SODIUM PHYSIOLOGY

Sodium is the most abundant positive ion of the ECF compartment and is critical in determining the extracellular and intracellular osmolality. The distribution of sodium between plasma and interstitial fluid is roughly 5 or 6 to 1 at equilibrium, and the distribution equilibrium time is 15 to 20 minutes. Extracellular sodium balance is determined by sodium intake relative to sodium excretion. Most humans consume far more salt than they need. In normal, healthy individuals, the kidney's main function in sodium balance is excretion of excess sodium.

Sodium requirements vary with age. For infants born before 32 weeks' gestation, requirements are 3 mEq/kg/day, and at term, requirements are 2 to 3 mEq/kg/day.^[2]

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Normally, as much as 10 mL of urine can be formed for each milliosmole of solute excreted by the kidney. Normal kidneys respond to a volume challenge with diuresis and to a sodium load with natriuresis; if there is decreased sodium intake or volume depletion, the kidney responds with antinatriuresis and antidiuresis (e.g., a patient undergoing surgery may excrete only 1.2 to 1.6 mOsm/mL of solute^[3] ). In various pathophysiologic processes, abnormally high or low urinary sodium excretion can occur and are outlined in the following text.

Many of the factors that control tubular sodium reabsorption are affected during the perioperative period, including hemodynamic and physical factors, hormonal factors, and renal sympathetic nerve activity. The balance of Starling forces is responsible for sodium and water transport across peritubular capillary walls. The net pressure in the peritubular capillaries is about 10 mm Hg in favor of uptake of reabsorbed fluid. Volume expansion with isotonic saline decreases plasma protein concentration and therefore lowers colloid osmotic pressure in peritubular capillaries.

The renin-angiotensin system (RAS) is involved in control of blood pressure and blood volume along with the sympathetic nervous system, the kinin-kallikrein system, and arginine vasopressin. The RAS plays a role in sodium homeostasis and renal function, particularly under stress conditions. The RAS may be initiated by decreases in blood pressure in the renal artery, by decreases in sodium delivery to the macula densa, or by sympathetic nervous system activation. In response, renin is synthesized from its precursor, prorenin, and secreted by the juxtaglomerular cells of the kidney. Renin, an aspartyl-protease (similar to pepsin and cathepsin), cleaves its substrate, angiotensinogen, which is an α₂ -globulin, to generate the decapeptide angiotensin I. Although renin is mostly produced by the kidney, renin isoenzymes have been found in many tissues, including brain, adrenals, vascular beds, uterus, and placenta.^{[4] [5] [6] [7]} The gene for human renin has been cloned. Angiotensinogen levels are increased after nephrectomy; by estrogens, thyroid hormones, and glucocorticoids; and during angiotensin I-converting enzyme inhibition.^{[8] [9] [10] [11]}

Angiotensin I is rapidly converted to the octapeptide angiotensin II by angiotensin I-converting enzyme or by an endopeptidase. The pulmonary circulation appears to be the major site of angiotensin-converting enzyme (ACE) activity, although ACE is also found in the vascular endothelium of the heart, kidney, adrenal cortex, testes, and brain.^[12]

Angiotensin II is a potent vasopressor that stimulates aldosterone secretion through the adrenal cortex. Angiotensin II has a vagal inhibitory effect and causes ganglionic stimulation.^{[13] [14] [15]} Angiotensin II partially suppresses renin secretion by a direct effect on the juxtaglomerular cells.^{[16] [17]} Studies suggest that angiotensin II may stimulate a local increase of adenosine, a known inhibitor of renin release and may therefore participate in a negative-feedback loop whereby angiotensin II limits its own biosynthesis. ^[18] Angiotensin II is degraded in the plasma to the carboxyl-terminal heptapeptide angiotensin III or the amino-terminal heptapeptide angiotensin (1–7), both of which appear to be biologically active.^{[19] [20]} A decline in blood pressure, a decrease in sodium delivery to the macula densa, or sympathetic stimulation may activate the RAS, generating angiotensin II. This results in an increase in blood pressure and sodium retention caused by enhanced aldosterone secretion. The RAS does not have an active role in maintaining blood pressure in the normal, sodium-replete, intact individual. Hydrostatic forces act to maintain a stable glomerular filling pressure. This affects venous return, cardiac output, and blood pressure. Superimposed on this mechanism under stress conditions are a variety of neurohumoral control systems, including the sympathetic nervous system, ADH, atrial natriuretic hormone, and prostaglandins ( Table 46-3 ).

