DISEASE OF THE MONTH

The Hyponatremic Patient: Practical Focus on Therapy

SANDRA M. LAURIAT and TOMAS BERLDepartment of Medicine, University of Colorado School of Medicine, Denver, Colorado.

Physicians must consider a number of factors when formulat-

ing a therapeutic plan for patients with hyponatremia. A pru-

dent assessment of the clinical situation would include the

following questions. Is the patient symptomatic? Is the dura-

tion of the hyponatremia known? Does the patient have risk

factors that could lead to neurological sequelae? Only after this

assessment is complete can a rational and safe therapeutic plan

be implemented. This article will focus on these questions and

outline specific therapeutic options as dictated by varying

clinical settings.

Is the Patient Symptomatic?The therapeutic approach to the hyponatremic patient is

determined more by the presence or absence of symptoms than

by the absolute level of serum sodium. At any level of serum

sodium, the development of symptoms is often related to the

rate at which the serum sodium has fallen. Although there is

considerable individual variation, symptoms are more likely to

occur when the serum sodium declines rapidly (at a rate of 0.5

mEq/L per h on greater) (1,2). Conversely, the absence of

symptoms in patients with severe hyponatremia strongly sug-

gests that the serum sodium has declined slowly over a longertime frame.

The signs and symptoms of hyponatremia are diverse and

nonspecific. As such, only a high index of suspicion in the

appropriate clinical setting allows the signs and symptoms to

be recognized as a consequence of the electrolyte disorder.

These symptoms occur more commonly, but not exclusively,

when the serum sodium has fallen below 125 mEqIL. The most

common symptoms are nausea, emesis, and headaches, fol-

lowed by seizures, respiratory arrest, and coma. The signs and

symptoms observed in 15 patients who developed hyponatne-

mia are summarized in Figure 1 (3). These clinical manifesta-

tions occur as a result of hypotonicity, which causes water to

equilibrate across cell membranes as it moves down an osmotic

gradient from the extracellular fluid into cells. As cellular

swelling ensues, the limits set by a rigid skull present a prob-

lem not shared by other cells. It is therefore not surprising that

neurologic symptoms frequently predominate the clinical pic-

ture. In its extreme form, if an adaptive response is not rapidly

activated, or if the serum sodium decreases at a rate greater

Correspondence to Dr. Tomas Berl, Division of Renal Diseases and Hyper-

tension, Department of Medicine, University of Colorado Health SciencesCenter, Campus Box C28l, 4200 East Ninth Avenue, Denver, CO 80262.

l046-6673/08010-1599$03.00/0

Journal of the American Society of Nephrology

Copyright © 1997 by the American Society of Nephrology

than the adaptive response can compensate, severe cerebral

edema may lead to increased intracranial pressure, tentorial

herniation, depression of the respiration center, and even death.

The presence of this constellation of neurological symptoms

reflects the fact that a patient is at great risk from hyponatre-

mic-induced cerebral edema and its long-term meurologic se-

quelae. Thus, when these neurological symptoms are present,

prompt correction of hyponatremia should be undertaken re-

gardless of the duration or the underlying cause of the condition.

Although most symptoms occur when the serum sodium

declines rapidly, symptoms may also be present when the

decline is more insidious. Symptoms are usually not as fulmi-

nant as described above, but when present, they require then-

apeutic intervention because they indicate severe cerebral dys-

function. These patients are at a much greater risk of

developing osmotic demyelination syndrome from rapid con-

rection, and thus their treatment must be cautiously undertaken

to prevent this complication.

Is the Duration of the Hyponatremia Known?Hyponatremia can be classified as acute or chronic with

regard to its duration, and treatment options cam be tailored to

this classification. These differences in chronicity are impor-

tant in the proper management of the condition, because each

is associated with different cerebral pathology and neurologic

syndromes. Thus, acute hyponatremic patients are at great risk

of permanent neurological sequelae from cerebral edema if the

hyponatremia is not promptly corrected. In contrast, chronic

hyponatremic patients are at risk of osmotic demyelination

syndrome if the hyponatremia is corrected too rapidly. Under-

standing the cerebral volume regulatory response to hypoto-

nicity is helpful in devising treatment strategies in both the

acute and chronic settings.

