Hyponatremic Syndromes

Hyponatremic Syndromes

Symposium on Renal Therapeutics Hyponatremic Syndromes Murray L. Levin, M.D.~' It is now well-recognized that patients may become hyponatremic in a...

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Symposium on Renal Therapeutics

Hyponatremic Syndromes Murray L. Levin,

M.D.~'

It is now well-recognized that patients may become hyponatremic in a wide variety of clinical situations. Hyponatremia may develop in circumstances as widely disparate as diarrhea with severe salt and water depletion and end-stage congestive heart failure, as a complication of altered salt and water homeostasis. Because of the markedly varied group of patients in whom hyponatremia may develop, the clinician must understand their modes of clinical presentation and the pathophysiologic processes involved prior to the initiation of appropriate therapy. Before discussing therapeutic approaches, however, it is necessary to define those physiologic factors which may contribute to hyponatremia in the vast majority of such patients and then to discuss those historical, physical, and laboratory data which enable the physician to select a rational approach to treatment.

PATHOGENESIS OF HYPONATREMIA The term hyponatremia (serum sodium less than 136 mEq per lit er) refers only to the concentration of sodium in serum or plasma. It carries no connotation regarding the absolute quantity of total body sodium. A low serum sodium concentration may be found in patients with low, normal, or elevated total body sodium content. Although the concentration of sodium in the extracellular fluid is the major determinant of extracellular osmolality, its effect is translated to intracellular water because of transmembrane osmolar equilibration. Additionally, intracellular potassium concentration affects transmembrane water movement, since potassium is the major intracellular cation. Therefore, serum sodium concentration is best ap-

*Associate Professor of Medicine, Northwestern University Medical School, Chief, Medical

Service, Veterans Administration Lakeside Hospital, Chicago, Illinois

Medical Clinics of North America - Vol. 62, No. 6, November 1978

1257

1258

MURRAY

L. LEVIN

proximated by the amount of total body sodium plus total body potassium dissolved in total body water as follows: N

_ TENa+TEK a,. TBW

where Na,. is the serum sodium concentration, TENa the total body isotopic ally exchangeable sodium, TEK = total body isotopically exchangeable potassium, and TBW the total body water. 8 Any alteration in any or all of the variables on the right side of this equation will result in the anticipated change in the variable on the left, the serum sodium concentration. POTASSIUM DEPLETION

There is a group of patients who become hyponatremic when they undergo acute diuretic-induced potassium depletion.lO These patients may have acute sequestration of sodium within cells. 16. 17 However, there is evidence for sustained secretion of antidiuretic hormone, perhaps in relation to hypo thalamic intracellular hypertonicity from the intracellular sodium shifts. An alternative explanation is that acute potassium loss results in intracellular hypotonicity causing a water shift out of hypothalaInic cells which, in turn, results in cell shrinkage and an outpouring of antidiuretic hormone. Water may also shift out of other cells, as well, causing a dilution of serum sodium. Regardless of whichever mechanism truly exists in these patients, the sustained secretion of antidiuretic hormone is unresponsive to volume repletion and to hypotonicity, but is abolished by potassium chloride replenishment. The above type of deranged serum sodium concentration is the major one known to be caused by changes in total body potassium. Most other patients with hyponatremia have disturbed relationships between total body sodium and total body water; i.e., the ratio of total body sodium to total body water is lower than normal. INADEQUATE WATER EXCRETION

Regardless of the total body sodium content, in the vast majority of cases, hyponatreInia results from an inability to excrete enough of ingested water (oral or intravenous) to maintain isotonicity. 4. 12 Thus, if we think of a patient as a beaker (Fig. 1, top) containing 1 liter of isotonic saline and having no insensible losses of water, the patient can not become hyponatreInic. However, if our patientlbeaker imbibes 1 liter of water, he will now contain 2 liters of fluid. Before mixing (Fig. 1, second row), 1 liter will have an osmolality of 300 mOsm per kg, and 1 liter will have an osmolality of zero. Thus, the added lit er of pure water is in excess of the amount of water needed for the mainte-

1259

HYPONATREMIC SYNDROMES

"""""} ~ ...........

