Renal Function and Disorders of Water and Sodium Balance Part 2

Disorder of Water Excess: Hyponatremia

Hyponatremia simply means a low plasma sodium concentration. In most cases, hyponatremia is associated with a low plasma osmolality level and body fluids that are too dilute (hy-potonic hyponatremia). However, there are exceptions to this rule [see Differential Diagnosis for Hyponatremia, below].

Pathogenesis of hyponatremia

Hypotonic hyponatremia results from two basic mechanisms, individually or together: (1) massive water intake, exceeding the capacity to excrete electrolyte-free water, or (2) impaired water excretion. Normally, the capacity for water excretion is rather large. In the absence of vasopressin, urine osmolality falls to approximately 50 mOsm/kg. A typical United States diet provides 600 to 900 mOsm of electrolytes and urea that must be excreted each day. At this rate of solute excretion, the volume of maximally dilute urine equals 12 to 18 L. Water intake can occasionally exceed the normal excretory capacity, primarily in psychotic patients who frantically ingest gallons of water over a few hours14 and in very heavy beer drinkers who ingest large volumes of fluid but take in small amounts of salt and protein.15 More commonly, hyponatremia occurs in patients with a diminished ability to excrete free water.8,12

Impaired Water Excretion

Water excretion is obviously compromised in severe renal failure; oliguric patients become hyponatremic if they are given too much water. However, most cases of hyponatremia occur in patients whose normal kidneys are unable to excrete maximally dilute urine.

Table 2 Control of Body Fluid Volumes

	Saltwater Balance	Electrolyte-Free Water Balance
		Day to Day	Emergency Backup
Regulated variable	Extracellular volume Vascular fullness	Cell volume	Arterial filling
Clinical indicator	Blood pressure Edema	Plasma sodium concentration	Blood pressure Edema
Sensors	Baroreceptors, atrial volume receptors	Hypothalamic osmoreceptors	Baroreceptors, atrial volume receptors
Mediators	Renin-angiotensin-aldosterone system Sympathetic nervous system Atrial natriuretic peptide Starling forces in peritubular capillaries	Antidiuretic hormone (arginine vasopressin) Thirst	Antidiuretic hormone (arginine vasopressin) Thirst
Affected variable	Urinary sodium excretion	Urine osmolality Water intake	Urine osmolality Water intake

A pathologically low plasma sodium concentration occurs when water is taken in at a time when renal diluting mechanisms are not functioning maximally because either (1) diuretics or tubular transport defects are blocking sodium reabsorption in the renal diluting segments or (2) ADH levels are elevated.

Nonosmotic Release of Vasopressin

Vasopressin is a water-retaining hormone that is released when water is needed. Because hypotonic hyponatremia normally inhibits vasopressin secretion, detectable vasopressin in a patient who is hyponatremic indicates that a nonosmotic stimulus for vasopressin release must be present. Vasopressin action increases the urine osmolality, which can be thought of as a bioassay for the hormone.

Hemodynamic stimuli for vasopressin Hypovolemia, heart failure, and cirrhosis are the most common nonosmotic stimuli for ADH secretion.16-18 The hemodynamic abnormalities that stimulate vasopressin release also promote sodium reabsorption by the renal tubules; thus, these conditions result in both sodium and water retention.

Inappropriate antidiuretic hormone secretion Nonosmot-ic release of vasopressin without a hemodynamic stimulus to account for it is considered "inappropriate." Patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) retain water because of nonosmotic release of vasopressin and abnormal thirst mechanisms but have no abnormality in sodium balance, evidence of volume depletion, or tendency to form edema; in the steady state, sodium excretion matches intake.8,12,19, 20 Because of water retention, SIADH causes mild, subclinical volume expansion. Any additional volume expansion is met by a brisk increase in urinary sodium excretion.

Reset osmostat Reset osmostat is a variant of SIADH, commonly seen in patients with chronic, debilitating illness; it is also a characteristic of normal pregnancy. Patients with this condition are able to dilute their urine normally but at a lower set point than in normal individuals. Such patients are thus mildly hyponatremic, but unlike other patients with SIADH, they are not predisposed to progressive water retention and do not require dietary water restriction or other measures used to treat chronic hyponatremia.11 Reset osmostat can, however, be seen in malignancies, and like other causes of SIADH, it requires a diagnostic evaluation to determine its cause.