As noted above, cerebral edema occurs as water moves from

the extracellular fluid into cells in an attempt to achieve os-

motic equilibrium between these two body fluid compartments.

It has been repeatedly observed that the increment in cerebral

water in response to hyponatremia is considerably lower than

would be predicted to achieve osmotic equilibrium. The brain

demonstrates volume regulation, which decreases the net

amount of water entry into the brain by increasing the flow of

water from the interstitium into the cerebrospinal fluid (4).

This excess fluid eventually re-enters the systemic circulation.

This mechanism is activated very promptly and is evident by

the loss of extracellular solutes (Na and Cl) as early as 30 mm

after the onset of hyponatremia. However, as hyponatremia

persists, the brain further adapts by losing cellular electrolyte

and organic solutes (5,6), which tends to lower the osmolality

llhIIlllllluhIlllllluhIIII

0 0 20 30 40 50 60

Percent of Patients

hostile

disoriented

depression

hallucinations

incontinent

obtunded

nausea

emesis

headache

Opisthotonus

unequal pupils

clonus

poSltive Babinskl

hemiparesis

stage IV coma

respiratory arrest

grants mal seizures

Percent of Patients

-� Ti Risk Factors for Development of Cerebral EdemaP-�:ii-- -I� The patients at risk for cerebral edema include postoperative

memstruamt women, elderly women recently placed on thiazide

diuretics, children, psychiatric patients with polydipsia, and

____________________________________ hypoxic patients.

+ I I C � In the hospital setting, hyponatremic memstruamt women are

0 20 40 60 80 100 more likely to have symptoms and complications related to

hypomatremia than post-menopausal women or men. One study

revealed that although hyponatnemia develops at approxi-

mately the same rate in both genders, women are more symp-

tomatic than men at similar serum sodium levels ( I I ). In

addition, women are at increased risk for neurologic compli-

catioms related to acute hyponatremia. In women, and, in

particular, menstruant women, the risk of developing neuro-

logical complications is 25 times greaten than nonmenstruant

I 6(X) Journal of the American Society of Nephrology

mately 5 d), at which time the electrolyte content also normal-

izes (8). The pathogenesis of osmotic demyelination syndrome

has not been fully defined (4,9), but it may be related to a

greater susceptibility to dehydration in brains previously

adapted to hyponatremia when serum osmolality is raised.

Such brains have sustained losses of electrolytes and osmolytes

and have a slower recovery of K and organic osmolytes (10).� Therefore, brains adapted to chronic hyponatremia may be less

able to buffer effectively against increases in serum sodium

that require repletion of these solutes to prevent cerebral de-

4 � � � hydration.

70 80 90 00 Frequently, the duration of hyponatremia is unknown. Be-

cause acute hypomatremia usually occurs only in well-defined

clinical settings (described below), when a patient presents

with hyponatremia of unknown duration, it is prudent to as-

sume that delays in seeking medical cane most likely indicate

that the process is chronic.

Figure 1. Signs and symptoms in 15 acute hyponatremic patients

(Reproduced with permission from Arieff Al: Ads’ Intern Med 32:328,

1987).

of the brain without substantial gain of water. This slower

defense mechanism is reflected by a decrease in brain potas-

sium content I to 3 h after a hyponatremic insult. Thereafter, if

the hyponatremia persists, other organic solutes, such as amino

acids and imositol, are lost (5,6). This allows the brain to

markedly decrease cellular swelling. In fact, this process is so

efficient that by 72 h brain water is only modestly increased

(approximately 10%). On the basis of the volume regulatory

response, acute hyponatremia has been, albeit somewhat arbi-

trarily, defined as occurring over a period of less than 48 h (7).

It is during this time period that symptoms related to cerebral

edema are most likely to occur.

The brain that has adjusted to low osmolality over at least

48 h is at risk for the osmotic demyelination syndrome when

hyponatnemia is corrected rapidly. When serum sodium is

increased, the brain again adapts to prevent cellular dehydra-

tion. This is mitigated initially by entry of NaCl into cells and

then by enhanced cellular K uptake. The organic osmolytes

return very slowly to normal brain content levels (at approxi-

Does the Patient Have Risk Factors for theDevelopment of Neurologic Complications?

