Hyponatremia: Evaluation and Treatment

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

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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. Sodium gain is usually iatrogenic from the infusion of hypertonic solutions. Laboratory studies are not necessary if the cause is apparent from the history, but frequent electrolyte checks are recommended during correction. When the cause is not clear, laboratory studies should be guided by the history 12 Figure 3 Clinical history of central nervous system insult; urinary concentration after administration of desmopressin.

History of nephrotoxic medication use amphotericin, demeclocycline [Declomycin], foscarnet, lithium, methoxyflurane , failure to concentrate urine after administration of desmopressin. History of hypertension and hypokalemia, plasma aldosterone-to-renin ratio, 3 history of hypertension and hypokalemia. Recent administration of hypertonic saline, enteral feedings, sodium bicarbonate infusion, or hypertonic dialysis. Information from references 3 , 12 , 33 , and Diabetes insipidus is caused by a defect in ADH, either at the level of the central nervous system central diabetes insipidus or kidneys nephrogenic diabetes insipidus.

Inappropriately dilute urine osmolality less than mOsm per kg in the setting of hypernatremia suggests diabetes insipidus. Hyperaldosteronism can cause mild hypernatremia but is rarely clinically relevant. Hyperglycemia can also cause hypernatremia, even after correction of glucose levels. The treatment of hypernatremia involves treating the underlying cause and correcting the water deficit.

Determining volume status and calculating the total body water deficit are important eTable A. When correcting the total body water deficit, oral or enteral free water should be used whenever possible. When intravenous fluids are required, hypotonic solutions should be used. Rapid over-correction can result in cerebral edema; therefore, the least amount of fluid possible should be used. In patients with rapid development of hypernatremia, sodium can be corrected quickly with isotonic saline or water without increasing the risk of cerebral edema.

A correction rate of 1 mEq per L per hour is considered safe in these patients.

Etiology and Pathophysiology

The search included meta-analyses, randomized controlled trials, clinical trials, and reviews. November 15, ; March 1, ; and October 5, The views expressed are those of the authors and do not reflect the official policy of the Department of the Army, the Department of Defense, or the U. Already a member or subscriber?

Address correspondence to Michael M. Reprints are not available from the authors. Hoorn EJ, et al. Mannesse CK, et al. Prevalence of hyponatremia on geriatric wards compared to other settings over four decades: Gankam-Kengne F, et al. Mild hyponatremia is associated with an increased risk of death in an ambulatory setting.

Age and gender as risk factors for hyponatremia and hypernatremia. Crestanello JA, et al. Preoperative hyponatremia predicts outcomes after cardiac surgery. Does preoperative hyponatremia potentiate the effects of left ventricular dysfunction on mortality after cardiac surgery? J Thorac Cardiovasc Surg. Vaishya R, et al. Mortality predictions in severe hyponatraemia in emergency inpatients. J Indian Med Assoc. Shchekochikhin DY, et al. Outcome differences in community- versus hospital-acquired hyponatremia in patients with a diagnosis of heart failure.

Hagino T, et al. Hyponatremia at admission is associated with in-hospital death in patients with hip fracture.

Differential Diagnosis of Hyponatremia

Arch Orthop Trauma Surg. Korkmaz I, et al. Baseline characteristics and the association between hyponatraemia and pulmonary embolism prognosis. J Pak Med Assoc. Verbalis JG, et al.

Diagnosis, evaluation, and treatment of hyponatremia: Spasovski G, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Masri G, et al.

Diagnostic Approach to Hyponatremia

Accessed October 8, Sarikonda KV, et al. Imbriano LJ, et al. Normal fractional urate excretion identifies hyponatremic patients with reset osmostat. Carvounis CP, et al. Significance of the fractional excretion of urea in the differential diagnosis of acute renal failure. Albert NM, et al. A randomized controlled pilot study of outcomes of strict allowance of fluid therapy in hyponatremic heart failure SALT-HF.