Urinary Electrolyte Losses: Desalination and Hyponatremia

If the urine is concentrated, urinary sodium and potassium losses can contribute to the pathogenesis of hyponatremia. The plasma sodium concentration can be reduced either by loss of sodium or potassium or by water gain. However, to lower the plasma sodium concentration, electrolytes must be lost in urine that has a higher electrolyte concentration than plasma. The combination of high vasopressin levels (which concentrate the urine) and a high rate of sodium and potassium excretion can yield hypertonic urine capable of generating free water, which in essence desalinates the plasma.

Figure 3 Graph depicts the normal relation between plasma vasopressin levels and urine osmolality (black line) and the plasma sodium concentration (blue line). Plasma vasopressin levels change within minutes in response to changes in plasma sodium, and urine osmolality changes within minutes in response to changes in vasopressin levels. When hydration reduces the plasma sodium level below 135 mEq/L, plasma vasopressin becomes undetectable and the urine becomes maximally dilute (osmolality, 50 mOsm/kg). Between sodium concentrations of 135 and 142 mEq/L, vasopressin levels are linearly related to the plasma sodium, causing nearly a 100 mOsm/kg increase in urine osmolality for every 0.5 mEq/L increase in sodium concentration. Above a plasma sodium concentration of 142 mEq/L, the urine is maximally concentrated; increased water intake, mediated by thirst, then becomes the major defense against progressive hypernatremia.

Differential diagnosis for hyponatremia

Several conditions can lower the plasma sodium concentration without causing hypotonicity and are referred to as nonhy-potonic hyponatremia [see Table 3]. The diagnostic and therapeutic approach to these conditions differs fundamentally from the approach to hypotonic hyponatremia. Thus, it is important that nonhypotonic hyponatremia be excluded whenever a low plasma sodium concentration is encountered.

Hyperglycemic Hyponatremia

Hyperglycemia lowers the plasma sodium concentration; in the absence of insulin, glucose is an effective osmole that holds water in the extracellular space, diluting extracellular sodium. A variety of correction factors have been offered to quantify this effect.22 However, a precise correction factor is probably unobtainable because in practice, hyperglycemia develops, in part, from the ingestion of glucose with water and resolves, in part, from the urinary excretion of glucose with water.23 As a rough estimate, the serum sodium concentration decreases 2 mEq/L for every 100 mg/dl increase in blood glucose.

Exogenous solutes such as mannitol and maltose (a sugar contained in intravenous immunoglobulin preparations) are confined to the extracellular space and have an effect on the plasma sodium concentration similar to that of hyperglycemia. When the clinical setting suggests that these solutes might be responsible for hyponatremia, their presence can be confirmed by measuring the plasma osmolality and comparing it with the calculated value to identify an osmolar gap [see Osmolality, above].

Postprostatectomy Syndrome and Hysteroscopic

Hyponatremia

Irrigants containing mannitol, sorbitol, or glycine are used for endoscopic transurethral and intrauterine procedures [see Table 3].2,24 Occasionally, several liters of irrigant may be absorbed sys-temically, reducing the plasma sodium in a matter of minutes. Immediately after surgery, the serum sodium concentration is much lower than would be anticipated, because the electrolyte-free solution is initially confined to the extracellular space. Glycine, the most commonly used irrigant in the United States, is metabolized to ammonia and eventually to urea and glucose. Hyperammonemia may be responsible for most of the symptoms in patients with postprostatectomy syndrome and hystero-scopic hyponatremia, and glycine itself has direct neuroinhibito-ry effects and may cause hypotension, bradycardia, and visual disturbances.

Pseudohyponatremia

High plasma concentrations of lipid or protein cause mild nonhypotonic hyponatremia because of an artifact of laboratory measurement [see Table 3].2,11,25 With extremely high concentrations of triglycerides (enough to give serum a milky appearance), hypercholesterolemia with lipoprotein X from obstructive or cholestatic jaundice, or very high serum protein levels (from multiple myeloma or Waldenstrom macroglobulinemia), plasma water may constitute a smaller fraction of the plasma sample than normal, which can result in an underestimate of the "true" sodium concentration. The plasma osmolality and the sodium concentration in plasma water (as measured in an undiluted sample by a sodium-sensitive electrode) are unaffected. There are no symptoms, and no therapy is required.

