Hypernatremic States

Significance of the Plasma Sodium Concentration

The total body water (about 60% of body weight in males and 50% in females) is distributed between the intracellular fluid (ICF, 60% of body water) and extracellular fluid (ECF, 40% of body water) spaces. Flame photometry and, more recently, ion selective electrode technology have made the plasma sodium concentration one of the simplest and most frequently measured constituents of the body fluids. It is not always appreciated that a given concentration of the plasma sodium may be consistent with different functional states. The plasma sodium is simply a concentration term, and as such reflects only the relative amounts of sodium and water present in the sample. The concentration is not a measure of total body sodium content. It is determined empirically by the following relationship:

The relationship indicates the fact that hypernatremia can occur as a consequence of a decrease in total body water, an increase in total body sodium or a combination of these events. It gives no information regarding replacement or removal of sodium. When flame spectrophotometry is used to measure the amount of sodium in a plasma sample, substances such as plasma proteins, abnormally high glucose, and lipid can occupy a large fraction of the plasma volume and underestimate the actual sodium concentration. The ionic composition of the plasma is measured as milliequivalents per liter of plasma. Only about 930 ml of each liter of plasma is water. The remaining 70 ml is occupied by the plasma proteins and, to a lesser degree, lipids. In the presence of hyperlipidemia or hyperproteinemia, the plasma water content may be less than 93%.

Generation of Hypernatremia

Since Na ⁺ and its accompanying anions are the major effective ECF osmoles, hypernatremia is a state of hyperosmolality. As a result of the fixed number of ICF particles, maintenance of osmotic equilibrium in hypernatremia results in ICF volume-contraction. The increase in the plasma osmolality induced by hypernatremia creates an osmotic gradient that results in water movement out of the cells into the ECF. A similar syndrome can be produced when plasma osmolality is elevated by hyperglycemia. When hyperosmolality is due to the accumulation of a cell-permeable solute, such as urea or ethanol, there is no water shift because osmotic equilibrium is reached by solute entry into cells. Therefore, both urea and ethanol are ineffective osmoles. Plasma osmolality can be measured directly by determining freezing point depression or vapor pressure. Variable changes in the plasma sodium concentration occur with hyperglycemia. Since glucose enters cells slowly, an increase in the plasma glucose concentration raises effective plasma osmolality and causes water to move from the cells into the ECF. By dilution, this lowers the plasma Na ⁺ concentration. In theory, every 62 mg/dl increment in the plasma glucose concentration should draw enough water out of the cells to reduce the plasma Na ⁺ concentration by 1 mEq/l.

The number of particles per gram of water determines the osmolality of a solution. Since sodium salts (particularly NaCl and NaHCO ₃ ), glucose, and urea are primary extracellular osmoles, the plasma osmolality can be approximated from:

where 2 reflects the osmotic contribution of the anion accompanying Na ⁺ , and 18 and 2.8 represent the conversion of the plasma glucose concentration and blood urea nitrogen (BUN) from units of milligrams per deciliter (mg/dl) into millimoles per liter (mmol/l).

Although urea contributes to the absolute value of the P _osm , it does not act to hold water within the extracellular space because of its membrane permeability. Therefore, urea is an ineffective osmole and does not contribute to the effective P _osm .

In general, the effective plasma osmolality can be calculated from or estimated from:

or estimated from

Under normal circumstances, glucose and urea contribute less than 10 mOsm/kg H ₂ O, and the plasma Na ⁺ concentration is the main determinant of the plasma osmolality, the osmolality of body fluids can be estimated to be twice the plasma sodium concentration.

The major ECF particles are Na ⁺ and its accompanying anions Cl ⁻ and HCO ₃ ⁻ ; a high plasma sodium concentration is always associated with a high osmolality. This indicates that water is needed to restore isotonicity. The water deficit can be estimated from the plasma sodium level. The percentage increase in sodium concentration approximates the percentage decrease in total body water. The water deficit can be estimated by the equation:

Total body water varies with body size and fat content. It is approximately 60% of body weight in young men, 50% of body weight in old men and young women, and only 40% in elderly women.

