What effect is seen when the extracellular concentration of sodium is increased?

What effect is seen when the extracellular concentration of sodium is increased?

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I can't seem to figure out how this would effect the cell since sodium is not very permeable.

The membrane isn't sodium permeable but it is water permeable. Water will move from areas of high concentrations to low. So when you increase the extracellular concentration of sodium, water will move out of the cell and into the extracellular matrix. This causes the cell to shrink.


Sodium (Na + ) is the major extracellular cation and is a primary determinant of plasma osmolality and extracellular fluid (ECF) volume. Sodium concentration is inextricably linked with ECF volume, therefore interpretation of sodium levels should always include consideration of the hydration status of the patient (and, therefore, changes in “free” water). The body attempts to maintain a constant ECF volume, as major changes in ECF volume can have profound effects on cells. The kidney plays a critical role in maintenance of ECF volume, via sodium and water retention in response to antidiuretic hormone (ADH) and aldosterone. Thirst is also stimulated by decreases in ECF volume (hypovolemia) or increases in effective osmolality (hypertonicity). Regulation of body water is accomplished through osmoreceptors and baroreceptors, with the kidney being the main organ where sodium is retained (for more on renal resorption of sodium, refer to the renal physiology page). Sodium concentrations can also be affected by epinephrine, which stimulates renin release and sodium absorption. This effect is transient (for example, an increase in sodium concentration of between 5-10 mEq/L was seen in goats 60 minutes after injection of 2 mg epinephrine and sodium normalized by 90 minutes (Abdelatif and Abdalla et al 2012).

  • Osmoreceptors: These receptors are found primarily in the hypothalamus, although peripheral osmoreceptors do exist (e.g. in the liver). These respond to changes in effective osmolality, principally sodium concentration (major effective osmol in health, whereas glucose only acts as an osmol when insulin is deficient or impaired from causing glucose movement into cells). Osmolality should be thought of as a relative change of sodium to water.
    • Increased osmolality: Increases in water intake and ADH-mediated water absorption in the kidney will result in water uptake without sodium and act to reduce sodium concentration. When there is hypertonicity and hypovolemia, the drive for water retention will continue.
      • ADH release: Hypernatremia will stimulate ADH release from the posterior pituitary gland (remember ADH is produced in the hypothalamus and released from the pituitary). ADH stimulates thirst and promotes water retention in the kidneys by binding to a receptor (VP-2), which results in opening up of water channels (aquaporin-2) in the luminal membrane of principle cells in the collecting ducts. This leads to passive water uptake by the principle cells along a concentration gradient into the hypertonic medullary interstitium and, thus, water retention by the kidney (water in excess of sodium).
      • Thirst: Thirst is stimulated by as little as a 1-2% increase in osmolality in humans (1-3% in dogs).
      • Hypovolemia: With hypovolemia (decreased ECV by 5-10%), the body responds as follows:
        • Juxtaglomerular apparatus: The drop in afferent arteriolar pressure is sensed by low-pressure baroreceptors which stimulate the renin-angiotensin system, the end result being mineralocorticoid (aldosterone) release from the adrenal cortex.
          • Angiotensin II:
            • Stimulates sodium resorption in the proximal convoluted tubules (water will follow).
            • Causes vasoconstriction (increasing blood pressure)
            • Stimulates thirst (increase water intake will take in water without sodium). A decrease in ECV of 8-10% is required for thirst stimulation. An inadequate thirst response will limit the body’s response to hypovolemia and may result in hypernatremia.
            • Stimulates increased absorption of Na and promotes the excretion of potassium and hydrogen (when K is deficient) in the connecting segment and collecting tubules of the distal nephron. NaCl retention promotes water resorption, thus correcting the hypovolemia (water follows sodium). This is very efficient.
            • ADH production in the hypothalamus and release from the pituitary. This will increase water retention (water > sodium) as indicated above. Remember that ADH needs functioning renal tubules and a hypertonic medulla (depends on sodium chloride absorption without water in the thick ascending limb of the loop of Henle and urea, which is absorbed in the distal nephron under the influence of ADH, but is produced in the liver). A hypertonic medulla also needs adequate (not increased) renal medullary blood flow in the vasa recta.
            • Catecholamine release. These cause:
              • Absorption of sodium (and water) in the proximal convoluted tubule (α1 effect).
              • Renin release (β1 effect)
              • Vasoconstriction
              • Low-pressure baroreceptors respond to increased volume in the cardiac atria (right):
                • Inhibit ADH secretion
                • Increase natrial natriuretic peptide. This:
                  • Is a vasodilator (decreases blood pressure). This is thought to be the main action of this hormone.
                  • Inhibits renin release and angiotensin release, as well as potassium-induced release of aldosterone. It also inhibits the response of the renal tubules to these hormones (particularly AgII).

                  Osmotic forces

                  The concentration of combined solutes in water is osmolarity (amount of solute per L of solution), which, in body fluids, is similar to osmolality (amount of solute per kg of solution). Plasma osmolality can be measured in the laboratory or estimated according to the formula

                  Estimated plasma osmolality in conventional units (mOsm/kg ) =

                  where serum sodium (Na) is expressed in mEq/L, and glucose and BUN are expressed in mg/dL. Osmolality of body fluids is normally between 275 and 290 mOsm/kg (275 and 290 mmol/kg). Sodium is the major determinant of plasma osmolality. Apparent changes in calculated osmolality may result from errors in the measurement of sodium (which can occur in patients with hyperlipidemia or extreme hyperproteinemia because the lipid or protein occupies space in the volume of serum taken for analysis the concentration of sodium in serum itself is not affected. Newer methods of measuring serum electrolytes with direct ion-selective electrodes circumvent this problem. An osmolar gap is present when measured osmolality exceeds estimated osmolality by ≥ 10 mOsm/kg ( ≥ 10 mmol/kg). It is caused by unmeasured osmotically active substances present in the plasma. The most common are alcohols (ethanol, methanol, isopropanol, ethylene glycol), mannitol , and glycine.

                  Water crosses cell membranes freely from areas of low solute concentration to areas of high solute concentration. Thus, osmolality tends to equalize across the various body fluid compartments, resulting primarily from movement of water, not solutes. Solutes such as urea that freely diffuse across cell membranes have little or no effect on water shifts (little or no osmotic activity), whereas solutes that are restricted primarily to one fluid compartment, such as sodium and potassium, have the greatest osmotic activity.

                  Tonicity, or effective osmolality, reflects osmotic activity and determines the force drawing water across fluid compartments (the osmotic force). Osmotic force can be opposed by other forces. For example, plasma proteins have a small osmotic effect that tends to draw water into the plasma this osmotic effect is normally counteracted by vascular hydrostatic forces that drive water out of the plasma.

                  The RAS Cascade

                  ANG II is synthesized by cleavage of angiotensinogen, an α2-globulin formed primarily in the liver and, to a lesser extent, in the kidney by the proteolytic enzyme renin to form angiotensin I (ANG I Fig. 1). ANG I is a decapeptide that is rapidly converted by angiotensin-converting enzyme (ACE) and, to a lesser extent, by chymase to ANG II, an octapeptide. The actions of ANG II are mediated by two G protein-coupled receptors: angiotensin type 1 (AT1) and angiotensin type 2 (AT2) receptors. In the kidney, all of the actions of ANG II on hemodynamic and tubular function are thought to be mediated via AT1 receptors, including afferent and efferent arteriolar vasoconstriction and enhanced sodium and fluid reabsorption. Similarly, the ANG II-induced stimulation of aldosterone release from the adrenal cortex is mediated via the activation of AT1 receptors.

                  Fig. 1.Renin-angiotensin system cascade for the formation of angiotensin II. AT1 receptors, angiotensin type 1 receptors.

                  Treatment of Hyponatremia

                  When hypovolemic, 0.9% saline

                  When hypervolemic, fluid restriction, sometimes a diuretic, occasionally a vasopressin antagonist

                  When euvolemic, treatment of cause

                  In severe, rapid onset or highly symptomatic hyponatremia, partial rapid correction with hypertonic (3%) saline

                  Hyponatremia can be life threatening and requires prompt recognition and proper treatment. Too-rapid correction of hyponatremia risks neurologic complications, such as osmotic demyelination syndrome. Even with severe hyponatremia, serum sodium concentration should not be increased by more than 8 mEq/L (8 mmol/L) over the first 24 hours. And, except during the first few hours of treatment of severe hyponatremia, sodium should be corrected no faster than 0.5 mEq/L/hour (0.5 mmol/L/hour). The degree of hyponatremia, the duration and rate of onset , and the patient's symptoms are used to determine which treatment is most appropriate.

                  In patients with hypovolemia and normal adrenal function, administration of 0.9% saline usually corrects both hyponatremia and hypovolemia. When the serum sodium is < 120 mEq/L (< 120 mmol/L), hyponatremia may not completely correct upon restoration of intravascular volume restriction of free water ingestion to 500 to 1000 mL/24 hours may be needed.