Acute hyponatremia (water intoxication)

The term water intoxication was coined in the early 1920s to describe a neurologic syndrome that develops when large volumes of water are retained within a relatively short period of time (< 48 hours). The syndrome is often referred to as acute hyponatremia.

Etiology

Acute hyponatremia develops when water intake is high and electrolyte-free water excretion is impaired. Potentially, hypona-tremia can develop rapidly in any patient predisposed to water retention who takes in a large volume of water in a short period of time. However, this is likely to occur in a limited number of settings [see Table 4], and such instances account for most cases of severe symptomatic hyponatremia and for most of the recorded fatalities.

Table 3 Causes of Nonhypotonic Hyponatremia

Condition	Plasma Osmolality	Pathogenesis	Therapeutic Implications
Hyperglycemia	High	Extracellular glucose osmotically draws water into the ECF, diluting extracellular sodium	During treatment of hyperglycemia, anticipate 3 mEq/L increase in serum sodium for every 200 mg/dl reduction in blood sugar
Intravenous hypertonic mannitol therapy	High	Water shift from ICF to ECF as with hyperglycemia	Mannitol is rapidly excreted when renal function is normal
Intravenous y-globulin therapy	High	Maltose present in solution acts like mannitol	Measure plasma osmolality when hypo-natremia is suspected
Irrigant absorption (prostatectomy or intrauterine surgery)	Normal or low (when hypo-osmolar irrig-ants are used)	Absorbed solute—mannitol, sorbitol, or glycine (most common)—initially confined to ECF, causing severe hypo-natremia but little change in plasma osmolality	Mannitol is rapidly excreted; sorbitol is metabolized, causing late-onset hypo-tonic hyponatremia; glycine is neurotox-ic and causes transient blindness and is metabolized to ammonia, causing en-cephalopathy; consider hemodialysis
Pseudohyponatremia (severe hyperlipidemia, multiple myeloma, macroglobulinemia)	Normal	Laboratory artifact; plasma water constitutes a smaller fraction of the plasma sample, causing a more serious underestimate of the true sodium concentration	Suspect when serum is lactescent; compare measured plasma osmolality with calculated osmolality or measure plasma sodium with direct-reading sodium electrode

ECF—extracellular fluid

ICF—intracellular fluid

Table 4 Causes and Treatment of Acute Hyponatremia

Causes	Pathogenesis	Effect of Treatment	Recommendations
Postoperative stress*	Vasopressin is secreted in response to surgical stress for 2 or more days; free water from hypotonic I.V. fluids is retained and sodium and potassium are excreted in urine at high concentrations	Normal saline ineffective for correction—administered sodium is excreted in concentrated urine, "desalinating" isotonic fluid and causing water retention	Avoid hypotonic fluid (e.g., D5W, 0.45% saline) and excessive volumes of isotonic fluid (lactated Ringer solution or 0.9% saline) after surgery; treat symptomatic hyponatremia with 3% saline and furosemide
Oxytocin	Used in obstetrics to induce labor; direct antidiuretic effect of drug mimics SIADH; free water from I.V. fluids retained	Urine becomes dilute when oxytocin is discontinued	Avoid administration of oxytocin in or with hypotonic fluids; treat hyponatremia by discontinuing drug
Cyclophosphamide	Drug has antidiuretic effect that persists for as long as 12 hours; patients are encouraged to drink large volumes of water to prevent chemically induced cystitis	Normal saline ineffective for correction as in other causes of persistent SIADH	Treat symptomatic hyponatremia with 3% saline and furosemide
Psychotic self-induced water intoxication	Extreme polydipsia (> 1 L/hr) common in patients with severe psychosis; retained water causes hyponatremia by late afternoon or evening, and water diuresis restores normonatre-mia by morning	Normal ability to dilute urine in most patients so hyponatremia self-corrects when water intake stops; some patients have vaso-pressin release (often transient) from stress, smoking, or medications (e.g., carbamazepine)	Monitor diurnal weight in institutionalized patients for early detection; avoid antidiuretic medications; treat hyponatre-mia with water restriction; use hypertonic saline and furosemide for occasional patient with SIADH
Marathon running	Extracellular volume depletion caused by saltwater losses from sweating and possibly stress are nonosmotic stimuli for vaso-pressin secretion; large volumes of sugar water consumed during race are retained	Isotonic saline restores ability to dilute urine	3% saline without furosemide for seizures; isotonic saline and water restriction for more moderate symptoms
Ecstasy (methylenedioxymetham-phetamine [MDMA]) use	Excessive fluid intake and inappropriate antidiuretic hormone secretion, induced by MDMA, is implicated	Isotonic saline ineffective; self-correction typical but may be delayed	Hypertonic saline for severe symptoms