/

',..........

I Liter

'::.:-:-:.:.:.:.:.:-:.'

300 mOsm

2 Liter 150 mO_m

Figure 1. The effects of addition of water with and without the ability to excrete free water. See text for discussion.

nance of isotonicity. Any quantity of water ingested or excreted in excess of the amount necessary to maintain isotonicity in the ingested solution or excreted urine is termed free water. If the 2 liters mix and remain in the beaker, the resultant osmolality will be 150 mOsm per kg and the serum sodium will be 75 mEq per liter. The patient/beaker will, then, suffer from rather profound hyponatremia. However, if a spigot is placed in the beaker in such a fashion as to drain off the liter of pure water (Fig. 1, third row), the beaker/patient is protected from hypotonicity. The human kidney functions in such a fashion to allow patients to excrete free (excess) water and retain a normal omolality and serum sodium (Fig. 1, bottom beaker). Patients become hyponatremic when they are unable to excrete ingested free water or when their urine plus insensible water losses have a combined osmolality which is greater than the osmolality of ingested (oral and/or intravenous) solutions. The inability to clear ingested free water is related to several variables, all of which impinge on renal function. Decreases in effective extracellular fluid volume and glomerular filtration rate as well as high titers of antidiuretic hormone will all decrease the ability of the kidney to excrete free water. In general, the renal responses in many cases of hyponatremia are directed toward the preservation or restoration of fluid volume even at the expense of extracellular tonicity. Perfusion of vital organs becomes paramount. The mechanisms by which the kidneys respond to the various hemodynamic and hormonal stimuli listed above offer adequate explanations for the generation and preservation of hyponatremia. An understanding, then, of the pathophysiology of the various hyponatremic

1260

M URRA Y L. LEVIN

states and their effects on renal function offers the potential for a diagnostic and therapeutic approach to these patients based on clinical and laboratory data. As stated above, the major pathophysiologic factor common to all cases of pathologic hyponatremia is an inability to excrete free water in sufficient quantities to maintain normal tonicity. The factors potentially responsible for this inability are summarized below. Decreased Volume of Tubular Contents Reaching Tubular Diluting Sites REDUCED GLOMERULAR FILTRATION RATE (GFR). If the glomerular filtration rate is reduced because of volume depletion, inadequate cardiac output, or renal disease, even if the reabsorption of salt and water remains normal in the proximal tubule arid descending loop of Henle, the absolute quantities of solute and water reaching the renal diluting sites will be decreased. An example of this effect is seen in the following:

GFR

Normal State

Decreased GFR

120 ml/min

60 ml/min

Per cent filtered water reabsorbed in proximal tubule and descending limb

90%

Amount of H 20 reaching diluting sites

12 ml/min

90%

6 ml/min

Reduction of the glomerular filtration rate has imposed an absolute limitation upon the kidneys' ability to create a large volume of dilute urine in the ascending limb of Henle's loop and distal nephron. INCREASED PROXIMAL TUBULAR REABSORPTION. The mechanisms responsible for increased proximal tubular reabsorption in states associated with renal underperfusion are as follows. Renal vasoconstriction is thought to occur in the efferent arterioles to maintain filtration pressure in the glomerular capillaries. 20 Thus, even if renal plasma flow falls, filtration rate is preserved until severe underperfusion occurs, resulting in an elevated filtration fraction (the ratio of glomerular filtration rate to renal plasma flow). For example, if renal plasma flow is 500 ml per min (as might occur in a small adult), 100 ml are usually ultrafiltered into Bowman's space under normal circumstances. Since the ultrafiltration process leaves the protein which had been present in the 500 ml remaining in the capillaries, the protein entering the efferent arterioles is suspended in 400 ml of water and is, therefore, concentrated by 5/4 (Fig. 2, left side). However, if renal plasma flow is reduced to 300 ml per min but the filtration rate is maintained at 100 ml per min (Fig. 2, right side), the protein will be

1261

HYPONATREMIC SYNDROMES

AFFERENT ARTERIOLE PROXIMAL TUBULE

EFFERENT ARTERIOLE

RPF GFR

-

Efferent

Flow

Efferent

Protein

.