                  In hypervolemic patients, in whom hyponatremia is due to renal sodium retention (eg, heart failure, cirrhosis, nephrotic syndrome) and dilution, water restriction combined with treatment of the underlying disorder is required. In patients with heart failure, an angiotensin-converting enzyme inhibitor, in conjunction with a loop diuretic, can correct refractory hyponatremia. In other patients in whom simple fluid restriction is ineffective, a loop diuretic in escalating doses can be used, sometimes in conjunction with IV 0.9% normal saline. Potassium and other electrolytes lost in the urine must be replaced. When hyponatremia is more severe and unresponsive to diuretics, intermittent or continuous hemofiltration may be needed to control ECF volume while hyponatremia is corrected with IV 0.9% normal saline. Severe or resistant hyponatremia generally occurs only when heart or liver disease is near end-stage.

                  In euvolemia, treatment is directed at the cause (eg, hypothyroidism, adrenal insufficiency, diuretic use). When SIADH is present, severe water restriction (eg, 250 to 500 mL/24 hours) is generally required. Additionally, a loop diuretic may be combined with IV 0.9% saline as in hypervolemic hyponatremia. Lasting correction depends on successful treatment of the underlying disorder. When the underlying disorder is not correctable, as in metastatic cancer, and patients find severe water restriction unacceptable, demeclocycline 300 to 600 mg orally every 12 hours may be helpful by inducing a concentrating defect in the kidneys. However, demeclocycline is not widely used due to the possibility of drug-induced acute kidney injury. IV conivaptan , a vasopressin receptor antagonist, causes effective water diuresis without significant loss of electrolytes in the urine and can be used in hospitalized patients for treatment of resistant hyponatremia. Oral tolvaptan is another vasopressin receptor antagonist with similar action to conivaptan . Tolvaptan use is limited to less than 30 days due to the potential for liver toxicity and it should not be used in patients with liver or kidney disease.

                  Mild to moderate hyponatremia

                  Mild to moderate, asymptomatic hyponatremia (ie, serum sodium ≥ 121 and < 135 mEq/L [≥ 121 and < 135 mmol/L]) requires restraint because small adjustments are generally sufficient. In diuretic-induced hyponatremia, elimination of the diuretic may be enough some patients need some sodium or potassium replacement. Similarly, when mild hyponatremia results from inappropriate hypotonic parenteral fluid administration in patients with impaired water excretion, merely altering fluid therapy may suffice.

                  Severe hyponatremia

                  In asymptomatic patients, severe hyponatremia (serum sodium < 121 mEq/L [< 121 mmol/L] effective osmolality < 240 mOsm/kg [< 240 mmol/kg] ) can be treated safely with stringent restriction of water intake.

                  In patients with neurologic symptoms (eg, confusion, lethargy, seizures, coma), treatment is more controversial. The debate primarily concerns the rate and degree of hyponatremia correction. Many experts recommend that, in general, serum sodium be raised no faster than 1 mEq/L/hour (1 mmol/L/hour). However, replacement rates of up to 2 mEq/L/hour (2 mmol/L/hour) for the first 2 to 3 hours have been suggested for patients with seizures or significantly altered sensorium. Regardless, the rise should be ≤ 8 mEq/L (≤ 8 mmol/L) over the first 24 hours. More vigorous correction risks precipitating osmotic demyelination syndrome.

                  Rapid-onset hyponatremia

                  Acute hyponatremia with known rapid onset (ie, within < 24 hours) is a special case. Such rapid onset can occur with

                  Acute psychogenic polydipsia

                  Use of the recreational drug ecstasy (MDMA)

                  Postoperative patients who received hypotonic fluid during surgery

                  Marathon runners who replace sweat loss with hypotonic fluids

                  Rapid-onset hyponatremia is problematic because the cells of the central nervous system have not had time to remove some of the intracellular osmolar compounds used to balance intracellular and extracellular osmolality. Thus, the intracellular environment becomes relatively hypertonic compared to the serum, causing intracellular fluid shifts that can rapidly cause cerebral edema, potentially progressing to brain stem herniation and death. In these patients, rapid correction with hypertonic saline is indicated even when neurologic symptoms are mild (eg, forgetfulness). If more severe neurologic symptoms, including seizures, are present, rapid correction of sodium by 4 to 6 mEq/L (4 to 6 mmol/L) using hypertonic saline is indicated. The patient should be monitored in an intensive care unit and serum sodium levels monitored every 2 hours. After sodium level has increased by the initial target of 4 to 6 mEq/L, the rate of correction is slowed so that serum sodium level does not rise by > 8 mEq/L (> 8 mmol/L) in the first 24 hours.

                  Hypertonic saline solution

                  Hypertonic (3%) saline (containing 513 mEq sodium/L (513 mmol/L)) use requires frequent (every 2 hours) electrolyte determinations. In some situations, hypertonic saline may be used with a loop diuretic. Equations are available to help predict the sodium response to a given amount of hypertonic saline, but these formulas are only rough guidelines and do not decrease the need to monitor electrolyte levels frequently. For instance, in hypovolemic hyponatremia the sodium level can normalize too quickly as volume is replaced and thus removes the hypovolemic stimulus for vasopressin secretion, causing the kidneys to excrete large amounts of water.

                  Another recommendation includes administration of desmopressin 1 to 2 mcg every 8 hours concurrently with hypertonic saline. The desmopressin prevents an unpredictable water diuresis that can follow the abrupt normalization of endogenous vasopressin that can occur as the underlying disorder causing hyponatremia is corrected.

                  For patients with rapid-onset hyponatremia and neurologic symptoms, rapid correction is accomplished by giving 100 mL of hypertonic saline IV over 15 minutes. This dose can be repeated once if neurologic symptoms are still present.

                  For patients with seizures or coma but slower onset hyponatremia, ≤ 100 mL/hour of hypertonic saline may be administered over 4 to 6 hours in amounts sufficient to raise the serum sodium 4 to 6 mEq/L (4 to 6 mmol/L). This amount (in mEq OR mmol) may be calculated using the sodium deficit formula as

                  where TBW is 0.6 × body weight in kg in men and 0.5 × body weight in kg in women.

                  For example, the amount of sodium needed to raise the sodium level from 106 to 112 mEq/L in a 70-kg man can be calculated as follows:

                  Because there is 513 mEq (mmol) sodium/L in hypertonic saline, roughly 0.5 L of hypertonic saline is needed to raise the sodium level from 106 to 112 mEq/L (mmol/L). To result in a correction rate of 1 mEq/L/hour, this 0.5 L volume would be infused over about 6 hours.

                  Adjustments may be needed based on serum sodium concentrations, which are monitored closely during the first few hours of treatment. Patients with seizures, coma, or altered mental status need supportive treatment, which may involve endotracheal intubation, mechanical ventilation, and benzodiazepines (eg, lorazepam 1 to 2 mg IV every 5 to 10 minutes as needed) for seizures.

                  Selective receptor antagonists

                  The selective vasopressin (V2) receptor antagonists conivaptan (IV) and tolvaptan (oral) are relatively new treatment options for severe or resistant hyponatremia. These drugs are potentially dangerous because they may correct serum sodium concentration too rapidly they are typically reserved for severe (< 121 mEq/L [< 121 mmol/L]) and/or symptomatic hyponatremia that is resistant to correction with fluid restriction. The same pace of correction as for fluid restriction, ≤ 10 mEq/L over 24 hours, is used. These drugs should not be used for hypovolemic hyponatremia or in patients with liver disease or advanced chronic kidney disease.

                  Conivaptan is indicated for treatment of hypervolemic and euvolemic hyponatremia. It requires close monitoring of patient status, fluid balance, and serum electrolytes and so its use is restricted to hospitalized patients. A loading dose is given followed by a continuous infusion over a maximum of 4 days. It is not recommended in patients with advanced chronic kidney disease (estimated glomerular filtration rate < 30 mL/minute) and should not be used if anuria is present. Caution is advised in moderate to severe cirrhosis.

                  Tolvaptan is a once daily tablet indicated for hypervolemic and euvolemic hyponatremia. Close monitoring is recommended especially during initiation and dosage changes. Tolvaptan use is limited to 30 days because of the risk of liver toxicity. Tolvaptan is not recommended for patients with advanced chronic kidney disease or liver disease. Its effectiveness can be limited by increased thirst. Tolvaptan use is also limited by excessive cost.

                  Both of these drugs are strong inhibitors of CYP3A (cytochrome P450, family 3, subfamily A) and as such have multiple drug interactions. Other strong CYP3A inhibitors (eg, ketoconazole , itraconazole , clarithromycin , retroviral protease inhibitors) should be avoided. Clinicians should review the other drugs the patient is taking for potentially dangerous interactions with V2 receptor antagonists before initiating a treatment trial.

                  Chronic hyponatremia

                  Patients with SIADH need chronic treatment for hyponatremia. Fluid restriction alone is frequently is not enough to prevent recurrence of hyponatremia. Oral salt (NaCl) tablets can be used with dosage adjusted to treat mild to moderate chronic hyponatremia in these patients.

                  Oral urea is a very effective treatment for hyponatremia, but it is tolerated poorly by patients due to its taste. A newer oral formulation of urea has been developed to enhance palatability.

