Abstract
Hyponatremia is the most common clinical electrolyte disorder, affecting up to 15% to 38% of hospitalized patients based on reports from multiple studies worldwide over the last several decades. Hyponatremia is important because it is associated with worse clinical outcomes, increased hospital costs, and higher readmission rates. In every disease studied, hyponatremia is an independent risk factor for increased mortality. Chronic hyponatremia has been linked to impaired gait and balance, falls, osteoporosis, and increased fracture rates, though its causal role for these associations remains unproven. Despite a widespread impression that correction of hyponatremia is beneficial, evidence-based data demonstrating a clinical benefit of correction of hyponatremia are limited, and treatment practices vary widely. The major barrier to optimal practice in patients with hyponatremia is lack of knowledge about which therapies are most suitable for which patients, including understanding predictors of failure of commonly employed therapies such as fluid restriction and isotonic saline administration. A second barrier is a general sense that most hyponatremic patients are not affected by modest decreases in serum sodium levels and therefore do not need effective therapies. A final barrier is concern about the potential for osmotic demyelination syndrome with overly rapid correction of hyponatremia, which often leads to failure to employ more effective methods to correct hyponatremia.
KeyWords
antidiuretic hormone, fluid restriction, hypertonic saline, hyponatremia, hypoosmolality, osmoregulation, osmotic demyelination syndrome, syndrome of inappropriate antidiuretic hormone secretion, vaptans, vasopressin
The incidence of hyponatremia depends on the patient population screened and the criteria used to define the disorder. Hospital incidences of 15% to 22% are common if hyponatremia is defined as any serum sodium concentration ([Na + ]) of less than 135 mmol/L, but in most studies only 1% to 4% of patients have a serum [Na + ] lower than 130 mmol/L, and fewer than 1% have a value lower than 120 mmol/L. Multiple studies have confirmed prevalence ranging from 7% in ambulatory populations up to 38% in acutely hospitalized patients. Older individuals are particularly susceptible to hyponatremia, with reported incidence as high as 53% among institutionalized geriatric patients. Although most cases are mild, hyponatremia is important clinically because (1) acute severe hyponatremia can cause substantial morbidity and mortality; (2) mild hyponatremia can progress to more dangerous levels during management of other disorders; (3) general mortality is higher in hyponatremic patients across a wide range of underlying co-morbidities; and (4) overly rapid correction of chronic hyponatremia can produce severe neurologic complications and death.
Definitions
Hyponatremia is of clinical significance only when it reflects corresponding plasma hypoosmolality. Plasma osmolality (P osm ) can be measured directly by osmometry and is expressed as milliosmoles per kilogram of water (mOsm/kg H 2 O). P osm can also be calculated from the serum [Na + ], measured in millimoles per liter (mmol/L), and the glucose and blood urea nitrogen (BUN) levels, both expressed as milligrams per deciliter (mg/dL), as follows:
P osm = 2 × Serum [ Na + ] + Glucose / 18 + BUN / 2.8
Because the glucose and BUN concentrations are normally dwarfed by the sodium concentration, osmolality can be estimated simply by doubling the serum [Na + ]. All three methods produce comparable results under most conditions. However, total osmolality is not always equivalent to effective osmolality , which is sometimes referred to as the tonicity of the plasma. Solutes that are predominantly compartmentalized in the extracellular fluid (ECF) are effective solutes because they create osmotic gradients across cell membranes and lead to osmotic movement of water from the intracellular fluid (ICF) compartment to the ECF compartment. In contrast, solutes that permeate cell membranes (e.g., urea, ethanol, methanol) are not effective solutes, because they do not create osmotic gradients across cell membranes, and therefore they are not associated with secondary water shifts. Only the concentration of effective solutes in plasma should be used to determine whether clinically significant hypoosmolality is present. In most cases, these effective solutes include sodium, its associated anions, and glucose (but only in the presence of insulin deficiency, which allows the development of an ECF/ICF glucose gradient); importantly, urea, a solute that penetrates cells, is not an effective solute.
