Nephrology Hypertension

Diseases of Water Balance: Hyponatremia

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Does this patient have hyponatremia?

The patient has hyponatremia if the serum sodium is < 135 meq/L.

What is the serum sodium a reflection of?

The measured serum sodium is a reflection of the body fluid osmolality. The formula for plasma osmolality (mOsm/kg) is:

  • Plasma Osmolality = 2(Na mEq/L)+ (urea mg/dl)/2.8+ (glucose mg/dl)/18

Hyponatremia is most often associated with hypotonicity. However, it can occur with normal or even high serum osmolality as in pseudohyponatremia and translocational hyponatremia.

Measure plasma osmolality to establish if the patient has hypotonic hyponatremia.

What are the signs and symptoms of hyponatremia?

The clinical manifestations of hyponatremia can vary from asymptomatic to mildly symptomatic (gait disturbances, falls) to severely symptomatic (obtundation, seizures). Both the level of hyponatremia and rate at which it develops are important determinants of symptoms.

What are pseudohyponatremia and translocational hyponatremia?

Pseudohyponatremia occurs in the setting of very high levels of plasma proteins and/or lipids that can falsely dilute the measured sodium content. In this setting, serum osmolality is normal. Only direct potentiometry with an undiluted sample can accurately measure the serum sodium.

Translocational hyponatermia reflects translocation of water from the intracellular fluid (ICF) to the extracellular fluid (ECF) which dilutes the plasma sodium concentration. This most commonly occurs with hyperglycemia but can also occur with mannitol, glycine, and maltose. To correct for the translocational effect of glucose, the plasma sodium concentration is increased by approximately 1.6 mEq/L for every 100 mg/dl of glucose above normal.

How does hypotonic hyponatremia occur?

The osmolality of body fluids is controlled in a very narrow range by hypothalamic osmoreceptors that regulate the synthesis and secretion of antidiuretic hormone (vasopressin/ADH). The defense against hyponatremia is dependant on the kidney's ability to excrete large volumes of ingested water - a setting that requires the absence of ADH.

Of the approximately 180 liters of glomerular filtrate per day, under normal circumstances, including normal dietary intake including sodium, potassium, and protein, as much as 15 liters of urine can be excreted in a 24-hour period. Conversely, in the presence of vasopressin, urinary dilution is impaired and this flexibility is markedly lost. Thus the continued ingestion of water in the presence of the hormone culminates in water retention and dilution of body fluids reflected by hypotonicity.

Of the above filtered volume, ~ 70% is reabsorped isotonically in the proximal convoluted tubule. Another 10% is reabsorbed in the descending limb of the Loop of Henle rendering the tubular fluid increasingly hypertonic as it travels down this segment of the nephron. Essentially no water is reabsorbed in the ascending limb of the Loop of Henle as this segment is water impermeable and tubular fluid is progressively diluted by the reabsorption of sodium chloride. Approximately 5% of the filtrate is reabsorbed in the distal convoluted tubule, but the critical final control of the excretion of water occurs at the collection duct.

The water permeability of the collecting duct is critically dependant on the presence of vasopressin and in its absence remains water impermeable allowing for the excretion of large volumes of water despite its proximity to an interstitium that is always at least isotonic. Vasopressin binds to the collecting duct via the V2 receptor which signals through cyclic-AM and regulates the insertion of the water channel (aquaporin-2) into the luminal membrane thereby rendering this epithelium with water permeability. The presence of vasopressin and the activation of this pathway in conjunction with persistent water intake underlies the mechanism of hyponatremia.

What is hypovolemic hyponatremia and why does it occur?

Hypovolemic hyponatremia is a result of intravascular volume depletion from a deficit in total body sodium that stimulates the non-osmotic release of vasopressin. This leads to water reabsorption from the kidney and hyponatremia.