                  Osmotic demyelination syndrome

                  Osmotic demyelination syndrome (previously called central pontine myelinolysis) may follow too-rapid correction of hyponatremia. Demyelination classically affects the pons, but other areas of the brain can also be affected. Lesions are more common among patients with alcohol use disorder, undernutrition, or other chronic debilitating illness. Flaccid paralysis, dysarthria, and dysphagia can evolve over a few days or weeks after a hyponatremic episode. The classic pontine lesion may extend dorsally to involve sensory tracts and leave patients with a "locked-in" syndrome (an awake and sentient state in which patients, because of generalized motor paralysis, cannot communicate, except by vertical eye movements controlled above the pons). Damage often is permanent. When sodium is replaced too rapidly (eg, > 14 mEq/L/8 hour [14 mmol/L/8 hours]) and neurologic symptoms start to develop, it is critical to prevent further serum sodium increases by stopping hypertonic fluids. In such cases, inducing hyponatremia with hypotonic fluid may mitigate the development of permanent neurologic damage.

                  Disorders of Sodium and Water Homeostasis

                  Blood volume and plasma osmolality are tightly regulated in the human body because they are essential for normal cellular function. Water balance determines the serum sodium concentration, and sodium balance determines the water status.

                  Hypovolemic hypotonic hyponatremia is relatively common in patients taking thiazide diuretics however, thiazide-induced hyponatremia is usually mild and relatively asymptomatic.

                  Euvolemic (isovolemic) hyponatremia is most often caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Common causes of SIADH include some cancers, central nervous system (CNS) and pulmonary disorders, and certain drugs.

                  Symptoms of hypo- or hypernatremia are usually neurologic and range from weakness, lethargy, restlessness, irritability, and confusion to twitching, seizures, coma, and death. Symptom severity depends on both the magnitude of the change in the serum sodium concentration and the rate at which it changes.

                  Treatment goals in patients with either hypo- or hypernatremia should include cautious correction of the serum sodium concentration and, when appropriate, restoration of a normal extracellular fluid (ECF) volume. Too rapid correction of the serum sodium can result in cerebral edema, seizures, neurologic damage, osmotic demyelination syndrome, and possibly death. To minimize the risk of these complications, the serum sodium concentration should be corrected at a rate not to exceed 6 to 12 mEq/L (6 to 12 mol/L) in 24 hours, depending on the rate of change in the serum sodium concentration.

                  Asymptomatic or mildly symptomatic hyponatremia should be managed conservatively with treatment directed at the underlying cause. IV infusion of 0.9% NaCl solution is most often used to correct the serum sodium concentration in patients with moderate to severe symptoms from hypovolemic hypotonic hyponatremia. A 3% NaCl infusion can be cautiously used in patients with moderate to severe symptoms and euvolemic or hypervolemic hypotonic hyponatremia (along with a loop diuretic).

                  Hypernatremia is always hypertonic and most commonly occurs when increased water or hypotonic fluid losses are not offset by increased water intake or administration.

                  Hypovolemic hypernatremia is relatively common in patients taking loop diuretics. After symptoms of hypovolemia are corrected with 0.9% NaCl solution, free water should be replaced.

                  Patients with central diabetes insipidus (DI) can be treated with desmopressin acetate, with a goal to decrease urine volume to less than 2 L per day while maintaining the serum sodium concentration between 137 and 142 mEq/L (137 and 142 mmol/L). Patients with nephrogenic DI should be treated by correcting the underlying cause, when possible, and sodium restriction in conjunction with a thiazide diuretic to decrease the ECF volume by approximately 1 to 1.5 L.

                  Edema develops as a primary defect in renal sodium handling or as a response to a decreased effective circulating volume. It is usually first detected in the feet or pretibial areas of ambulatory patients. Pulmonary edema, evidenced by auscultatory crackles, can be life threatening.

                  Diuretics are the primary pharmacologic means for minimizing edema and improving organ function. Diuretic resistance often can be overcome by using an increased dose or by using a combination of a loop diuretic and a thiazide or thiazide-like diuretic.

                  Both blood volume and plasma osmolality are tightly regulated in the human body because they are essential for normal cellular function. Blood volume is a determinant of effective tissue perfusion which is required to deliver oxygen and nutrients to and remove metabolic waste products from tissues. Plasma osmolality, the primary determinant of which is sodium concentration, is an important determinant of intracellular fluid (ICF) volume. Maintenance of normal ICF volume is particularly critical in the brain, which is 80% water, and where alterations, especially rapid changes, can result in significant dysfunction and potentially death.

                  Simply put, water balance determines the serum sodium concentration, and sodium balance determines the volume status. Thus, the homeostatic mechanisms for controlling blood volume are focused on controlling sodium balance, and, in contrast, the homeostatic mechanisms for controlling plasma osmolality are focused on controlling water balance. Disorders of sodium and water homeostasis are common, caused by a variety of diseases, conditions, and drugs, and potentially serious. This chapter reviews the etiology, classification, clinical presentation, and therapy for disorders of sodium and water homeostasis.


                  Hypo- and hypernatremia are syndromes of altered plasma tonicity and cell volume that reflect a change in the ratio of total exchangeable body sodium to total body water (TBW). TBW is distributed primarily into two compartments: the intracellular compartment (ICF 60% of TBW) and the extracellular compartment or extracellular fluid (ECF 40% of TBW). Sodium and its accompanying anions (chloride and bicarbonate) comprise more than 90% of the total osmolality of the ECF whereas ICF osmolality is primarily determined by the concentration of potassium and its accompanying anions (mostly organic and inorganic phosphates). The intra- and extracellular sodium and potassium concentrations are maintained by the sodium–potassium–adenosine triphosphatase (Na + -K + -ATPase) pump. Most cell membranes are freely permeable to water, and thus the osmolalities of the ICF and the ECF are equal.

                  Effective osmoles are solutes that cannot freely cross cell membranes, such as sodium and potassium. The ECF concentration of effective osmoles determines its tonicity, which directly affects the distribution of water between the extra- and intracellular compartments. Addition of an isotonic solution (e.g., 0.9% sodium chloride [NaCl] solution) to the ECF will result in no change in intracellular volume because there will be no change in the effective ECF osmolality. However, addition of a hypertonic solution (e.g., 3% NaCl) to the ECF will result in a decrease in ICF (cell) volume, and addition of a hypotonic solution (e.g., 0.45% NaCl) to the ECF will result in an increase in cell volume. Table 34-1 summarizes the composition of commonly used IV solutions and their respective distribution into the ICF and ECF compartments following IV administration.

                  TABLE 34-1 Composition of Common IV Solutions

                  Edelman’s equation defines serum sodium as a function of the total exchangeable sodium and potassium in the body and the TBW: Na S = Na total body + K total body /TBW, where Na S is the serum sodium concentration Na total body is the total body sodium content K total body is the total body potassium content and TBW is the total body water in liters. 1 The serum sodium concentration is tightly regulated and thus usually varies by no more than 2% to 3%. Regulation of the serum sodium concentration occurs indirectly via mechanisms that control its determinants: plasma osmolality and blood volume. The kidney regulates water excretion through a hypothalamic feedback mechanism, such that the serum osmolality remains relatively constant (275 to 290 mOsm/kg [275 to 290 mmol/kg]) despite day-to-day variations in water intake. Plasma osmolality is primarily determined by the sodium concentration, but serum glucose and blood urea nitrogen (BUN) may contribute significantly at times. Serum osmolality can be estimated as:

                  where Osm S is the serum osmolality in mOsm/kg Na S is the serum sodium concentration in mEq/L Glucose S is the serum glucose concentration in mg/dL and BUN is the blood urea nitrogen concentration in mg/dL. Alternatively, when using SI units the equation becomes:

                  where Osm S is the serum osmolality in mmol/kg Na S is the serum sodium concentration in mmol/L Glucose S is the glucose concentration in mmol/L and BUN is the blood urea nitrogen concentration in mmol/L.

                  Arginine vasopressin (AVP), commonly known as antidiuretic hormone (ADH), is synthesized in the hypothalamus and released from the posterior pituitary as a result of both osmotic and nonosmotic regulators. When the plasma osmolality increases by 1% to 2% or more AVP is released and binds to the vasopressin 2 (V2) receptors on the basolateral surface of renal tubular epithelial cells, resulting in the insertion of water channels (aquaporin 2) into the apical tubular lumen surface of the cell. 2 Water can then pass through the cell into the peritubular capillary space where it is reabsorbed into the systemic circulation. As serum osmolality increases, even as little as 1%, AVP is released and thirst is stimulated. The combined effects of increased water intake and decreased water excretion (kidney’s response to AVP) result in a decrease in the serum osmolality and inhibition of further AVP secretion, once the normal plasma osmolality is restored.

                  Nonosmotic AVP release occurs when osmoreceptors in the brain detect a 6% to 10% reduction in the effective circulating blood volume or arterial blood pressure. The effective circulating volume is that part of the ECF responsible for organ perfusion. A decrease in the effective circulating volume (more accurately, the pressure associated with that volume) activates arterial baroreceptors in the carotid sinus and glomerular afferent arterioles, resulting in stimulation of the renin–angiotensin system and increased angiotensin II synthesis. Angiotensin II stimulates both nonosmotic AVP release and thirst. This volume stimulus can override osmotic inhibition of AVP release. Conservation of water then restores the effective circulating volume and blood pressure at the expense of producing a decreased serum osmolality and hyponatremia. 2 Although hyponatremia and hypernatremia can be associated with conditions of high, low, or normal ECF sodium and volume, both conditions most commonly result from abnormalities of water homeostasis.