Several groups of patients are at risk of developing cerebral

edema from acute hyponatremia, and other groups are at risk of

developing the osmotic demyelination syndrome (Table 1)

when hyponatremia is corrected.

Table 1. Patient groups at increased risk for neunologic

complication of hyponatremia

Acute cerebral edema

postoperative menstruant women

elderly women on thiazide diuretics

children

psychiatric polydipsic patients

hypoxemic patients

Osmotic demyelinatiom syndrome

alcoholics

malnourished patients

hypokalemic patients

burn patients

elderly women on thiazide diuretics

The Hyponatremic Patient: Focus Ofl Therapy 1601

women or men. This increased risk was independent of the rate

of development, as well as the magnitude, of the hypomatremia

(1 1 ). The increased risk for menstruamt women may be related

to estrogen-induced defects in brain volume regulation ( 1 2). In

addition, experimental data support gender differences in argi-

nine vasopressin release, with its action on cerebral vessels

interfering with the process of cerebral adaptation (13).

It must be noted that other clinical studies have failed to

demonstrate a higher female predisposition for hypomatremia

or its neurological sequelae (14, 15). Despite the absence of

accurate prevalence data, at present, menstruant women with

hypomatremia should be considered at high risk for both cere-

bral edema and its complications. The best approach to this

problem is clearly a preventive one. In this regard, it must be

emphasized that the administration of hypotonic fluids has no

place in the postoperative setting. It should be noted, however,

that hypomatremia may occur even when isotonic saline is

given if the concentration of Na + K in the urine exceeds that

of serum sodium (16). Serum sodium, therefore, needs to be

carefully monitored in this group of patients, particularly when

nausea or other symptoms require the continuous admimistra-

tion of parenteral fluids.

Elderly women are also at risk for acute symptomatic hy-

ponatremia soon after being placed on thiazide diuretics. The

majority will present within 2 wk from beginning the diuretic,

although one-third of the patients will present within 5 d (17).

The mechanism appears to be related to an altered hypotha-

lamic response and imtrarenal water excretion defects, panic-

ularly in those with a low body mass.

Age may also be a risk factor for symptomatic hyponatre-

mia, as children are particularly vulnerable to acute cerebral

edema (18). This may be due to physical factors, such as the

relatively high ratio of brain volume to skull volume. In addi-

tion, in animal experiments, there may be a decreased capacity

for cerebral adaptation to low osmolality in young rats, and this

can contribute to cerebral edema ( 12). At present, the actual

risk of meurologic complications in the pediatric population

remains to be determined. However, with current data it would

be prudent to consider this group at major risk for cerebral

edema.

Psychiatric patients who may have compulsive water drink-

ing and increased levels of arginine vasopressin may also be

predisposed to symptomatic hyponatremia. Fortunately, these

patients rarely develop long-term sequelae.

Am important role for hypoxia in cerebral edema has been

suggested. The deleterious effect of hypoxia has been demon-

strated in experimental animals, because in such animals the

presence of hypoxia greatly increases brain edema and mon-

tality (19).

Risk Factors for the Osmotic Demyelination Syndrome

The osmotic demyelinatiom syndrome appears to occur when

there is a rapid correction of low osmolality in a brain already

chronically adapted. Several patient groups are at risk (Table

1). In addition to its occurrence in patients with chronic hypo-

natnemia, other risk groups include alcoholics, malnourished

patients, burn patients, and patients with hypokalemia (20). As

with cerebral edema, the elderly woman on thiazide diuretics is

also susceptible to this injury.

It is of interest that many of the predisposimg clinical settings

are associated with potassium depletion. The significance of

this association is not fully understood. Potassium may be

important in the cerebral recovery process of hypomatremia,

because the cellular uptake of potassium is a critical response

to increasing extracellular tonicity. Therefore, hypokalemia

may predispose a patient to demyelimatiom by limiting the

availability of potassium in the brain, thereby rendering it more

prone to dehydration.