500 100

RPF

-

GFR

-

400

Efferent

300 100 200

Flow

Efferent _ Protein -

5/4 Afferent

3/2 Afferent

Peritubular Oncotic Pressure Peritubular Hydrostatic

Pressure

Figure 2. The effects of reduction in renal plasma flow with concurrent maintenance of filtration rate on postglomerular protein concentration. See text for discussion.

concentrated by a factor of 3/2. The elevation of protein in the peritubular capillaries in combination with the lowered hydraulic pressure and plasma flow within the capillaries (a consequence of reduced flow) results in increased reabsorption of fluid from the cortical interstitium surrounding the proximal tubules. 5 This results in a reduction of fluid backflux from interstitium to tubular lumen. 15 Since net reabsorption from the proximal tubule is the resultant of two opposing forces, active reabsorption and passive backflux, the reduction of passive backflux secondary to elevated peritubular capillary oncotic pressure and reduced hydraulic pressure results in a net increase in proximal reabsorption. Even if glomerular filtration rate is maintained, increased proximal reabsorption can lead to decreased delivery of solute and water to the diluting sites (ascending loop of Henle and early distal tubule) as the following exemplifies.

GFR

Normal

Increased Proximal Reabsorption

120 ml/min

120 ml/min

Per cent Reabsorption in proximal tubule

60

90

Ml of urine entering Henle's loop

48

12

Maximum possible urine volume reaching ascending limb if papilla is 4 x concentration of cortex

12

3

1262

MURRAY

L.

LEVIN

Thus, if the percentage of water extracted from the descending limb in both states is the same, the absolute volume of water reaching the diluting sites in the sample associated with increased proximal reabsorption is only 25 per cent of normal. Therefore, either a reduced glomerular filtration rate or increased proximal tubular reabsorption can severely limit a patient's ability to excrete a water load. If both of these phenomena occur concurrently, the ability to form an appreciable volume of dilute urine is markedly restricted. Elevated Circulating Levels of Antidiuretic Hormone When so-called effective vascular volume (arterial filling) is reduced by 10 per cent or more, the threshhold for hypothalamicopituitary release of antidiuretic hormone is made more sensitive, and, for every rise in serum osmolality, antidiuretic hormone output is increased over the normal response. 21 Thus, even when hypotonicity is present, volume depletion of sufficient degree will induce antidiuretic hormone secretion. It should be stressed that this release, although inappropriate to plasma osmolality, is quite appropriate to the patient's volume requirements. In summary, decreased delivery of solute and water to diluting sites because of hemodynamic changes plus high antidiuretic hormone titers serve to decrease free water excretion. The combination of these factors causes a low urine volume with high osmolality. The retained water remains in the patient to dilute the patient's solutes and cause hyponatremia. SIGNS AND SYMPTOMS OF HYPONATREMIA Muscle cramps may be prominent and especially involve the lower extreInities and abdomen. Adynamic ileus, abdominal bloating and pain may be present. Signs and symptoms of nervous system derangement are prominent and can be quite dramatic. Their severity depends upon both the severity of the hyponatremia and the rapidity with which the patient becomes hyponatremic. 1 Patients who become hyponatremic rapidly tend to develop lethargy, disorientation, abnormal reflexes (including transient Babinski's sign), coma, and seizures at higher serum sodium concentrations. It is rare to see coma and seizures in chronic hyponatremia above serum sodium of 115 mEq per liter. However, fatal cerebral edema can ensue at higher sodium levels if the development of hyponatremia is rapid. CLINICAL STATES ASSOCIATED WITH HYPONATREMIA The clinical states associated with hyponatremia can be conveniently divided into those in which patients have total body volume depletion, those in which there is total body excess volume (edema) but diminished effective vascular volume, and those in which total body sodium is close to normal, but body water is present in great excess.

