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Sodium is the major ion in the ECF, and its normal concentration is 135 to 145 mMol/L. Sodium and chloride, as a molecule, maintain about 93% of the plasma and ECF osmolality. Sodium is primarily responsible for maintaining intravascular and ECF volume. Serum osmolality can be estimated as follows:

SerumOsm = 2Na (mMol/L)+ glucose(mg/dL)/18 (I)+BUN (mg/dL)/2.8

...where Na is sodium and BUN is blood urea nitrogen. Sodium also plays a physiologic role in the generation of the membrane resting potential, action potential, arid glucose and amino acid transport.

Normally, the body's water and electrolyte compositions are maintained by ingestion of more salt and water than is needed, and by the renal capacity to excrete the excess. In the presence of adequate intake, regulation is predominantly exerted by renal function. Renal regulation of salt and water is govemed by the juxtaglomerular apparatus and the renin-aldosterone-angiotensin axis. For example, sensing mechanisms thought to be in the juxtaglomerular apparatus cause diuresis of salt and water, while volume loss by hemorrhage stimulates vasopressin and aldosterone secretion, thereby increasing water retention. Water retention is also increased by diminished renal water clearance, nutritional deficiency, a shift of Na+ into the cells concomitant with the release of cellular K+, and release of endogenous Na+-poor water from posttraumatic catabolism. Approximately 750 ml of water may be released with the breakdown of 1 kg of lean tissue or fat.

Circulating sodium concentration is regulated by the renal and endocrine systems. The kidneys conserve sodium during hypovolemia and states of sodium depletion. Normal kidneys can decrease sodhim excretion to less than 10 mMol/day. Sodium conservation effected in the renal tubules is controlled by intrinsic renal mechanisms and influenced by hormones. Aldosterone, the major hormone regulating renal sodium excretion, stimulates distal renal tubule absorption of sodium in exchange for tubule excretion of hydrogen or potassium. Aldosterone does not concentrate urine, because it exchanges one ion for another. The kidneys are also capable of excreting large amounts of sodium during states of sodium overload. Sodium excretion is controlled by intrinsic renal mechanisms, suppression of aldosterone excretion, and stimulation of secretion of atrial natriuretic factor (ANF). ANF is a cardiac hormone capable, of producing natriuresis. Antidiuretic hormone (ADH) and thirst do not regulate sodium directly; rather, they control water balance by affecting water absorption in the collecting duct of the nephron or altering water intake. However, absorption and excretion of water do alter the concentration of sodium in the ECF. When positive free water balance lowers the serum sodium concentration to less than 135 mMol/L, cell volume receptors in the hypothalamus inhibit the secretion of ADH. Free water is excreted and circulating sodium is returned to normal levels. ADH secretion and thirst are stimulated by hyperosmolality and volume depletion by panisympathetic inpsit from baroreceptors and volume receptors in the great vessels and heart. Because of differences between the regulation of total-body volume and sodium concentration, it is possible to have hyponatremia or hypernatremia in the state of hypovolemia, euvolemia, or hypervolemia.

Sodium circulates in the plasma as free ions. The normal circulating sodium concentration is between 135 ind 145 mMol/L. The serum sodium concentration does not reflect the state of sodium balance; it primarily reflects body water content. The average 70-kg adult has a whole-body sodium content of 5000 to 6000 mMol.

Too Much,Too Little or Not Sure?



Hyponatremia, one of the most common electrolyte disorders, may occur with normal, elevated, or low serum osmolality, and with normal, elevated or low intravascular volume.

Hyponatremia also may result from high concentrations of impermeant solutes. The impermeant solutes replace sodium as osmotically active particles in the blood and are usually associated with hyperosmolality. The most common causes of hypertonic hyponatremia are glucose, mannitol, and toxin ingestion. The osmolar gap is equal to the [measured osmolality - calculated osmolality] in mOsm/kg. An osmolar gap indicates additional osmoles. Urea and ethanol also may elevate the serum osmolality, but these substances distribute into TBW. They do not cause a shift in water and do not themselves cat hyponatremia. However, disorders associated with ethanol or urea concentrations, such as renal failure, can result in hyponatremia because of impaired water excretion.

Hyponatremia is most commonly associated with hypoosmolality and occurs if the intake of free water exceeds ft water losses. Three categories of hypoosmolar hyponatremia are based on a clinical assessment of total-body volume: hypovolemic, hypervolemic and isovolemic (i.e. euvolemic).

