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because the hyponatremia may actually worsen as the infused sodium is quantitatively lost in the urine, and the elevated levels of ADH will cause water retention.

      In euvolemic or hypervolemic hyponatremia, total fluid restriction between 500 and 1500 mL/day may be required.^1,8 Symptomatic hyponatremia with serum sodium less than 120 mEq/L usually requires correction with intravenous sodium. The concept is to eliminate presumed excess water and restore fluid balance (assuming non‐solute losses).^9,10 The treatment plan is to remove a calculated proportion of the free water excess over 24 hours to accommodate an increase in serum sodium of 4–8 mEq/L and not to completely correct the serum sodium to normal. Recommendations for correcting symptomatic hyponatremia are therefore made using 3.0% (513 mEq/L) saline solutions. Various protocols have been described^9,10 with a recommendation to infuse 3% saline at 0.5–1.0 mL/kg per hour, which may depend on the urine output. Therefore, the 3% saline infusion may replace urinary sodium losses to maintain total body sodium and intravascular volume, and urinary volume losses may only be in the range of 2–4 litres over 24 hours. Serum sodium measurements are then monitored at two‐hour intervals with the goal of discontinuing the saline infusion if the rate of rise of serum sodium is greater than 0.5 mEq/L/hour. There were no overcorrections in one study involving the continuous‐infusion protocol.⁴⁵ From these limited data, it is unknown whether bolus or continuous infusions or a hybrid combination of both protocols will be better in real‐world conditions or whether ‘reversal’ of overcorrection of hyponatremia will reverse ODS once started.

      Medications have been used to assist in free water clearance and may be used in patients with mild symptomatic hyponatremia in the place of fluid restriction, or may be used as adjuvants to hypertonic saline infusions in cases of symptomatic euvolemic or hypervolemic hyponatremia. Demeclocycline, in doses as high as 1200 mg per day, may induce nephrogenic diabetes insipidus. Other agents such as lithium, diphenylhydantoin, and urea have not been as reproducible or effective.⁸

      The newer vaptans allow a further dimension in the therapy of mild symptomatic hyponatremia. Two vasopressin receptor antagonists are currently approved for use in correcting euvolemic and hypervolemic hyponatremia.^4,46 The vaptans are nonpeptide, small‐molecular‐weight antagonists of the vasopressin receptor. They bind to an internal domain in the receptor molecule and alter the configuration for normal vasopressin binding and coupling to the internal G protein.⁴⁶ Conivaptan is a combined V1a receptor and V2 receptor antagonist, and tolvaptan is a selective V2 receptor antagonist. Conivaptan is approved for intravenous administration, and tolvaptan is an oral antagonist, but both are to be started in hospitalized patients.⁴⁶ Conivaptan is administered by intravenous infusion of 20 mg over 30 minutes followed by 20 mg over 24 hours, with the subsequent dose increased to 40 mg/24 hours if required. It is approved only for four days. Tolvaptan may be given at 15 mg once daily and may be titrated up as needed once daily to a maximum dose of 60 mg per day. Both drugs are metabolized by the hepatic cytochrome P‐450 system of CYP3A and are contraindicated for use with other drugs that are CYP3A inhibitors (clarithromycin, itraconazole, fluconazole, ritonovir, and cyclosporine).⁴⁶ Both drugs have been shown to improve serum sodium, with rare increases in the level above the desired 12 mEq/L over 24 hours.

      Tolvaptan has been shown to have modest clinical benefits as determined by a quality of life questionnaire in hyponatremic subjects with serum sodium less than 130 mEq/L²³ and patients with acute congestive heart failure by alleviating feelings of fatigue and dyspnea.⁴⁷

      A recent meta‐analysis suggests that the vaptans significantly improve serum sodium, but there was no evidence of any benefit to mortality or clinically significant cognitive improvement.⁴¹ Long‐term tolvaptan has been associated with liver disease in people treated for polycystic kidney disease, with the recommendation that vaptans should not be used in patients with liver disease and should not be used for longer than 30 days.² Clinical treatment indications for the outpatient management of hyponatremia with tolvaptan are not well defined, and the cost is approximately $360 per day.⁴⁸

Workup and treatment of hypernatremia

      Hypernatremia ([Na⁺] >145 mEq/L) is associated with extravascular hypertonicity with resultant intracellular dehydration.

Clinical presentations may include altered mental status, irritability, hyperreflexia, tachycardia, orthostasis, and dry mucous membranes.^3,7,10,21 The differential diagnosis would less commonly include salt overload (iatrogenic saline infusion or tube feedings), nephrogenic diabetes insipidus (e.g. associated with lithium exposure), or central diabetes insipidus (due to central nervous system disorders). Salt overload may be diagnosed by the patient’s history. The urine osmolality will be inappropriately low for the serum osmolality (or iso‐osmolar) to the serum in cases of diabetes insipidus. Response to DDAVP or measurement of copeptin^49,50 will distinguish central from nephrogenic diabetes insipidus.

      As discussed previously, the more common causes of hypernatremia in the frail elderly are due to diminished thirst, inadequate access to fluids, and superimposed water losses due to gastrointestinal and febrile illnesses.^{2,3,13,14,20,51} People with dementia may have further diminished thirst responses and inadequate ADH responses similar to those observed in partial central diabetes insipidus.¹⁷

      The most clinically significant symptoms are associated with central nervous system dysfunction, ranging from confusion to coma. In extreme cases, brain dehydration may be associated with vascular rupture and subarachnoid haemorrhage. Chronic dehydration results in adaptive responses by the intracellular generation of organic osmoles. Correcting chronic hypernatremia must consider that the overly rapid correction of the hyponatremia may result in cerebral oedema. Therefore, acute management must follow the serum sodium on a regular basis (q 4 hours) to adjust the regimen.^1,2

      Treatment should reverse the underlying causes, such as treating pyrexia, managing gastrointestinal fluid losses, and withholding diuretics or lactulose. Correcting the hyperosmolality should then proceed with a goal to decrease serum osmolality incrementally by approximately 10 mOsm/kg over 24 hours rather than full correction of serum sodium to normal levels.¹⁰ There are various formulas for correction, which are usually based on the correction of total body water (see below).^9,10 One must also supplement for anticipated continuing obligatory water losses (insensible, urinary, and gastrointestinal water loss). Obligatory water loss may range from 0.5 to 1.5 litres per day of free water. Replacement fluids may include 0.9% saline, 0.45% saline, and 5% dextrose in water. If the dehydration is purely due to water without solute loss, the regimen for D5% water may be the easiest to calculate. The concept is to supplement the free water losses with obligatory losses. The calculated free water should reduce the current serum sodium by 10 mOsm/kg over 24 hours:

      where TBW is total body water, and

      and

      or

      In situations where solute is lost in addition to pure water, 0.45% saline may be a more appropriate intravenous infusion. The infused sodium will stay in the intravascular space to raise the blood pressure. However, 0.45% saline corrects the osmolality by the free water component.¹⁰ Thus an infusion with 0.9% saline (154 mEq/L) will only add free water relative to the difference from the patient’s serum sodium, and 0.45% saline is only 50% free water. Because of the fear that overly rapid correction of the hypernatremia will cause hyponatremic cerebral oedema, clinicians are prone to use 0.9% saline for the correction. However, infusion of 0.9% saline, although hypotonic to the existing serum sodium, will not reduce the serum osmolality and may not supply sufficient free water to keep up with obligatory losses.¹⁰ It should be noted that there are many

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