Control of ADH Secretion

Hypernatremia results in the stimulation of both the antidiuretic hormone (ADH) release and thirst by the hypothalamic osmoreceptors ( Figure 45.1 ). Argenine vasopressin is the ADH in humans. Argenine vasopressin binds to specific receptors on collecting ducts (V ₂ receptors), which are coupled to cyclic AMP (cAMP) formation. The regulation of ADH release from the posterior pituitary is dependent primarily on two mechanisms: osmotic and nonosmotic pathways ( Figure 45.2 ). The osmotic regulation of ADH is dependent on osmoreceptor cells in the anterior hypothalamus. These cells, most likely by altering their volume, recognize changes in ECF osmolality. Cell volume is decreased readily by substances that are restricted to the ECF, such as hypertonic saline or hypertonic mannitol. These substances are effective in stimulating ADH release. In contrast, urea moves readily into cells, and therefore does not alter cell volume and does not effectively stimulate ADH release. A similar response pattern is evident when vasopressin release is studied in the hypothalamo–neurohypophyseal complex in organ culture. Specifically, sodium chloride, sucrose, and mannitol at 310 mOsm/kg H ₂ O cause a three-fold increase in argenine vasopressin release, while urea and glucose fail to stimulate vasopressin. These studies also support the view that the receptor responds to changes in osmolality rather than sodium. The effects of increased osmolality on vasopressin release are associated with a measurable increase in vasopressin precursor messenger RNA (mRNA) in the hypothalamus and salt-loading increases vasopressin RNA in the pituitary. Vasopressin release can also occur in the absence of changes in plasma osmolality. Physical pain, emotional stress, hypoglycemia, and a decrease in blood pressure or blood volume are important nonosmotic stimuli for vasopressin release. A 7 to 10% decrement in blood pressure or blood volume causes the prompt release of vasopressin ( Figure 45.2 ). Although there are considerable genetically-determined individual variations in both the threshold and sensitivity, a close correlation between argenine vasopressin and plasma osmolality has been demonstrated in subjects with various states of hydration ( Figure 45.3 ).

The secretion of ADH generally begins when the plasma osmolality exceeds 275 to 285 mOsm/kg H ₂ O. The threshold for thirst appears to be approximately 10 mOsm/kg H ₂ O above that of vasopressin release. Prevention of a total body water deficit is thus largely dependent on water intake as modulated by thirst. The thirst center appears to be closely associated anatomically with the osmoreceptors in the region of the hypothalamus. Defects in thirst response may involve either organic or generalized central nervous system lesions, and can lead to severe water deficit even in the presence of a normal concentrating mechanism. The water deficit will occur more promptly if renal concentrating ability is also impaired.

Thirst and the Maintenance of Hypernatremia

Thirst is, in fact, so effective that even patients with complete diabetes insipidus avoid hypernatremia by fluid intake in excess of 10 l/day. Hypernatremia supervenes, therefore, only when hypotonic fluid losses occur in combination with a disturbance in water intake. This is most commonly seen in the aged with an alteration in level of consciousness, in the very young with inadequate access to water or in a rare subject with a primary disturbance in thirst. Prevention of a total body water deficit is thus largely dependent on water intake as modulated by thirst. The thirst center appears to be closely associated anatomically with the osmoreceptors in the region of the hypothalamus. Defects in thirst response may involve either organic or generalized central nervous system lesions, and can lead to severe water deficit even in the presence of a normal concentrating mechanism.

In summary, persistent hypernatremia does not occur in normal subjects, because the ensuing rise in plasma osmolality stimulates both the releases of ADH, thereby minimizing further water loss and, more importantly, thirst. The associated increase in water intake then lowers the plasma sodium concentration back to normal. This regulatory system is so efficient that the plasma osmolality is maintained within a range of 1% to 2%, despite wide variations in sodium and water intake. Even patients with diabetes insipidus, who often have marked polyuria due to diminished ADH effect, maintain a near-normal plasma sodium concentration by appropriately increasing water intake. The net effect is that hypernatremia primarily occurs in those patients who cannot express thirst normally: infants and adults with impaired mental status. The latter most often occurs in the elderly, who also appear to have diminished osmotic stimulation of thirst. A patient with a plasma sodium concentration of 150 mEq/l or more who is alert but not thirsty has, by definition, a hypothalamic lesion affecting the thirst center.