Medical history should point to volume depletion such as:

  • Gastrointestinal losses: vomiting, nasogastric suctioning, diarrhea

  • Renal losses: diuretic therapy, osmotic diuresis, postobstructive diuresis

  • Dermal losses: sweating, burns

  • Hemorrhage

What are the physical exam findings of a patient with hypovolemic hyponatremia?

Weight loss, low blood pressure, low central venous pressure, tachycardia, orthostatic hypotension, reduction in urine output, poor skin turgor, dry mucous membranes.

What is and what causes euvolemic hypotonic hyponatremia?

Euvolemic hyponatremia occurs in individuals with normal total body sodium content. Unprovoked elevated levels of vasopression leads to water retention and hyponatremia. This can be seen in a variety of conditions:

  • Glucocorticoid deficiency

  • Severe hypothyroidism

  • Stress - psychic, physical, nausea, pain, anesthesia, and endurance exercise

  • Drugs: SSRIs, antipsychotic drugs, narcotics, tricyclic antidepressants, arginine vasopressin analogues, and others

  • Syndrome of inappropriate antiduretic hormone secretion (SIADH)

    • Malignancies

    • Pulmonary disorders

    • Central nervous system disorders

  • Aging

  • Hereditary causes (gain-of-function mutations of the vasopressin V2 receptor) - perhaps better designanted as nephrogenic syndrome of inappropriate anti-diuresis (NSIAD)

What are the physical exam findings of euvolemic hyponatremia?

Normal vital signs, no edema, and no signs of volume depletion as delineated above, or fluid overload. It can sometimes be difficult to distinguish between euvolemia and hypovolemia on physical exam alone.

What is and what causes hypervolemic hyponatremia?

Hypervolemic hyponatremia occurs as a result of arterial underfilling or a decrease in the effective renal blood volume, which leads to activation of neurohumoral pathways including the sympathetic nervous system, renin-angiotensin-aldosterone system and the non-osmotic release of vasopressin leading to sodium and water retention. This can occur in pathologic settings:

  • Congestive heart failure

  • Cirrhosis

  • Nephrotic syndrome

  • Physiologically in pregnancy

What are the physical exam findings in hypervolemic hyponatremia?

Lower extremity edema, ascites, pulmonary edema, pleural effusions, or elevated jugular venous pressure. Patients with decompensated heart failure or cirrhosis may have hypotension in the setting of hypervolemia due to poor cardiac output and splanchnic vasodilatation, respectively.

What is the definition of acute hyponatremia and how does it present?

Acute hyponatremia is defined as the new onset of hyponatremia within 48 hours. Symptoms vary depending on the degree of hyponatremia and usually occur at a serum sodium < 125 mEq/L. They include gastrointestinal complaints, lethargy, apathy, agitation, cramps, seizures, and coma.

The most severe symptom is the development of cerebral edema. The brain attempts to adapt to the rapid decrease in serum osmolality and is thwarted in some at risk patients such as:

  • Pre-menopausal women with hospital-acquired hyponatremia

  • Those using of thiazide diuretics

  • Children

This results in cerebral edema, which can be aggravated by the coexistence of hypoxemia.

What is the definition of chronic hyponatremia and how does it present?

Hyponatremia is considered chronic if it is present for more than 48 hours or if the duration is unknown. In this setting, the loss of intracellular osmolytes (inositol, taurine, sorbitol, and others) decreases brain water content. Therefore the risk of cerebral edema is markedly decreased and symptoms are often less dramatic. These include:

  • Anorexia and/or nausea

  • Gait disturbances/ataxia

  • Falls

  • Lethargy, apathy, and/or disorientation

  • Muscle cramps

  • Seizures may occur if hyponatremia is severe

What tests to perform?

Once hypotonic hyponatremia has been confirmed, what is the next step?

After confirmation that the patient has hypotonic hyponatremia, the next step is to measure the urine osmolality which can be done on a spot urine collection.

How do I interpret the urine osmolality?

