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Treatment of Chronic Hyponatremia
Author: Phuong-Chi T. Pham, M.D., Phuong-Mai T. Pham, M.D., Jeffrey Miller, M.D., Hai V. Pham, M.D., Son V. Pham, M.D., Phuong-Anh T. Pham, M.D., Phuong-Thu T. Pham, M.D.
Last Revised: Sun, 01-Sep-2002
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CLINICAL COMMENTARY

Treatment of Chronic Hyponatremia

Phuong-Chi T. Pham, M.D., Phuong-Mai T. Pham, M.D., Jeffrey Miller, M.D., Hai V. Pham, M.D., Son V. Pham, M.D., Phuong-Anh T. Pham, M.D., Phuong-Thu T. Pham, M.D.

Introduction

Most physicians now recognize that the rate and magnitude of correction of sodium concentration in patients with chronic hyponatremia must be carefully monitored within the first 24-48 hours.1-5 Nevertheless, osmotic demyelinolysis secondary to overly rapid corrections of chronic hyponatremia continues to be observed. At the other end of the spectrum, attempts at the correction of hyponatremia in some cases may actually result in no improvement or further lowering of the existing sodium concentra-tion.6,7 Recently, we reported cases where attempts at the correction of hyponatremia resulted in unexpected changes in sodium concentration.6,8 Our analysis revealed that these unexpected changes were preventable if the physicians were aware that factors other than normal saline infusion could have contributed to the correction of hyponatremia.

Hyponatremia and the Brain

In response to a fall in plasma osmolality, the brain undergoes rapid solute loss to prevent passive intracellular water movement and brain edema. Sodium and chloride loss from the interstitial fluid into the cerebral spinal fluid occurs within minutes followed by a slower loss of intracellular potassium and organic solutes.2,9,10 Reaccumulation of solutes to the brain during correction of chronic hyponatremia, however, occurs more slowly. Whereas intracellular sodium and potassium can be rapidly restored, regeneration of organic solutes or \"idiogenic osmoles\" may require 5 to 7 days.11 The slow reaccumulation of brain solutes during correction of hyponatremia therefore, renders the brain more susceptible to cellular dehydration and neurological complications with rapid correction.

The osmotic demyelination syndrome, previously referred to as central pontine myelinolysis, is a neurological complication that has been shown to be associated with an overly rapid correction of hypona-tremia.12-17 Histologic characteristics of osmotic demyelination syndrome include symmetric, midline demyelinating lesions in the pons and/or extrapontine areas, loss of oligodendrocytes, reactive glial cell infiltration, and relative preservation of axonal fibers.12 The actual incidence of osmotic demyelination syndrome, central pontine myelinolysis and/or extrapontine myelinolysis associated with overly rapid correction of chronic hyponatremia cannot be easily determined because not all cases are properly diagnosed or reported. Nonetheless, neurological sequelae have been reported to occur in 5%-50% of cases when correction rates were greater than 10 mmol/L/24 hours.1,18,19 Clinical manifestations of osmotic demyelination syndrome range from headache to alteration in affect/behavior, poor motor coordination, dysarthria, dysphagia, lethargy, obtundation, coma, and death. Certain patients may be more prone to suffer from neurological sequelae from hyponatremia and/or its rapid correction. They include alcoholics, malnourished individuals, menstruating females, and those who have concurrent hypokalemia or hypoxic brain injury.12,20-26 These patients may have suppressed Na+-K+-ATPase activity required for efficient volume regulation during acute osmotic changes. Although osmotic demyelination syndrome may be fatal, partial and even complete recoveries have been reported.3

Treatment of Chronic Hyponatremia

In hypovolemic patients, saline infusion is undoubtedly necessary. In mild hyponatremic cases where water retention occurs secondary to the syndrome of inappropriate ADH release (SIADH), fluid restriction alone is often adequate. Ongoing clinical trials have also been designed to evaluate the use of vasopressin antagonists (ADH antagonists) in various hyponatremic conditions including congestive heart failure, liver cirrhosis, and SIADH. Preliminary data are encouraging for moderate to relatively mild hyponatremic patients.27 Currently however, ADH antagonists are not clinically available and saline infusion is still warranted in the treatment of moderate to severe symptomatic hyponatremic cases.

In general, the rate of correction of chronic hyponatremia is recommended to be 1/2 mEq/L/hour not to exceed 10 mEq/L/day.1-5 In treating hyponatremia, sodium concentration can be easily predicted as total body salt divided by total body volume (TBV). Total body volume is approximated as (0.60 x body weight in kg).8 Predicted sodium concentration can be estimated as [formula 1].