HYPOVOLEMIC. Patients with low intravascular volume have hypotension, orthostatic hypotension, tachycardia, and signs of skin dehydration. Fluid loss may result ftom renal or nonrenal causes and occur with diuretic use, renal tubular dysfunction, and aldosterone deficiency. Nonrenal fluid losses may be caused by gastrointestinal losses (e.g. diarrhea) or skin losses. Volume loss stimulates the secretion ADH, retention of free water, and dilution of the plasma sodium level. In patients with normal renal function, urine osmolality is high (>500 m0sm/kg) and urine sodium is high (>20 mMol/L). In patients with renal tubular dysfunction and salt wasting, urine sodium is high (>50 mMol/L) and urine osmolality is usually isotonic.
Classic examples of hypovolemic hyponatremia is the cerebral salt wasting syndrome seen in patients with subarachnoid hemorrhage and Guillain Barre Syndrome.

HYPOVOLEMIC:THERAPY. Volume depletion is treated by replacing intravascular volume with fluids, which suppresses ADH secretion. Initial therapy involves use of isotonic crystalloids, colloid, or blood. Restoration of volume and treatment of the underlying disease may correct the serum sodium, without the need for additional therapy.
After intravascular volume is replenished, further therapy replaces free water with sodium, should hyponatremia persists. This goal is best accomplished by restricting free water, preventing free water generation in the kidneys with furosermide, and replacing urine output with isotonic or hypertonic saline. Usually total fluids need not be restricted as long as free water intake is limited. Continued nutritional intake is desirable to blunt catabolism and improve recovery from illness. Hyperglycemia can be corrected with insulin. Other nonsodium solutes, such as toxins, should be treated appropriately. Hyponatremia secondary to mannitol administration usually suggests overdosage with the agent.

HYPERVOLEMIC. Patients with elevated TBW have edema and include patients with congestive heart failure, cirrhosis, and nephrosis. Although TBW is increased, the effective circulating volume is low, stimulating ADH and aldosterone secretion. The net result is retention of free water and hyponatremia. These patients have low urine sodium levels (less than 20 mMol/L) and high urine osmolality (>500 mOsm/kg).

HYPERVOLEMIC: THERAPY. Patients with hyponatremia and elevated TBW have an excess of salt and water. Sodium should be restricted and free water intake minimized. Therapy is directed at improving effective circulating volume, renal perfusion, cardiac function, and improving distal tubule delivery of sodium (e.g., with diuretics). The combination of furosemide and an angiotensin converting enzyme (ACE) inhibitor is particularly effective. ACE inhibitors blunt the stimulating effect of angiotensin II on thirst and ADH secretion. Thiazides should be avoided in these patients, because the drugs impair the formation of maximally dilute urine. Hypertonic saline maybe dangerous because of rapid correction of hyponatremia and volume overload, but it may be indicated in seizures, coma, and water intoxication. Rapid infusion of hypertonic saline should be used only to correct the serum sodium to non-life-threatening levels (i.e., rate <12 mMol/L/day) concentration of 130 mEq/L).
CNS signs of hyponatremia usually improve within 24 to 72 hours after correction of the hyponatremia. A large increase in sodium conccntration is not needed to reduce cerebral edema caused by hyponatremia. A small increase in plasma osmolality is sufficient to reduce brain swelling. Because brain water content cannot increase by more than about 10% because of the confines of the skull, a 5% to 10% increase in sodium concentration (i.e., 6 to 12 mMol) can markedly reduce cerebral edema. Continued CNS abnormalities suggest another cause or permanent damage from the hyponatremia.

EUVOLEMIC. SIADH. Patients with euvolemia and hyponatremia usually have the syndrome of inappropriate anti-diuretic hormone (SIADH). ADH secretion is stimulated by nonosmotic, nonvolume factors, and is thus considered inappropriate. SIADH may result from:

a) pain,
b) nausea,
c) drugs,
d) central nervous system (CNS) disease,
e) pulmonary disease, or
f) endocrine disease (e.g., glucocorticoid deficiency, hypo-thyroidism)

Patients receiving hypotonic fluids may become acutely hyponatremic resulting from impaired water excretion. Many cases of parenteral water intoxication have been seen after surgery. Anesthesia and surgery are common stimulants to ADH secretion. Women, children, and the elderly are more susceptible to hyponatremia because of a lower body water content. Drugs associated with SIADH include:

a) vincristine
b) oxytocin
c) carbamazepine
d) clofibrate
e) chlorpropamide
f) morphine
g) nonsteroidal antinflammatory agents