                  Epidemiology and Etiology

                  Hyponatremia, usually defined as a serum sodium concentration less than 135 mEq/L (135 mmol/L), is the most common electrolyte abnormality encountered in clinical practice in both adults and children. 1, 3– 6 Although the prevalence is not well established and varies with the patient population studied, it has been estimated to be as high as 28% in patients admitted to an acute care hospital. 7 Mild hyponatremia (serum sodium concentration less than 136 mEq/L [136 mmol/L]) was observed in 42.6%, while 6.2% of patients had values less than 126 mEq/L (126 mmol/L), and 1.2% had values less than 116 mEq/L (116 mmol/L). The incidence has been reported to be as high as 21% in patients seen in ambulatory hospital clinics, and 7% in community clinics. 7 Drug-induced hyponatremia especially that associated with thiazide diuretics, 8, 9 and psychotropic medications, 10, 11 is common. Advancing age (older than 30 years) is also a risk factor for hyponatremia, independent of sex. 7

                  Residents in nursing homes have a twofold higher incidence of hyponatremia than that observed in age-matched, community-dwelling individuals. 3 More than 75% of these hyponatremic episodes were precipitated by increased intake of hypotonic oral or IV fluids. Similarly, ingestion of excessive fluid volumes has been identified as a key risk factor in the development of hyponatremia in marathon runners. Although women had a threefold higher rate of hyponatremia, smaller body size and longer racing time, not sex, appear to be the principal factors accounting for the increased incidence. 11

                  Recognition of the high prevalence of hyponatremia is essential because this condition is associated with significant morbidity and mortality. 2, 12– 15 Transient or permanent brain dysfunction can result from either the acute effects of hypoosmolality or too rapid correction of hypoosmolality in patients with hyponatremia. Hyponatremia is predominantly the result of an excess of extracellular water relative to sodium because of impaired water excretion. The kidney normally has the capacity to excrete large volumes of dilute urine after ingestion of a water load. Nonosmotic AVP release, however, can lead to water retention and a drop in the serum sodium concentration, despite a decrease in both serum and intracellular osmolality. The causes of nonosmotic AVP release include hypovolemia, decreased effective circulating volume as seen in patients with chronic heart failure (HF), nephrosis, and cirrhosis. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH), a common cause of hyponatremia, is associated with some oncologic diseases, especially small cell lung cancer, and CNS damage (e.g., head trauma, meningitis). The pathophysiology, clinical features, and management of hyponatremia are detailed below.


                  Hyponatremia can be associated with normal, increased, or decreased plasma osmolality, depending on its cause. Figure 34-1 provides an algorithm for diagnosing patients with hyponatremia. Hyponatremia in patients with normal serum osmolality can be caused by hyperlipidemia or hyperproteinemia. This form of hyponatremia, termed pseudohyponatremia, is an artifact of a specific laboratory method (flame photometry) used to measure serum sodium concentration. This laboratory method is used rarely today, replaced by the use of ion-specific electrodes to measure the serum sodium concentration. If flame photometry is used, the serum volume will be overestimated because the elevated lipids or proteins account for a greater proportion of the total sample volume (Fig. 34-2). Because sodium is distributed in the water component of serum only, the measured serum sodium concentration will be falsely decreased. The measurement of serum osmolality, however, is not significantly affected, leading to a discrepancy between the calculated and measured serum osmolality.

                  FIGURE 34-1 Diagnostic algorithm for the evaluation of hyponatremia. (CHF, congestive heart failure SIADH, syndrome of inappropriate secretion of antidiuretic hormone UNa, urine sodium concentration [values in mEq/L are numerically equivalent to mmol/L] Uosm, urine osmolality [values in mOsm/kg are numerically equivalent to mmol/kg].)

                  FIGURE 34-2 Elevated lipids or proteins result in a larger discrepancy between the volume of the sample and plasma water, leading to a falsely low measurement of the serum sodium concentration when using the method of flame photometry. (S Na , serum sodium concentration [values in mEq/L are numerically equivalent to mmol/L].)

                  Hyponatremia associated with an increased serum osmolality, hypertonic hyponatremia, suggests the presence of excess, effective osmoles (other than sodium) in the ECF. This type of hyponatremia is most frequently encountered in patients with hyperglycemia. The elevated glucose concentration provides effective plasma osmoles, resulting in diffusion of water from the cells (ICF) into the ECF, thereby decreasing the ICF, expanding the ECF, and decreasing the serum sodium concentration. In fact, this relationship can be quantified: for every 100 mg/dL (5.6 mmol/L) increase in the serum glucose concentration, the serum sodium concentration decreases by 1.7 mEq/L (1.7 mmol/L) or 0.29 mmol/L for every 1 mmol/L decrease, and the serum osmolality increases by 2 mOsm/kg (2 mmol/kg). This correction is only a rough estimate because the decrease in the serum sodium concentration may vary significantly with any degree of hyperglycemia. 15 Other substances such as mannitol, glycine, and sorbitol that do not cross cell membranes provide effective osmoles and can also cause hypertonic hyponatremia. The presence of any one of these unmeasured osmoles should be suspected in patients with hypertonic hyponatremia if there is a significant osmolal gap, defined as the difference between the measured and calculated plasma osmolality.

                  Hyponatremia associated with decreased plasma osmolality, hypotonic hyponatremia, is the most common form of hyponatremia and has many potential causes (see Table 34-2). Clinical assessment of ECF volume is an important step in the diagnostic evaluation of a patient with hypotonic hyponatremia. Categorization of these patients into one of three groups (decreased, increased, or clinically normal ECF volume) is essential in identifying the pathophysiologic mechanisms responsible for the hyponatremia and developing an appropriate treatment plan.

                  TABLE 34-2 Characteristics of Hypotonic Hyponatremic States

                  Hypovolemic Hypotonic Hyponatremia

                  Most patients with ECF volume contraction lose fluids that are hypotonic relative to plasma and thus can become transiently hypernatremic. This includes patients with fluid losses caused by diarrhea, excessive sweating, and diuretics. This transient hypernatremic hyperosmolality results in osmotic AVP release and stimulation of thirst. If sodium and water losses continue, the resultant hypovolemia results in more AVP release. Patients who then drink water (a hypotonic fluid) or who are given hypotonic IV fluids retain water, and hyponatremia develops. These patients typically have a urine osmolality greater than 450 mOsm/kg (450 mmol/kg), reflecting AVP action and formation of a concentrated urine. The urine sodium concentration is less than 20 mEq/L (20 mmol/L) when sodium losses are extrarenal, as in patients with diarrhea, and greater than 20 mEq/L (20 mmol/L) in patients with renal sodium losses, as occurs with thiazide diuretic use or in adrenal insufficiency. 17

                  Hypotonic hyponatremia is relatively common in patients taking thiazide diuretics. 9, 18 Thiazide-induced hyponatremia is usually mild and relatively asymptomatic only occasionally is it severe and symptomatic. 18 Hyponatremia typically develops within 2 weeks of therapy initiation, but can occur later in therapy, particularly after dosage increases or if other causes of hyponatremia develop. 18 The elderly, especially women, are at the greatest risk for thiazide diuretic-induced hyponatremia.

                  The mechanism of thiazide-induced hyponatremia is likely related to the balance of its direct and indirect effects. Thiazide diuretics exert their effects by blocking sodium reabsorption in the distal tubules of the renal cortex, thereby increasing sodium and water removal from the body. The resulting decrease in effective circulating volume stimulates AVP release, resulting in increased free water reabsorption in the collecting duct, as well as increased water intake because of stimulation of thirst. Hyponatremia develops when the net result of these effects is the loss of more sodium than water.

                  Conversely, hyponatremia occurs infrequently with loop diuretics due to their different sites of action. Loop diuretics exert their diuretic effect by blocking sodium reabsorption in the ascending limb of the loop of Henle. This action decreases medullary osmolality. Thus, when the loop diuretics decrease effective circulating volume and stimulate AVP release, less water reabsorption occurs in the collecting ducts than would occur if the osmolality of the renal medulla were normal. Thiazide diuretics do not alter medullary osmolality because their site of action is in the renal cortex not the medulla. In addition, most loop diuretics have a shorter half-life than the thiazides, and patients can usually replete the urinary sodium and water losses prior to taking the next dose, thereby minimizing AVP stimulation.

                  Euvolemic Hypotonic Hyponatremia

                  Euvolemic (isovolemic) hypotonic hyponatremia is associated with a normal or slightly decreased ECF sodium content and increased TBW and ECF volume. The increase in ECF volume is usually not sufficient to cause peripheral or pulmonary edema or other signs of volume overload, and thus patients appear clinically euvolemic. Euvolemic hyponatremia is most often caused by SIADH.

                  In SIADH, water intake exceeds the kidney’s capacity to excrete water, either because of increased AVP release via nonosmotic and/or nonphysiologic processes or enhanced sensitivity of the kidney to AVP. In patients with SIADH, the urine osmolality is generally greater than 100 mOsm/kg (100 mmol/kg), and the urine sodium concentration is usually greater than 20 mEq/L (20 mmol/L) due to the ECF volume expansion (Table 34-2).

