Hyponatremia: Evaluation and Treatment

If liver injury is suspected, tolvaptan should be discontinued. Recently FDA has recommended Tolvaptan use but not for greater than 4 wks. Fluid restriction should not be used during the active phase of correction, thereby allowing the patient's thirst to compensate for vigorous aquaresis. Appropriate caution should be exercised in patients treated with tolvaptan for hyponatremia for extended periods e. Patients who are refractory to or unable to tolerate or obtain other therapies for hyponatremia and in whom the benefit of tolvaptan treatment outweighs the risks, remain candidates for long- term therapy with tolvaptan; but in such cases, liver function tests should be monitored carefully and serially i.

Conivaptan is FDA approved for euvolemic hyponatremia in hospitalized patients. It is available only as an intravenous preparation and is given as a mg loading dose over 30 min, followed by a continuous infusion. Generally, the mg continuous infusion is used for the first 24 h. Therapy is limited to a maximum duration of 4 days because of drug-interaction effects with other agents metabolized by the CYP3A4 hepatic isoenzyme.

Hyponatremia in CHF is chronic and should be corrected till serum Na is normal and symptoms improve. The level of serum Na should be normalized so that diuretic therapy for CHF can be optimised. In some studies, hyponatremia was associated with increased mortality and increased rate of re-hospitalization in patients of acute heart failure. Further studies of the Vaptans are necessary to determine whether serum sodium normalization will be translated into a better long-term prognosis in patients with CCF.

However Tolvaptan has been found to be hepatotoxic and hence USFDA has limited their use only in those hyponatremic patients with end-stage liver disease who are awaiting imminent liver transplantation, who are at little risk of added hepatic injury and will benefit from correction of hyponatremia before surgery to decrease the risk of ODS postoperatively. In earlier studies the patients with cirrhosis were found to have improved serum sodium levels with vaptans however therewas no clear difference between Vaptans and control groups regarding mortality, variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome, or renal failure.

Hence is contraindicated in cirrhosis. Satvaptan was found to maintain sodium levels long term in cirrhotics however it's use is also limited. Contraindications to vaptans-Vasopressin receptor antagonists should not be used in hyponatremic patients who are volume depleted.

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2. Diagnosis and Management of Sodium Disorders: Hyponatremia and Hypernatremia.
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Vaptans should not be used to treat the type of euvolemic hyponatremia caused by emetic stimuli or secondary adrenal insufficiency and they are ineffective in the vasopressin-independent form of SIADH caused by an activating mutation of the V 2 receptor. They are ineffective where AVP levels are appropriate, for example, cerebral salt wasting and psychogenic polydipsia.

Tolvaptan has less potential for drug-drug interactions. Coadministration of conivaptan with potent inhibitors of CYP3A4 , such as ketoconazole, itraconazole, clarithromycin, ritonavir and indinavir is contraindicated. Weight, serum sodium, Blood pressure, liver functions should be monitored every 15 days for months then monthly. Serum potassium and kidney functions should be monitored regularly. Hyponatremia is a frequently encountered problem in clinical practice and is an important cause of morbidity and mortality.

Establishment of etiology and appropriate treatment improves outcome. A knowledge of recent guidelines of treatment and the appropriate use of vaptans is essential for all clinicians for proper diagnosis and management. National Center for Biotechnology Information , U. Indian J Endocrinol Metab. Manisha Sahay and Rakesh Sahay. Author information Copyright and License information Disclaimer. This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.

This article has been cited by other articles in PMC. Abstract Hyponatremia is an important and common clinical problem. Pathogenesis of hyponatremia Hyponatremia results from the inability of the kidney to excrete a water load or excess water intake. Normal but persistent ADH secretion-In volume depletion the effect of decreased volume counteracts the effect of hypoosmolality and ADH stimulation continues to occur. Effective arterial blood volume depletion occurs by two mechanisms: True volume depletion; and in edematous patients with heart failure or cirrhosis in whom tissue perfusion is reduced because of a low cardiac output or arterial vasodilation, respectively.

The reduction in tissue perfusion is sensed by baroreceptors at three sites: As a result there is water retention. Classification of hyponatremia Hyponatremia is classified as pseudo hyponatremia, true and translocational hyponatremia [ Figure 1 ]. Open in a separate window. Etiology of true hyponatremia Hypovolemia hyponatremia It is associated with low plasma volume. Type A — there is unregulated release of ADH that has no relation to plasma osmolality.