The urine osmolality (Figure 1) assesses whether the patient is capable of diluting the urine. If the urine osmolality is < 100 mOsm/kg, the kidney is appropriately diluting the urine and is suggestive of water intoxication that occurs in psychogenic polydipsia, low solute intake (alcoholics, "tea and toast"), and infants that are fed dilute formula.

Figure 1.

Evaluation of hypotonic hyponatremia.

If the urine osmolality is > 100 mOsm/kg, a diluting defect is present and is almost always mediated by vasopressin.Vasopressin limits the diluting ability of the kidney thereby limiting renal water excretion. In the face of continued water intake, a positive water balance underlies the pathogenesis of hyponatremia in most cases.

What is the next step in determining the etiology of hypovolemic hyponatremia?

Obtain a spot urine sodium to determine if the hypovolemia is due to renal or extra-renal losses.

How do I interpret the urine sodium?

Urine sodium > 20 mEql/L is suggestive of renal losses:

  • Diuretics

  • Mineralocorticoid deficiency

  • Salt-losing nephropathy

  • Ketonuria

  • Bicarbonaturia

  • Cerebral salt wasting

Urine sodium < 20 mEq/L is suggestive of extrarenal losses:

  • Gastrointestinal losses

  • Third spacing of fluids from burns, pancreatitis, trauma

  • Poor oral intake

Patients with chronic kidney disease or acute kidney injury may be unable to reabsorb sodium due to tubular injury and therefore the urine sodium may be useful if it is <20mmol/L but may be difficult to interpret if high.

What is the next step in the evaluation of euvolemic hypotonic hyponatremia?

  • Spot urine sodium should be checked and should be > 20 mEq/L in the absence of diuretic use, reflecting normal dietary sodium intake. A low urine sodium could either indicate inadequate dietary sodium intake or intravascular volume depletion'

  • TSH to evaluate for hypothyroidism

  • Cortisol stimulation test to evaluate for adrenal insufficiency.

  • Plasma uric acid may be helpful in confirming SIADH. Levels < 4 mg/dl is suggestive of SIADH.

  • Elevated plasma vasopressin levels in the setting of hypotonicity and euvolemia confirms SIADH but is rarely performed.

If SIADH is suspected, an extensive evaluation for the etiology is warranted and should include

  • Complete review of medications

  • Age appropriate cancer screening

  • Chest x-ray and/or computed tomography (CT) scan depending on risk factors and clinical scenario

  • Imaging of the central nervous system with either a CT scan or magnetic resonance imaging (MRI)

What lab tests should be ordered for evaluation of hypervolemic hyopnatremia?

A spot urine sodium can be helpful.

  • Urine sodium < 20 mEq/L is suggestive of decreased effective renal blood flow and is seen in nephrotic syndrome, cirrhosis, heart failure

  • Urine sodium > 20 mEq/L can occur with acute or chronic renal failure and pregnancy

How should patients with hyponatremia be managed?

How do I approach a patient with hypotonic hyponatremia and a urine osmolality > 100 mOsm/kg?

An assessment of the patient's extracellular fluid volume is necessary.

Hypotonic hyponatremia can occur in three settings:

  • Hypovolemia (low total body sodium)

  • Euvolemia (normal total body sodium)

  • Hypervolemia (high total body sodium)

The medical history and physical exam can provide clues as to the etiology of hyponatremia. Laboratory data may help distinguish between the above listed three types of hypotonic hyponatremia. Accurate diagnosis is crucial to management.

How do I treat acute symptomatic hyponatremia?

Acute symptomatic hyponatremia is a medical emergency and therapy (Figure 2) should be immediately initiated. The initial goal is to reverse potentially life threatening cerebral edema and herniation.

Figure 2.

Management of symptomatic hyponatremia.

  • Administer 3% saline (513 mEq/L of sodium) at 1-2 cc/kg/hr until life-threatening symptoms subside. Typically an ~ 4-6 mEq/L increase in serum sodium will stop seizures and eliminate the risk of herniation.

