1 Why is sodium balance critical to volume control?

Sodium and its corresponding anions represent almost all of the osmotically active solutes in the extracellular fluid under normal conditions. Therefore the serum concentration of sodium reflects the tonicity of body fluids. Small changes in osmolality are counteracted by thirst regulation, antidiuretic hormone (ADH) secretion, and renal concentrating or diluting mechanisms. Preservation of normal serum osmolality (i.e., 285-295 mOsm/L) guarantees cellular integrity by regulating net movement of water across cellular membranes.

2 What is another name for ADH? What is its mechanism of action?

ADH is also called arginine vasopressin or simply vasopressin. ADH is a small peptide hormone produced by the hypothalamus that binds to the vasopressin 1 and 2 receptors (V1 and V2). Vasopressin release is regulated by osmoreceptors in the hypothalamus, which are sensitive to changes in plasma osmolality of as little as 1% to 2%. Under hyperosmolar conditions, osmoreceptor stimulation leads to stimulation of thirst and vasopressin release. These two mechanisms result in increased water intake and retention, respectively. Vasopressin release is also regulated by baroreceptors in the carotid sinus and aortic arch; under conditions of hypovolemia, these receptors stimulate vasopressin release to increase water retention by the kidney. At very high concentrations, vasopressin also causes vascular smooth muscle constriction through the V1 receptor, increasing vascular tone and therefore the blood pressure. Accordingly, vasopressin is often administered parenterally as a vasopressor agent in patients with hypotension that is refractory to volume resuscitation.

3 Does hyponatremia simply mean there is too little sodium in the body?

No. The serum sodium concentration is not a reflection of the total body sodium content; instead, it is more representative of changes in the total body water. With hyponatremia, defined as serum sodium level less than 135 mEq/L, there is too much total body water relative to the amount of total body sodium, thereby lowering its concentration. Despite this key observation, the serum sodium concentration is not a reflection of volume status, and it is possible for hyponatremia to develop in states of volume depletion, euvolemia, and volume excess. Assessing a patient’s volume status is therefore the key step in identifying the underlying cause of hyponatremia (Fig. 45-1). Helpful physical findings include tachycardia, dry mucous membranes, orthostatic hypotension, increased skin turgor (associated with hypovolemia) or edema, an S₃ gallop, jugular venous distention, and ascites (present in hypervolemic states).

Figure 45-1 Diagnostic algorithm for hyponatremia. Na⁺, Sodium concentration.

4 Are hyponatremia and hypoosmolality synonymous?

No. Hyponatremia can occur without a change in total body sodium or total body water in two settings. The first is pseudohyponatremia, which is a laboratory artifact in patients with severe hyperlipidemia or hyperproteinemia. This laboratory abnormality has been essentially eliminated by the use of ion-specific electrodes (rather than flame photometry) to determine the serum sodium concentration. The second setting occurs when large quantities of osmotically active substances (such as glucose or mannitol) cause hyponatremia but not hypoosmolality, a condition known as translocational hyponatremia. In such states, water is drawn out of cells into the extracellular space, diluting the plasma solutes and equilibrating osmolar differences. In addition, use of large quantities of irrigant solutions that do not contain sodium (but instead contain glycine, sorbitol, or mannitol) during gynecologic or urologic surgeries can also cause severe hyponatremia.

5 How can hyponatremia develop in a patient with hypovolemia?

Hypovolemic hyponatremia represents a decrease in total body sodium in excess of a decrease in total body water. Simultaneous sodium and water loss can be due to renal (such as diuretic use) or extrarenal causes. Hypovolemia results in a decrease in renal perfusion, a decrement in the glomerular filtration rate, and an increase in proximal tubule reabsorption of sodium and water; all three mechanisms contribute to decreased water excretion. Furthermore, hypovolemia supersedes the expected inhibition of vasopressin release by hypoosmolality and maintains the secretion of the hormone. In other words, the body protects volume at the expense of osmolality.

6 How does hypervolemic hyponatremia differ from hypovolemic hyponatremia?

In hypervolemic hyponatremia, the kidneys are at the center of the problem because of either intrinsic renal disease or the renal response to extrarenal pathophysiology. Physical examination reveals edema and no evidence of volume depletion. Intrinsic renal disease with a compromised glomerular filtration rate (acute or chronic) prevents adequate excretion of sodium and water. Intake of sodium in excess of what can be excreted leads to hypervolemia (edema), whereas excessive intake of water leads to hyponatremia. In contrast, in congestive heart failure, hepatic cirrhosis, and nephrotic syndrome, the intrinsically normal kidney is stimulated to retain sodium and water in response to perceived decrements in intravascular volume and renal perfusion; as a result, hypervolemia and hyponatremia develop. In general, hypervolemic hyponatremia due to an extrarenal cause is characterized by a low urine sodium concentration (≤ 10-20 mEq/L); this distinguishes it from hypervolemic hyponatremia due to intrinsic renal causes, where the urine sodium is > 20 mEq/L.

