Hyponatremia

Physicians may face difficulties treating patients who have hyponatremia.The risks of rapid correction, such as pontine myelinosis, are well known.Also, many and sometimes complex factors influence the serum sodiumconcentration.

A 72-year-old woman from a nursing home presents to the emergencydepartment with a change in her mental state over the past few hours. She hasa medical history of coronary artery disease and hypertension. Her medicationsinclude hydrochlorothiazide. 25 mg a day, and aspirin, 81 mg a day. Onphysical examination, she has decreased skin turgor, orthostatic hypotension,and disorientation to time, place, and person without focal neurologicdeficits. Initial laboratory tests show a serum sodium level of 110 mmol/L;blood urea nitrogen, 23.2 mmol/L (65 mg/dL); creatinine, 318 μmol/L (3.6mg/dL); triglycerides, 2.75 mmol/L (244 mg/dl); and plasma osmolality, 278mmol/kg of water (278 mOsm/kg of water). Other laboratory findings are abicarbonate value of 29 mmol/L; hematocrit, 0.35 (35%); potassium, 4.0 mmol/L;uric acid, 0.42 mmol/L (7.0 mg/dL); urine osmolality, 450 mmol/kg of water;and urine specific gravity, 1.019. Her serum sodium level 2 months beforeadmission was 135 mmol/L, and her urine output was 400 mL a day. She isadmitted to the hospital, and a regimen of intravenous isotonic sodiumchloride solution is started at a rate of 84 mL per hour in the first 24hours.

METHODS

Searching the literature

Once we had formulated the specific clinical questions, we searched theOVID database using the search term hyponatremia. We limited thesearch to the subheadings diagnosis, complications, andtherapy and the publication years of 1991 through 2001. The searchelicited 126 articles, of which 17 were relevant and in peer-reviewedjournals.

PERTINENT QUESTIONS

How common is hyponatremia?

Hyponatremia is the most frequent electrolyte abnormality seen in generalhospital patients, with an incidence of about 1%. Symptomatic hyponatremia isequally common in men and women, but children and menstruating women are morevulnerable to hyponatremic braindamage.¹

What are the symptoms of hyponatremia?

The symptoms of hyponatremia are primarily neurologic and are related bothto the severity and in particular to the rapidity of onset of the change inthe plasma sodium concentration. Patients also have symptoms related toconcurrent volume depletion and to possible underlying neurologic disordersthat predispose to the electrolyteabnormality.^2,3,4The presence of symptoms and the duration of the hyponatremia guide thetreatmentstrategy.⁵

Nausea and malaise are the earliest findings and may be seen when theplasma sodium concentration falls below 125 to 130 mmol/L. This may befollowed by headache, lethargy, obtundation, and eventually seizure, coma, andrespiratory arrest if the plasma sodium concentration falls below 115 to 120mmol/L.^6,7In one study of 184 patients with a plasma sodium concentration of 120 mmol/Lor less, 11% presented incoma.⁷

Hyponatremic encephalopathy is often reversible. The degree of cerebraledema and, therefore, the likelihood of neurologic symptoms is much less withchronic than with acutehyponatremia.⁸ Whenpatients with chronic hyponatremia have symptoms, the plasma sodiumconcentration is generally below 110 mmol/L, and there has usually been anacute exacerbation of the hyponatremia.

What are the common causes of hyponatremia?

In almost all patients, hyponatremia results from the intake (either oralor intravenous) and subsequent retention of water (seebox1).¹ Awater load will, in healthy persons, be rapidly excreted; the dilutional fallin plasma osmolality suppresses the release of antidiuretic hormone (ADH),thereby allowing the excretion of dilute urine. The maximum rate of waterexcretion on a regular diet is more than 10 L per day, thereby providing anenormous range of protection against the development of hyponatremia.

Box 1.

Major causes of hyponatremia

Disorders in which ADH levels are elevated

Effective circulating volume depletion True volume depletion—vomiting, diarrhea, bleeding, urinary loss Congestive heart failure and cirrhosis Thiazide diuretics Syndrome of inappropriate ADH secretion Hormonal changes: adrenal insufficiency, hypothyroidism, and pregnancy

Disorders in which ADH may be appropriately suppressed

Advanced renal failure Primary polydipsia Beer drinkers' potomania

Pseudohyponatremia

High plasma osmolality: hyperglycemia or mannitol Normal plasma osmolality: hyperlipidemia, glycine solutions, andhyperproteinemia

Many commonly used drugs can cause hyponatremia, either by dilution (suchas antipsychotic drugs, carbamazepine, cyclophosphamide, desmopressin acetate,vincristine sulfate, and octreotide acetate) or by salt wasting (such asenemas).

How is the fluid status of a patient assessed?