*Excluding irrigant absorption syndromes [see Table 3].

D5W—5% dextrose in water

SIADH—syndrome of inappropriate antidiuretic hormone

Postoperative hyponatremia Vasopressin is released immediately after surgical procedures in what appears to be a stress response [see Table 4].21,27 Particularly during the first 24 hours, the concentration of urinary cations (sodium plus potassium) may greatly exceed the plasma sodium concentration. As a result, even isotonic fluids may be "desalinated" and can lower the plasma sodium concentration.21 Thus, all hypotonic fluids and excessive amounts of isotonic fluids should be avoided after surgery. As noted, endoscopic prostatectomy and intrauterine procedures can cause hyponatremia if the irrigant used in the procedures is absorbed systemically. The management of irrig-ant absorption syndromes differs from that of other causes of postoperative hyponatremia [see Postprostatectomy Syndrome and Hysteroscopic Hyponatremia, above].

Oxytocin infusions Oxytocin, which is used in obstetrics to induce labor, has a direct antidiuretic effect. If the drug is administered in 5% dextrose in water (D5W), which was formerly a common practice, symptomatic hyponatremia may emerge after the infusion of less than 3 L of fluid [see Table 4].11 Termination of the infusion permits a water diuresis and correction of hyponatremia; however, the syndrome is best avoided by using isotonic saline as a vehicle for the drug.

Cyclophosphamide infusion Intravenous cyclophopha-mide impairs water excretion by an unknown mechanism.28 The antidiuretic effect of the drug begins 4 to 12 hours after injection and persists for as long as 12 hours. Patients receiving cy-clophosphamide are particularly susceptible to hyponatremia because they are encouraged to drink large volumes of water to prevent chemically induced cystitis [see Table 4].

Psychotic self-induced water intoxication Extreme poly-dipsia is relatively common in patients with psychiatric illnesses, particularly schizophrenia, and it may lead to symptomatic hyponatremia [see Table 4].14 Daily intake of 10 to 15 L has been documented, and much of the intake may take place over a few hours. Many patients become hyponatremic in the late afternoon and evening; however, water diuresis typically restores normonatremia by the following morning. Occasionally, individuals drink enough water to produce seizures. By monitoring diurnal changes in body weight, water intoxication can be recognized before the onset of severe neurologic symptoms. Transient release of vasopressin (most commonly provoked by nausea and vomiting) may contribute to water retention. There is little evidence that any of the major tranquilizers has a significant antidiuretic effect; however, carbamazepine, an anticonvulsant, enhances sensitivity to vasopressin.

Water intoxication during exercise Hyponatremia is disturbingly common in nonelite marathon runners; it is associated with slow finishing times and with excessive consumption of fluids while running, as evidenced by substantial weight gain.29,30 Severe symptomatic hyponatremia has mostly been reported after participation in marathons or ultramarathons, but symptomatic hyponatremia may also occur after recreational running and military fitness training.

Water intoxication from the drug ecstasy During the 1990s, 3,4-methylenedioxymethamphetamine (MDMA, or ecstasy) gained widespread popularity as a recreational drug taken at dances.31 When malignant hyperthermia was recognized as a complication associated with this drug, MDMA users were advised in underground magazines and the lay press to drink plenty of fluids. Subsequently, acute water intoxication emerged as a potentially lethal complication of the drug [see Table 4]. Excessive fluid intake and SIADH, induced by MDMA, have been implicated.