7 What is the syndrome of inappropriate secretion of antidiuretic hormone (SIADH)?

SIADH is a common cause of euvolemic hyponatremia and is associated with malignancies, pulmonary disease, central nervous system disorders, pain, nausea, and many drugs. Common offending medications include hypoglycemic agents, psychotropics (including antipsychotics and antidepressants), narcotics, and chemotherapeutic agents. Other causes of euvolemic hyponatremia include psychogenic polydipsia, a low-solute diet (beer potomania or the tea and toast diet), hypothyroidism, and adrenal insufficiency.

8 What diagnostic tests are useful in the evaluation of hyponatremia?

The physical examination is critical to the determination of volume status, as previously described. Serum electrolyte and serum and urine osmolality measurements are useful. High urine osmolality despite low serum osmolality suggests either hypovolemic hyponatremia or SIADH if the patient is in a euvolemic state. Very low urine osmolality suggests excessive water intake, as in psychogenic polydipsia or a low-solute diet. Measurements of thyroid-stimulating hormone and cortisol can be used to assess endocrine causes of hyponatremia. As mentioned above, the urine sodium concentration can help distinguish renal and extrarenal causes of hypervolemic hyponatremia.

9 Why do patients with diabetic ketoacidosis frequently have hyponatremia?

Diabetic ketoacidosis is an example of hyperosmotic hyponatremia. In general, serum sodium decreases by approximately 2.4 mEq/L for every increase of 100 mg/dL over normal glucose levels. In this setting, the serum sodium level should not be interpreted without an accompanying serum glucose measurement, and the appropriate correction should be made if the glucose exceeds 200 mg/dL.

10 What is the difference between acute and chronic hyponatremia?

11 What are the signs and symptoms of hyponatremia?

Hyponatremia is the most common electrolyte disorder in hospitalized patients, with a prevalence of approximately 2.5%. Although the majority of patients have no symptoms, symptoms often develop in patients with a serum sodium concentration < 125 mEq/L or in whom the sodium has decreased rapidly. Gastrointestinal symptoms of nausea, vomiting, and anorexia occur early, but neuropsychiatric symptoms such as lethargy, confusion, agitation, psychosis, seizure, and coma are more common. Clinical symptoms roughly correlate with the amount and rate of decrease in serum sodium levels.

12 What drugs, if any, are associated with hyponatremia?

Many drugs are associated with hyponatremia, but several warrant special note. Thiazide diuretics frequently cause hyponatremia by promoting sodium excretion in excess of water. Of note, because loop diuretics directly impair the creation and maintenance of the medullary osmotic gradient, they are far less likely to cause hyponatremia, as little stimulus for water reabsorption occurs as urine passes through the collecting duct. Selective serotonin reuptake inhibitors and several chemotherapeutic agents cause hyponatremia, and this is thought to occur through the inappropriate release of ADH. Nonsteroidal antiinflammatory drugs block the production of renal prostaglandins and allow vasopressin to act unopposed in the kidney, which can lead to water retention. Tricyclic antidepressants and a number of anticonvulsants are also associated with hyponatremia. Last, use of 3,4-methylenedioxymethamphetamine, or Ectasy, particularly in combination with consumption of large volumes of water, is associated with severe, life-threatening hyponatremia.

13 Is there a standard therapy for hyponatremia?

Although controversy exists regarding treatment strategies, there is a consensus that not all patients with hyponatremia should be treated alike. Duration (acute vs. chronic) and the presence or absence of neurologic symptoms are the most critical factors in determining the therapeutic strategy. The prescribed therapy must take into consideration the patient’s current symptoms and the risk of provoking a demyelinating syndrome with overly rapid correction. The first priority is circulatory stabilization with normal saline solution in patients with significant volume depletion. In patients with acute symptomatic hyponatremia, the risks of delaying treatment, which could lead to cerebral edema, subsequent seizures, and respiratory arrest, clearly outweigh any risk of treatment. Hypertonic (3%) saline solution, with or without furosemide (which promotes free water excretion), should be given until symptoms subside. It is possible to calculate the expected change in serum sodium concentration on the basis of the volume of and rate at which hypertonic saline solution is infused, and this should be done before its administration. In contrast, the patient with asymptomatic chronic hyponatremia in high-risk categories (e.g., alcoholism, malnutrition, and liver disease) is at greatest risk for complications of the correction of hyponatremia, namely central pontine myelinolysis. Such patients are best treated with water restriction. Vasopressin V2 receptor antagonists are newer agents (also known as aquaretics or vaptans) that are available in the United States for treatment of hypervolemic and euvolemic hyponatremia; these agents promote free water excretion and are useful in selected patients.

14 What are some helpful guidelines for treatment of hyponatremia?

In patients with chronic asymptomatic hyponatremia, simple free water restriction (e.g., 1000 mL/day) allows a slow and relatively safe correction of the serum sodium concentration. This strategy, however, requires patient compliance, which may be particularly challenging in the outpatient setting. In selected patients who are behaviorally or physiologically resistant to free water restriction, administration of salt tablets, an ADH antagonist (e.g., demeclocycline, 600-1200 mg/day), or a maneuver to increase urinary solute excretion, such as the ingestion of a high-solute diet, may be necessary.