                  The most common causes of SIADH include tumors such as small cell lung or pancreatic cancer, CNS disorders (e.g., head trauma, stroke, meningitis, pituitary surgery), and pulmonary disease (e.g., tuberculosis, pneumonia, acute respiratory distress syndrome). Patients with kidney and adrenal insufficiency or hypothyroidism can also present with euvolemic hyponatremia, and the evaluation of patients with suspected SIADH should always include consideration of these disorders as the etiology. A variety of drugs can cause SIADH by enhancing AVP release, the effect of AVP on the kidney, or by other unknown mechanisms 10, 14,15, 20 (Table 34-3). The differential diagnosis of euvolemic hypotonic hyponatremia also includes primary or psychogenic polydipsia. Patients with this disorder drink more water (usually more than 20 L/day) than the kidneys can excrete as solute-free water. However, unlike in SIADH, AVP secretion is suppressed, resulting in a urine osmolality that is less than 100 mOsm/kg (100 mmol/kg). The urine sodium is typically low (less than 15 mEq/L [15 mmol/L]) as a result of dilution. 11 Hyponatremia can develop even with more modest water intakes in patients who are ingesting very low-solute diets.

                  TABLE 34-3 Potential Causes of SIADH

                  Hypervolemic Hypotonic Hyponatremia

                  Hyponatremia associated with ECF volume expansion occurs in conditions in which the kidney’s sodium and water excretion are impaired. Patients with cirrhosis, HF, or nephrotic syndrome have an expanded ECF volume and edema, but a decreased effective arterial blood volume (EABV). This decreased volume results in renal sodium retention, and eventually ECF volume expansion and edema. At the same time, there is nonosmotic stimulation of AVP release and water retention in excess of sodium retention, which perpetuates the hyponatremic state.

                  Some clinicians advocate using combinations of diuretics in cases of diuretic-resistant edema associated with nephrotic syndrome, while others prefer to use larger-than-average doses of single agents to overcome enhanced protein binding in the tubular lumen associated with proteinuria.

                  Clinical Presentation

                  The clinical presentation of patients with hyponatremia is summarized in Table 34-4. Patients with chronic (defined as lasting longer than 48 hours), mild hyponatremia (serum sodium concentration 125 to 134 mEq/L [125 to 134 mmol/L]) are usually asymptomatic, with hyponatremia being discovered incidentally when serum electrolytes are measured for other purposes. 21 However, mild symptoms of hyponatremia are frequently unnoticed by both clinicians and patients. 22 Chronic, mild hyponatremia is associated with impairment of attention, posture, and gait, all of which contribute to a substantially increased fall risk. Even “asymptomatic” patients, when formally tested, have impaired attention and gait to a degree that is comparable to symptoms seen with a blood alcohol level of 0.06% (13 mmol/L). 23, 24

                  TABLE 34-4 Clinical Presentation of Hyponatremia

                  Patients with moderate (serum sodium concentration 115 to 124 mEq/L [115 to 124 mmol/L]), severe (serum sodium concentration 110 to 114 mEq/L [110 to 114 mmol/L]), or rapidly developing hypotonic hyponatremia often present with a range of neurologic symptoms resulting from hypoosmolality-induced brain cell swelling. Classic neurologic symptoms include nausea, malaise, headache, lethargy, restlessness, and disorientation. In severe cases, seizures, coma, respiratory arrest, brainstem herniation, and death can occur.

                  The presence of these symptoms and their severity depend on both the magnitude of the hyponatremia and the rate at which the hyponatremia develops. The magnitude of the hyponatremia is important because serum osmolality decreases in direct proportion to the serum sodium concentration, and water movement into brain cells increases as serum osmolality decreases. The rate of change of the serum osmolality is an important factor because brain cells are able to adjust their intracellular osmolality to minimize cellular volume changes in response to volume changes, but time is required for this adaptation to occur. 25 When a decline in plasma osmolality causes water movement into brain cells, inorganic Cl – and K + , and organic osmolytes, such as taurine, glutamate, and myoinositol, move out of the cells to decrease intracellular osmolality and minimize intracellular water shifts. 26 Organic osmolytes, such as myoinositol, a osmotically active substances contribute substantially to controlling intracellular osmolality in the brain without directly altering cellular function. 25,26 The various components of this adaptive mechanism occur over different time frames, with sodium and potassium efflux occurring within minutes to several hours and organic osmolyte efflux occurring within hours to several days. 25,26 Maximal compensation for decreased plasma osmolality typically requires up to 48 hours. Thus, acute changes in plasma osmolality are more likely to be associated with symptoms. Concurrent respiratory failure and hypoxemia increase the risk of adverse neurologic outcomes because hypoxemia diminishes the brain’s capacity to actively transport solute out of cells, leading to a higher incidence of cerebral edema. 25,26 Children and women have poorer clinical outcomes than adults and males, respectively. For example, post-menopausal women have a 25-fold higher risk of death or permanent neurological damage with acute hypervolemic hypotonic hyponatremia than men. 27 Hyponatremia is a severe risk factor for morbidity and mortality in patients with HF and cirrhosis. 2

                  In addition to neurologic symptoms, patients with hypovolemic hyponatremia can present with signs and symptoms of hypovolemia, including dry mucous membranes, decreased skin turgor, tachycardia, decreased jugular venous pressure, hypotension, and orthostatic hypotension. These findings often are helpful in identifying the type of hyponatremia present.

                  The brain’s adaptation to a chronic change in the plasma osmolality leads to development of neurologic symptoms if hyponatremia (hypoosmolality) is corrected too rapidly. The combination of the adaptive decrease in intracellular osmolality and rapid increase in serum osmolality results in excessive movement of water out of the brain cells and ICF volume depletion. Too rapid correction of the serum sodium concentration can lead to an acute decrease in brain cell volume, which contributes to the pathogenesis of osmotic demyelination syndrome (ODS), 2, 28 also known as central pontine myelinolysis, because the demyelinated lesions, which appear on magnetic resonance imaging, most often occur in the central pons however, it can extend to extrapontine structures. 1 Patients with this complication might develop hyperreflexia, para- or quadriparesis, parkinsonism, pseudobulbar palsy, locked-in syndrome (a condition in which a patient is aware and awake but cannot move or communicate verbally due to complete paralysis of nearly all voluntary muscles in the body except for the eyes), or death approximately 1 to 7 days after treatment. 1,12, 29 Patients with a significant degree of cerebral adaptation (e.g., chronic serum sodium concentration less than 110 mEq/L [110 mmol/L]) to hypotonic hyponatremia are at highest risk of developing this syndrome because these patients have lower intracellular osmolalities at the initiation of therapy, resulting in a greater decrease in intracellular volume in brain cells when the plasma osmolality is raised too rapidly. 28 Other conditions that increase the risk of ODS include alcoholism, liver failure, orthotopic liver transplantation, potassium depletion, and malnutrition. Thus, if duration of hyponatremia is unknown then it is generally safer to treat as if it is chronic when developing an initial treatment plan. 1


                  The following principles serve as general guidelines for the treatment of patients with hyponatremia: 1,18,21, 30 (a) It is important for both short- and long-term management to treat the underlying cause of hyponatremia. (b) Appropriate treatment of hypotonic hyponatremia requires balancing the risks of hyponatremia versus the risk of ODS. In general, patients who acutely developed moderate to severe hyponatremia and/or patients who have severe symptoms are at greatest risk and potentially benefit most from more rapid correction of hyponatremia. (c) Correction of hypovolemic hypotonic hyponatremia is usually best accomplished with 0.9% NaCl solution, as these patients have both sodium and water deficits. (d) Active correction of euvolemic and hypervolemic hypotonic hyponatremia in patients who do not require rapid correction is usually best accomplished by water restriction. Demeclocycline, AVP vasopression 2 receptor antagonists ( vaptans ), or 0.9% NaCl solution plus a loop diuretic (furosemide, bumetanide) can be used if the initial response to water restriction is not adequate. (e) In patients with severe symptoms, 3% NaCl solution (possibly combined with a loop diuretic) should initially be used to more rapidly correct the hyponatremia. A loop diuretic such as furosemide can be administered concurrently with 3% NaCl to enhance the serum sodium correction by increasing free water excretion. (f) Long-term management will be required for patients in whom the underlying cause of hyponatremia cannot be corrected. Depending on the cause, water restriction, increasing sodium intake, and/or the use of an AVP antagonist (vaptan) can be used. Application of these principles to the treatment of patients with various forms of hypotonic hyponatremia is discussed in the following sections.