It must be emphasized that an element of chromicity of

hyponatremia is the most important factor that predisposes

patients to the osmotic demyelimatiom syndrome. As described

above, it is rarely seem in patients with a serum sodium greater

than 120 mEq/L or in patients with hypomatremia of less than

48 h duration. Likewise, in animal models the development of

cerebral lesions also requires pre-existemt hyponatremia of this

duration.

What is the Treatment Strategy forHyponatremia?

The treatment strategy for the hyponatremic patient will

differ depending on the clinical situation. We will briefly

outline the approach to the symptomatic patient with either

acute or chronic hypomatremia, as well as the approach to the

asymptomatic patient (Figure 2).

Acute Symptomatic Hyponatremia

Acute symptomatic hyponatremia, defined as hyponatremia

known to be of less than 48 h duration, is most commonly

observed in postoperative hospitalized patients receiving hy-

potonic fluids. Treatment in this setting needs to be immediate

when symptoms are present, because the risk of cerebral edema

far outweighs any risk of the osmotic demyelimation syndrome.

Serum sodium should be raised by 2 mEqIL per h until symp-

toms resolve. Although full correction is probably safe, it is by

no means necessary. The correction cam be achieved by ad-

ministration of I to 2 mI/kg per h hypertonic saline (3% NaCl).

The coadministration of a loop diuretic enhances free water

excretion and thereby accelerates the correction process. In

patients with seizures or other severe neurologic symptoms

(obtundation, coma), a more rapid infusion of 3% NaCI (4 to 6

mI/kg per h) or even 50 ml of 29.2% NaCl have been safely

used (7). In all patients, close monitoring of serum sodium and

neurologic symptoms is imperative.

Symptomatic Chronic Hvponatretnia

In symptomatic hypomatremia of an unknown duration on of

a duration greater than 48 h, one must be cautious to avoid

complications of therapy. Neunologic symptoms such as a

depressed sensorium on seizures reflect cerebral dysfunction

and the need for some correction, while simultaneously avoid-

ing the osmotic demyelinatiom described previously. The key

controversy centers on the question of whether it is the rate or

the magnitude of correction that increases the risk of compli-

Figure 2. Treatment of severe (< 125 mM/L) euvolemic hyponatremia (Modified with permission from Halterman R, Berl T: Therapy of

dysnatremic disorders. In: Therapy in Nephrology and Hypertension, edited by Brady H, Wilcox C, Philadelphia, W. B. Saunders, 1997, in

1602 Journal of the American Society of Nephrology

= desired SNa X new TBW

press).

cations. These two variables in the correction of hypomatremia

are not readily dissociated, because a rapid correction rate

usually is accompanied by a greater absolute magnitude of

correction over a given time period. Nonetheless, this distinc-

tion is potentially of great importance in the approach to the

patient with symptomatic hypomatremia. Evidence from exper-

imental animals strongly points to a very important role for

magnitude of correction; however, the rate of correction also

clearly plays a role, because if either of these variables is

exceeded, the incidence of neurologic lesions increases (6). A

similar conclusion cam be reached from less controlled human

studies. Therefore, because the rate and magnitude of correc-

tiom are not completely independent of each other, each of

these variables should be considered when designing therapy

for the symptomatically hyponatremic patient. The following

guidelines are useful:

1 . Because cerebral water is increased only by approximately

10% in severe chronic hyponatremia, promptly increase the

serum sodium by 10%, or approximately 10 mEqIL.

2. After the initial correction, do not exceed a correction rate

of 1.0 to 1.5 mEqfL per h.

3. Do not increase serum sodium by more than 15 rnEqIL per

d.

The rate at which the serum sodium will increase is depen-

dent on the rate and electrolyte content of infused fluids, as

well as the rate and electrolyte content of the urine. This is

illustrated in the following example.

A patient is admitted with progressive changes in mental

status and is found to have a serum sodium level of 1 10 mEqfL,

which is thought to be secondary to the syndrome of inappro-

priate antidiuretic hormone (SIADH) based on his recently

diagnosed small cell lung cancer. The patient weighs 50 kg. A

computed tomography scan reveals no focal abnormalities, but

mild cerebral edema. The physician wants to increase the

patient’ s serum sodium from 1 10 to 120 mEq/L in 10 h.