The kidneys possess a large capacity to excrete free water. In the absence of ADH, urine osmolality usually falls 50 to 100 mOsm/kg 1120. Given a normal daily diet of 1000 mOsm of solute, a maximally dilute urine allows excretion of 20 L of fluid each day. If water intake exceeds the capacity of the kidneys to excrete it, hyponatremia results. SIADH patients cannot maximally dilute their urine and develop hyponatremia at levels of free water intake that are considered normal. Such patients have high urine sodium levels (>40 mMol/L) and high urine osmolalities (>500 mOsm/kg). Na-triuresis results from elevated atrial natriuretic hormone levels and suppressed aldosterone concentrations, resulting in the production of concentrated urine from high ADH levels.

Water Intoxication. Other causes of hyponatremia associated with euvolemia include water intoxication (e.g., psychotic patients with a syndrome called psychogenic polydipsia, heavy beer drinkers, and absorption of hypoosmolar fluids during prostate resection). These patients have low urine osmolalities (usually <100 mOsm/kg 1120) and polyuria. Diuretics are an important cause of hyponatremia in euvolemic patients. Thiazides and metolazone block reabsorption of sodium chloride in the distal convoluted tubule, preventing the formation of maximally dilute urine, but they leave intact the ability to excrete maximally concentrated urine.

EUVOLEMIC: THERAPY. The cornerstone of therapy for SIADH is correction of the cause (e.g., tumor, pain, nausea, stress), free water restriction, and replacement of water loss with fluids higher in sodium content. The goal is a net negative water balance. Even if the source of ADH secretion cannot be removed or suppressed, water restriction decreases intra-vascular fluid volume. The result is decreased renal blood flow (RBF) and glomerular filtration rate (GFR), which enhances proximal tubular reabsorption of salt and water, decreases free water generation, and increases aldosterone secretion, enhancing distal tubule sodium reabsorption. However, decreased renal blood flow may predispose the patient to renal failure. Net negative water balance also may be obtained by using furosemide to promote free water loss in the kidney. Furosemide frequently produces a urine sodium loss of 40 to 70 mMol/L, but the exact amount can be measured every 6 to 12 hours.
Excreted water and salt can be replaced with isotonic or hypertonic saline solution that is more concentrated than the fluid excreted. This technique can rapidly restore serum sodium levels to normal values. Isotonic saline (154 mMol/L) alone may not correct hyponatremia, although it is hypertonic compared with the patient's plasma, because the infused sodium can be excreted in a more concentrated form than it is administered. The net effect is further water retention and worsening hyponatremia. Loop diuretics may be useful in these situations by impairing the patient's ability to concentrate the urine. Loop diuretics also casi be corn-bined with hypertonic saline or oral salt. Saline should be used to replace urinary sodium losses and not urine volume, to avoid excess volume expansion.

Care must be taken not to correct chronic hyponatremia too rapidly and to prevent saline overload, which is more common with the use of hypertonic saline. The adaptations that defend against brain swelling during hyponatremia predispose to complications if a chronic distur-bance is corrected too quickly. While serum sodium concentration is corrected, solutes lost in the adaptation to hyponatremia must be recovered. Rapid correction of chronic hyponatremia may result in brain dehydration, cerebral bleeding, demyelination, neurologic injury, or death.

The osmotic pontine demyelination syndrome (i.e. pontine myelinolysis) is a delayed complication of rapid reversal of hyponatremia (i.e., correction by >12 mMol/day). In this syndrome, hyponatremic symptoms improve during correction of the electrolyte disorder, but improvement is followed within one to several days by neurologic deterioration (e.g., seizures, movement disorders, akinetic mutism, pseudobulbar palsy, quadriparesis, unresponsiveness). Although no consensus has been reached on how rapidly to correct acute hyponatremia (<2-day duration), we recommend that the serum sodium level be corrected no faster than 1 to 2 mMol/hour and that the serum sodium be increased to only 130 mMol/L. Hypernatreinia should be avoided. In chronic hyponatremia, we recommend a correction rate of less than 12 mMol/day. These rates of correction usually can be accomplished by measuring the sodium concentration in urine after 10 to 40 mg of furosemide over 1 to 2 hours and replacing the sodium content with a more concentrated fluid (i.e., 0.9% or 3% saline).