  • Attend to any hypoxemia.

  • Once the life-threatening symptoms have resolved, further management will depend on the underlying etiology of hyponatremia.

  • Full correction in this setting is probably safe but not necessary.

How do I treat chronic symptomatic hyponatremia?

Slow correction of the sodium is crucial (see Figure 2). Patients with chronic hyponatremia are at high risk for the development of osmotic demyelination syndrome (see below) and therefore the sodium concentration should not be increased by more than 12 mEq/L in 24 hours and 18 mEq/L in 48 hours. These are limits of correction. The goal correction is ~ 8-10 mEq/L in the first 24 hours.

What is osmotic demyelination syndrome (ODS)?

In chronic hyponatremia, intracellular osmolytes leave the brain in response to a fall in the serum tonicity. Rapid correction of the serum sodium then leads to cerebral dehydration as water moves out of the cells. This can result in demyelination, classically in the central basis pontis, but can also occur in extrapontine sites.

Risk factors for the development of ODS:

  • Rapid correction of serum sodium > 12 mEq/L/24 hours (> 0.5 mEq/L/hour) or > 18 mEq/L/48 hours

  • Serum sodium < 120 mEq/L for more than 48 hours with an even higher risk if serum sodium is < 105 mEq/L

  • Alcoholism

  • Malnutrition

  • Hypokalemia

  • Thiazide induced hyponatremia in the elderly

  • Highly catabolic patients (i.e. burns)

  • Liver disease

Symptoms include altered mental status, lethargy, obtundation, seizures, coma, and motor abnormalities such as quadriplegia, respiratory paralysis, and pseudobulbar palsy. It is often but not always fatal.

Neurologic symptoms from hyponatremia may initially improve but then rapidly deteriorate due to the development of ODS, which typically develops a few days after the hyponatremia has been corrected.

ODS can be confirmed if head magnetic resonance imaging (MRI) shows demyelination. However a normal MRI does not exclude the diagnosis. Some patients have the clinical symptoms of ODS in the absence of MRI findings. ODS is primarily a clinical diagnosis.

There is no treatment for ODS therefore prevention with careful and slow correction of the serum sodium is crucial.

What are my treatment options for patients with chronic symptomatic hyponatremia?

The serum sodium concentration is a function of ([TbNa] + [TbK])/[Tb water] where Tb stands for total body. A decrease in the numerator results in depletional/hypovolemic hyponatremia. An increase in the denominator leads to dilutional/euvolemic hyponatremia

Treatment of hypovolemic hyponatremia is volume resuscitation using normal saline. Patients with hypovolemia are also at risk for ODS and therefore rapid correction should be avoided. If the serum sodium is correcting too quickly, then free water or DDAVP should be given to maintain the serum sodium within the therapeutic goal. As per the above formula, the repletion of potassium in itself also results in an increase in the serum sodium (Figure 2).

Most cases of hyponatremia are dilutional with excessive free water. The goal of therapy is to remove free water from the patient, resulting in an increase in the serum sodium concentration. A number of therapeutic options are available, depending on the degree of hyponatremia and underlying etiology:

  • Free water restriction: If a patient excretes more free water than is consumed (either intravenously or orally) the serum sodium should increase. To determine if this is a reasonable option, it is helpful to assess whether the patient is excreting free water. Free water is excreted if the ratio of (UrineNa + urine K)/Serum Na < 1. Such a patient may respond to water restriction if severe enough and if he/she is compliant with this difficult regimen.

    • If the ratio is > 1, water restriction is unlikely to be effective.

  • Administration of loop diuretics +/- repletion of solutes (Na, K): Loop diuretics result in excretion of electrolyte free water with an electrolyte clearance approximating half normal saline.