Sterns RH, et al. The treatment of hyponatremia. Sood L, et al. Hypertonic saline and desmopressin: Hew-Butler T, et al. Clin J Sport Med. Moritz ML, et al. Tolvaptan, an oral vasopressin antagonist, in the treatment of hyponatremia in cirrhosis. Hauptman PJ, et al. Clinical course of patients with hyponatremia and decompensated systolic heart failure and the effect of vasopressin receptor antagonism with tolvaptan. Schrier RW, et al.

Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. Josiassen RC, et al. Clin Schizophr Relat Psychoses. Oral tolvaptan is safe and effective in chronic hyponatremia [published correction appears in J Am Soc Nephrol. J Am Soc Nephrol. Mc Causland FR, et al. Association of serum sodium with morbidity and mortality in hospitalized patients undergoing major orthopedic surgery. Leung AA, et al. Preoperative hypernatremia predicts increased perioperative morbidity and mortality.

Funder JW, et al. Case detection, diagnosis, and treatment of patients with primary aldosteronism: 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. 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.

Hyponatremia: A practical approach

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. Mild chronic hyponatremia is associated with falls, unsteadiness and attention deficits.

A new method for determining plasma water content: Am J Physiol Renal Physiol. Effects of protein and triglycerides on serum sodium and potassium values obtained by the Kodak dry film potentiometric technique. Can J Med Technol. Evaluating the correction factor for hyperglycemia. Clinical disorders of urinary dilution and concentration. J Am Soc Nephrol. N Engl J Med. The challenge of hyponatremia. Thiazide-induced hyponatremia associated with death or neurologic damage in outpatients.

A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone.

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Ellison DH, Berl T. The syndrome of inappropriate antidiuresis. Hypouremia in the syndrome of inappropriate secretion of antidiuretic hormone. Disordered control of thirst in hypothalamic-pituitary sarcoidosis. A metabolic study of patients with lung cancer and hyponatremia of malignancy. Inappropriate antidiuresis during carbamazepine treatment.

Water intoxication and thioridazine Mellaril Ann Intern Med. The agony of ecstasy: MDMA 3,4-methylenedioxymethamphetamine and the kidney. This was the case especially for vaptans, which will therefore be discussed in more detail below. Vaptans block vasopressin type 2 receptors in collecting duct principal cells and therefore induce aquaresis for comprehensive review, see Berl, 84 Hoorn and Zietse, 85 Lehrich et al. Several vaptans were developed, including tolvaptan, satavaptan, lixivaptan, and conivaptan which also targets vasopressin type 1a receptors.

On the basis of their mechanism of action, vaptans are a logical and targeted therapy for hyponatremic patients with excess vasopressin. Indeed, several large clinical trials have shown that vaptans are clearly effective in increasing S Na in patients with hyponatremia due to SIAD, heart failure, or liver cirrhosis. Meanwhile, one meta-analysis has suggested improved survival with correction of hyponatremia, 93 although bias is difficult to exclude because no randomized controlled trials are available. Furthermore, there is evidence for potential harm of vaptans, including overcorrection, and liver toxicity.

This includes improvements in some neurocognitive symptoms, 98 performance status in cancer patients, 99 dyspnea in patients with heart failure, and ascites in patients with liver cirrhosis. Both guidelines suggest an interesting alternative to vaptans for chronic hyponatremia due to SIAD, namely urea. Decaux and colleagues pioneered the use of urea in the s for SIAD, but also for other forms of hyponatremia.

Although urea does not prevent overcorrection, it may reduce the risk of the associated brain damage. Histologic analysis showed that, in comparison to the two other treatments, urea reduced demyelination, microglial activation, and changes in the blood-brain barrier, and increased astrocyte viability.