Plasma ADH levels are above that required for maximum antidiuresis, so urine osmolality is very high. Type C- there is downward resetting of osmostat. Type D- is the least common.

Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations.

Osmoregulation is normal i. ADH secretion varies appropriately with the plasma osmolality , but the urine is concentrated even with suppressed ADH release. There are 3 mechanisms a germ cell mutation in which the V2 vasopressin receptor is activated. Exercise-associated hyponatremia Marathon runners may develop severe hyponatremia due to excessive water intake associated with persistent ADH secretion in some. Low dietary solute intake Beer drinkers or other malnourished patients those with low-protein, high water intake diets have a marked reduction in water excretory capacity despite suppressed ADH.

Primary polydipsia Is characterized by increase in thirst and is most often seen in patients with psychiatric illnesses. Hypervolemic hyponatremia It is seen in congestive heart failure and cirrhosis of liver, nephrotic syndrome and chronic kidney disease. Diagnosis of hyponatremia History and examination Drug and diet history, history of volume loss i. Serum osmolality It differentiates true, pseudo or translocational hyponatremia [ Figure 1 ]. Urine osmolality Urine osmolality can be used to distinguish between impaired water excretion and hyponatremia with normal water excretion [ Table 5 ].

Table 5 Urine osmolality for differential diagnosis of hyponatremia. If the patient is hypovolemic, 0. Stimulation of the vasopressor V1a receptor also contributes to the uric acid wasting. Water retention also causes low BUN. Thiazide diuretic-induced hyponatremia similar reductions in uric acid and urea levels can occur in patients with thiazide diuretic-induced hyponatremia where thiazides are used for water overload. Metabolic acidosis and hyperkalemia - primary adrenal insufficiency in patients without renal failure.

Mild metabolic alkalosis and normal K- is seen in hypopituitarism because of higher plasma aldosterone levels. Euvolemic hyponatremia General treatment Acute hyponatemia is generally symptomatic. The risk of brain herniation is high and rapid correction is needed. Acute hyponatremia is common in marathon runners, patients with primary polydipsia and users of ecstasy.

These patients have not had time for the brain adaptations to occur. Chronic hyponatremia- It is generally asymptomatic or has mild symptoms. However; it may present with seizures if hyponatremia is very severe. Among patients with urine to serum electrolyte ratio greater than 1, in whom fluid restriction will not be sufficient to achieve the desired goal, additional therapy includes salt tablets and if necessary, a loop diuretic. An alternative approach is the initiation of a vasopressin antagonist without fluid restriction.

Potassium added to the solution should be included in the formula i. However, these formulae have limitations and cannot be used to accurately predict the magnitude of change in serum sodium and frequent measurements are necessary. In the current guidelines these formulae are not used. Role of vaptans in euvolemic hyponatremia is discussed below. Adrenal insufficiency Glucocorticoid deficiency should be excluded by proper tests.

Hypovolemic hyponatremia Presentation may be acute or chronic. K may be added if required. Gastrointestinal losses- may be acute or chronic. Urine Cl is a better marker for volume status in patients with vomiting instead of Urine Na. Both K and bicarbonate deficits should be corrected along with volume correction. CSW may present acutely. Thiazides induced hyponatremia is usually chronic and should be corrected slowly as risk of ODS is high.

K should also be supplemented. Patients with thiazide-induced hyponatremia are at high risk for a recurrence and should not be rechallenged with a thiazide. Mineralocorticoid deficiency associated hyponatremia is chronic and responsds to 0. Fludrocortisone may be need for long term treatment.

Hypervolemic hyponatremia Hypervolemic hyponatremia is seen in CHF and cirrhosis. Water restriction is the mainstay of therapy. Vasopressin receptor antagonists Vaptans Vaptans act on vasopressin receptors as antagonists. There are both oral and IV preparations available. Nelivaptan, V2 selective V2RA: Lixivaptan, Moxavaptan, Satavaptan, Tolvaptan. Only tolvaptan and conivaptan are currently available in India.