                  Desired Outcome

                  Regardless of the type or cause of hyponatremia, the goals of treatment for all patients are to resolve the underlying cause of the sodium and ECF volume imbalance, if possible, and to safely correct the sodium and water derangements. The treatment plan for patients with hyponatremia depends on the underlying cause of the hyponatremia and the severity of the patient’s symptoms. Patients with an acute onset of hyponatremia or severe symptoms require more aggressive therapy to correct the hypotonicity. The initial goal for these patients is to increase plasma tonicity just enough to control severe symptoms this typically requires only a small increase (5%) in serum sodium concentration. Once severe symptoms have abated, then continued correction of the serum sodium concentration should be achieved at a controlled rate. Patients who are asymptomatic or who have only mild to moderate symptoms do not require rapid correction of the serum sodium concentration. Treatment is dictated by the underlying etiology. In all cases the goal is to avoid an increase in the serum sodium concentration of more than 12 mEq/L (12 mmol/L) in 24 hours or 0.5 mEq/L (0.5 mmol/L) per hour. 1,2,21,30 However, because of the usual uncertainty regarding duration of hyponatremia, correction of no more than 6 to 8 mEq/L (6 to 8 mmol/L) or 0.33 mEq/L/h (0.33 mmol/L/h) is prudent to avoid ODS. 1


                  A patient who has or is at high risk of experiencing severe symptoms caused by hyponatremia should receive either 3% NaCl (513 mEq/L [513 mmol/L]) or 0.9% NaCl (154 mEq/L [154 mmol/L]) solution until severe symptoms resolve. 1,3,18,22, 32 Resolution of severe symptoms frequently requires only a small (

                  5%) increase in serum sodium concentration although, some clinicians suggest that the initial safe target should be a serum sodium concentration of approximately 120 mEq/L (120 mmol/L). 3, 33 The relative concentrations of urine sodium and potassium (osmotically effective urine cations) must be compared with those of the infusate in planning a treatment regimen for patients with hypotonic hyponatremia. For the serum sodium concentration to increase after infusion of a sodium chloride solution, the sodium concentration of the infusate must exceed the sum of the urinary sodium and potassium concentrations to produce an effective net free-water excretion.

                  Patients with SIADH often have urinary concentrations of osmotically effective cations that exceed the sodium concentration of 0.9% NaCl. In this case, use of isotonic sodium chloride can actually worsen hyponatremia. 31 These patients should be preferentially treated with 3% NaCl solution. The relatively high urinary sodium concentration in patients with SIADH is due to ECF expansion, which minimizes sodium reabsorption along the nephron. When the urine osmolality exceeds 300 mOsm/kg (300 mmol/kg), it is generally advisable to administer an IV loop diuretic, not only to increase solute-free water excretion but also to prevent volume overload, which can result from infusion of hypertonic sodium chloride. IV furosemide, 20–40 mg every 6 hours, or bumetanide, 0.5 to 1 mg/dose every 2 to 3 hours for two doses, is generally sufficient to prevent volume overload and to decrease the urinary concentration of osmotically active cations to less than 150 mEq/L (150 mmol/L). If intermittent loop diuretic doses are not sufficient to manage edema, then continuous infusions have been used. Furosemide, 20 to 40 mg, given IV, followed by a 10 to 40 mg/h infusion, or bumetanide 1 mg given IV followed by a 0.5 to 2 mg/h infusion have been used.

                  Patients with hypovolemic hypotonic hyponatremia can be treated with 0.9% NaCl solution. In contrast to patients with SIADH, patients with this condition avidly reabsorb sodium throughout the nephron because the effective circulating blood volume is decreased. Thus, the urine sodium concentration is often less than 20 mEq/L (20 mmol/L), substantially less than the sodium content of 0.9% NaCl solution. While the use of 3% NaCl solution will correct hyponatremia in these patients, it will not correct the hypovolemia thus, its use should be reserved for patients with severe symptoms requiring very rapid correction of the serum sodium concentration.

                  Acute hypervolemic hypotonic hyponatremia is particularly problematic to manage because the sodium and volume needed to minimize the risk of cerebral edema or seizures can worsen already compromised liver, heart, or kidney function. These patients generally should be treated with 3% NaCl and initiation of fluid (water) restriction. Loop diuretic therapy will also likely be required to facilitate urinary free water excretion.

                  Determination of a Sodium Chloride Infusion Regimen

                  Several methods for determining the correct sodium chloride solution infusion regimen for a patient with hyponatremia have been proposed. 1,2,18,29,32,33 These empiric approaches provide only an initial estimate of the correct infusion regimen. More complex equations have been derived, but improved outcomes using these equations have not been demonstrated. 18,29

                  One common approach to acute treatment of hyponatremia is to estimate the change in serum sodium concentration resulting from the infusion of 1 L of 3% or 0.9% NaCl solution. An example of this approach is shown in Box 34-1. Another method involves calculating the sodium deficit, then replacing one-third of the deficit in the first 6 hours with the remaining two thirds being replaced over the following 24 to 48 hours. Sodium deficit can be calculated using the following equation:

                  where Na D is the goal serum sodium (usually 125 to 130 mEq/L [125 to 130 mmol/L] to avoid too rapid correction) Na S is the patient’s current serum sodium concentration and, TBW is the patient’s current total body water calculated as shown in Box 34-1. The appropriate infusion volume for a given patient can then be estimated using the desired proportion of the estimated change that would result from a 1-L infusion or the amount of fluid needed to provide the calculated sodium deficit. The final step is to calculate an appropriate infusion rate for the calculated volume that will control the rate of increase of the serum sodium concentration to 6 to 12 mEq/L (6 to 12 mmol/L) in 24 hours (Box 34-1). Using desmopressin in combination with 3% NaCl solution to minimize the risk of treating hyponatremia has been suggested but is generally not recommended. 1

                  A Study of the Change in Sodium and Potassium Ion Concentrations in Stored Donor Blood and Their Effect on Electrolyte Balance of Recipients

                  Background. Preserved blood cells undergo progressive structural and functional changes that may affect their function, integrity, and viability after transfusion. The impact of transfusion of stored blood on potassium, sodium, or acid-base balance in the recipient may be complex, but information on it is inconsistent. This study therefore sought to determine the changes in the potassium and sodium levels in whole blood stored at 4°C for 28 days and clinical outcomes when such blood are transfused. Methods. Whole blood were taken into double CPDA-1 bags and 50 ml transferred into the satellite bags for the study. Electrolyte concentration determinations were made on each of the blood sample on days 0, 7, 14, 21, and 28 using the Vitalab Selectra Junior chemistry analyser. The remaining blood in the main bags was transfused after the 28-day period, and biochemical analysis carried out on the patients before and after the transfusion. One-way ANOVA was used for the analysis of variance between the weekly ion concentrations and independent sample Mann–Whitney U test for the data obtained from the patients. Results. The mean potassium level of all the samples started with a normal value of 3.45 mmol/L on the first day followed by a sharp rise to 9.40 mmol/L on day 7, 13.40 mmol/L on day 14, 14.60 mmol/L on day 21, and 15.40 mmol/L on day 28. Sodium on the other hand started with a high value of 148.4 mmol/L on day 0 and then reduced to 146.4 mmol/L on day 7, 140.8 mmol/L on day 14, 135.6 mmol/L on day 21, and a low value of 130.8 mmol/L on day 28. No adverse clinical outcomes were seen in patients after they were transfused with the blood. Conclusion. It can be deduced that potassium concentration in refrigerated blood increases, whilst sodium concentration reduces with time and when such blood is transfused, it may not result in any adverse clinical outcome.

                  1. Introduction

                  Blood transfusion is a vital life-saving measure and is administered under various pathological conditions. While blood component therapy has become the standard practice in the developed world, millions of whole blood are transfused annually in resource limited countries bringing into question the aspect of long-term storage and preservation [1]. The Food and Drug Administration (FDA) of the USA has set storage period of up to 35 days for blood anticoagulated in citrate phosphate dextrose adenine-1 (CPDA-1) which has been accepted in many countries worldwide [2]. It has however been postulated that when blood for transfusion has been stored for so long, it increases the risk of transfusion complications. This is because red blood cells (RBCs) undergo both structural and functional changes which can affect their posttransfusion overall viability and function [2].

                  Furthermore, the bioreactive substances such as histamine, lipids, and cytokines released by the “passenger” leucocytes that may exert direct effect on metabolic and physical changes associated with the senescence in cells are related to RBC storage medium lesion [3]. Other evidence also suggests that hypothermic storage of red blood cells may lead to reduced metabolism and energy demand, subsequently rendering ATP-dependent sodium potassium pump inoperative and ultimately leading to the free movement of sodium into the cells and potassium out of the cells [4]. Current research indicates that RBC hypothermic storage lesion is responsible for the association of blood transfusion with an increased length of stay in the hospital, increased infections, multiple organ system failure, and ultimately increased morbidity and mortality [5].

                  Hyperkalaemia is defined as a serum potassium level above the reference range, and arbitrary thresholds such as >5.00, >5.50, or >6.00 mmol/L are used to indicate degree of severity [6]. In situations where some comorbid conditions and other factors that interfere with the excretion of kidney potassium are seen, patients with chronic and advanced kidney diseases may be at high risk of increased plasma potassium [6]. It has also been seen that increased plasma potassium tend to be high in people with chronic kidney disease than in the general population [6]. This is because the kidneys play a major role in maintaining potassium homeostasis by matching potassium intake with potassium excretion. Any increase in serum potassium levels in people with severe hyperkalaemia especially the critically ill cases may result in serious complications and even death [7].

                  The major electrolyte in the extracellular fluid (ECF) is sodium which has about 98% of its total quantity in the ECF, and only about 2% is found in the intracellular fluid (ICF). Sodium has a reference range of 135.0–145.0 mmol/L. Subsequently, sodium levels above 145.0 mmol/L will result in hypernatremia, which is generally associated with a hyperosmolar state. When extracellular sodium is increased, it causes intracellular fluid to escape out of cells into extracellular spaces and this may result in cellular dehydration. On the other hand, a sodium level below 135.0 mmol/L is low and may result in a hyponatraemia condition [8]. This can cause cellular oedema which may affect the central nervous system as well as depression and cerebral oedema [9].