    • In the setting of SIADH, continued use of a loop diuretic will result in hypovolemia due to urinary sodium losses. This decrease in total body sodium and potassium will also alter the numerator of the above relationship impeding the correction of the serum sodium concentration. Therefore patients will need sodium and potassium supplementation.

    • In the setting of hypervolemic hyponatremia (heart failure, cirrhosis), loop diuretics will lead to both sodium and water excretion which is appropriate.

  • Hypertonic saline and DDAVP: The use of 3% saline will increase the serum sodium. In the setting of a reversible cause of ADH elevation (i.e.dehydration, drugs, polydipsea), the correction of the underlying problem will lead to a water diuresis and overcorrection. Therefore if hypertonic saline is given in conjunction with DDAVP, this can be avoided. However, it may lead to worsening hyponatremia if the patient is not monitored closely.

  • Vasopressin antagonists: Conivaptan and tolvaptan are U.S. Food and Drug Administration approved vasopressin antagonists for use in euvolemic and hypervolemic hyponatremia. These drugs increase free water excretion and raise serum sodium concentrations. Both must be administered in the hospital setting with frequent sodium monitoring.

    • Conivaptan is an intravenous V1/V2 receptor antagonist with a half-life of 5-12 hours.

    • Tolvaptan is an orally active selective V2 receptor antagonist with a half-life of 6-8 hours. Patients with SIADH and congestive heart failure have similar rates of correction of serum sodium while those with cirrhosis have a more modest response.

    • Cessation of these medications will lead to recurrent hyponatremia unless the underlying process is reversed.

What do I do if the treatment limits were exceeded?

What do I do if the treatment limits were exceeded?

If the serum sodium increases by more than 12 mEq/L in the first 24 hours, re-lowering the serum sodium is indicated.

This can be accomplished by the administration of free water (IV D5W or oral intake) at a rate greater than what is being excreted. If necessary, DDAVP (desmopressin) can be administered to prevent further renal losses of free water. In patients who are treated with a V2 antagonist, the DDAVP may fail to abrogate free water losses.

How do I manage a patient with chronic mildly symptomatic hyponatremia?

Most patients with mildly symptomatic hyponatremia (gait disturbances, falls, attention deficits, etc) are chronic and therefore there is typically no urgency to correct them rapidly.

Treatment options include:

  • Demeclocycline: This medication acts on the collecting duct to decrease responsiveness to ADH and therefore can lead to a nephrogenic diabetes insipidus. The starting dose is 300-600 mg twice a day. Side effects include photosensitivity, gastrointestinal symptoms, and reversible nephrotoxicity (especially inpatients with hepatic disease or congestive heart failure). It should be avoided in pregnancy and in children.

  • Maneuvers that increase solute excretion:

    • Salt tablets (2-3 grams/day) plus a loop diuretic

    • Urea (30 grams/day). This is almost always found to be unpalatable.

  • V2 Antagonists: Tolvaptan is the only one approved for chronic use. Patients must be hospitalized for 24 hours while starting therapy.

  • Free water restriction: This is effective in patients with mild diluting defects and compliance is often difficult.

How should a patient receiving treatment for hyponatremia be monitored?

Patients with acute symptomatic hyponatremia or a serum sodium < 120 mEq/L should be monitored in a controlled environment, such as the intensive care unit, where they can undergo frequent lab testing and close monitoring of their urine output.

Patients should have a serum sodium checked every 2-4 hours depending on the clinical scenario. This will help determine if the therapy is being effective and to avoid overcorrection.

Urine output should be monitored every 1-2 hours. Once the stimulus for ADH is removed (ie, resolution of hypovolemia), a free water diuresis can develop. These patients may require hypotonic fluids or DDAVP to avoid rapid correction of serum sodium.

Neurologic status should be assessed every few hours to evaluate for improvement in symptoms.

How to utilize team care?

Nephrologists should be consulted for the use of hypertonic saline, the use of vasopressin antagonists, or any time the primary medical team feels uncomfortable managing the hyponatremia.