It is crucial that all sources of sodium and potassium administered/loss and net total body volume be taken into account during the treatment of hyponatremia. In most cases where urinary salt loss and fluid balance are not problematic, the predicted corrected sodium concentration can be simplified as [formula 2].

Treatment of severe chronic hyponatremia remains a challenge for physicians. Whereas slow correction predisposes patients to neurological complications associated with cerebral edema, overly rapid correction may result in equally dire sequelae of osmotic demyelinolysis.

Unexpected Problems in the Correction of Hyponatremia

Both overly rapid correction and unexpected lowering of sodium level may be encountered in the treatment of hyponatremia. Overly rapid correction of hyponatremia may occur due to excessive salt (sodium and potassium) administration and/or excessive water diuresis.(Table 1) On the contrary, a fall in sodium level may occur during the treatment of hyponatremia when salt loss is in excess of water excretion as seen with SIADH.

Excessive Sodium Administration

We speculate that excessive sodium administration is generally not due to miscalculations, but rather, unawareness of the amount of sodium already given to patients. Lack of communication between physicians may contribute to this problem. For example, if a patient presenting with severe hyponatremia has already received a large amount of normal saline in the emergency department prior to admission and the admitting physician on the wards uses the initial admitting sodium concentration to determine the amount of sodium to be administered to the patient, then he/she can be surprised with a faster rate of

Table 1: Causes of Over Correction of Hyponatremia

  • Unawareness of the recommended rate of correction for chronic hyponatremia
  • Miscalculations
  • Unrecognized sources of sodium
    • Exogenous: Sodium administered from emergency room or different unit prior to transfer
    • Endogenous: Potassium supplementation
  • Excess free water loss
    • Water deprivation in primary polydipsia
    • Withdrawal of thiazides during correction of hyponatremia
    • Glucocorticoid replacement in patients with cortisol insufficiency
    • Recovery from acute respiratory failure
    • Excessive gastrointestinal or skin free water loss
    • Severe hyponatremia with subsequent cerebral edema and pituitary infarction

correction. When a theoretical 70 kg patient receives 2L of normal saline in the emergency department, his/her sodium concentration is expected to increase by approximately 7.3 mmol/L without further intervention.

Excessive Potassium Administration

Excessive salt administration also includes large potassium supplement. Potassium infusion into a patient with hyponatremia may increase sodium concentration by several mechanisms.28-30 First, potassium infusion into a hyponatremic patient may induce an extracellular sodium shift in exchange for intracellular movement of potassium. Second, an extracellular shift of protons (H+) may occur in exchange for cellular uptake of potassium. While the extracellular proton is taken up by the extracellular buffer system and does not raise the extracellular osmolality, the cellular uptake of potassium creates an increased intracellular osmolality and promotes cellular uptake of free water. The fall in extracellular free water in turn increases the serum sodium concentration. Third, chloride may follow cellular potassium uptake and results in an increased intracellular osmo-

lality with associated cellular uptake of free water. Again, the fall in extracellular free water can increase the serum sodium concentration. Finally, it has also been suggested that volume expansion induced by potassium chloride administration may inhibit ADH, thereby promoting excess free water excretion to result in an increased serum sodium concentration.31 The latter mechanism is particularly applicable to volume-depleted patients. Whatever the mechanism whereby potassium chloride administration results in a rise in serum sodium, the amount of potassium administered should be assumed to be equivalent to sodium in the correction of hyponatremia. Failure to recognize the effect of potassium administration on serum sodium concentration may potentially lead to adverse neurological outcomes. Of note, it has been reported that hyponatremic patients with concomitant hypokalemia have been suggested to have an increased risk of developing osmotic demyelination syndrome with treatment. In a literature review involving patients with osmotic demyelination syndrome following correction of hyponatremia, Lohr reported that 66 out of 74 patients had concomitant hypokalemia.25 This phenomenon may have occurred due to the unrecognized effect of simultaneous administration of potassium on extracellular sodium concentration and overly rapid correction of the existing hyponatremia. In a teaching case, we previously demonstrated that the corrected sodium concentration may be more accurately determined if all sodium and potassium administered and loss are accounted for in the treatment of hyponatremia.8

As potassium infusion may increase serum sodium concentration, it is important to recognize that concurrent hyponatremia and hypokalemia is not uncommon especially in the setting of diuretic use. Although the exact incidence of concurrent hyponatremia and hypokalemia is not known, it has been reported that diuretic use is responsible for approximately 50% of chronic hyponatremic cases and that potassium deficiency is a common finding with diuretic use.1,32-35 In a study evaluating skeletal potassium concentration in 25 patients on diuretics (11 thiazides and 14 loop diuretics), Dorup et al reported that 14 out of 25 patients had potassium concentration below control range despite potassium supplements in all but one patient.35 In a clinical review involving 22 patients with diuretic induced hyponatremia, Sterns et al reported concurrent hypokalemia with level less than 3.3 mmol/L in all but one patient.34 A small analysis of our own hospitalized patients revealed that approximately 20% of hyponatremic patients also have concurrent hypokalemia. Despite the common occurrence of combined hyponatremia and hypokalemia and the potentially frequent need for simultaneous administration of sodium and potassium, physicians may not be aware that administration of potassium to a hyponatremic patient may increase the serum sodium.