1263

HYPONATREMIC SYNDROMES

CLINICAL EVALUATION

Because of this variability in clinical presentation and the marked differences in therapeutic approach to these three different groups, the initial approach to the hyponatremic individual must be clinical. A careful history and physical examination must be performed. Important historical points to be sought are the following: history of vomiting, di arrhe a, fistula drainage, "third spacing," diuretic therapy, excess perspiration, medications (especially those which result in increased action of antidiuretic hormone), congestive heart failure, cirrhosis, nephrotic syndrome, central nervous system disease, malignancy, porphyria, pulmonary disease, or endocrine disease. Physical examination should be directed toward those signs which allow the physician to discriminate between the three groups of patients. Thus, skin turgor, presence or absence of perspiration, postural hypotension, edema, venous congestion, pulmonary congestion, and ascites should all be examined for carefully. Following the history and physical examination, several simple laboratory tests should be obtained. Obviously the serum sodium concentration has already been determined for the diagnosis of hyponatremia to have been made. Other serum electrolytes, urea nitrogen (BUN or SUN), creatinine, osmolality and albumin are helpful. Urine osmolality sodium, chloride, and potassium should be obtained on a "spot" basis. It is generally not necessary to obtain 24 hour urine collections prior to initiating therapy, but "spot" urine electrolyte and osmolality determinations are essential. Diuretics should not be administered prior to obtaining the urine. Only 2 to 3 ml of urine are required. SPECIFIC CLINICAL CONDITIONS

States Associated with Primary Volume Depletion but with Subsequent Water Retention These states are characterized by a history of volume loss such as vomiting, diarrhea, diuresis, fistula drainage, urinary losses from adrenal or renal insufficiency, or excess perspiration. None of these states is associated with solute loss in excess of water loss per se. In fact, many are associated with greater water loss and may present as hypernatremia if the patient does not have access to water. However, volume depletion induces thirst,ll and, if no salt is ingested with ingested water, the patients become hyponatremic because they are unable to excrete ingested free water. The free water ingested is distributed throughout total body water while the original volume loss had been predominantly from the extracellular space. Thus, more than twice the original volume loss must be ingested to restore extracellular volume if only water is taken by the patient or administered by the physician. The physical signs are those of hypovolemia, especially postural h otension diminished ers iration and oor skin h dration. The

t t

Diuretics

It

t

AdTfillal Insufficiency

Salt-Wasting Renal Disease

t

(SUN)

NITROGEN

SERUM UREA

Gastrointestinal Losses

SODIUM

SERUM

t

nl-> t

t

nl->t

nl-> t

NINE (CR)

CREATI-

>20

variable

t >20

t >20

eR

SUN/

>20

>20

>20

<10

SODIUM

URINE

Table 1. Hyponatremia Associated with Primary Volume Depletion But Subsequent Water Retention URINE

variable

250-350

>400

>400

OSMOLALITY

....

Z

<: >-<

~ t"" to

><

~

~ C :>J

Cl) ~

NI

HYPONATREMIC SYNDROMES

1265

reasons for the inability to excrete the free water load are those summarized earlier. Decreased glomerular filtration rate, increased proximal reabsorption secondary to decreased effective volume, possible increased collecting duct reabsorption of both salt and water,23.24 and increased antidiuretic hormone titer, if sufficient volume stimulus exists, all reduce the ability to excrete free water. In fact, water is usually reabsorbed maximally in the collecting ducts, and a highly concentrated urine is found despite systemic hypotonicity. Additionally, because of the overall tubular avidity for most solutes, urea and uric acid are re absorbed in excess, leading to elevated serum urea nitrogen and uric acid. Creatinine levels are maintained normal so long as the glomerular filtration rate is normal, but may become elevated if underperfusion becomes sufficiently severe. Thus, a high serum urea nitrogen/creatinine ratio usually exists. Clinical examples with expected blood and urine values are shown in Table 1. The primary treatment of hyponatremia of this type consists of salt replacement (oral if mild, intravenous if severe) plus treatment of the primary disease. If severe signs and symptoms of hyponatremia are present (coma or seizures), hypertonic saline should be administered as described below.