Hyponatremia is defined as a decrease in the serum sodium concentration toa level below 136 mmol/L. It can be associated with low, normal, or hightonicity. Effective osmolality or tonicity refers to the contribution to theosmolality of solutes (eg, sodium and glucose) that cannot move across thecell membranes, thereby inducing transcellular shifts in water. Dilutionalhyponatremia, by far the most common cause of hyponatremia, is caused by waterretention. If water intake exceeds the capacity of the kidneys to excretewater, body solutes dilute, causing hypoosmolality and hypotonicity.

An accurate history and physical examination can help to determine whetherthe patient has hypovolemia, euvolemia, or hypervolemia and the cause ofvolume depletion. Hypovolemia refers to any condition in which theextracellular fluid volume is reduced. When severe, it leads to a clinicallyapparent reduction in tissue perfusion. It can be produced by salt and waterloss or by water loss alone (ie, dehydration). Salt and water loss comesprimarily from the extracellular fluid, whereas pure water loss comes from thetotal body water, only about 40% of which is extracellular. Thus, fordehydration to produce the same degree of extracellular volume depletion assalt and water loss, 2.5 times as much fluid would have to be lost.

A decrease in the interstitial volume can be detected by examining the skinand mucous membranes. If the skin of the arm, calf, or thigh is pinched inhealthy subjects, it will immediately return to its normally flat state whenthe pinch is released. This elastic property, called turgor, is lost whenthere is a loss in the interstitial fluid. A decrease in the plasma volume canlead to variations in the systemic blood pressure and the venous pressure inthe jugular veins. The arterial blood pressure changes from normal to low inthe upright position and then, with progressive volume depletion, topersistently low despite posture.

What laboratory tests are most useful in finding the cause ofhyponatremia?

After a thorough history and physical examination, essential laboratorytests include the plasma osmolality, the urine osmolality, and the urinesodiumconcentration.²Baseline thyroid-stimulating hormone, hemoglobin, albumin, potassium, andbicarbonate levels can also be valuable, for reasons discussed later.

The plasma osmolality is reduced in most hyponatremic patients because itis primarily determined by the plasma sodium concentration and accompanyinganions. In some patients, however, the plasma osmolality is either normal orelevated.^2,9

The normal response to hyponatremia is to completely suppress ADHsecretion, resulting in the excretion of a maximally dilute urine with anosmolality below 100 mmol/kg of water and a specific gravity of 1.003 orlower. Higher values indicate an inability to normally excrete free water thatis generally due to the continued secretion of ADH. Most hyponatremic patientsare unable to produce dilute urine, and their urine osmolality may be 300mmol/kg of water or even greater.

In those patients with hyponatremia and a low plasma osmolality, the urineosmolality can be used to distinguish between impaired water excretion andprimary polydipsia, in which water excretion is normal but intake is so highthat it exceeds excretory capacity. In patients with impaired water excretiondue to hypovolemia, the urine osmolality often exceeds 450 mmol/kg ofwater.

In the absence of adrenal insufficiency or hypothyroidism, the two majorcauses of hyponatremia with hypoosmolality and inappropriately concentratedurine are volume depletion and the syndrome of inappropriate ADH secretion(SIADH). These disorders can usually be distinguished by measuring the urinesodium concentration, which is typically below 25 mmol/L with volume depletionand above 40 mmol/L in patients withSIADH.¹⁰ Theinitial water retention and volume expansion in patients with SIADH leads toanother frequent finding that is the opposite of that typically seen withvolume depletion: hypouricemia due to increased uric acid excretion in theurine.¹¹

Either hypokalemia or hyperkalemia can occur in hypovolemic patients. Theeffect of fluid loss on the acidbase balance also varies; either metabolicalkalosis or acidosis can occur. Because red blood cells and albumin areessentially limited to vascular space, a reduction in the plasma volume tendsto elevate both the hematocrit and the plasma albumin concentration.

In acute renal failure, the fractional excretion of sodium is a moreaccurate assessment of volume status than the urine sodium concentration (seebox 2). A value of less than 1%in patients with acute renal failure suggests effective volume depletion. Butthe fractional excretion of sodium is more difficult to evaluate in patientswith a normal glomerular filtration rate.

Box 2.

Fractional excretion of sodium

How fast should the sodium be replaced in patients with symptomatichyponatremia?

When considering the treatment of hyponatremic patients, four issues mustbe addressed: the risk of osmotic demyelination, the appropriate rate ofcorrection to minimize this risk, the optimal method of raising the plasmasodium concentration, and estimation of the sodium deficit of sodium is to begiven.

The adaptation that returns the brain volume toward normal in patients withchronic hyponatremia protects against the development of cerebral edema butalso creates a possible problem for therapy. In patients with acutehyponatremia, an overly rapid increase in the plasma sodium concentration canlead to osmotic demyelinationsyndrome.^2,8,12The changes can lead to possibly severe neurologic symptoms that are delayedfor 2 to 6 days after correction and that may beirreversible.^12,13,14

Based on a retrospective analysis of 64 patients, Sterns found thatneurologic complications tend to occur if the rate of correction exceeds 0.6mmol/L per hour. Of 62 of the 64 patients who were treated, 5 died (for amortality of 8%). He concluded that most of the observed neurologiccomplications were not caused by the hyponatremia per se but were related to arate of correction of the serum sodium concentration exceeding 0.55 mmol/L perhour.¹⁵ On theother hand, other reviewers have indicated that the magnitude rather than therate of correction is responsible for the development of neurologiccomplications.^15,16In acute symptomatic hyponatremia that develops within 48 hours, treatmentshould be prompt because the risk of cerebral edema far exceeds the risk ofosmotic demyelination.