This problem has been solved by developing a formulation in which urea is combined with sodium bicarbonate, citric acid, and sucrose see European guideline for prescription 7 and by the development of a commercially available urea powder drink mix Ure-Na by Nephcentric. Our impression is that the development of the United States and European guidelines has helped to standardize and improve the management of hyponatremia.

The two guidelines are more often in agreement than in disagreement. The discrepancies are likely related to the interpretation of the limited evidence and the methodology used to draft the guidelines. That said, which evidence does the field need for the coming years? First, it would be useful to evaluate if a combination of the traditional and newer diagnostic tests would improve not only diagnosis but also outcomes. Second, the approach of giving a bolus of hypertonic saline should be studied to address the optimal volume, whether this should be on the basis of ideal body weight, and how often it should be repeated to reach the desired increase in S Na.

For example, it would be important to analyze whether the copeptin-based subtypes of SIAD respond differently to vaptans Figure 2. Finally, studies analyzing the effect of a vaptan in comparison with another active treatment rather than placebo on patient-relevant outcomes rather than S Na are warranted. Published online ahead of print. Publication date available at www. National Center for Biotechnology Information , U. J Am Soc Nephrol. Published online Feb 7. Hoorn and Robert Zietse. Author information Copyright and License information Disclaimer.

This article has been cited by other articles in PMC. Abstract Hyponatremia is a common water balance disorder that often poses a diagnostic or therapeutic challenge. Open in a separate window. Differential Diagnosis of Hyponatremia Although the United States guideline did not present a diagnostic algorithm, the classifications of hyponatremia on the basis of tonicity and volume status were discussed.

Vasopressin Arginine vasopressin the antidiuretic hormone plays a central role in the pathogenesis of hyponatremia. Copeptin Enzymatic cleavage of the vasopressin prohormone produces not only vasopressin, but also neurophysin and copeptin also called C-terminal proarginine vasopressin. General Approach to Treatment A cutoff of 48 hours is usually used to differentiate acute from chronic hyponatremia Table 1. Comparison of the United States and European guidelines.

Treatment of Acute Hyponatremia Several settings predispose to acute hyponatremia, especially if combined with increased free water intake. Vaptans Vaptans block vasopressin type 2 receptors in collecting duct principal cells and therefore induce aquaresis for comprehensive review, see Berl, 84 Hoorn and Zietse, 85 Lehrich et al.

Urea Both guidelines suggest an interesting alternative to vaptans for chronic hyponatremia due to SIAD, namely urea. Summary and Conclusions Our impression is that the development of the United States and European guidelines has helped to standardize and improve the management of hyponatremia.

Footnotes Published online ahead of print. The challenge of hyponatremia. J Am Soc Nephrol Current treatment practice and outcomes. Report of the hyponatremia registry. Disorders of plasma sodium--causes, consequences, and correction. N Engl J Med Long-term outcome of profound hyponatremia: A prospective 12 months follow-up study. Eur J Endocrinol Mortality and serum sodium: Do patients die from or with hyponatremia? Clin J Am Soc Nephrol 6: Clinical practice guideline on diagnosis and treatment of hyponatraemia. G1—G47, [ PubMed ]. Nephrol Dial Transplant 29 [ Suppl 2 ]: Intensive Care Med Diagnosis, evaluation, and treatment of hyponatremia: Am J Med [ Suppl 1 ]: S1—S42, [ PubMed ].

Panel recommendations on hyponatremia. Am J Med Diagnosis and treatment of hyponatremia. Am J Kidney Dis Reference change values for sodium are ignored by the American and European treatment guidelines for hyponatremia. The clinical practice guideline on diagnosis and treatment of hyponatraemia: A response from Otsuka Pharmaceutical Europe Ltd. Preventing a drop in effective plasma osmolality to minimize the likelihood of cerebral edema during treatment of children with diabetic ketoacidosis. The rational clinical examination.

Is this patient hypovolemic? Combined fractional excretion of sodium and urea better predicts response to saline in hyponatremia than do usual clinical and biochemical parameters.

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

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