Saline infusion alone often results in only a transient increase in the circulating sodium concentration. In the face of an expanded intravascular volume, which is common in patients with SIADH, aldosterone suppression and elevated ANF levels, the administered saline is quickly excreted in the urine. In addition, the basic fluid problem in SIADH is water overload and not salt depletion. Demeclocycline (900 to 1200 mg/day) and lithium produce a state of nephrogenic diabetes insipidus (NDI) and have been used effectively to treat patients with SIADH (usually patients in whom the primary disease cannot be reversed). Demeclocychne is better tolerated than lithium, but both drugs have significant toxicities. Occasionally, di-phenylhydantoin may inhibit neurohypophyseal release of ADH in a patient with SIADH and may be useful in management.
Psychogenic polydipsia usually autocorrects rapidly by water diuresis after water intake is curtailed. In these patients, it is difficult to prevent rapid correction of the serum sodium level. Hypertonic saline is rarely required.

CNS Effects. Sodium primarily affects osmolality and cellular volumes. The cells most affected by changes in osmolality are those in the CNS. When blood sodium concentration falls, the brain gains fluid and swells. The CNS can compensate for slow or chronic changes in osmolality. Thus, acute changes in sodium concentration should be treated rapidly and chronic changes more slowly.
Acute hyponatremia may produce lethargy, disorientation, obtundation, coma, impaired mentation, wekness, respiratory failure, cerebral edema, uncal or tonsillar herniation, neuronal death and seizures. Other symptoms of hyponatremia relate to the underlying cause and intravascular volume status. These include nausea, vomiting, anorexia, cramps and generalized weakness. Severe acute hyponatremia (<125 mMol/L) is associated with significant morbidity and mortality. Although less symptomatic, chronic hyponatremia is not synonymous with asymptomatic hyponatremia. Patients with low serum sodium concentrations usually have neurologic symptoms.
CNS signs of hyponatremia usually improve wtihin 24-72 hours after correction of the hyponatremia. A large increase in Na+ concentration is not needed to reduce cerebral edema caused by hyponatremia. A small increase in plasma osmolality is sufficient to reduce brain swelling. Because brain water content can not increase by more than about 10% of the confines of the skull, a 5-10% increase in sodium concentration (i.e. 6-12 mMol) can markedly reduce cerebral edema. Continued CNS abnormalities suggest another cause or permaent damage from the hyponetremia. After hyponatremia is corrected, careful monitoring of fluid and electrolytre status is required to prevent recurrence.

The Post-Surgical Patient

Schroeder described postsurgical patients with oliguria not repsonding to large infusions of D5W, rising BUN, urea clearance less than 10% of normal and progressive hyponatremia. They progressed tyo anuria and CNS deterioration in spite of increased amounts of D5W administered. They finally responded to 6% saline.This has been observed by other authors both in humans and animals. The hyponatremia of the postoperative state may significantly affect renal water and solute excretion.

Lack of Solute for Urine Formation

A second cause for oliguria in a patient given only D5W is the lack of solute available for excretion. A few normal values involving water and solute formation and renal function must be appreciated:

a) Insensible water loss averages 1000 ml/m2/24h
b) Water of oxidation averages 200 ml/m2/24h
c) Solute excretion on IV D5W averages 200 mOsm/m2/24h
d) Maximum range of urinary concentration and dilution in a healthy kidney, in a nonstressed person, is 0.7-10 ml of water/mOsm of solute

The postsurgical patient is even snore severely limited with respect to the handling of solute-free-water. His maximum urinary dilution frequently is in the range of 1.2 to 1.6 ml/mOsm of solute, rather than 10 ml/mOsm in the nonstressed patient. Causative factors include depression of RBF and GFR and hyponatremia. The unreplaced deficit in the FECV plays a part in many patients. Increased ADH secretion undoubtedly is a factor. With a maximum urinary dilution of 1.6 ml/mOsm of solute and 200 mOsm of solute, if D5W is administered, only 320 ml of water/m2/24 hours (a 24-hour urine volume of 550 ml in a 70-kg man) can be excreted. This value is the usual urinary output of a major surgical patient treated only with D5W intraoperatively and postoperatively. The forcing of additional D5W to increase urine output is of little avail, because without supplemental insulin, humans normally cannot use more than 50 to 75 g of glucose/m2/24 hours; the additional glucose, therefore, does not lead to any appreciable increase in solute production.
Reports of oliguria postoperatively ill pabents given only D5W, and the occurrence of water intoxication when additional D5W is "pushed", thus are to be expected. Likewise, the prompt diuresis and symptomatic improvement seen upon the administration of hypertonic saline or other solute is not surprising, although the rapidity with which correction should be achieved is debated.