The anesthesiologist should understand that nitroprusside-induced hypotension is associated with increases in renin activity and marked elevations in the plasma concentrations of ADH, which are not seen with trimethaphan-induced blood pressure reductions.^{[21] [22]} Conversely, propranolol administration during nitroprusside-induced hypotension prevents rises in plasma renin activity.^[23]

Hyponatremia

Hyponatremia, typically defined as a plasma sodium concentration less than 135 mEq/L, can result from excessive

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Normal ADH secretion is mediated by an increase in plasma osmolality higher than 280 mOsm or a decrease in effective circulating volume. Other factors that result in release of ADH include pain, sympathetic stimulation, and nausea. After release, ADH binds to the V2 receptors in the medullary collecting ducts. ADH increases the water permeability of these segments by facilitating the fusion of water channels to the apical cell membrane.^{[24] [25]} When ascertaining the cause of hyponatremia, serum osmolality must be obtained to determine whether the hyponatremia reflects true hypotonicity. This gives insight into the underlying cause of low sodium levels. Hyponatremia can occur in patients who are hypotonic, normotonic, or hypertonic. Patients' volume status must be evaluated to further understand the underlying problem leading to abnormalities in sodium physiology ( Table 46-4 ).

Factitious hyponatremia can be seen in hyperlipidemia (i.e., chylomicronemia) or hyperproteinemia. Hyperosmolality resulting from nonsodium molecules (e.g., hyperglycemia, mannitol overdose) draws water from the intracellular space to dilute the extracellular sodium concentration. Significant decreases in total-body sodium most commonly occur from diuretic administration. This is a case of normotonic hyponatremia.

Transurethral prostate (TURP) syndrome is a recognized cause of hyponatremia. TURP syndrome is caused by intravascular absorption of irrigation solution, which typically contains glycine.^[26] The absorption of free water causes hyponatremia because of the dilution of serum sodium. TURP syndrome is a case of true hypotonic hyponatremia.

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is associated with a number of processes, including pulmonary and cranial disorders, and with several neoplasms, particularly oat cell carcinoma of the lung. Sympathetic activation (i.e., postoperative pain) also can lead to significantly increased levels of ADH in the absence of volume constriction. SIADH may occur with administration of various drugs, including oral hypoglycemics, tricyclic antidepressants, and diuretics. ^[27] High levels of vasopressin are secreted intermittently at an abnormally low threshold or continuously despite low osmolality. The presence of hyponatremia plus a urine osmolality higher than maximal dilution confirms the diagnosis. In patients with SIADH, the urinary sodium concentration usually exceeds 30 mEq/L, the fractional excretion of sodium is greater than 1%, and the serum uric acid is reduced. Patients with SIADH exhibit a characteristic response to water restriction; a 2- to 3-kg weight loss is accompanied by correction of hyponatremia and cessation of salt wasting over 2 to 3 days.^[28] This is another example of true hypotonic hyponatremia.

Hyponatremia also occurs in mixed disorders, in which nonosmotic ADH release and reductions in the rate of urinary sodium excretion blunt urinary diluting capacity. This can occur in advanced volume contraction, intractable heart failure, and advanced hepatic cirrhosis with ascites.

