolemia.
Accurate diagnosis requires that the clinician uncover the source of water loss or sodium gain. A careful assessment of the patient’s volume status, access to water, ongoing water losses, and renal response to water loss are also important (see Fig. 1). Additionally, if impaired thirst is present, the clinician should inquire into possible causes, such as delirium (e.g., from any cause) or the development of a new lesion in the CNS (e.g., stroke).
Whereas the cause of hypernatremia is usually apparent (e.g., diarrhea), the urine osmolality may be useful in clarifying the cause in patients without obvious GI or insensible water losses. During hypernatremia caused by extrarenal water losses, the renal response should be to generate a hypertonic urine with an osmolality of 700 to 800 mOsm/kg.
If the urine osmolality (Uosm) is lower than 300 mOsm/kg, then water loss is occurring via the kidneys, secondary to decreased hypothalamic release of ADH (central diabetes insipidus) or impaired sensation in the cortical collecting tubule (nephrogenic diabetes insipidus). In central diabetes insipidus, provision of ADH results in an increase in Uosm, whereas in nephrogenic diabetes insipidus, it results in little to no increase in Uosm.
If Uosm is between 300 and 800 mOsm/kg, patients might have partial forms of nephrogenic or central diabetes insipidus or an osmotic diuresis from urea or glucose. In patients believed to have diabetes insipidus, a water deprivation test can be performed to assess the integrity of pituitary release and renal response to ADH.12
The management of hypernatremia involves the following principles:
Importantly, if hypovolemia is present, plasma volume should be restored with isotonic saline or colloid before the correction of the water deficit. Correction of the underlying cause of the water losses can include withdrawal of loop diuretics or mannitol, treatment of diarrhea with antimotility agents or antibiotics, provision of ADH to correct central diabetes insipidus, or use of pharmacologic agents to treat nephrogenic diabetes insipidus (see later).
Correction of the water loss requires an assessment of the current water deficit and ongoing rate of water losses. The following equation can be used to estimate the water deficit:
where TBW (total body weight) = 0.6 × weight (in kg) for male patients, or 0.5 x weight (in kg) for female and obese patients. The factor of multiplication may be closer to 0.4 in critically ill cachectic patients.
The rate of correction is controversial, but most experts recommend that in the absence of symptoms of hypernatremia, the serum sodium level should be corrected by no more than 0.5 mEq/L/hour. To avoid the development of cerebral edema, the water deficit should not be replaced too quickly. Severely symptomatic patients require a more rapid correction to ameliorate symptoms. Once symptoms have abated, the pace of water provision is decreased to allow a rate of correction of 0.5 mEq/L/hour. The actual rate of fluid replacement needs to account for ongoing fluid losses (e.g., GI and insensible).
It must be remembered that this is only an estimate. The serum sodium level and neurologic function should be monitored frequently to ensure the proper rate of correction.
In patients with central diabetes insipidus, ADH must be provided exogenously via intranasal or oral desmopressin (DDAVP). In more acute cases, with large water losses, ADH can be replaced with subcutaneous aqueous vasopressin. In the absence of a reversible cause (e.g., hypercalcemia, hypokalemia), patients with nephrogenic diabetes insipidus are generally treated chronically with a low-sodium, low-protein diet along with a thiazide diuretic. The diuretic and low-sodium diet act to create a mild volume depletion and therefore result in a reduction in urine output. A decrease in protein intake results in a decrease in obligate renal solute excretion and therefore a decrease in water excretion and urine flow.
In patients with hypervolemic hypernatremia, sources of hypertonic fluids containing excess sodium (e.g., parenteral nutrition, sodium bicarbonate) should be eliminated. In addition, a loop diuretic is administered to promote sodium loss and correct hypervolemia. Dialysis may be required if there is concomitant renal failure.