After weighing the available evidence and the all-too-real risk ofovershooting the mark, we recommend a targeted rate of correction that doesnot exceed 8 mmol/L on any day of treatment. Should severe symptoms notrespond to correction to the specified target, this limit may be cautiouslyexceeded because the imminent risks of hypotonicity override the potentialrisk of osmoticdemyelination.¹⁷The aim should be to raise the serum sodium concentration by 2 mmol/L per houruntil symptoms haveresolved.¹⁸Complete correction is unnecessary, although no risks are involved inrestoring plasma sodium to normal levels.

If hyponatremia has been present for longer than 48 hours or the durationis unknown, as in the case of our patient, correction should be handledcarefully.⁵ In thetreatment of hyponatremia, it is currently recommended that the plasma sodiumconcentration in asymptomatic patients should be elevated at a maximum rate of10 to 12 mmol/L during the first 24 hours and 18 mmol/L over the first 48hours.^8,12Even at this rate, however, neurologic symptoms candevelop.^15,19

It is probably wise, therefore, to correct the hyponatremia at less thanthe maximum rate in asymptomatic patients. This can be accomplished by fluidrestriction. To be effective, fluids need to be restricted to less than freewater loss (free water loss is equal to urine output plus the water lossthrough sweating andstool).^18,20

Vasopressin antagonists will soon become available. Preliminary experiencehas shown that they are effective in causing sustained diuresis and incorrectinghyponatremia.²¹

How to calculate the sodium deficit

When an isotonic sodium chloride solution is given to treat hyponatremia,the quantity of sodium chloride required to achieve the desired elevation inthe plasma sodium concentration can be estimated by multiplying the plasmasodium deficit per liter with the total body water, which represents theosmotic space of distribution of the plasma sodium concentration. Normalvalues for the total body water are 0.5 and 0.6 times the lean body weight (inkilograms) in women and men, respectively.

• The Initial aim in our patient (who weighed 60 kg [132 lb]) was to raisethe plasma sodium concentration from 110 to 120mmol/L.²

• Plasma sodium deficit per liter: 120 - 110 = 10 mmol

• Total body water: 0.5 × 60 = 30

• Sodium deficit for initial therapy = plasma sodium deficit per liter× total body water: 10 × 30 = 300 mmol

Thus, 600 mL of hypertonic sodium chloride (which contains roughly 1 mmolof sodium per 2 mL) should be given over 24 hours at a rate of 25 mL an hour;or 2,000 mL of isotonic sodium choride (which contains 1.5 mmol of sodium per100 mL) should be given over 24 hours at a rate of about 84 mL an hour. Thisregimen should raise the plasma sodium concentration at the desired rate of 10mmol/L during the first day.

The plasma sodium concentration will increase by one of two mechanisms:sodium retention in patients who are hypovolemic, or initial retention of thesodium followed by the excretion of water in patients with SIADH. In thelatter disorder, volume regulation is intact and the administered sodium willbe excreted in the urine through associated volume expansion. The water lossinduced by excretion of the extra sodium is responsible for the steady-stateelevation in the plasma sodium concentration.

HYPONATREMIA IN ELDERLY PATIENTS: A SPECIAL SITUATION

Older people may be predisposed to hyponatremia because of medications ordiseases that cause or are associated with low concentrations of serumsodium.²² Anothercontroversial proposed cause is an enhanced vasopressin response tohyperosmolarity that may occur with increasingage.²²

Congestive heart failure is an important cause of hyponatremia in elderlypeople. Although the total extracellular fluid volume is increased in patientswith heart failure, they are functionally hypovolemic because of low cardiacoutput. The decrease in tissue perfusion stimulates the release of ADH. Thisprocess is directly related to the severity of the hemodynamic impairment. Asa result, hyponatremia in congestive heart failure is a marker of a poorprognosis. Symptoms of hyponatremia occur primarily with acute reductions inthe plasma sodium concentration and are vague and unreliable in elderlypeople. Symptoms that may be seen include lethargy, confusion, agitation,weakness, and anorexia.

An important aspect of the evaluation of elderly patients who have lowplasma osmolality is an accurate assessment of their volume status—achallenging task in these patients.

Our patient was treated with intravenous isotonic sodium chloride solution,and her serum sodium level was corrected to 120 mmol/L after the first 24hours, Her neurologic state improved gradually over the next 3 days. A regimenof lisinopril, 10 mg a day, was started for blood pressure control, and thepatient was discharged to home in good condition.