The signs and symptoms associated with hyponatremia are critical for the anesthesiologist, particularly for TURP syndrome managed with regional anesthesia. Nausea, vomiting, visual disturbances, depressed level of consciousness, agitation, confusion, coma, seizures, muscle cramps, weakness, or myoclonus can be seen, depending on the level of hyponatremia. Cerebral edema occurs at or below a serum level of 123 mEq/L, and cardiac symptoms occur at 100 mEq/L. Hyponatremia associated with increased intravascular volume can result in pulmonary edema, hypertension, and heart failure.^[29]

Because TURP syndrome is a case of water overload, the treatment should be water restriction. A loop diuretic may be added to facilitate free water excretion.

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If needed, the dose of sodium required to correct a deficit may be calculated using the following formula:

Dose (mEq) = (Weight (kg) × (140 − [Na⁺ ]) (mEq/L)) × 0.6

The optimal rate of correction appears to be 0.6 to 1 mmol/L/hour until the sodium concentration is 125 mEq/L, and then correction proceeds at a slower rate. One half the deficit can be administered over the first 8 hours and the next half over 1 to 3 days if symptoms remit. Potential complications of hypertonic saline include cerebral edema and central pontine myelinolysis. However, the appropriate treatment of hyponatremia, particularly in patients with neurologic symptoms, continues to be an area of controversy. Sodium concentration should be monitored every 1 to 2 hours during rapid correction. Menstruant female patients are at greater risk for developing significant neurologic sequelae after hyponatremia. Ayus and colleagues^[31] found that despite equal incidence of postoperative hyponatremia among men and women, 97% of those with permanent brain damage were women, and 75% of those were of reproductive age. The mechanism of this gender difference is unknown; however, a potential explanation involves alterations in the brain's adaptive processes to hyponatremia. Estrogens appear to alter the function of the Na⁺ /K^- -ATPase in the rat brain, which could alter the brain's compensatory mechanisms for hyponatremia.^[32] Several agents that interfere with urine concentration at the collecting duct, including lithium and demeclocycline, have been used to manage chronic hyponatremia. ADH antagonists and the administration of urea as an osmotic diuretic are under investigation, although additional studies are needed.

Rapid treatment of hyponatremia can lead to central pontine myelinolysis. Management of hyponatremia involves elimination of the underlying condition when possible (e.g., stop the TURP as soon as possible). The use of normal saline (308 mOsm/L) alone may make the

TABLE 46-5 -- Major causes of hyponatremia

Causes	Mechanisms
Pseudohyponatremia (normal osmolality)	Hyperlipidemia, hyperproteinemia
Hyponatremia with increased effective osmolality	Hyperglycemia, mannitol accumulation
True hyponatremia with normal effective osmolality	Gamma-globulins, lithium, trishydroxymethylaminomethane (THAM)
True hyponatremia with edema (sodium excess): low effective osmolality	Congestive heart failure, nephrotic syndrome, cirrhosis of the liver, idiopathic edema, hypoalbuminemia due to malnutrition
True hyponatremia (sodium depletion): low effective osmolality	Renal or extrarenal wasting
Hyponatremia with normal or expanded effective arterial volume	Syndrome of inappropriate antidiuretic hormone (SIADH) secretion, water intoxication due to primary polydipsia, water overload in advanced renal failure, vascular or inflammatory renal disease
Reduced sodium delivery to the diluting segment	Starvation; myxedema?
Adapted from Oh M, Carrol H: Disorders of sodium metabolism: Hypernatremia and hyponatremia. Crit Care Med 20:94, 1992; and from Andreoli TE: Disorders of fluid volume, electrolyte, and acid-base balance. In Wyngaarden JB, Smith LH Jr (eds): Cecil Textbook of Medicine, 17th ed. Philadelphia, WB Saunders, 1985, p. 525.

hyponatremia worse, depending on the patient's serum and urine osmolality.^[33] Severe coma or seizures can be managed with one or more approaches: 3% hypertonic saline (513 mEq/L), fluid restriction, or furosemide.^[34] The most likely cause of postoperative hyponatremia is the SIADH secretion ( Table 46-5 ).