States Characterized by Edema with Overabundance of Water Patients with these clinical states exhibit edema and/or ascites. The genesis of their hyponatremia is very similar to that of the group described above. Renal underperfusion with restfitant changes in glomerular filtration rate and proximal reabsorption combined with high antidiuretic hormone titers result in free water retention. 3. 15 One can look upon the pathogenesis of hyponatremia in this group as representing the extreme end of the same pathophysiologic phenomena responsible for the patients' edema. However, the role of increased proximal reabsorption in cirrhosis and the nephrotic syndrome has been questioned recently. 13. 18 Nonetheless, free water ingestion is frequently increased in these patients because of poor appetite for solids, increased thirst, and physician-ordered dietary salt restriction while their ability to excrete free water is impaired. It should be stressed that these patients do not develop hyponatremia until the disease process is far advanced or they are challenged with unusual water loads. Clinical examples of these states with expected serum and urine values are shown in Table 2. Treatment of the hyponatremia in these patients is complicated and may be quite dangerous. Initial attempts should be directed at treating the primary disease. Obviously, this is easier said than done since these patients have ordinarily been seen by physicians for a considerable time already. However, the optimal dosage of digitalis should be obtained in heart failure, hepatotoxins (especially ethanol) should be removed in cirrhotics, renal disease causing the nephrotic syndrome should be treated, and thyroid hormone should be carefully administered in myxedema. Since all these patients have vast excesses of total body water, water intake should be restricted to levels below urine volume plus insensible loss. Sodium intake should also be restricted.

t

variable (depends on primary renal disease) nl->t

variable

nl-> t

nl-> t

t

(formation)

nl or s1I

(t urea)

CREATININE (CR)

variable

±t

t

CR

SUN/

URINE*

URINE

variable

variable

<25

>400

<10

<10

>400

OSMOLALITY

<10

SODIUM

*Values for urine sodium and osmolality given are those expected when patients are not receiving diuretics.

Myxedema

Nephrotic Syndrome

Hepatic Cirrhosis

t

(SUN)

SODIUM

t

NITROGEN

SERUM

SERUM UREA

Hyponatremia Associated with Edema with Overabundance of Water

Congestive Heart Failure

Table 2.

51

<:

l'J

r

r

><

~

~

c:

Q'l Q'l

N)

-

HYPONATREMIC SYNDROMES

1267

Thiazide diuretics should be avoided in these hyponatremic patients since they interfere with diluting capacity, but not with concentrating capacity. In general, if diuretics are to be used in these patients (they may be very dangerous in cirrhosis), loop-acting diuretics are the agents of choice. These agents abolish both conentrating and diluting capacities, but tend to allow a slightly dilute urine to be passed, thus modestly enhancing free water excretion. 22 Albumin ~nf\l­ sions may be helpful in acutely expanding blood volumes inpatients with cirrhosis or the nephrotic syndrome. However, their value is limited since the albumin may be transuded into ascites or excreted in the urine, depending on the existing disease state. Finally, many patients with heart failure have responded to fluid removal by hypertonic peritoneal dialysis when all else has failed. It ,has been thought that, by lowering total body salt and water, venous return to the heart is diminished, and the cardiac output curve shifted to a more favorable one.

