The hypothalamus located below the thalamus on either side of the third ventricle is responsible for maintaining homeostasis through its ability to coordinate both the endocrine and the ANS. The hypothalamus controls temperature regulation, food and water intake, cyclic body functions, sexual behavior, reproduction, and the release of eight major hormones by the pituitary gland.

The hypothalamus is made up of several major groups of neurons including the preoptic, supraoptic, paraventricular, and the arcuate nuclei. Each region is responsible for the production of certain neuromediators and hormones. The preoptic nuclear region contains fibers that carry several neuromediators including angiotensin II and endorphins. In addition, reproduction and sexual arousal are regulated by this region through the production of gonadotropin releasing hormone (GRH). The supraoptic and paraventricular nuclei, located above the optic chiasm, are responsible for the release of several hormones that affect the pituitary gland including arginine vasopressin, oxytocin, thyrotropin releasing hormone (TRH), and corticotropin releasing hormone (CRH) (Fig. 10-1). Once created, vasopressin and oxytocin are transported through the infundibulum to the posterior pituitary where they are stored until needed for release into the bloodstream. Conversely, CRH is taken up by a hypothalamic-hypophyseal portal vein where it is transported to the anterior lobe of the pituitary gland influencing the production of adrenocorticotropic hormone (ACTH). The arcuate nucleus also referred to as the periventricular nucleus, is responsible for the production of growth hormone-releasing hormone (GHRH) and the growth hormone inhibiting factor, somatostatin. Releasing and inhibiting factors produced by the hypothalamus connect with the pituitary where they directly influence the production of pituitary hormones.

In addition to the above endocrine functions, the hypothalamus is also responsible for the synthesis of various neurotransmitters which affect the ANS including acetylcholine, GABA, glutamate, serotonin, dopamine, norepinephrine and others.

The pituitary gland (hypophysis) lies in the sella turcica, or “saddle” of the sphenoid bone just below the hypothalamus and is divided into two major parts, the anterior (adenohypophysis) and posterior (neurohypophysis).

Sitting atop bilateral kidneys, the adrenals are responsible for a variety of endocrine functions. The chief function of the adrenal gland is to provide a response to stress through the production of corticosteroids and catecholamines. Secondary functions include the regulation of serum osmolality, electrolytes, androgens, and blood pressure. The adrenals are regulated by three feedback systems including the HPA axis responsible for the maintenance of cortisol and androgen levels, the renin-angiotensin-aldosterone (RAA) system responsible for the regulation of aldosterone, and the ANS.

The adrenal gland comprises two distinct regions, the outer cortex and the inner medulla. The cortex consists of three functional zones, each responsible for the synthesis of one type of steroids. The zona fasciculata is mainly responsible for the synthesis of glucocorticoids, while the production of mineralocorticoids occurs in the adjacent zona glomerulosa. The most inner zone of the cortex, the zona reticularis, is responsible for androgen production. At the core of the adrenal gland, the medulla, made up of masses of neurons, regulates the fight or flight response through the secretion of epinephrine and norepinephrine.

The human body comprises approximately 60% water though age, gender, and percentage of body fat influence the exact percentage. Two thirds of TBW is intracellular, while only one third is extracellular (Fig. 10-4). The body maintains its fluid volume through regulation of water intake and output. The majority of water gain comes from oral intake regulated by the hypothalamus through a thirst mechanism. Renal control of sodium and water secretion is the largest contributor to fluid volume management. Most water loss occurs primarily in the form of urine, though some insensible loss also occurs through respiration and perspiration.

Osmolarity is a measure of the osmoles of solute per liter of solution whereas osmolality is a measure of the osmoles of solute per kilogram of solvent or water. Serum osmolality is a sensitive measure of hydration status. The normal range of plasma osmolality is 282 to 295 mOsm/kg, although it can vary slightly from laboratory to laboratory. The body maintains a near-constant body fluid osmolality primarily by regulating water balance within a narrow range rather than by regulating solute balance.³ Sodium, BUN, glucose, and urea comprise most of the solutes found in the extracellular
fluid (ECF). Plasma osmolality can be directly measured or estimated using the following formula.

(Na is sodium and BUN is blood urea nitrogen; 18 and 2.8 are derived from the conversion of mg/dL to mOsm/L) Sodium is ×2 in order to calculate for the accompanying anions.

Comparable results can usually be derived by simply doubling the serum sodium.⁵

A discrepancy between measured and calculated osmolarity (known as an osmolar gap) may help identify exogenous solutes such as mannitol, ethanol, ethylene glycol, and methanol.

Tonicity is often confused with osmolality. Osmolality is simply a count of the number of dissolved particles in a solution; whereas, tonicity describes the osmotic pressure gradient of two solutes that are separated by a semipermeable membrane. Tonicity is most often used to describe the osmotic pressure effect that an IV solution has on cells.

In a healthy person, water continuously moves between intracellular fluid (ICF) and ECF and is driven by osmotic pressure differences. Intracellular osmolality must always equal extracellular osmolality. Therefore, both fluid compartments are in osmotic equilibrium unless the ECF osmolality is disrupted such as with IV fluid administration. In general, isotonic fluids are maintained primarily in the extracellular space whereas hypotonic fluids are distributed throughout. Therefore, isotonic saline (NS) administration will influence blood pressure more than hypotonic solutions. When hypotonic solutions are given into the intravascular space, the body will attempt to equalize the osmotic pressure gradients by moving water from the now hypotonic intravascular compartment to the intracellular space resulting in cellular swelling. An increase in extracellular solutes, by administration of hypertonic fluids, will result in fluid shifting from the cells to the extracellular space, resulting in cellular dehydration. In contrast, isotonic solutions have an osmotic pressure similar to that of the intracellular space and will result in no water movement.