A difficult therapeutic dilemma is posed by patients with neurologic symptoms and hyponatremia of unknown duration. Such patients are at risk for development of a demyelinating disorder if treated too aggressively, yet the presence of symptoms is reflective of central nervous system dysfunction. These patients should be given treatment with hypertonic saline solution (and furosemide if necessary), and their serum sodium level should be monitored every 1 to 2 hours initially. The rate of increase should not exceed 8 to 10 mEq/L in a 24-hour period. Acute therapy can be slowed once symptoms have improved or a safe serum sodium level (typically 120-125 mEq/L) is stably attained (note that if the serum sodium level is extremely low, this may be too aggressive a correction for the first 24 hours).

15 What is central pontine myelinolysis?

Central pontine myelinolysis is a rare neurologic disorder of unclear cause characterized by symmetric midline demyelination of the central pons. Extrapontine lesions can occur in the basal ganglia, internal capsule, lateral geniculate body, and cortex. Symptoms include motor abnormalities that can progress to flaccid quadriplegia, respiratory paralysis, pseudobulbar palsy, mental status changes, and coma. Central pontine myelinolysis is often fatal in 3 to 5 weeks; of the patients who survive, many have significant residual deficits. Alterations in the white matter are best visualized by magnetic resonance imaging. Central pontine myelinolysis is one of the most feared complications of therapy for hyponatremia. Risk factors include a change in serum sodium level of > 12 mEq/L in 24 hours, correction of serum sodium level to a normal or hypernatremic range, symptomatic and coexistent alcoholism, malnutrition, and liver disease.

16 Can hypernatremia also occur in hypovolemic, euvolemic, and hypervolemic states?

Yes, and these categories, based on physical examination, provide a useful framework for understanding and treating patients. Hypernatremia, defined as a serum sodium concentration greater than 145 mEq/L, occurs when too little total body water exists relative to the amount of total body sodium, thereby raising the sodium concentration. Given that even small rises in the serum osmolality trigger the thirst mechanism, hypernatremia is relatively uncommon unless the thirst mechanism is impaired or access to free water is restricted. As a result, hypovolemic hypernatremia tends to occur in the very young, the very old, and the debilitated. It is typically due to extracellular fluid losses accompanied by inability to take in adequate amounts of free water. Febrile illnesses, vomiting, diarrhea, and renal losses are common causes.

Euvolemic hypernatremia can also be due to extracellular loss of fluid without adequate access to water or from impaired water hemostasis. Diabetes insipidus, either central (i.e., inadequate ADH secretion) or nephrogenic (i.e., renal insensitivity to ADH), results in the inability to reabsorb filtered water, which causes systemic hyperosmolality but hypoosmolar (dilute) urine. Hypervolemic hypernatremia, although uncommon, is iatrogenic. Sodium bicarbonate injection during cardiac arrest, administration of hypertonic saline solution, saline abortions, and inappropriately prepared infant formulas are several examples of induced hypernatremia.

17 What are the causes of diabetes insipidus?

Central diabetes insipidus can result from trauma, tumors, strokes, granulomatous disease, and central nervous system infections, and it commonly occurs after neurosurgical procedures. Nephrogenic diabetes insipidus can be congenital or it can occur in acute or chronic renal failure, hypercalcemia, hypokalemia, and sickle cell disease, or after treatment with certain drugs (e.g., lithium, demeclocycline).

18 What are the signs and symptoms of hypernatremia?

In awake and alert patients, thirst is a prominent symptom. Anorexia, nausea, vomiting, altered mental status, agitation, irritability, lethargy, stupor, coma, and neuromuscular hyperactivity are also common symptoms.

19 What is the best therapy for hypernatremia?

The first priority is circulatory stabilization with normal saline solution in patients with significant volume depletion. Once normotensive, patients can be rehydrated with oral water, intravenous 5% dextrose in water (D₅W), or even one-half normal saline solution. Overly rapid correction of long-standing hypernatremia can result in cerebral edema. Water deficit can be calculated with the formula in question 20. Some investigators have suggested that in patients with long-standing hypernatremia, the water deficit should be corrected by no more than 10 mEq/L/day or 0.5 mEq/L/hr. If the hypernatremia has occurred over a short period (hours), it can be corrected more rapidly, with the goal of correcting half of the water deficit in the first 24 hours. In addition to correcting the already established free water deficit, daily ongoing losses of free water in the urine and stool and from the respiratory tract and skin (particularly in patients with fever) should be replaced. In patients with central diabetes insipidus, a synthetic analog of ADH (i.e., 1-deamino-8-D-arginine vasopressin) can be administered, preferably by the intranasal route.

20 What are some helpful formulas for assessing sodium abnormalities?