Treatment of Hyponatremia
Clinical Case
A 76-year-old conscious woman living in a nursing home had no health complaints until the previous 2 months, when a visiting family physician prescribed a thiazide diuretic (hydrochlorothiazide 25 mg/day) for the treatment of arterial hypertension. Before the medication was prescribed, the patient’s arterial blood pressure was 165/85 mm Hg. The family physician instructed her to substantially reduce her salt intake. After 6 weeks of therapy, her blood pressure had decreased to 135/80 mm Hg, but the nursing home staff and the patient’s daughter noticed changes in her mental status, including impaired concentration and drowsiness. During the previous week, the patient’s appetite had decreased, although her fluid intake remained unchanged (5–7 cups of tea per day). Nursing home staff also noticed gait instability. Two weeks before hospitalization, she had fallen, although no fractures occurred. The patient had no history of heart or liver disease and, in addition to hydrochlorothiazide 25 mg/day, was taking aspirin 80 mg/day.
On admission, the patient’s skin turgor was normal, with no clear signs of decreased blood pressure or increased pulse rate (blood pressure 125/80 mm Hg). Neurological examination showed that she was oriented and had no focal neurological signs; however, her gait was impaired, requiring the use of a walker. Her weight (58 kg) had remained unchanged over the previous several weeks. An electrocardiogram (ECG) showed signs of mild hypokalemia. Laboratory findings are presented in Table 1.
Initial laboratory tests showed a serum sodium concentration of 116 mmol/L, potassium 2.8 mmol/L, chloride 74 mmol/L, bicarbonate 30 mmol/L, elevated serum creatinine (123 μmol/L) and urea (6 mmol/L), and serum osmolality of 244 mOsm/kg. Serum uric acid concentration was 291.4 μmol/L. Serum glucose concentration was within the normal range, and no other abnormalities were detected. The calculated fractional excretion of uric acid was 9%, and the estimated glomerular filtration rate (eGFR) was 39 mL/min/1.73 m².
In summary, the woman, who had been taking hydrochlorothiazide 25 mg/day, developed hypotonic hyponatremia, moderate hypokalemia, and mild metabolic alkalosis. Previous electrolyte and renal function test results were unknown.
Considering that the patient had no liver or heart disease and appeared euvolemic, euvolemic hyponatremia was suspected. However, continued use of a thiazide diuretic, a blood pressure of 125/80 mm Hg on admission, which was substantially lower than her previous blood pressure, and elevated creatinine and urea concentrations could also indicate a mildly reduced circulating blood volume. Several important questions arise from this clinical case and are discussed below.
Table 1. Patient’s Laboratory Test Results
| Parameter | Plasma | Urine | Calculated Values |
|---|---|---|---|
| Na⁺ (mmol/L) | 116 | 65 | |
| K⁺ (mmol/L) | 2.8 | 60 | |
| Cl⁻ (mmol/L) | 74 | 60 | |
| HCO₃⁻ (mmol/L) | 30 | ||
| Creatinine (μmol/L) | 123 | ||
| Urea (mmol/L) | 6 | ||
| Osmolality (mOsm/kg) | 244 | 340 | |
| Uric acid (μmol/L) | 291.4 | ||
| Fractional excretion of uric acid (%) | 9 | ||
| eGFR (mL/min/1.72 m²) | 39 |
1. Is the Hyponatremia Truly Hypotonic?
A decreased serum sodium concentration usually, but not always, reflects a hypotonic state—a situation in which both the sodium concentration and serum osmolality are reduced.
An increased concentration of certain substances (e.g., glucose, mannitol, glycine) may lead to the development of translocational hyponatremia due to the movement of water from the intracellular to the extracellular space. Such patients may have normal or even elevated serum osmolality. Other circumstances associated with hyponatremia include high lipid and protein concentrations. This results in so-called pseudohyponatremia. Serum osmolality remains normal in pseudohyponatremia. This patient’s serum osmolality was 244 mOsm/kg, reflecting a hypotonic state. None of the causes that could have resulted in hypertonic or isotonic hyponatremia were identified; therefore, hypotonic hyponatremia was diagnosed.
2. In This Particular Case, Is It Important to Initiate Immediate Therapeutic Measures to Correct the Electrolyte Disturbances on Admission?
In this case, there was no evidence of hemodynamic instability or an acute neurological condition. Furthermore, there were no symptoms suggesting acute-onset hyponatremia, i.e., hyponatremia that had developed within 48 hours. Mild disorientation and the fall 2 weeks earlier were more suggestive of chronic hyponatremia.
3. What Is the Best Diagnostic Approach?
Several expert algorithms for the correction of hyponatremia have been published [1, 2], but evidence-based guidelines have only recently become available [3]. Although there are no major differences between the algorithms and the guidelines, several discrepancies are important to discuss in the context of this case.
In the traditional diagnostic algorithm for hyponatremia, one of the most important diagnostic steps is assessment of extracellular fluid volume, which allows differentiation between hypervolemic, hypovolemic, and euvolemic causes of hyponatremia [1]. However, because clinical assessment of volume status is difficult [4, 5], particularly in older patients, guideline experts recommend beginning the diagnostic evaluation by determining the urinary sodium concentration [3].