1 . Calculate the net water loss needed to raise serum so-

dium (SNa) to 120 mEq.

Present SNa X total body water (TBW)

Assume TBW = 60% of body weight - 50 X 0.6 = 30 L

New TBW =

Present 5Na X TBW

Desired SNa

New TBW =

Table 3. Solute and water balance during the second hour

1 10 mEq/L X 30 L

120 mEq/L 27.5 L

Table 2. Solute and water balance during the first hour

The Hyponatremic Patient: Focus on Therapy 1603

Net electrolyte-free water loss to raise 5Na

=present TBW - new TBW = 30 - 27.5 = 2.5 liters

2. Calculate the time course in which to raise the serum

sodium by 1 mEq/h. To increase the serum sodium, 1

rnEq/h from 1 10 to 120 mEqfL should occur over 10 h, or

2.5 L of electrolyte-free water should be lost in 10 h,

which equals 250 ml of free water loss per hour.

3. Administer furosemide, monitor urine output, andreplace any sodium and potassium or excess free Wa-ter that is lost in the urine. In this patient, furosemide

was administered and a brisk diunesis resulted in a 1-L

urine output in the first hour with a urine sodium level of

75 mEq/L and urine potassium level of 20 mEqIL. Be-

cause this patient only needed to lose 250 ml of electrolyte-

free water, 750 ml of water plus 75 mEq of sodium and 20

mEq of potassium need to be given back to the patient. This

can be given in any combination of fluid, sodium, and

potassium supplement, such as 500 ml of normal saline and

250 ml of D5W with 20 mEq KC1 (Table 2).

CharacteristicWater

(ml)Solutes Na/K

(mEq)

Intake 750 75/20

500 ml normal saline

250 ml D5W + 20 mEq KC1

Output 1000 75/20

Balance -250 0

4. Continue to monitor urine output and replace anysodium, potassium, or excess electrolyte-free waterthat has been lost in the urine.

In this patient, the second hour resulted in only 800 ml of

urine output, with a urine sodium of 75 mEq/L and urine

potassium of 30 mEq/L. This represents a loss of only 60 mEq

sodium and 25 mEq potassium. Only 250 ml of electrolyte-free

water should be lost; therefore, during this hour, 550 ml of free

water needs to be replaced with 60 mEq sodium and 25 mEq

potassium. This cam be accomplished by the administration of

400 ml of normal saline + 150 ml of D5W with 20 mEq KC1

(Table 3).

As the diuresis slows, additional doses of furosemide may be

necessary. It is important to periodically measure serum Na, K,

and spot urine Na and K to ensure that the correction is

CharacteristicWater

(ml)Solutes Na/K

(mEq)

Intake 550 60/20

400 ml normal saline

150 ml D5W + 20 mEq KC1

Output 800 60/25

Balance (second hour) -250 -5

Balance (cumulative) -500 -5

proceeding properly. Free water is being excreted only in UNa

+ UK < �Na (P stands for plasma . After the desired increment

is attained, therapy can be continued in the form of water

restriction.

How is Chronic Asymptomatic HyponatremiaManaged?

The asymptomatic patient requires none of the intensive

treatment described above. Initially, the physician should look

for am underlying disorder. If one is identified and treated, such

as thyroid or adrenal insufficiency, its treatment will resolve

the hyponatnemia. This is also true in cases of the SIADH. Any

drugs that can be implicated in limiting water excretion also

should be discontinued.

When the underlying cause of chronic hyponatremia is SI-

ADH and its etiology is not known or cannot be effectively

treated, SIADH must be treated as a chronic disorder. The best

management of chronic hyponatremia is conservative, because

rapid increases in serum tonicity lead to a greater degree of

cerebral water loss and possible demyelimation. The treatment

options as outlined in Table 4 include fluid restriction, use of

pharmacologic agents (lithium, demeclocycline, loop diuret-

ics), and increased solute intake (urea). In addition, vasopressin

receptor antagonists will soon be available.