Hyponatremic States Associated with Relatively Normal Total Body Sodium but with Increased Total Body Water There are two clinical states characterized by hyponatremia with relatively normal total body sodium and increased total body water. N either signs of volume depletion nor signs of edema are present in these patients. The first of these is psychogenic water drinking. It may be very difficult to obtain a history of vastly increased water intake. However, these individuals have a low serum urea nitrogen, relatively low urinary sodium, very high urine volumes when hyponatremic, and a maximally dilute urine. The latter finding distinguishes this group of patients from all others with hyponatremia. The second group of hyponatremic patients characterized by relatively normal total body sodium and elevated total body water is one which has attracted considerable interest over the last 20 years. These patients have the syndrome of inappropriate secretion of antidiuretic hormone. 2 The primary disorder in these patients is the continued secretion or potentiated pharmacologic action of antidiuretic hormone either by a tumor, by the hypothalamic-pituitary axis, or by pharmacologic interaction. 2 , 19 The secretion is truly inappropriate since neither primary physiologic stimulus to secretion of antidiuretic hormone (hypertonicity and hypovolemia) is present. Causes of inappropriate secretion of antidiuretic hormone are summarized in Table 3. 2 The continued secretion or enhanced activity of ADH causes continuous renal water reabsorption in excess of normal requirements. The retained water dilutes all body solutes (including sodium) and expands volume as well. The resulting volume expansion causes increased GFR, decreased proximal tubular and collecting duct reabsorption, and possible decreased aldosterone secretion, all of which may result in a mild natriuresis. Thus, these patients demonstrate higher than expected urinary sodium concentrations. Additionally, because of dilution and, perhaps, decreased tubular reabsorption, both serum urea and uric acid are decreased.

1268

MURRAY

Table 3. Classification of Causes of Syndrome of Inappropriate Secretion of Antidiuretic Hormone Tumors with Aberrant Production of Antidiuretic Hormone 1. Lung Carcinoma 2. Carcinoma of Duodenum 3. Carcinoma of Pancreas 4. Thymoma 5. (?) Hodgkin's Disease, Carcinoma of Ureter Endogenous Antidiuretic Hormone 1. Pulmonary Disease a. Pneumonia b. Cavitation (aspergillosis) c. Tuberculosis 2. Central Nervous System Disorders a. Meningitis b. Head injury c. Brain abscess d. Encephalitis e. Guillain-Barre syndrome f. Subarachnoid hemorrhage g. Acute intermittent porphyria h. Brain tumor 3. Endocrine Disease - Questionable a. Addison's disease b. Myxedema c. Hypopituitarism 4. Disorders in which SIADH may Play a Part a. Cardiac failure b. Cirrhosis whith ascites c. The syndrome of juxtaglomerular hyperplasia with hypokalemia alkalosis and normal blood pressure d. Hyponatremia of positive-pressure breathing 5. "Idiopathic" SIADH Drugs 1. Vasopressin 2. Oxytocin 3. Vincristine, cyclophosphamide 4. Chlorpropamide and degradation products 5. Thiazides when associated with hypokalemia 6. Clofibrate 7. Tegretal 8. Nicotine 9. Tricyclic antidepressants

L.

LEVIN

t

(SUN)

t

NITROGEN

SERUM

SODIUM

SERUM UREA

nlorslt

nl or sI t

NINE (CR)

CREATI-

t

CR

SUN/

URINE

>20'"

<15

SODIUM

Psychogenic Water Drinking and SIADH

*Urine sodium is usually elevated above 30 if patients have normal salt intake.

SIADH

Psychogenic Water Drinking

Table 4. URINE

t(usually above plasma)

<100

OSMOLALITY

.... (,C)

O'l

Nl

'"

o

~ a::l'l

~

rJl

r;

a::

l'l

I"

'"

o Z >

~

:::r:

1270

MURRAY

L.

