In symptomatic patients with manifestations such as lethargy or confusion or more serious manifestations such as obtundation or seizures, measures to quickly increase the serum sodium concentration are urgently needed to prevent cerebral edema. In contrast, particularly when the hyponatremia is less severe and more gradual in onset, the risk of cerebral edema is lower, and more conservative treatment is preferable.
Acute Management of Symptomatic TIH. Patients with symptomatic hyponatremia, in whom the serum sodium concentration is often <120 mEq/L, should be treated aggressively, as more thoroughly discussed in previous reviews.12,24 Prevention of cerebral edema is paramount, and use of saline or hypertonic saline to quickly raise the serum sodium level is appropriate. The initial goal is rapid but partial correction of serum sodium concentration, to reduce the likelihood of developing cerebral edema, followed by more gradual correction, to avoid the risk of central pontine myelinosis that can accompany overly rapid correction. Complete resolution of hyponatremia can take up to a week; therefore, continued monitoring of water intake and of serum sodium concentration is needed.28
In symptomatic patients, the two main treatment options are infusion of either normal saline or hypertonic saline. The choice between isotonic vs hypertonic saline depends, to a large extent, on the state of the intravascular volume (ie, whether the patient is hypovolemic).3,13 Clinical clues that suggest hypovolemia include hypotension, azotemia, and hyperuricemia. In patients with hypovolemic TIH, in whom ADH secretion stimulated by hypovolemia contributes to the inability to excrete free water, normal saline infusion is appropriate because it will restore volume and suppress ADH secretion, leading to increased free water excretion and increased serum sodium concentration.24 If there is no increase in serum sodium after 2 hours of saline infusion, then hypertonic saline should be administered. In patients with severe manifestations such as seizures or coma, initiation of treatment with hypertonic saline to assure rapid onset of response is recommended.12,24 In patients with hypovolemic TIH, treating solely by restricting fluid intake would be inappropriate.
In contrast, in patients with euvolemic or hypervolemic TIH, who tend to have lower serum levels of uric acid, blood urea nitrogen, and creatinine, ADH is not a factor, and normal saline will not restore free water clearance or serum sodium concentration. Further, serum sodium concentration can actually fall if the infused sodium is excreted to a greater extent than the infused water. In such patients, hypertonic saline will predictably raise serum sodium concentration and is preferable.
Three percent NaCl (5 mEq NaCl per 10 cc) is initiated at 1 to 2 cc/kg/h with the goal of initially increasing serum sodium concentration by 1 to 2 mEq/L/h for 3 to 4 hours, aiming for a 6 to 8 mEq/L increase.3,19,24,29 The higher dose (2 cc/kg/h) can be given to severely symptomatic patients—for example, patients with seizures or coma—and the lower dose (1 cc/kg/h) to less symptomatic patients.29 The serum sodium level should be monitored every 2 to 3 hours.
The use of hypertonic saline should be limited to the first few hours. After the initial correction, the rate of correction should be slowed, with a goal of increasing serum sodium concentration by no more than 12 mEq/L/d (0.5 mEq/L/h), to prevent development of central pontine myelinosis.24
In patients with euvolemic or hypervolemic hyponatremia, administration of furosemide in addition to the hypertonic saline can increase free water clearance and thus hasten the increase of the serum sodium concentration while avoiding volume overload.24 The more rapid increase in sodium concentration is related more to a negative water balance than to a positive sodium balance.30 Diuresis with furosemide causes sodium loss equivalent to half of that with isotonic saline.24 Net sodium loss due to the loop diuretic will be limited by the infused hypertonic saline, assuring that water will be excreted in excess of sodium.
The combination of hypertonic saline and furosemide has been reported to be associated with a better neurologic outcome than treatment with hypertonic saline alone.30 However, in patients with hypovolemic hyponatremia or in whom volume status is unclear, a loop diuretic should not be administered.
It is important to bear in mind that the acute treatment of TIH can restore sodium concentration faster than intended. Free water clearance can increase rapidly due to withholding of the offending thiazide and due to suppression of ADH by saline infusion in hypovolemic patients. This underlines the need for careful monitoring of the serum sodium concentration. Tolvaptan, a V2-selective arginine vasopressin-receptor antagonist, has been shown to hasten the increase in serum sodium in patients with hyponatremia, but its role in the treatment of TIH has not been assessed.31
Replacement of the Thiazide Diuretic With Another Agent. A thiazide diuretic can usually be replaced without compromising blood pressure control either with an agent other than a diuretic or, in patients who clearly require a diuretic, a loop diuretic. In treating hypertension in the elderly, calcium channel blockers are an effective alternative to diuretics and do not confer a risk of hyponatremia.