Excessive Water Diuresis

Excessive water diuresis has been reported to occur during correction of hyponatremia to result in an overly rapid correction of hyponatremia and even cause hypernatremia.6,8,36 In most settings, water diuresis probably occurs via acute suppression of ADH. In acute severe hyponatremia, the rapid hypotonic volume expansion may induce ADH inhibition with resultant large urinary free water excretion. In the acute setting of severe hyponatremia, an ADH deficient state may also occur when severe cerebral edema induces pituitary infarction.36 In the chronic setting, water diuresis may occur with water restriction alone in patients with either primary polydipsia or volume depletion following achievement of euvolemia. The appropriate inhibition of ADH due to hyponatremia in the former and volume expansion in the latter may result in excess water to be rapidly excreted.30 Water diuresis presumably due to ADH suppression has also been described in patients with adrenal insufficiency/panhypopituitarism following administration of glucocorticoids.6,37 Other conditions where water diuresis may be problematic due to presumed suppression of ADH include withdrawal of thiazide diuretics during treatment of hyponatremia and recovery from acute respiratory failure.2 As water diuresis is a potential complicating factor in the treatment of hyponatremia, we estimate that 1-2 L of water diuresis may increase the serum sodium concentration in a 70 kg patient by 2.9-6.0 mmol/L. Generally, a urine output greater than 40 ml/kg/day and a urine to serum osmolality ratio less than 0.7 should alert the physician of a water diuresis. When water diuresis occurs, the rate of saline infusion as well as the tonicity of saline fluid used must be re-evaluated [formula 1]. In cases with a high degree of water diuresis, hypotonic fluid infusion may be required to prevent overly rapid correction of hyponatremia and/or development of hypernatremia.

Care must also be taken while correcting hyponatremia in patients with severe burns or gastrointestinal fluid loss due to their excessive hypotonic fluid loss.

Fall in Serum Sodium Concentration during Treatment of Hyponatremia--SIADH

Another major problem encountered in the treatment of hyponatremia does not involve over correction of hyponatremia, but rather, worsening of the existing hyponatremia. Actual lowering of sodium concentration or resistant hyponatremia despite treatment may be observed when a subset of patients with SIADH receives normal saline infusion.6 The syndrome of inappropriate release of antidiuretic hormone has been reported to be responsible for 8%-33% of chronic hyponatremic cases.1,16,34 SIADH is characterized by an inappropriately high urine osmolality in the presence of hyponatremia in euvolemic patients. Consider an SIADH patient who is inappropriately set to concentrate the urine to 600 mosm/kg. Infusion of 1 L of normal saline (approximately 300 mosm/kg) into this patient may result in a urinary excretion of 500 ml of 600 mosm/kg and retention of 500 ml of free water. Similarly, infusion of 1 L of half normal saline (approximately 150 mosm/kg) may result in a urinary excretion of 250 ml of 600 mosm/kg and retention of 750 ml of free water. Failure to recognize this free water retention can precipitate profound worsening of hyponatremia. It should therefore be cautioned that any saline fluid administered to SIADH patients should have a higher osmolality than that of urine to avoid worsening of the existing hyponatremia.

In summary, we have presented potential complicating factors in the treatment of hyponatremia. (Table 2) With our analysis and discussion, we hope that hyponatremia treatment-related neurological complications will be minimized.

Table 2: Tips in the Management of Hyponatremia

  1. Check for all sources of salt administered by other physicians
  2. All K+ administered = Na+
  3. Monitor urine output
    • If urine output > 40 ml/kg/day, suspect water diuresis
    • If high urine output occurs, check urine osmolality (Urine osmolality to serum osmolality ratio less than 0.7 suggests water diuresis)
    • Recalculate rate of saline infusion using [formula1]
    • Consider switching to more hypotonic fluid

4. If SIADH is suspected, any saline fluid used should have a higher osmolality than that of urine

 

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Treatment of Chronic Hyponatremia
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