Hypernatremia results from the loss of free water or gain of sodium ions in excess of water. The net result is an increase in the concentration of sodium in the blood. Most patients wil hypenatremia have impaired thirst or inaccessibility to water. Thirst usually results in increased water intake in awake patients. Hyperosmolality always exists with hypernatremia. Because sodium is an impermeant soluble, hypernatremia produces cellular dehydration. However, hypernatremia can exist with hypovolemia, euvolemia, or hypervolemia. Approximately half the cases of hypernatremia are present on admission to the hospital, and the other half develop after admission. Severe hypernatremia is associated with high mortality (30% to 90%).

Hypernatremic hypovolemia results:

a) renal water losses
- impaired response to ADH,
- diabetes insipidus (DI),
- osmotic diuretics,
- adrenal failure
b) nonrenal water losses - diarrhea,
- severe sweating from fever or thyrotoxicosis

Hypernatremia with hypervolemia (e.g., edematous states) usually results from iatrogenic sodium administration or states of mineralocorticoid excess (eg. primary or secondary hyperaldosteronism).

Hypernatremia in relative euvolemia usually results from excess water losses (e.g., fever), diarrhea, or impaired secretion or response to ADH (e.g., diabetes insipidus).

CNS Dysfunction. Hypernatremia primarily affects CNS function by causing cellular dehydration. Because the CNS can compensate for slow or chronic changes in sodium level, acute changes should be treated acutely and chronic changes should be treated slowly. Clinical features of hypernatremia include impaired mentation, weakness, lethargy, obtundation, coma, thirst, irritability, respiratory failure, focal deficits, seizures, cerebral hemorrhage and cerebral dehydration. Severe brain dehydration puts mechanical traction on cerebral blood vessels and may cause bleeding.

Other clinical features reflect the underlying causes of hypernatremia and intravascular volume status. Severe water loss may cause dehydration, oliguria, hypotension, and shock. The renal effects of hypernatremia include polyuria, oliguria and renal insufficiency. The cardiovascular effects of salt overload include peripheral and pulmonary edema. With hypovolemia, one may see shock, hypotension, dehydration and tachycardia. Patients with diabetes insipidus usually have polydipsia and polyuria. Polyuria may also result from renal water losses (e.g., osmotic diuretics) and salt overload states.

Treatment.Hypernatremia indicates intracellular volume depletion and a relative or absolute need for water. Treatment consists of water replacement and addressing underlying medical conditions, associated electrolyte abnormalities, and intravascular volume status. If the patient is hypovolemic, intravascular volume should be replaced with isotonic saline, colloid, or blood. After intravascular volume is restored, water is replaced using hypotonic intravenous fluids (i.e., 5% dextrose in water) or enteral water. In patients with sodium overload, sodium can be removed from the body with diuretics or dialysis and volume replaced with hypotonie fluids. Hypernatremia resulting from glucose-induced osmotic diuresis can he treated with insulin after repletion of intravascular volume. The rate of correction depends on how quickly it developed. Acute hypernatremia can be corrected fairly rapidly, but chronic hypernatremia should be corrected slowly to avoid neurologic sequelae such as seizures and cerebral edema. We recommend that chronic hypernatremia be corrected no faster than 1 to 2 mMol/L/hour. The water deficit is replaced over 24 to 48 hours.


Treat underlying cause
Remove offending drugs
Correct electrolyte abnormalities


Remove sodium with loop diuretic or dialysis
Replace volume with hypotonic fluids


Replenish intravascular volume with isotonic saline
Give hypotonic fluids if intravascular volume repleted

EUVOLEMIC STATES Give hypotonic fluids
Treat diabetes insipidus


Hyponatremia occurring with a normal serum osmolality (pseudohyponatremia) usually results from severe hyperlipidemia or markedly elevated serum proteins, as in multiple myeloma.

Lipid and protein represent solid components of the blood (normally 7%). Standard laboratory techniques for measuring serum sodium assume a constant solid component of blood. If these components are elevated, these techniques underestimate the true sodium concentration in the liquid portion of the blood. Ion-selective electrode systems measure ion concentrations by activity and are not affected by lipid and protein levels.

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