Nevertheless, in many cases, hypertension simply cannot be well controlled without a diuretic. In such cases, a loop diuretic can be prescribed, albeit with careful monitoring of serum sodium, beginning within a week or two of initiation. Similarly, in patients with borderline hyponatremia before treatment with a diuretic, use of a loop diuretic rather than a thiazide merits consideration as a cautionary measure. There are insufficient data concerning the effects on sodium of indapamide, also a nonthiazide diuretic.
Loop Diuretics. As discussed above, loop diuretics are less likely than thiazide diuretics to cause hyponatremia.3,16–19 However, for several reasons, there is a traditional reluctance to prescribe a loop diuretic instead of a thiazide in treating essential hypertension. First, in the management of hypertension, long-term studies have not been conducted to determine whether loop diuretics prevent cardiovascular events as effectively as thiazide diuretics. Second, the diuresis caused by loop diuretics is inconvenient. Third, many physicians incorrectly assume that the powerful loop diuretics are as likely as a thiazide to cause hyponatremia. Fourth, most physicians almost automatically prescribe thiazide diuretics when treating hypertension. Finally, there are no formal studies assessing the incidence of hyponatremia in patients treated with a loop diuretic after prior documentation of TIH.
Despite these concerns, a loop diuretic is a reasonable alternative to a thiazide. Although unassessed in long-term hypertension trials, it is likely that if it controls the hypertension to the same degree, the cardiovascular protection should be substantially the same. The loop diuretic torsemide, with more reliable absorption than furosemide and a slightly longer duration of action, is reported to be more effective than furosemide and as effective as a thiazide in treating hypertension.32,33 The problem of symptomatic diuresis can be ameliorated to some extent by varying the time of dosing to suit the convenience of the patient.
Potassium-Sparing Diuretics. Potassium-sparing diuretics also reduce free water clearance but seem less likely than a thiazide to cause hyponatremia. Combining a potassium-sparing diuretic with a thiazide could enhance the reduction in maximal dilution of urine.16 Combining it with a loop diuretic can increase the antihypertensive effect with less risk of hyponatremia than a potassium-sparing diuretic/thiazide combination, although studies to demonstrate this have not been performed.
Dose Reduction. In general, in patients with TIH, replacement of the thiazide with a nondiuretic antihypertensive agent (or if a diuretic is needed, a loop diuretic) is the safest approach. However, sometimes a thiazide diuretic is needed. For example, a diuretic is needed in some patients to control their hypertension, but they may not tolerate a loop diuretic. In such patients, a case can be made for continuation of the thiazide at a reduced dosage in concert with avoidance of excessive fluid intake, as long as the degree of hyponatremia has been minimal (129–132 mEq/L), normalization of serum sodium concentration is documented, and careful follow-up is assured. A lower dose would increase the ability to excrete free water, would reduce the hypovolemic stimulus for ADH secretion, and can correct borderline hyponatremia in many cases.
Monitoring of Serum Sodium Concentration. Current guidelines recommend assessing serum sodium concentration within a month of initiating therapy with a thiazide diuretic. However, most cases of TIH develop within 1 to 2 weeks. It would make sense to assess serum sodium concentration within a 1 or 2 weeks of initiating treatment with a thiazide diuretic in patients older than 70 who are at higher risk for TIH. Similarly, serum sodium should be checked in elderly patients in whom the dose is being increased or who are being switched from a thiazide to the more potent chlorthalidone. The cost-effectiveness of earlier monitoring needs to be assessed.
Management of Patients With Borderline Hyponatremia. There are currently no guidelines in place concerning management of individuals who have borderline or minimal hyponatremia (129–132 mEq/L) while taking a thiazide diuretic, a condition that might not be entirely harmless.34 Such patients would seem to be at increased risk for developing more severe hyponatremia in the event of increased fluid intake, reduced sodium intake, intercurrent stress or illness, or addition of commonly used drugs that can affect sodium handling, such as a nonsteroidal anti-inflammatory drug. In such patients, the habitual amount of fluid intake should be ascertained, and in those with excessive intake (>1.5–2 L/d), it should be reduced. The second major issue concerns whether diuretics should be avoided. At one extreme, the not uncommon practice of many physicians of continuing thiazide diuretic therapy in such patients must be questioned, both because of the potential risk and because a nonthiazide diuretic or an antihypertensive drug other than a diuretic can usually be substituted without compromising blood pressure control. At the other extreme, the practice of many physicians of rigidly avoiding the use of all diuretics, including loop diuretics, in such patients must also be challenged, since in some cases it denies diuretic therapy to patients who truly need a diuretic. Although controlled trials are lacking, if the hypertension cannot be controlled with agents other than diuretics, a loop diuretic, with careful monitoring of serum sodium, merits consideration.