LEVIN

Expected laboratory values in psychogenic water drinking and SIADH are as shown in Table 4. TREATMENT. The primary treatment of both groups of patients is the restriction of water intake to levels below the sum of urine volume plus insensible loss. The combination of furosemide diuresis plus hourly replacement of urinary sodium losses with hypertonic saline has proved useful in patients with severe symptomatic hyponatremia. '4 However, the latter should be undertaken carefully with rigid control of sodium infusion keyed to the measured sodium loss. Ready access to rapid measurement of serum and urine sodium concentrations is mandatory. Long-term management of patients with inappropriate secretion of antidiuretic hormone can be accomplished by water restriction, but, if this proves impractical, demeclocycline, 300 mg every 8 hours, is quite useful in inhibiting the action of antidiuretic hormone at the tubular level. 6.7 Lithium carbonate is a somewhat more toxic alternative. 25 Obviously, if the patient has been taking pharmacologic agents which can cause inappropriate secretion of antidiuretic hormone, the drugs should be withdrawn. Osmotically Induced Hyponatremia The extracellular presence of osmotically active substances such as glucose (in the absence of insulin) or mannitol will exert an osmotic effect to draw water out of cells, causing hyponatremia. Serum sodium will fall 1 mEq per liter every 3 millimoles of glucose or mannitol present in excess per liter of serum. 9 Serum osmolality under these circumstances is either normal or high because of the glucose or mannitol. Factitious Hyponatremia When serum sodium concentration is determined, it is determined by introducing whole serum into a flame photometer. However, the sodium is confined to the serum water and is excluded from suspended protein and lipoprotein. If the protein and/or lipoprotein components of serum should be increased, they will occupy a larger than normal fraction of serum, and the sodium-containing aqueous phase will be diminished. Thus, even if the sodium concentration in the aqueous phase is normal, total sodium per unit of serum will be decreased, and the sodium concentration in serum will be read as being low. Under these circumstances serum osmolality is normal since osmolality is measured by depression of the freezing point of serum water. There are no symptoms of hyponatremia since there is no osmotic stimulus to cause water shifts into cells.

TREATMENT OF PATIENTS WITH SEVERE HYPONATREMIA If the hyponatremic patient is severely symptomatic (coma, seizures), and the symptoms are thought to be secondary to the hypona-

1271

HYPONATREMIC SYNDROMES

tremia with resultant brain swelling, emergency measures must be taken to prevent permanent brain damage or death. Disagreement exists regarding the speed with which hypertonic saline should be administered under these conditions because of the fear of causing tearing of bridging veins with too rapid reduction of brain swelling. It is the author's custom to administer sufficient 3 per cent sodium chloride to cause a 50 per cent correction in serum sodium toward normal over a 2 to 3 hour period. The remaining correction can be accomplished by water restriction in the edematous group of patients and in those with psychogenic water-drinking or inappropriate secretion of antidiuretic hormone. Those patients suffering from salt deficits can be repleted with isotonic saline. The excess free water still retained by the patient will be excreted when volume (saline) has been repleted. For example, if a 70 kg patient has a seizure with a serum sodium of 105 mEq per liter, the amount of 3 per cent saline to be administered is calculated as follows: Final Desired Serum Sodium Observed Serum Sodium

135 mEq/L 105 mEq/L

Difference 30 mEq/L 1/2 Difference 15 mEq/L 15 x 42 (total body water)= 630 mEq/L 3% saline contains 514 mEq NaiL Therefore 630/514 = 1.23liters of 3 per cent saline.

Another very effective method for correction of hyponatremia is the initiation of diuresis with 20 mg of furosemide administered intravenously as mentioned.14 Furosemide can be administered hourly in 10 to 20 mg increments. Three or 5 per cent saline can then be administered to replace hourly measured sodium losses. The author has successfully treated patients with heart failure with hyponatremic seizures by replacing only one-half the sodium losses in conjunction with frequent measurement of pulmonary capillary wedge pressure to ensure that neither diuresis nor replacement are too rapid. Obviously, larger doses of furosemide may be necessary to initiate diuresis in these patients, and such therapy should be carried out in a coronary care unit or intensive care unit. Finally, it should be mentioned that hemodialysis may be used quite effectively to reverse hyponatremia. REFERENCES 1. Arieff, A. 1., and Guisado, R.: Effect on the central nervous system of hypernatremic

and hyponatremic states. Kidney 1nt., 10:104-116,1976. 2. Bartter, F. C.: The syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Disease-a-Month, November, 1973. 3. Bell, N. H., Schedl, H. P., and Bartter, F. C.: An explanation for abnormal water retention and hypoosmolality in congestive heart failure. Amer. J. Med., 36:351-360, 1964. 4. Bed, T., Anderson, R. J., McDonald, K. M., et al.: Clinical disorders of water metabolism. Kidney 1nt., 10:117-132, 1976.