Fluid Restriction

Fluid restriction is frequently successful in normalizing the

serum sodium concentration and preventing symptomatic hy-

ponatremia. The following approach is useful in calculating a

fluid restriction that will maintain a specific serum sodium. A

patient’s maximal urine volume (Vmax) �5 determined by the

daily osmolar load (OL) and the minimal urinary osmolality

(Uosmolmjn). This latter parameter is a function of the severity

of the diluting disorder. Thus, the more severe the disorder, the

higher the minimal osmolality. Thus,

OLVmax

On a normal diet, osmolan load is approximately I 0

mosmol/kg (700 mosmol in a 70-kg person). In a healthy

person, urine osmolality can be as low as 50 mosmol/kg;

therefore 14 L of water cam be excreted pen day. A patient with

SIADH who cannot lower the Uosmol below 500 mosmol/kg

but who has the same osmolar load cam only excrete 1 .4 L of

1604 Journal of the American Society of Nephrology

Table 4. Treatment options for SIADH�

Treatment Mechanism of Action Dose Advantages Disadvantages

Fluid restriction Decreases availability

of free water

Variable Effective and

inexpensive

Noncompliance

Pharmacologic agents

lithium Inhibits response of

kidney to ADH

900 to 1200 mg/d Unrestricted water

intake

Polyuria

Narrow therapeutic range

Neunotoxicity

Nephrotoxicity

demeclocycline Inhibits response of

kidney to ADH

I 200 mg/d initially

then 300 to 900

mg/d

Effective;

unrestricted water

intake

Polyuria

Photosensitivity

Nephrotoxicity

funosemide Increases free water

clearance

Titrate to optimal

dose ; coadmimistration

of 2 to 3 g of

NaCI

Effective Ototoxicity

K depletion

Increased solute intake

urea Osmotic diunesis 30 to 60 g/d Effective;

unrestricted water

intake

Polyuria

Unpalatable

GI symptoms

V2 receptor antagonist Antagonizes

vasopressin action

Ongoing trials

a SIADH, syndrome of inappropriate antidiuretic hormone; ADH, antidiuretic hormone; GI, gastrointestinal.

water per day. If such a patient drinks more than I .4 L pen day,

the serum sodium will fall. Although fluid restriction is con-

sistently effective and inexpensive, fluid restriction of this

degree is accompanied by a very high probability of noncom-

pliamce. Hence, a variety of other approaches have been used.

Pharmacologic Agents

Lithium was the first pharmacologic agent used in the treat-

ment of hypomatremia after diabetes insipidus was noted to be

a common adverse effect. This effect occurs in 30 to 70% of

patients taking therapeutic doses. Lithium acts to increase

serum sodium by inhibiting the kidney’s response to antidi-

uretic hormone, thereby increasing the excretion of water. An

inhibition of vasopressin-stimulated cAMP formation, as well

as a decrement in the synthesis of vasopressin-regulated water

channels (AQP2), underlies the defect (2 1). A dose of 900 to

1 200 mg/d is usually effective. However, the agent has a

marrow therapeutic range and both renal and neurologic toxic-

ity have limited its usefulness as a chronic therapeutic agent.

Demeclocycline was first noted to cause polyuria by Singer

and Rotenberg in a group of patients treated for skin disorders

(22). These investigators found that the polyuria was due to the

drug’s ability to inhibit both the formation and the action of

cAMP in the collecting duct of the renal tubule. This resulted

in a kidney that was unresponsive to antidiuretic hormone

(mephnogenic diabetes insipidus). This adverse effect was ob-

served in patients receiving large doses of demeclocycline (600

to 1200 mg/d), but was virtually nonexistent in patients receiv-

ing smaller doses (less than 600 mg/d). Since then, the drug has

been valuable in the treatment of SIADH. In a comparative

study with lithium, it was found to also be more predictable in

normalizing the serum sodium (23). The onset of action is

usually 3 to 6 d after beginning treatment with the drug, at

which time the urine osmolality decreases. Polyuria then be-

comes evident after 7 to 10 d. When diuresis begins, the patient

must be allowed free access to water to prevent hypernatremia

from water depletion. After an initial response is seen, the dose

of demeclocyclime should be decreased gradually to the lowest

level (usually between 300 and 900 mg/d), which keeps the

serum sodium normal with unrestricted fluid intake. To ensure

adequate absorption, the drug should be given 1 to 2 h after

meals, and antacids (calcium, aluminum, or magnesium)

should be avoided.