I Vaptans in euvolemic hyponatremia Treatable causes of Euvolemic Hyponatremia should be excluded e. Adverse effects Thirst, Dryness of mouth, Orthostatic hypotension, Encephalopathy. Footnotes Source of Support: Nil Conflict of Interest: Diagnosis, evaluation and treatment of hyponatremia: Incidence and prevalence of hyponatremia.

Clinical assessment of extracellular fluid volume in hyponatremia. Diagnostic approach to a patient with hyponatraemia: Traditional versus physiology-based options. Utility and limitations of the traditional diagnostic approach to hyponatremia: Seek and you will find. Comparison between copeptin and vasopressin in a population from the community and in people with chronic kidney disease.

J Clin Endocrinol Metab Ellison DH, Berl T.: The syndrome of inappropriate antidiuresis. Musch W, Decaux G.: Treating the syndrome of inappropriate ADH secretion with isotonic saline. Postoperative hyponatremia despite near-isotonic saline infusion: A phenomenon of desalination. Ann Intern Med Development of severe hyponatraemia in hospitalized patients: Treatment-related risk factors and inadequate management.

Nephrol Dial Transplant Hypertonic saline and desmopressin: A simple strategy for safe correction of severe hyponatremia. DDAVP is effective in preventing and reversing inadvertent overcorrection of hyponatremia. Clin J Am Soc Nephrol 3: Value of fractional uric acid excretion in differential diagnosis of hyponatremic patients on diuretics. Evaluation of copeptin and commonly used laboratory parameters for the differential diagnosis of profound hyponatraemia in hospitalized patients: Clin Endocrinol Oxf Is it cerebral or renal salt wasting?

Incidence and pathophysiology of severe hyponatraemia in neurosurgical patients. Postgrad Med J Truths, fallacies, theories, and challenges. Crit Care Med A prospective analysis of its epidemiology and the pathogenetic role of vasopressin. Hoorn EJ, Zietse R.: Translating physiology to practice. Reproducibility by single dose rechallenge and an analysis of pathogenesis.

Thiazide-induced hyponatraemia is associated with increased water intake and impaired urea-mediated water excretion at low plasma antidiuretic hormone and urine aquaporin Regulation of arginine vasopressin in the syndrome of inappropriate antidiuresis.

Differential Diagnosis of Hyponatremia

S36—S42, [ PubMed ]. Olfactory neuroblastoma with hyponatremia. J Clin Oncol Effect of administration of corticotropin-releasing hormone and glucocorticoid on arginine vasopressin response to osmotic stimulus in normal subjects and patients with hypocorticotropinism without overt diabetes insipidus. The contribution of undiagnosed adrenal insufficiency to euvolaemic hyponatraemia: Results of a large prospective single-centre study.

Misinterpretation of serum cortisol in a patient with hyponatraemia. Severe hyponatremia with high urine sodium and osmolality. Role of renal aquaporins in escape from vasopressin-induced antidiuresis in rat. J Clin Invest Carbamazepine can induce kidney water absorption by increasing aquaporin 2 expression. Fluoxetine effect on kidney water reabsorption. Nephrogenic syndrome of inappropriate antidiuresis. Moses AM, Clayton B.: Impairment of osmotically stimulated AVP release in patients with primary polydipsia.

Am J Physiol R—R, [ PubMed ]. Assay for the measurement of copeptin, a stable peptide derived from the precursor of vasopressin.

Christ-Crain M, Fenske W.: Copeptin in the diagnosis of vasopressin-dependent disorders of fluid homeostasis. Nat Rev Endocrinol Copeptin in the differential diagnosis of hyponatremia. Robertson GL, Athar S.: The interaction of blood osmolality and blood volume in regulating plasma vasopressin in man. Zhang Z, Bourque CW.: Amplification of transducer gain by angiotensin II-mediated enhancement of cortical actin density in osmosensory neurons. A copeptin-based classification of the osmoregulatory defects in the syndrome of inappropriate antidiuresis.

Mid-regional pro-atrial natriuretic peptide and the assessment of volaemic status and differential diagnosis of profound hyponatraemia. J Intern Med Apelin counteracts vasopressin-induced water reabsorption via cross talk between apelin and vasopressin receptor signaling pathways in the rat collecting duct. Clin Chem Lab Med Osmotic demyelination syndrome following correction of hyponatremia.