                  The impact of transfusion of stored blood on the potassium or sodium and acid-base balance in the recipient is very complex. It is, however, largely dependent on the volume of blood that is transfused, the rate of transfusion, the rate of citrate metabolism, and the changing state of the peripheral perfusion of the patient/recipient [10]. Failure to establish the apparent electrolyte changes has been found to be fatal in some instances [10]. This study therefore sought to determine the changes in the potassium and sodium levels in whole blood stored at 4°C and over 28-day period in order to eliminate a potential source of high potassium vs. low sodium for those with severe hyperkalaemia vs. hyponatremia requiring blood transfusion in resource-limited settings.

                  2. Materials and Methods

                  2.1. Ethics

                  Ethical approval was sought from the Ethics and Protocol Review Committee of the School of Biomedical and Allied Health Sciences before the study was carried out. Written informed consent was obtained from the blood donors and recipients before the study commenced. Written informed consent was also sought from the blood bank and the management of the Ho municipal hospital.

                  2.2. Procedure
                  2.2.1. Sampling Method

                  Thirty donated whole blood that have been screened using the protocol of the transfusion medicine unit of the hospital were used for the study. Approximately 450 ml of whole blood were taken into double citrate phosphate dextrose adenine-1 (CPDA-1) bags containing 63 ml of the anticoagulant bringing the total volume to approximately 513 ml. Each bag therefore had an average blood volume of about 500 ml. Following this, 50 ml of the thoroughly mixed blood were transferred into the satellite bags and stored at 4°C to be used for the study. The remaining blood (≈450 ml) in the main bags were transfused to 16 patients (3 received 3 units each, 8 received 2 units each, and 5 received 1 unit each) after the 28-day period. The transfusion took between 2 and 3 hours depending on the patient’s condition to complete. Five electrolyte concentration determinations were made on each of the 30 samples on day 0 (before storage), day 7, day 14, day 21, and day 28 of storage. Venous samples were taken from patients on the first day of transfusion, second and third days, and the average of the values obtained was used to compute the posttransfusion biochemical markers. On the respective days of analysis, 2 ml of the whole blood sample was placed into a gel separator tube and spun at 1500 rpm for 3 minutes to obtain plasma which was then analysed for sodium, potassium, and chloride using the ion-selective electrode of the Vitalab Selectra Junior chemistry analyser (Elitech Group, Netherland). Urea and creatinine were assayed using the ELITech chemistry reagents kit from ELITech Group Clinical Systems (Paris, France). The chloride, urea, and creatinine were assayed to rule out any undiagnosed kidney disease.

                  2.2.2. Data Analysis

                  The mean sodium and potassium ion concentrations for the weekly readings were determined from the stored blood and also the patient samples. The change in ion concentrations in reference to the baseline measurements was also determined. A paired t test was used to compare means of quantitative variables such as the relationship between the baseline sodium and potassium concentrations and the subsequent weekly measurements. The one-way ANOVA was used for analysis of variance between the weekly ion concentrations. The data from patients were expressed as median (Q1–Q3) and analysed using the independent sample Mann–Whitney U test.

                  3. Results

                  The mean plasma potassium level of all the samples in relation to the various days’ readings started with a normal average value of 3.45 mmol/L on the first day (day 0), followed by a sharp rise to 9.40 mmol/L up to day 7, followed by a similar increase to 13.40 mmol/L on day 14. The mean plasma potassium values however stabilised with slight increases from 14.60 mmol/L on day 21 to 15.40 mmol/L on day 28. The mean plasma sodium on the other hand started with a high value of 148.4 mmol/L on the first day and then reduced to 146.4 mmol/L on day 7, 140.8 mmol/L on day 14, 135.6 mmol/L on day 21, and a low value of 130.8 mmol/L on day 28 (Figure 1).

                  The trend line from the graph indicates that, with initial mean plasma potassium concentration of 2.63 mmol/L, there was a unit rise in plasma concentration of 2.88 mmol/L per week (7 days) whilst with an initial mean concentration of 154.19 mmol/L, plasma sodium decreased by 4.57 mmol/L per week (7 days). This means that there was a steady increase of plasma potassium and a steady decrease in plasma sodium as the whole blood aged in storage. The rate of increase of plasma potassium however slowed down with aging erythrocytes while the rate of decrease of plasma sodium remained the same from day 7 onward.

                  Table 1 shows the mean and standard deviation of potassium and sodium on each of the days examined.

                  The maximum change in potassium concentration over the storage period was 170.00% increase in the basal value of 3.45 mmol/L recorded in the first seven days. The increase however slowed down after day 21. In all, there was a total increase of 11.9 mmol/L (224.42%) from the day of blood donation to the 28 th day. The total change in the sodium between the start to the end of the study was 17.6 mmol/L (12.38%). The changes in concentrations of the analytes are presented in Table 2.

                  The one-way ANOVA was used for analysis of variance between the weekly ion concentrations (Table 3). As can be seen, the variation between groups and within groups for both analytes was significant.

                  A follow-up study was carried out where the units of blood under investigation were transfused at the end of the storage period and the patients monitored for clinical effects. The patients who received the transfusion were postoperative surgical patients with haemoglobin ≤8.0 g/dl. There was pretransfusion analysis of the analytes of interest before the posttransfusion analysis was carried out (Table 4).

                  4. Discussion

                  Blood transfusion as a therapeutic procedure can be harmful instead of saving lives, and this is because every transfusion is carried out with it a potential risk for the recipient [11]. The transfusion of whole blood with relatively high potassium concentration and low sodium concentration has been associated with worse outcomes in several populations of patients, including critically ill patients [12]. The blood transfusion services which have a duty of care towards blood recipients must therefore take steps to forestall these occurrences. Determining what happens during storage of blood with regards to sodium and potassium is therefore in line with such efforts. This study was therefore carried out to determine the changes in potassium and sodium ion concentrations in stored donor blood over a 28-day storage period and their effects on the electrolyte balance in recipients when such blood are transfused.

                  The results showed a general steady increase of plasma potassium with a steady decrease in plasma sodium over the 28-day storage period as the whole blood aged in the storage. The readings started with a normal average potassium value of 3.45 mmol/L on the first day which was followed by a sharp rise in value (9.40 mmol/L) on day 7. This was followed by a similar increase in value to 13.40 mmol/L on day 14. There values however stabilised with only slight increase to 14.60 mmol/L on day 21 and 15.40 mmol/L on day 28. The results of plasma sodium on the other hand started with a high value of 148.4 mmol/L on the first day and then reduced to 146.4 mmol/L on the 7 th day. This was followed by a decrease to 140.8 mmol/L on day 14, 135.6 mmol/L on day 21, and a low value of 130.8 mmol/L on the 28 th day. The rate of increase of plasma potassium however slowed down with aging whole blood while the rate of decrease of plasma sodium remained the same from day 7 onward. The trend line from Figure 1 indicates that with an initial mean plasma potassium concentration of 2.63 mmol/L, there was a unit rise in plasma concentration of 2.88 mmol/L per week whilst sodium had an initial mean concentration of 154.2 mmol/L that decreased by 4.6 mmol/L per week.

                  At the end of the 28 days, the units of stored blood were transfused and biochemical components of the patients examined to see if any moderation has taken place. Even though we observed a marginal increase in all analytes except sodium when basal values were compared with posttransfusion values, no significant changes were seen (Table 4). This finding supports the assertion that red blood cells can be stored for a period of 35 days or more, without much clinical adverse outcomes in patients. The chloride, serum urea, and creatinine in the blood of the transfused patients were estimated as a way of finding out if any of them had any renal impairment that could have bearings on the results of the potassium and sodium. It was realised that all three analytes showed marginal increases between the pre- and posttransfusion test results but the changes were not significant. Indicators of clinical outcome of the patients included length of hospital stay, mortality, loss of pallor, increased haemoglobin levels, and transfusion reaction or complications.

                  The results of the study agree with a similar study by Adias et al., which also recorded an increase in potassium concentration and decrease in sodium concentration during storage of blood [13]. Furthermore, the overall daily changes in both potassium and sodium agree with the work done by others that showed that the plasma level of potassium may increase by 0.5–1.0 mmol/L per day of refrigeration [14]. Other research works have also indicated that RBCs restore intracellular potassium by active transport after the transfused RBCs recover metabolic activity and adenosine-5′-triphosphate production [15]. However, paediatric patients and those with renal failure may not be able to handle this potassium load effectively and could lead to complication and even death if transfused with blood stored for longer periods. The lack of expected adverse clinical outcome might have been due to the insufficient blood units transfused which is a limitation in the study. Other limitations worthy of mention are the sample size that perhaps can be increased and the storage period that can be extended the in future work.

                  5. Conclusion

                  From the results of the study, it can be deduced that plasma potassium concentration in refrigerated blood increases with storage time whilst plasma sodium concentration decreases with storage time. However, the rate of increase and decrease may differ, and when this blood was transfused, no clinical adverse outcomes were seen in the patients. This work has added to other published works related to blood storage, and it is our belief that the results will go a long way to inform practitioners what goes on in stored blood and who can be given what blood as far as blood transfusion therapy is concerned as well as help address some of the storage issues associated with blood transfusion.