Diagnosis

Symptoms of water intoxication include headaches, weakness, nervousness, and vomiting, progressing to disorientation, delirium, tremulousness, and ultimately convulsions and coma.12,26 The pupils are often dilated, and bilateral Babinski signs may be present. On occasion, patients may present with hemiparesis, mimicking a cerebrovascular accident. The syndrome reflects cerebral edema, which can lead to herniation of the brain and death. Clinical findings may emerge explosively. Complaints of headache and mild confusion may be followed within hours by respiratory arrest and, in some cases, neuro-genic pulmonary edema. For reasons that remain obscure, almost all reported fatalities from acute postoperative hypona-tremia have been in women (usually of childbearing age) and young children. Fatal cases of acute hyponatremia from other etiologies have been recorded in men and women.

Acute hyponatremia should be suspected in any patient who has unexplained neurologic symptoms, especially in psychiatric patients, marathon runners, users of ecstasy, and patients receiving hypotonic fluids intravenously (e.g., after surgery). Serum electrolyte levels should be obtained immediately. In the proper setting, a tentative diagnosis of water intoxication is advisable when symptoms develop in a patient whose serum sodium concentration is lower than 130 mEq/L (provided that causes of nonhypotonic hyponatremia have been excluded). Although severe neurologic symptoms do not usually appear until the sodium level has fallen below 120 mEq/L, some patients (particularly young women and children) may be unusually susceptible to brain edema when they become acutely hypona-tremic; in rare cases, fatalities have been reported at plasma sodium concentrations between 120 and 128 mEq/L.21,27

Elderly patients can tolerate acute hyponatremia better than the young, because brain atrophy affords more room for brain cell swelling. The same water load per kilogram of body weight can cause a much more severe degree of acute hyponatremia when water is ingested rapidly, especially if the person has a much smaller muscle mass (the reservoir for a water load that limits brain cell swelling). When the serum sodium concentration is falling rapidly, the arterial sodium concentration (to which the brain responds) may be lower than the venous sodium concentration (which is measured in most clinical electrolyte assays).

Computed tomography demonstrates cerebral edema in severe cases of water intoxication, and it rules out other potential explanations for neurologic findings. However, when symptoms are severe, therapy should not be delayed while imaging studies are being obtained.

Treatment

Free-water intake should be stopped immediately whenever water intoxication is suspected. Hypertonic saline is the treatment of choice for water-intoxicated patients who cannot auto-correct their electrolyte disturbance, including patients with neurogenic pulmonary edema.26,27 Each 1 ml of 3% saline contains 0.5 mEq of sodium. Because there are approximately 0.5 L of body water for every 1 kg of body weight, 1 ml of 3% saline per 1 kg of body weight can be expected to increase the plasma sodium concentration by 1 mEq/L. For patients with severe neurologic symptoms, an infusion of 3% saline at 1 to 2 ml/kg/hr will increase the plasma sodium concentration by approximately 1 to 2 mEq/L/hr, a rate that is considered appropriate for initial therapy. Hypertonic saline is best infused in 100 ml containers to avoid inadvertently giving an excessive dose. Concurrent administration of a loop diuretic (furosemide, bumetanide, or torsemide) is advisable. The diuretic prevents volume overload and, by blocking sodium reabsorption in the loop of Henle, impedes the formation of concentrated urine.

The goal of therapy in acute hyponatremia is to decrease the severity of cerebral edema and to stop seizures. A 4 to 6 mEq/L increase in plasma sodium concentration is usually sufficient to accomplish these goals. Thus, the plasma sodium concentration should be monitored frequently during therapy, and emergency treatment with hypertonic saline should be stopped after 2 to 3 hours. Once initial therapy with high-dose hypertonic saline has been completed, more conservative measures should be substituted to gradually return the plasma sodium concentration to normal. To avoid complications from excessive correction of hy-ponatremia, the plasma sodium concentration should not be intentionally increased by more than 12 mEq/L during the first day of therapy or by more than 6 mEq/L/day thereafter.