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5. Brenner, B. M., and Troy, J. L.: Postglomerular vascular protein concentration: Evidence for a causal role in governing fiuid reabsorption and glomerulotubular balance by the renal proximal tubule. J. Clin. Invest., 50:336-349, 1971. 6. Cherrill, D. A., Stote, R. M., Birge, J. R., et al.: Demeclocycline treatment in the syndrome of inappropriate antidiuretic hormone secretion. Ann. Intern. Med., 83:654-656, 1975. 7. DeTroyer, A., and Demanet, J. c.: Correction of antidiuresis by demecJocycJine. New Eng. J. Med., 293:915-918, 1975. 8. Edelman, I. S., Leibman, J., O'Meara, M. P., et al.: Interrelations between serum sodium concentration, serum osmolarity and total exchangeable sodium, total exchangeable potassium and total body water. J. Clin. Invest., 37:1236-1256, 1958. 9. Feig, P. V., andMcCurdy, D. K.: The hypertonic state. New Eng. J. Med., 297:14441454,1977. 10. Fichman, M. P., Vorherr, H., Kleeman, C. R., et al.: Diuretic-induced hyponatremia. Ann. Intern. Med., 75:853-863,1971. 11. Fitzsimmons, J. T.: The physiological basis of thirst. Kidney Int., 10:3-11,1976. 12. Fuisz, R. E.: Hyponatremia. Medicine, 42(2):149-170, 1963. 13. Grausz, H., Lieberman, R., and Earley, L.: Effect of plasma albumin on sodium reabsorption in patients with nephrotic syndrome. Kidney Int., 1 :47-54, 1972. 14. Hantman, 0., Rossier, B., Zohlman, R., et al.: Rapid correction of hyponatremia in the syndrome of inappropriate secretion of antidiuretic hormone. Ann. Intern. Med., 78:870-875, 1973.

15. Humes, H. D., Gottlieb, M. N., and Brenner, B. M.: The kidney in congestive heart failure. In Brenner, B. M., and Stein, J. H., eds. Sodium and Water Homeostasis. New York, Churchill Livingstone, 1978, pp. 51-72. 16. Levin, M. L., Rector, F. C., Jr., and Seldin, D. W.: Effects of potassium and ouabain on sodium transport in human red bells. Amer. J. Physiol., 214: 1328-1331, 1968. 17. Levin, M. L., Rector, F. C., Jr., and Seldin, D. W.: The effects of chronic hypokalemia, hyponatremia, and acid-base alterations upon erythrocyte sodium transport. Clin. ScL, 43:251-263, 1972. 18. Levy, M.: Sodium retention in dogs with cirrhosis and ascites: Efferent mechanisms. Amer. J. Physiol., 233:F586-F592, 1977. 19. Miller, M., and Moses, A. M.: Drug-induced states of impaired water excretion. Kidney Int., 10:96-103, 1976. 20. Myers, B. D., Deen, W. M., and Brenner, B. M.: Effects of norepinephrine and angiotensin II on the determinants of glomerular ultrafiltration and proximal tubule fluid reabsorption in the rat. Circ. Res., 37:101-110, 1975. 21. Robertson, G. L., Shelton, R. L., and· Athar, S.: The osmoregulation of vasopressin. Kidney Int., 10:25-37, 1976. 22. Schrier, R. W., Lehman, D., Zacherle, B., et al.: Effect of furosemide on free water excretion in edematous patients with hyponatremia. Kidney Int., 3:30-34, 1974. 23. Sonnenberg, H.: Proximal and distal tubular function in salt-deprived and in saltloaded deoxycorticosterone acetate-escaped rats. J. Clin. Invest., 52:263-272, 1973. 24. Stein, J. H., and Reineck, H. J.: Effect of alterations in extra-cellular fluid volume on segmental sodium transport. Physiol. Rev., 55:127-141,1975. 25. White, M. G., and Fetner, C. D.: Treatment of the syndrome of inappropriate secretion of antidiuretic hormone with lithium carbonate. New Eng. J. Med., 292:390-392, 1975. Medical Service VA Lakeside Hospital 333 East Huron Chicago, Illinois 60611