Hyponatremia and hypoosmolality are usually synonymous, with two important exceptions. First, pseudohyponatremia can be produced by marked elevation of serum lipids or proteins. In such cases, the concentration of Na + per liter of serum water is unchanged, but the concentration of Na + per liter of serum is artifactually decreased because of the increased relative proportion occupied by lipid or protein. Although measurement of serum or plasma [Na + ] by ion-specific electrodes, currently used by most clinical laboratories, is less influenced by high concentrations of lipids or proteins than is measurement of serum [Na + ] by flame photometry, such errors nonetheless can still occur when serum samples are diluted before measurement in autoanalyzers. However, because direct measurement of P osm is based on the colligative properties of only the solute particles in solution, increased lipids or proteins will not affect the measured P osm . Second, high concentrations of effective solutes other than Na + can cause relative decreases in serum [Na + ] despite an unchanged P osm ; this commonly occurs with marked hyperglycemia. Misdiagnosis can be avoided again by direct measurement of P osm or by correcting the serum [Na + ] by 1.6 mmol/L for each 100 mg/dL increase in blood glucose concentration greater than 100 mg/dL (although some studies have suggested that 2.4 mmol/L may be a more accurate correction factor, especially when the glucose is very high).
Pathogenesis
The presence of significant hypoosmolality indicates an excess of water relative to solute in the ECF. Because water moves freely between the ICF and ECF, this also indicates an excess of total body water relative to total body solute. Imbalances between water and solute can be generated initially either by depletion of body solute more than body water or by dilution of body solute because of increases in body water out of proportion to body solute ( Box 7.1 ). However, this distinction represents an oversimplification, because most hypoosmolar states include variable contributions of both solute depletion and water retention. For example, isotonic solute losses occurring during an acute hemorrhage do not produce hypoosmolality until the subsequent retention of water from ingested or infused hypotonic fluids causes a secondary dilution of the remaining ECF solute. Nonetheless, this concept has proved useful because it provides a logical framework for understanding the diagnosis and treatment of hypoosmolar disorders.
Depletion (Primary Decreases in Total Body Solute + Secondary Water Retention) a
a Virtually all disorders of solute depletion are accompanied by some degree of secondary retention of water by the kidneys in response to the resulting intravascular hypovolemia; this mechanism can lead to hypoosmolality, even when the solute depletion occurs via hypotonic or isotonic body fluid losses.
Renal Solute Loss
Diuretic use
Solute diuresis (glucose, mannitol)
Salt-wasting nephropathy
Mineralocorticoid deficiency
Nonrenal Solute Loss
Gastrointestinal (diarrhea, vomiting, pancreatitis, bowel obstruction)
Cutaneous (sweating, burns)
Blood loss
Dilution (Primary Increases in Total Body Water ± Secondary Solute Depletion) b
b Disorders of water retention primarily cause hypoosmolality in the absence of any solute losses, but in some cases of SIADH, secondary solute losses occur in response to the resulting intravascular hypervolemia and can further aggravate the hypoosmolality. (However, this pathophysiology probably does not contribute to the hyponatremia of edema-forming states such as congestive heart failure and cirrhosis, because in these cases, multiple factors favoring sodium retention result in an increased total body sodium load.)
Impaired Renal Free Water Excretion
Increased proximal reabsorption
Hypothyroidism
Impaired distal dilution
SIADH
Glucocorticoid deficiency
Combined increased proximal reabsorption and impaired distal dilution
Congestive heart failure
Cirrhosis
Nephrotic syndrome
Decreased urinary solute excretion
Beer potomania
Low protein/solute diet
Excess Water Intake
Primary polydipsia
Dilute infant formula
Fresh water drowning
SIADH, Syndrome of inappropriate antidiuretic hormone secretion.
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