                  Data Availability

                  The data used to support the findings of this study are available from the corresponding author upon request.

                  Conflicts of Interest

                  The authors declare that they have no conflicts of interest.


                  We are grateful to the management of the school of biomedical and allied health sciences as well as the directors and laboratory managers of the Ho municipal hospital for their assistance in carrying out this study. The study was funded using the University of Ghana book and research allowances of the research team members.


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                  Copyright © 2019 Samuel Antwi-Baffour et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                  Psychological and Neurological Effects of Sodium Deficiency/Depletion

                  Several studies have been conducted looking at the psychological effects of sodium deficiency. In several studies, excessive sweating has been shown to cause fatigue, headaches, sleeplessness, and inability to concentrate. A case study of a miner also reported severe cramping in addition to fatigue as a result of extreme sodium loss.

                  The symptoms of chronic fatigue syndrome seem to be similar to those of having an excess loss of bodily fluids, which contain lots of sodium. Those symptoms include weakness, muscle pain, impaired memory and/or mental concentration, and insomnia. There was also another separate study that measured the correlation between extracellular dehydration and cognitive function in the elderly.

                  Some recent studies have also support for the argument that sodium depletion causes anhedonia, or a lack of pleasure in life.

                  Looking on a neural level, sodium deficiency causes changes in the neural wiring in the brain, leading to increased salt consumption. The changed neural wiring does not return to its previous state, which affects the “normal” salt consumption, increasing what the brain and body think is “normal.”

                  In essence, many studies that have been conducted have found that sodium deficiency has a relationship with cognitive dysfunction.

                  Effects of extracellular sodium concentration on null potential, conductance and open time of endplate channels

                  (i) Effects of extracellular sodium concentration, [Na]o, on endplate channel characteristics were investigated in voltage-clamped, glycerol- treated toad sartorius fibres. (ii) The relation between [Na]o (and [K]o) and acetylcholine null potential could be reasonably well fitted by the Goldman-Hodgkin-Katz type of equation, except when [Na]o was higher than normal. Anions had no significant effect on the null potential. (iii) Endplate channel open time (ז), whether measured from miniature endplate currents or from current fluctuations induced by iontophoresis of acetylcholine, varied inversely with [Na]o. The relation between ז -1 (=α) and [Na]o could be fitted by α = αmax [Na]o/ ( Km+|[Na]o) with a Km of 92 mM. (iv) Endplate conductance, measured at the peak of endplate currents or at the peak of spontaneous miniature endplate currents, increased nonlinearly with [Na]o. (v) Single channel conductance, γ, also increased nonlinearly with [Na]o. Experimental observations at -90 mV could be fitted by the relation γ = γmax [Na]o/ (Km+ [Na]o), giving values for γmax and Km of 47 pS and 146 mM respectively. Correcting channel conductance for the contribution from potassium ions gave values of γmax and Km of 78 pS and 423 mM respectively. (vi) The results are consistent with the hypothesis that binding sites for Na ions can modulate both channel lifetime and conductance and that these sites become saturated at higher sodium concentrations.

                  Extracellular Osmolarity and Cell Volume

                  We can now apply the principles learned about osmosis to cells, which meet all the criteria necessary to produce an osmotic flow of water across a membrane. Both the intracellular and extracellular fluids contain water, and cells are surrounded by a membrane that is very permeable to water but impermeable to many substances (nonpenetrating solutes).

                  About 85 percent of the extracellular solute particles are sodium and chloride ions, which can diffuse into the cell through protein channels in the plasma membrane or enter the cell during secondary active transport. As we have seen, however, the plasma membrane contains Na,K-ATPase pumps that actively move sodium ions out of the cell. Thus, sodium moves into cells and is pumped back out, behaving as if it never entered in the first place that is, extracellular sodium behaves like a nonpenetrating solute. Also, secondary active-transport pumps and the membrane potential move chloride ions out of cells as rapidly as they enter, with the result that extracellular chloride ions also behave as if they were nonpenetrating solutes.

                  Inside the cell, the major solute particles are potassium ions and a number of organic solutes. Most of the latter are large polar molecules unable to diffuse through the plasma membrane. Although potassium ions can diffuse out of a cell through potassium channels, they are actively transported back by the Na,K-ATPase pump. The net effect, as with extracellular sodium and chloride, is that potassium behaves as if it were a nonpenetrating solute, but in this case one confined to the intracellular fluid. Thus, sodium and chloride outside the cell and potassium and organic solutes inside the cell behave as nonpenetrating solutes on the two sides of the plasma membrane.

                  The osmolarity of the extracellular fluid is normally about 300 mOsm. Since water can diffuse across plasma membranes, the water in the intracellular and extracellular fluids will come to diffusion equilibrium. At equilibrium, therefore, the osmolarities of the

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                  Movement of Molecules Across Cell Membranes CHAPTER SIX

                  intracellular and extracellular fluids are the same— 300 mOsm. Changes in extracellular osmolarity can cause cells to shrink or swell as a result of the movements of water across the plasma membrane.

                  If cells are placed in a solution of nonpenetrating solutes having an osmolarity of 300 mOsm, they will neither swell nor shrink since the water concentrations in the intra- and extracellular fluid are the same, and the solutes cannot leave or enter. Such solutions are said to be isotonic (Figure 6-20), defined as having the same concentration of nonpenetrating solutes as normal extracellular fluid. Solutions containing less than 300 mOsm of nonpenetrating solutes (hypotonic solutions) cause cells to swell because water diffuses into the cell from its higher concentration in the extracellular fluid. Solutions containing greater than 300 mOsm of nonpenetrating solutes (hypertonic solutions) cause cells to shrink as water diffuses out of the cell into the fluid with the lower water concentration. Note that the concentration of nonpenetrating solutes in a solution, not the total osmolarity, determines its tonicity—hypotonic, isotonic, or hypertonic. Penetrating solutes do not contribute to the tonicity of a solution.

                  In contrast, another set of terms—isoosmotic, hyperosmotic, and hypoosmotic—denotes simply the osmolarity of a solution relative to that of normal extracellular fluid without regard to whether the solute is penetrating or nonpenetrating. The two sets of terms are therefore not synonymous. For example, a 1-L solution containing 300 mOsmol of nonpenetrating NaCl and 100 mOsmol of urea, which can cross plasma membranes, would have a total osmolarity of 400 mOsm and would be hyperosmotic. It would, however, also be an isotonic solution, producing no change in the equilibrium volume of cells immersed in it. The reason is that urea will diffuse into the cells and reach the same concentration as the urea in the extracellular solution, and thus both the intracellular and extracellular solutions will have the same osmolarity (400 mOsm). Therefore, there will be no difference in the water concentration across the membrane and thus no change in cell volume.

                  Table 6-3 provides a comparison of the various terms used to describe the osmolarity and tonicity of solutions. All hypoosmotic solutions are also hypotonic, whereas a hyperosmotic solution can be hypertonic, isotonic, or hypotonic.

                  Hypertonic solution Isotonic solution Hypotonic solution

                  Cell shrinks No change in cell volume Cell swells

                  Changes in cell volume produced by hypertonic, isotonic, and hypotonic solutions.

                  Hypertonic solution Isotonic solution Hypotonic solution

                  Cell shrinks No change in cell volume Cell swells

                  Changes in cell volume produced by hypertonic, isotonic, and hypotonic solutions.

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                  PART ONE Basic Cell Functions

                  6. Movement of Molecules Across Cell Membranes

                  © The McGraw-Hill Companies, 2001

                  TABLE 6-3 Terms Referring to Both the Osmolarity and Tonicity of Solutions

                  TABLE 6-3 Terms Referring to Both the Osmolarity and Tonicity of Solutions

                  A solution containing 300 mOsmol/L of nonpenetrating solutes, regardless of the concentration of membrane-penetrating solutes that may be present

                  A solution containing greater than 300 mOsmol/L of nonpenetrating solutes, regardless of the concentration of membrane-penetrating solutes that may be present

                  A solution containing less than 300 mOsmol/L of nonpenetrating solutes, regardless of the concentration of membrane-penetrating solutes that may be present

                  A solution containing 300 mOsmol/L of solute, regardless of its composition of membrane-penetrating and nonpenetrating solutes

                  A solution containing greater than 300 mOsmol/L of solutes, regardless of the composition of membrane-penetrating and nonpenetrating solutes

                  A solution containing less than 300 mOsmol/L of solutes, regardless of the composition of membrane-penetrating and nonpenetrating solutes

                  As we shall see in Chapter 16, one of the major functions of the kidneys is to regulate the excretion of water in the urine so that the osmolarity of the extracellular fluid remains nearly constant in spite of variations in salt and water intake and loss, thereby preventing damage to cells from excessive swelling or shrinkage.

                  The tonicity of solutions injected into the body is of great importance in medicine. Such solutions usually consist of an isotonic solution of NaCl (150 mM NaCl—isotonic saline) or an isotonic solution of glucose (5% dextrose solution). Injecting a drug dissolved in such solutions does not produce changes in cell volume, whereas injection of the same drug dissolved in pure water, a hypotonic solution, would produce cell swelling, perhaps to the point that plasma membranes would rupture, destroying cells.