Nurses should be educated as to the importance of notifying the primary team if a patient's urine output significantly increases. In addition, they can monitor fluid intake and fluid restrictions.

Pharmacists can assist in concentrating intravenous medications if indicated and ensuring that the amount of free water the patient is receiving with medications is minimized.

Dieticians can counsel patients about what a fluid restriction entails. A fluid restriction includes not only water but other liquids (juice, tea, etc.) and foods with a high water content, such as fruits.

Are there ongoing clinical trials of therapeutic significance?

A phase 3B, multicenter, randomized, single blinded study to compare the effectiveness of oral tolvaptan (titrated at doses between 15 mg/day to 60 mg/day) without fluid restriction to placebo plus fluid restriction on length of hospital stay and symptoms in patients with dilutional hyponatremia is currently enrolling patients.

Recently, a multicenter, randomized, double-blinded, placebo-controlled study evaluating the safety and efficacy of oral lixivaptan for euvolemic hyponatremia was completed. The results are still pending. An open labeled observational longer term follow-up study is currently ongoing.

Other considerations

N/A

What is the evidence?

Thurman, JM, Berl, T, Wilcox, CS. "Therapy of Dysnatremic Disorders". Therapy in Nephrology and Hypertension. Saunders Elsevier. 2008. pp. 337-347.

(A comprehensive review on the treatment of hyponatremia with clinical examples.)

Tzamaloukas, AH, Ing, TS, Siamopoulos, KC, Rohrscheib, M, Elisaf, MS, Raj, DSC, Murata, GH. "Body fluid abnormalities in severe hyperglycemia in patients on chronic dialysis: review of published reports". J Diabetes Complications. vol. 22. 2008. pp. 29-37.

(A review of the effects of hyperglycemia and its consequences on fluid compartments.)

Ellison, DH, Berl, T. "The syndrome of inappropriate antidiuresis". N Eng J Med. vol. 356. 2007. pp. 2064-2072.

(A review focused on the syndrome of inappropriate antidiuresis.)

Berl, T, Rastegar, A. "A patient with severe hyponatremia and hypokalemia: osmotic demyelination following potassium repletion". AJKD. vol. 55. 2010. pp. 742-748.

(A patient report illustrating the effects of potassium repletion on serum sodium.)

Sterns, RH, Cappuccio, JD, Silver, SM, Cohen, EP. "Neurologic sequelae after treatment of severe hyponatremia: A multicenter perspective". J Am Soc Nephrol. vol. 4. 1994. pp. 1522-1530.

(Results of the national survey on the neurological outcomes of treatment of acute and chronic hyponatremia.)

Sterns, RH, Silver, SM. "Brain volume regulation in response to hypo-osmolality and its correction". Am J Med. vol. 119. 2006. pp. S12-16.

(A description of how the brain adapts to acute and chronic changes in serum sodium.)

Elhassan, EA, Schrier, RW. "Hyponatremia: diagnosis, complications, and management including V2 receptor antagonists". Curr Opin Nephrol Hypertens. vol. 20. 2011. pp. 161-168.

(An overall discussion on hyponatremia and its treament with V2 antagonists.)

Berl, T, Quittnat-Pelletier, F, Verbalis, JG, Schrier, RW, Bichet, DG, Quyang, J, Czerwiec, FS. "Oral Tolvaptan Is safe and effectivive in chronic hyponatremia". J Am Soc Nephrol. vol. 21. 2010. pp. 705-712.

(An open label long term study of the effects of the V2 antagonist on serum sodium.)

Schrier, RW, Gross, P, Gheorghiade, M, Berl, T, Verbalis, JG, Czerwiec, FS, Orlandi, C. "Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia". N Engl J Med. vol. 355. 2006. pp. 2099-2112.

(Original double blind controlled trial of tolvaptan in the treatment of euvolemic and hypervolemic hyponatremia.)
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