Hyponatremia Demystified: Integrating Physiology to Shape Clinical Practice

Abstract

Hyponatremia is one of the most common problems encountered in clinical practice and one of the least-understood because accurate diagnosis and management require some familiarity with water homeostasis physiology, making the topic seemingly complex. The prevalence of hyponatremia depends on the nature of the population studied and the criteria used to define it. Hyponatremia is associated with poor outcomes including increased mortality and morbidity. The pathogenesis of hypotonic hyponatremia involves the accumulation of electrolyte-free water caused by either increased intake and/or decrease in kidney excretion. Plasma osmolality, urine osmolality, and urine sodium can help to differentiate among the different etiologies. Brain adaptation to plasma hypotonicity consisting of solute extrusion to mitigate further water influx into brain cells best explains the clinical manifestations of hyponatremia. Acute hyponatremia has an onset within 48 hours, commonly resulting in severe symptoms, while chronic hyponatremia develops over 48 hours and usually is pauci-symptomatic. However, the latter increases the risk of osmotic demyelination syndrome if hyponatremia is corrected rapidly; therefore, extreme caution must be exercised when correcting plasma sodium. Management strategies depend on the presence of symptoms and the cause of hyponatremia and are discussed in this review.

Keywords: Arginine vasopressin; Hyponatremia; Osmotic demyelination syndrome; Plasma tonicity; Urea.

Figure 1.

Synthesis of Arginine Vasopressin and Copeptin AVP = arginine vasopressin, EABV = effective arterial blood volume The prohormone Pro-AVP is synthesized in the magnocellular neurons located in the supraoptic and paraventricular nucleus of the hypothalamus. During axonal transport of the granules from the hypothalamus to the posterior pituitary, enzymatic cleavage of the prohormone generates the final products of AVP, neurophysin II and the COOH-terminal glycoprotein copeptin. When afferent stimulation depolarizes the AVP-containing neurons, the three end products are released into capillaries of the posterior pituitary in equimolar manner. Main stimuli for release are an increase in plasma osmolality and a drop in blood pressure or volume. AVP acts on the collecting duct to increase water absorption and decrease urine volume.

Figure 2.

Edelman Gambelgrams Edelman et al empirically demonstrated that plasma sodium concentration (PNa) is a function of total body exchangeable sodium (Na_E), total body exchangeable potassium (K_E) and total body water (TBW). The main variables of the equation are depicted in a Gambelgram. Based on this equation, hypotonic hyponatremia will occur when the ratio between the sum of total body exchangeable sodium (Na_E) and total body exchangeable potassium (K_E) and total body water (TBW) decreases. There are four different scenarios where this can occur leading to hypotonic hyponatremia: 1) Normal Na_E and K_E with increased TBW, e.g. primary polydipsia; 2) Increased Na_E and K_E and increased TBW but with a proportionally higher increase in TBW, e.g., cirrhosis and heart failure; 3) Decreased Na_E and K_E and decreased TBW but with a proportional higher decrease in TBW, e.g. hypovolemia; and 4) Decreased Na_E and K_E with increased TBW, e.g. syndrome of inappropriate antidiuresis (SIAD). As inferred from the figure, hypotonic hyponatremia is always caused by electrolyte free water (EWF) excess, i.e., TBW is proportionally higher to the sum of Na_E and K_E.

Figure 3.

Brain adaptation to acute and chronic hyponatremia Severity of symptoms of hyponatremia correlates with the degree of brain edema. Severe symptoms occur more frequently in acute hyponatremia (duration <48 hours) where full brain adaptation to hypotonicity has not occurred yet and less frequently in chronic hyponatremia (duration ≥ 48 hours) where full brain adaptation has taken place. However, the adaptation to chronic hyponatremia has also been proposed as possible mechanism for mild neurocognitive deficits, gait disturbances and falls associated with chronic hyponatremia.

Figure 4.

Diagnostic approach to hyponatremia PNa = Plasma sodium concentration; POsm = Plasma osmolality; UOsm = Urine osmolality; AVP = Arginine vasopressin; UNa = Urine sodium concentration; RAAS = Renin-Angiotensin-Aldosterone System; EABV = Effective arterial blood volume; SIAD = Syndrome of inappropriate antidiuretic hormone

Figure 5.

Desmopressin strategies to prevent and manage overly rapid correction of hyponatremia PNa = plasma sodium concentration, D5W = dextrose 5% in water. The figure illustrates hypothetical scenarios where a patient presents with an initial PNa of 108 mEq/L. Desmopressin has been used to prevent or treat excessively rapid correction. Desmopressin is usually given at a dose of 2–4 mcg IV every 6–8 hours. Three distinctive strategies have been described: A) The proactive approach integrates the use of desmopressin with hypertonic saline from the start of PNa correction; B) The reactive approach is indicated when the trajectory of PNa correction is worrisome and seems likely to result in overcorrection (i.e., a PNa goal of 6 mEq/L/24h has been achieved); C) The rescue approach is indicated when overcorrection had occur and combines the use of desmopressin with hypotonic fluids such as D5W aiming to relower PNa just below the therapeutic limits. The recommended volume of NaCl 3% to increase PNa by ≈1 mEq/L is 1–1.5 ml/kg and this volume is to be administered over 6 hours (rate of 0.16 to 0.25 ml/kg/h). Alternatively, in symptomatic patients, bolus of 100 or 150 ml can be administered intermittently. The recommended volume of D5W to decrease PNa by ≈1 mEq/L is 3 ml/kg.