Measurement of urinary sodium concentration or fractional sodium excretion is considered a standard method for differentiating hypovolemic from hypervolemic disorders (urinary Na⁺ concentration –+ urinary concentration – >30 mmol/L), for example, in the syndrome of inappropriate antidiuretic hormone secretion (SIADH) [6]. However, the diagnostic usefulness of urinary sodium concentration or fractional sodium excretion is limited in patients taking diuretics because inhibition of tubular sodium reabsorption results in increased sodium excretion. In patients taking diuretics,
In this clinical case, as expected, urinary sodium concentration was elevated because of thiazide use, whereas urate excretion and eGFR were reduced. This indicates a reduction in circulating blood volume. It is worth remembering that despite reduced sodium and potassium concentrations, most patients taking thiazide diuretics clinically appear euvolemic or even hypervolemic, as in the clinical case described here [8–11].
4. What Are the Risk Factors, Symptoms, and Pathophysiology of Thiazide Diuretic-Induced Hyponatremia?
In a 2004 study involving 223 patients with chronic thiazide-induced hyponatremia (mean serum sodium concentration 116 mmol/L), the most commonly observed symptoms were lethargy, episodes of dizziness, vomiting, falls, headaches, and seizures [13]. A 10-year study of adult outpatients with arterial hypertension found that 3 out of 10 patients taking thiazide diuretics were diagnosed with hyponatremia [14]. The risk of hyponatremia is increased in older people, particularly those receiving high doses of thiazide diuretics. In cases where older patients are treated with selective serotonin reuptake inhibitors for depression or anxiety, concomitant use of diuretics may further increase the risk of hyponatremia [15–17].
Although the precise pathophysiological mechanisms of diuretic-induced hyponatremia are unknown, thiazide diuretics may cause sodium and water loss, increased thirst, impaired ADH secretion, hypokalemia, and ADH-independent water retention.
The thiazide effect most strongly associated with thiazide diuretic-induced hyponatremia is a reduction in renal free-water clearance. Thiazide diuretics impair the kidney’s diluting capacity by blocking the Na-Cl cotransporter in the distal tubule, the principal diluting segment of the kidney. Sodium excretion is increased, while free-water excretion is reduced [18].
5. What Is the Role of Hypokalemia in the Pathophysiology of Hyponatremia?
Thiazide diuretic-induced hypokalemia is an independent prognostic factor for the development of hyponatremia. Because intracellular and extracellular osmolality are always equal, loss of sodium or potassium, except when lost together with water, will result in hypotonicity. The principal mechanism is that potassium loss causes sodium to move into the cell, with a proportional movement of potassium out of the cell into the extracellular fluid. The reverse occurs when potassium is replaced; therefore, administration of oral potassium chloride to patients with hyponatremia increases the serum sodium concentration without the administration of sodium.
6. What Therapy Can Be Used to Increase This Patient’s Plasma Sodium Concentration?
The main causes of hyponatremia in the case described were NaCl and potassium deficiency and a positive water balance. Although modest fluid restriction may be advisable, the primary goal is to administer NaCl and KCl. It is important that therapies used to treat chronic euvolemic or hypervolemic hyponatremia, including therapies that interfere with the renal effects of vasopressin, are not used in cases of hypovolemic hypotonic hyponatremia.
In the presented case, KCl was administered together with isotonic NaCl (1 L of 0.9% NaCl + KCl 30 mmol/L) at a rate of 250 mL/hour for 4 hours, with the aim of increasing the plasma sodium concentration by 4–6 mmol/L over 24 hours because the patient was at risk of osmotic demyelination (an older woman with hypokalemia). Plasma electrolytes were initially measured every 2 hours and, after the initial therapy, every 6 hours. When diuresis developed, the infusion rate was reduced. If the plasma sodium concentration increases too rapidly, low-dose desmopressin may be administered at regular intervals to control the rate of increase in plasma sodium concentration.
After 48 hours of treatment, the plasma sodium concentration was 128 mmol/L. Water intake was restricted, and an oral KCl solution was prescribed. Thiazide diuretics were discontinued throughout hospitalization. The patient was discharged from the hospital after 10 days, with serum sodium and potassium concentrations of 134 mmol/L and 3.8 mmol/L, respectively. Her blood pressure was 145/85 mm Hg. The patient was advised to follow a balanced diet with a salt intake of at least 5–8 g/day.
A decreased potassium concentration presents a challenge in the treatment of hyponatremia. It is important to consider the effect of potassium on sodium concentration to avoid osmotic demyelination; therefore, the physician’s initial priority should be potassium replacement. Depending on the clinical circumstances, potassium may be administered orally, intravenously, or by both routes. Oral potassium administration is safer because it avoids local vascular injury caused by the high local potassium concentrations associated with intravenous administration. Oral administration also allows KCl to be given without large volumes of intravenous fluids. Frequent ECG monitoring is necessary until the plasma potassium concentration reaches a safe level of 3.5 mmol/L.
Patients who have previously experienced episodes of thiazide-induced hyponatremia are at greater risk of recurrent hyponatremia. Compared with both older and younger control patients, patients who have experienced episodes of hyponatremia have lower urine osmolality, and their serum sodium concentration decreases more after administration of a single dose of a diuretic [19].
7. What Can Be Learned From This Case?
Most patients with chronic hyponatremia, even when severe (sodium concentration
Summary
Although many questions remain regarding the optimal correction of hyponatremia in specific patient groups, an increasing number of studies indicate that appropriate treatment of hyponatremia reduces morbidity and the duration of hospitalization.
Prepared according to: Lameire N. The management of hyponatremia. Nephrology @ Point of Care 2015; 1 (1): e2-e11.
Mindaugas Petrašiūnas, MD
Vilnius University Faculty of Medicine
Journal “Inkstų ir širdies kraujagyslių ligos,” 2018