Brain volume regulation in response to hypo-osmolality and its correction. S12—S16, [ PubMed ]. What is all the controversy about? Central pontine and extrapontine myelinolysis: The osmotic demyelination syndromes. J Neurol Neurosurg Psychiatry 75 [ Suppl 3 ]: Therapeutic approach in patients with dysnatraemias. Re-induction of hyponatremia after rapid overcorrection of hyponatremia reduces mortality in rats.

Electrolyte disorders in community subjects: Prevalence and risk factors. How innocent is the bystander? More than just a marker of disease severity? Nat Rev Nephrol 9: Biochemical and etiological characteristics of acute hyponatremia in the emergency department. J Emerg Med Moses AM, Miller M.: A review of drug-induced hyponatremia. Agarwal R, Emmett M.: The post-transurethral resection of prostate syndrome: Arch Intern Med Current prescriptions for the correction of hyponatraemia and hypernatraemia: Are they too simple?

A novel treatment for hyponatremic encephalopathy. Metab Brain Dis Hypertonic saline for hyponatremia: Risk of inadvertent overcorrection. Clin J Am Soc Nephrol 2: New approach to disturbances in the plasma sodium concentration. If plasma osmolality increases, ADH is secreted and water is retained by the kidneys, thus decreasing serum osmolality.

If plasma osmolality decreases, ADH also decreases, resulting in diuresis of free water and a return to homeostasis. Symptoms of hyponatremia depend on its severity and on the rate of sodium decline. Gradual decreases in sodium usually result in minimal symptoms, whereas rapid decreases can result in severe symptoms.

Polydipsia, muscle cramps, headaches, falls, confusion, altered mental status, obtundation, coma, and status epilepticus may indicate the need for acute intervention. Most patients with hyponatremia are asymptomatic, and hyponatremia is noted incidentally. Volume status should be assessed to help determine the underlying cause 11 , 13 Figure 1 11 — 16 [ corrected ]. Information from references 11 through The diagnostic workup should include a history and physical examination with specific attention to cardiac, cancer, pulmonary, surgical, endocrine, gastrointestinal, neurologic, and renal histories Table 1.

Serum and urinary monoclonal protein, bone marrow biopsy, lytic bone lesions detected on radiography. Diagnosis of exclusion e. Therapy to decrease alcohol use and nutritional counseling to increase protein intake. Low aldosterone, morning cortisol, and adrenocorticotropic hormone levels, hyperkalemia, increased plasma renin level. SIADH secondary to medication use e.

Correct underlying disease with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Laboratory tests include a complete metabolic panel and urinary sodium and creatinine levels. Measurement of thyroid-stimulating hormone, urinary uric acid, adrenocorticotropic hormone, plasma cortisol, and brain natriuretic peptide may be considered in select patients to rule out other causes.

Online calculators available at http: Online calculators for the rate of infusion and the concentration of sodium required are available at http: Serum sodium correction should generally not proceed faster than 0. The goal is to raise the serum sodium level not to exceed 10 to 12 mEq per L in the first 24 hours and 18 mEq per L in the first 48 hours.

In patients with hyperglycemia, uncorrected sodium should be used to calculate the osmolality. Online calculator available at http: N Engl J Med. Bhagat CI, et al. Calculated vs measured plasma osmolalities revisited. Hillier TA, et al. Hyperglycemia-induced hyponatremia—calculation of expected serum sodium depression. Pfennig CL, et al. Sodium disorders in the emergency department: Pseudohyponatremia occurs when seemingly low sodium levels are actually normal.

Diagnosis and Treatment of Hyponatremia: Compilation of the Guidelines

Causes include hyperglycemia, hyperproteinemia, mannitol use, or laboratory errors. Osmolality remains unchanged, and patients are usually euvolemic. There are numerous causes of hypovolemic hyponatremia Table 1. Urinary sodium levels are typically less than 20 mEq per L unless the kidney is the site of sodium loss. Fractional excretion of sodium is often inaccurately elevated in patients receiving diuretics because of diuretic-induced natriuresis; fractional excretion of urea can be utilized in these patients instead.