There are also some adverse effects and serious toxicities

that must be considered when using demeclocycline. Some

patients are inconvenienced by the polyuria and become non-

compliant. Skim photosensitivity may occur. In the pediatric

population, demeclocyclime can cause tooth or bone abnormal-

ities. In addition, azotemia can occur with or without mephno-

toxicity. Nephrotoxicity occurs most often in patients with

liver disease and is postulated to occur because of decreased

hepatic metabolism of the drug and subsequent elevated drug

levels.

Loop diuretics such as furosemide have also been used in the

treatment of SIADH. In 1983, Decaux studied the efficacy of

the loop diuretics ethacrynic acid and furosemide in the treat-

ment of chronic SIADH. In 1 1 of 1 2 patients with chronic

SIADH, the serum sodium increased from an average of I 20.4

to 136 mmol/L (24). This occurred despite the patients’ free

access to water, as long as urinary losses of sodium and

The Hyponatremic Patient: Focus on Therapy 1605

potassium were replaced. This requires the administration of 2

to 3 g of NaCl per day. In the remaining patients, resistance to

the diuretic was thought to be secondary to the combination of

a decreased GFR (55 ml/min), a limited increase in funo-

semide-induced diuresis, and a large fluid intake (2 1 beers/d).

A single diuretic dose (40 mg of furosemide) was enough to

induce a large diunesis in most patients. Diuretic doses should

be doubled if the diuresis induced in the first 8 h is less than

60% of the total daily urine output.

increased Solute intake

An alternative option for the chronic management of hypo-

natremia is to increase solute intake with urea. Urea is am

important component of the osmotic gradient in the renal

interstitium and allows for proper concentration and dilution of

urine. By increasing the solute load with oral urea, an osmotic

diuresis occurs, and this increase in urine flow permits a more

liberal water intake without worsening the hypomatnemia. This

occurs without altering urinary concentration. The effect of the

increased solute load can be demonstrated by the quantification

of electrolyte-free water excretion both before and after urea is

administered in the example shown below.

Assume that a patient has a serum sodium level of 134

mEq/L, a fixed urine concentration of 800 mosmol/d, with a

daily obligatory solute load of 500 mosmol/d, a dietary sodium

intake of 100 mmol/d, and a potassium intake of 40 mmol/d.

Calculating the volume required to excrete the daily solute load

at baseline reveals:

Solute excretion 500 mosmol/dv= = =0.625L/d

Uosmol 800 mosmol/kg H2O

The concentration of sodium and potassium in this volume

can be determined as follows:

100 mmol[UNa] 0.625 L = 160 mM/L

40 mmol[UK] �OT�25 L = 64 mM/L

These values may then be used to compute the electrolyte-

free water clearance:

cH2Oe V(1 - [UNa] + [UK])/PNa

=0.625(1 _ 134 ) =0.625(1 - 1.67)160 + 64�

= -0.418 L/d

The negative value for excretion of electrolyte-free water

clearance suggests net free water absorption, a setting that

could lead to worsening hyponatnemia.

Under the same conditions of sodium and potassium intake,

urine concentration, and serum sodium level, administration of

urea at 30 g/d adds approximately 500 mosmol/d to the oblig-

atory solute load that must be excreted. This has a profound

effect on electrolyte-free water clearance, because the daily

solute excretion is increased from 500 to 1000 mosmol.

Volume required for excretion of a solute load

1 000 mosmol/d=�- -�-=l.25L/d

800 mosmol/kg H2O

As a result of the increased urinary volume, urinary electro-

lyte concentrations decrease:

Daily sodium excretion = 100 mmol

100 mrnol[UNa] � = 80 mM/L

1.25 L

Daily potassium excretion = 40 mmol

40 mmol[UK] = 32 mM/L

1.251.