Sodium and intravascular fluid volumes are affected by various hormonal and nonhormonal “mediators” including ADH, aldosterone, angiotensin, natriuretic peptides, and renal preload. Distinguishing disorders of osmoregulation versus those of volume regulation is important since the body can regulate water and sodium independently. While ICF volume is affected primarily by ADH and cellular sodium-potassium pumps, ECF volumes are maintained primarily through the regulation of sodium by the kidney.

Osmoreceptors are specialized cells that sense changes in serum osmolality. Located in the hypothalamus near the cells that produce ADH, osmoreceptors respond to changes in concentration of ECF. Concentrated ECF stimulates the supraoptic nuclei to send impulses to release ADH, which causes reabsorption of water in the kidney. Conversely, dilute ECF around the hypothalamic osmoreceptors inhibits the generation of impulses for the release of ADH. Changes in osmolality as small as 1% are sufficient to alter ADH secretion significantly.⁶ Since the osmolality of plasma is determined by the concentration of a number of different solutes, including urea and glucose, the total plasma osmolality alone is not always clearly related to the ADH level.² Serum hyperosmolality most often causes release of ADH, but this not always the case. While hypertonic saline or sucrose solutions do stimulate ADH release, certain hyperosmolar solutes such as hypertonic urea and glucose do not. The ability of osmotic particles to cross the osmoreceptor membrane may account for these differences.

The ventromedian nucleus, also known as the thirst center, is within the lateral hypothalamus. The osmoreceptors that stimulate the supraoptic and paraventricular nuclei also stimulate the thirst center. The thirst center, in turn, stimulates the cerebral cortex, signaling the need to drink fluids. So long as the person is able to respond to this impulse, fluid and electrolyte balance can be maintained. However, motor deficits, dysphagia, or a decreased level of consciousness may interfere with the person’s ability to respond appropriately to the thirst stimuli.

Extrarenal baroreceptors, located in the chest, left atrium, aortic arch, and carotid sinuses, are specialized cells that sense changes in blood volume and blood pressure. Impulses from the baroreceptors travel via the vagus and glossopharyngeal nerves to the supraoptic and paraventricular nuclei. A decreased blood volume of 5% to 10% stimulates the secretion of ADH. ADH has important vasopressor and antidiuretic effects. Under ordinary circumstances, changes in osmolality of body fluids play the most important role in regulating ADH secretion. However, in situations of severe volume depletion, stimulation of ADH secretion via baroreceptors occurs despite significant hypoosmolality.

Intrarenal receptors, located in the JGA, are able to sense fluctuations in intravascular volume indirectly by sensing changes in intrarenal pressure and sodium concentration in the tubular fluid of the macula densa. A drop in intravascular volume leads to dilation of the afferent renal arterioles and excretion of renin by the JGA. Secretion of renin into the bloodstream activates the RAA system to augment ECF volume and blood pressure. Renin acts upon circulating angiotensinogen converting it to angiotensin I. In the endothelium of the lungs, angiotensin-converting enzyme removes two amino acids from angiotensin I converting it to angiotensin II. Angiotensin II causes arteriolar vasoconstriction, stimulates the thirst center in the brain, signals the release of ADH from the posterior pituitary, and prompts aldosterone synthesis in the adrenal cortex. In the case of hypervolemia, the cardiac muscle stretches releasing natriuretic peptides located in cardiac myocytes. Atrial natriuretic peptide (ANP) found in the cardiac atria and brain natriuretic peptide (BNP) found in both the ventricles and the hypothalamus are released when cardiac chambers are stretched secondary to increased intravascular volume. Effects of natriuretic peptide release include increased renal sodium and water excretion, vasorelaxation, and inhibition of RAA system.

Hyponatremia, defined as serum sodium level of less than 135 mEq/L, is one of the most common electrolyte disorders seen in neuroscience patients. Serum sodium concentrations are regulated by several mechanisms such as stimulation of thirst, secretion of ADH, and renal filtration as described above. The manifestations depend not only on the sodium level but also on the rapidity of development of hyponatremia. Patients with acute hyponatremia (i.e., develops rapidly in <24 to 36 hours) may be symptomatic with mild hyponatremia whereas patients with chronic hyponatremia (i.e., develops slowly and is present for >36 to 48 hours) may be asymptomatic. The signs and symptoms are nonspecific and related to the effects on the central nervous system (CNS). Patients with a serum sodium between 125 and 130 mEq/L with an acute onset may complain of headache, nausea, myalgia, and generalized malaise.⁸ In the range of 115 to 120 mEq/L, mental status changes from lethargy, confusion, disorientation, and agitation followed by seizures, coma, and death are noted (Table 10-3). Cerebral edema may occur, especially with rapid decline of serum sodium.⁹

Assessment should include not only the neurological system but also the hydration-volume status. Tachycardia, orthostatic hypotension, dry mucous membranes, decreased skin turgor, and sunken eyes are indicators of hypovolemia. The initial laboratory work-up for a patient with hyponatremia includes serum electrolytes, renal function, plasma and urine osmolality, and urine sodium concentration (Table 10-4).

Hyponatremia is more than a low sodium level. Disturbances of sodium are most commonly linked to a water imbalance and not a deficiency of sodium. To understand the underlying pathophysiology and basis for treatment, patients should be classified according to two-tier schemata. First, all hyponatremic patients are categorized into iso-osmolar, hyperosmolar, and hypo-osmolar states based on plasma osmolality.¹⁰ Hypo-osmolality is a state of excess body water whereas hyperosmolality is a state of depletion of body water. Second, if the hyponatremia is classified as hypo-osmolar hyponatremia, then it is further classified into hypovolemic, euvolemic, or hypervolemic hypo-osmolar hyponatremia.