Euvolemic hyponatremia is most commonly caused by SIADH, but can also be caused by hypothyroidism and glucocorticoid deficiency. Euvolemia is diagnosed by findings from the history and physical examination, low serum uric acid levels, a normal blood urea nitrogen—to-creatinine ratio, and spot urinary sodium greater than 20 mEq per L. Diuretic therapy can artificially elevate urinary sodium, whereas a low-salt diet can artificially lower urinary sodium, thus clouding the diagnosis of hypovolemia vs.

Treatment generally consists of fluid restriction and correcting the underlying cause. Fluid restriction should be limited to mL less than the daily urinary volume. Predictors of failure with fluid restriction include urinary osmolality greater than mOsm per kg, hour urinary volume less than 1. The use of demeclocycline Declomycin and lithium is not recommended because of an increased risk of harm. Hypervolemic hyponatremia occurs when the kidneys cannot excrete water efficiently. In volume overload states, the effective arterial blood volume is decreased compared with venous volume, resulting in excess ADH secretion.

The most common causes of hypervolemic hyponatremia are heart failure, cirrhosis, and kidney injury. Treatment consists of correcting the underlying cause, sodium and fluid restriction, and diuretic therapy to increase excretion of solute-free water. Severe symptomatic hyponatremia occurs when sodium levels decrease over less than 24 hours.

Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations.

Severe symptomatic hyponatremia must be corrected promptly because it can lead to cerebral edema, irreversible neurologic damage, respiratory arrest, brainstem herniation, and death. At this time, vaptans have no role in the treatment of symptomatic hyponatremia because of the potential for overcorrection of sodium and variable sodium fluctuations. The rate of sodium correction should be 6 to 12 mEq per L in the first 24 hours and 18 mEq per L or less in 48 hours.

Overcorrection is common and is typically caused by rapid diuresis secondary to decreasing ADH levels. Every attempt should be made not to overcorrect sodium levels. This method increased sodium levels by 1. Information from references 13 , 14 , and 20 through Vaptans conivaptan [Vaprisol] and tolvaptan [Samsca] are vasopressin-receptor antagonists approved for the treatment of hospitalized patients with severe hypervolemic and euvolemic hyponatremia eTable B.

However, their use in the management of hyponatremia is controversial. Several trials have demonstrated that vaptans increase sodium levels in patients with cirrhosis and heart failure. Patients with moderate hepatic impairment: Change intravenous site every 24 hours; avoid corn products. Do not use for more than 30 days or in patients with underlying liver disease because of risk of hepatotoxicity; avoid consumption of grapefruit juice. Contraindicated in patients with anuria or concurrent use of CYP3A inhibitors.

Not recommended for patients with creatinine clearance less than 30 mL per minute per 1. Contraindicated in patients with hypovolemic hyponatremia, anuria, or concurrent use of CYP3A inhibitors, or when there is an urgent need to increase sodium levels. Not recommended for patients with creatinine clearance less than 10 mL per minute per 1. No reports of osmotic demyelination; however, vaptans can rapidly overcorrect. Hypovolemic hyponatremia should be ruled out before initiating therapy.

Should not be used in patients with severe symptomatic hyponatremia. Good safety profile for limited use in current studies; further study needed to evaluate long-term use, effects, cost-effectiveness, and effects on morbidity and mortality. Optimal regimens and dosages are unclear. Lixivaptan is awaiting approval from the U. Food and Drug Administration for use in patients with euvolemia and hypervolemic hyponatremia. Dahl E, et al. Lehrich RW, et al. Role of vaptans in the management of hyponatremia. Am J Kidney Dis. J Clin Endocrinol Metab. Hypernatremia is defined as a serum sodium level greater than mEq per L.

It is associated with increased morbidity and mortality in the inpatient setting.

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Patients at increased risk include those with an impaired thirst mechanism or restricted access to water e. Symptoms of hypernatremia in infants can include tachypnea, muscle weakness, restlessness, a high-pitched cry, insomnia, lethargy, and coma. Seizures usually occur only in cases of inadvertent sodium loading or rapid rehydration.

In adults, symptoms tend to be mild and may include anorexia, muscle weakness, restlessness, nausea, and vomiting. Severe symptoms are likely to occur with acute increases in plasma sodium levels or at concentrations greater than mEq per L. Hypernatremia can cause brain shrinkage, resulting in vascular rupture and intracranial bleeding. The cause of hypernatremia is usually evident from the history and physical examination, and is typically water loss e.

Water loss can be pure water loss e.