Note the resulting changes in electrolyte-free water clean-

ance:

�/ [UNa] + [UK]\ f 80 + 32cH-,Oe=V(1- D J=l.25(1-

\ rNa I

= 1.25(1 - 0.83) = +0.2125 L/d

Now electrolyte-free water excretion is positive, allowing

for higher water intake. Urea is usually given in doses of 30 to

60 g/d, and its onset of action is immediate. As with demeclo-

cycline, urea permits unrestricted fluid intake. The major side

effect is gastrointestinal symptoms and its unpalatability.

Vasopressin Antagonists

Vasopressin (V2) receptor antagonists are currently being

investigated. OPC 3 1 260 is a novel oral V2 vasopressin recep-

ton antagonist, which when tested in hyponatnemic, cirrhotic

rats more than normalized the urinary excretion rate of water

after an oral loading test (25). This agent may become an

effective therapeutic agent for the vasopressin-dependent water

retention associated with decompensated liven cirrhosis. OPC

3 1 260 has also been studied in SIADH in rats. Saito et al. first

treated vasopressin-deficient Battlebono rats with antidiunetic

hormone and showed that OPC 3 1260 entirely reversed the

effects of vasopressin (26). In human studies, OPC 3 1 260 was

given to normal volunteers. When compared with a loop di-

uretic, OPC 3 1260 induced a significant water diuresis without

altering the urinary excretion of sodium or potassium (27).

This class of drugs, now designated as �‘aquaretics,” are not yet

available for clinical use.

Treatment of Hypovolemic and HypervolemicHyponatremia

Much of the preceding discussion assumed that the patient

under consideration was euvolemic, a condition that represents

the majority of hyponatnemic subjects. However, we want to

conclude with some comments on the treatment of hypov-

olemic and hypervolemic hyponatremic patients (Table 5).

Hypovolemic hyponatreinia results from the loss of both

16()6 Journal of the American Society of Nephrology

Table 5. Treatment of noneuvolemic hyponatnemia

Hypovolemic hypomatremia

volume restoration with isotonic saline

identify and correct etiology of water and sodium losses

Hypervolemic hypomatremia

water restriction

sodium restriction

substitute loop diuretics in place of thiazide diuretics

treatment of stimulus for sodium and water retention

V2 receptor antagonists (ongoing trials)

water and solute, with a greater relative loss of solute. The

nomosmotic release of argimine vasopressin in response to

reduced effective circulating volume perpetuates the hypona-

tremia by producing a state of antidiuresis. Patients with this

type of hypomatremia are usually asymptomatic, probably be-

cause the losses of sodium and water limit the development of

cerebral edema. The cornerstone of therapy is the administra-

tion of isotonic saline, with concomitant resolution of the

underlying disturbance. Resolution of the volume disturbance

removes the stimulus for arginine vasopressin and restores

serum sodium to normal levels.

Hvjwrt’olemie hvponatretnia is observed when both water

and solute are increased, but in this situation water is increased

to a greater extent. This condition is very difficult to treat, as

it often reflects severe, irreversible dysfunction of either the

liver, heart, or kidney. In heart failure, cirrhosis, and nephrotic

syndrome, reduced effective arterial volume results in the

notlosmotic stimulation of arginine vasopressim and an increase

in thirst. Therefore, compliance with water restriction is diffi-

cult. Diuretics are the primary therapeutic agents for edema,

but caution must be used in selecting the appropriate regimen.

Thiazide diuretics impair urinary dilution and may exacerbate

hyponatremia, whereas loop diuretics increase free water ex-

cretion and can improve the serum sodium. Correction or

improvement of the underlying disturbances would be ideal,

but this is usually not attainable. At present, therapy relies on

fluid restriction, salt restriction, and loop diuretics. The afore-

mentioned oral V2 antagonists are currently being tested in

hyponatremic subjects who have presented with congestive

heart failure and cirrhosis. The results of these trials are eagerly

awaited, because they could provide a valuable alternative in

the management of this electrolyte disorder.

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