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There is dual control of water and serum osmolality.^1,2 The hypothalamus and posterior pituitary are involved in water retention, and the renin‐angiotensin‐aldosterone axis is involved in sodium retention. The supraoptic and paraventricular nuclei of the hypothalamus respond primarily to increases in serum osmolality with the release of arginine vasopressin (AVP), also known as antidiuretic hormone (ADH) (see Figure 15.1). The release of ADH is mediated through changes in an electrochemical gradient in these magnocellular neurons to maintain serum osmolality at 285±2 mOsm/kg. These neurons are also under the influence of neurotransmitters such as acetylcholine (i.e. through the vagus nerve, as described below), catecholamines, opioids, and angiotensin. Small changes in osmolality allow for acute adjustment in serum ADH levels with resulting water retention or free water clearance by the kidney.^1,2

There is also parallel autonomic nervous system regulation of water retention in which vascular receptors respond to decreases in total body water and changes in organ perfusion. There are high‐pressure (blood pressure) baroreceptors in the carotid sinus and aortic arch and low‐pressure stretch receptors in the cardiac atria and pulmonary venous systems. Both types of receptors transmit regulatory impulses via the vagus nerve to the hypothalamic neurons to stimulate ADH in the event of low effective arterial blood volume (EABV).^1,2 Pathophysiological states of diminished EABV stimulate the release of ADH above that due to osmolality. Thus, ADH may be ‘appropriate’ for the diminished EABV but appears inappropriate for serum osmolality. Conditions that may increase ADH release are shown in Figure 15.2. The baroreceptors may respond to changes in blood pressure associated with volume loss (gastrointestinal losses or diuretic‐induced volume loss), decreased intravascular volume in hypoalbuminemic oedema‐forming states (ascites or nephrotic syndrome), orthostatic hypotension (due to adrenal cortical insufficiency, mineralocorticoid insufficiency, or autonomic neuropathy), and decreased arterial perfusion (due to reduced cardiac output such as cardiac tamponade, cardiomyopathy, or severe hypothyroidism). Decreased stretch of the volume receptors in the cardiac left atrium may occur in states of low EABV as described above. Diminished stretch in these receptors may also ‘appear’ as low pressure due to restrictions in pulmonary vascular return to the heart, as a result of increased intra‐thoracic pulmonary pressure in severe reactive airway disease, or with mechanical ventilation.^1,2

Vasopressin activates V2 receptors in the distal collecting tubules of the kidney (Figure 15.3). In the absence of ADH, the tubule is impermeable to water transport. As shown in Figure 15.3, 15 to 30 litres/day of free water may reach the distal collecting tubules. The entire volume may be potentially lost through the urine in central diabetes insipidus (lack of renal concentration ability due to partial or complete ADH deficiency). In the presence of ADH, water is transported from the intraluminal collecting duct through aquaphorin‐2 channels, across a concentration gradient to the intra‐renal capillaries to reabsorb free water. The concentration gradient is derived at the loop of Henle through the medullary urea countercurrent system. The urea is freely permeable into the collecting duct. In the presence of ADH, the kidney may concentrate the urine to a volume of 0.7 litres per day with an osmolality of 600–1200 mOsm/kg, made up primarily of the secreted urea.

Thirst, the conscious desire to drink, is another active component of water retention.^6,7 Thirst is under the control of a closely located series of hypothalamic neurons in the organum vasculosum of the lamina terminalis (OVLT).^1,2 This area is independent of the blood‐brain barrier. These neurons, like ADH‐secreting neurons, are under similar influence of serum osmolality, neurotransmitters, and angiotensin. Normally, thirst lags behind ADH release in response to increases in serum osmolality. The threshold of thirst, as measured on a visual analogue scale or the volume of water ingested, is approximately 10 mOsm/kg greater than the ADH threshold.^5,6 There are pathological conditions in which thirst may be independent of ADH release. Thirst is inappropriately diminished in response to serum osmolality in central nervous system conditions characterized by a reset or diminished thirst response to serum osmolality (essential hypernatremia) or in complete lack of thirst response to severe hypernatremia (adipsia) (Figure 15.4).⁶

Figure 15.1 Osmotic control of water balance. The hypothalamus supraoptic (SO) and paraventricular (PV) nuclei release antidiuretic hormone (ADH) through neural tracts to the posterior pituitary. Thirst is under the control of a closely located series of hypothalamic neurons in the organum vasculosum of the lamina terminalis (OVLT).

Whereas ADH is the main hormone involved in water homeostasis, the renin‐angiotensin‐aldosterone system is a primary factor in sodium retention and systemic blood pressure/volume control. Renin is released from the juxtaglomerular apparatus of the kidney in response to low perfusion, low intravascular volume, and low tubular sodium. Renin is an enzyme that converts liver‐derived angiotensinogen to angiotensin 1, and lung‐derived angiotensin‐converting enzyme further metabolizes conversion to angiotensin 2. Angiotensin 2 stimulates the release of the mineralocorticoid aldosterone to retain sodium and stimulates the hypothalamic neuron to release ADH and provoke thirst (Figure 15.2).

Figure 15.2 Pressure‐volume control of water and sodium balance. Baroreceptors (systemic blood pressure) in the aortic arch and volume receptors in the atria respond to changes in effective arterial blood volume (EABV) to induce release of ADH through vagal stimuli. Decreased intrarenal perfusion induces renin activation of the renin‐angiotensin‐aldosterone system to increase sodium retention.

Figure 15.3 Renal action of ADH in water conservation.

Figure 15.4 Comparisons of disorders of thirst. Serum ADH levels increase with serum osmolality at a threshold of 280 mOsmol/kg (solid line). Thirst responses (rate of fluid intake or sensation of thirst) start to increase at approximately 5–10 mOsmol/kg higher than that of ADH release (‐‐‐‐ dotted line). Abnormally decreased thirst responses are found in essential hypernatreamia (‐ ‐ ‐ ‐ dashed line), and severely impeded thirst responses are found in adipsia (‐ ‐ ‐ ‐ ‐ interrupted dashed line).

Syndromes of hyponatremia may reflect physiological ‘appropriate’ release of ADH in response to vagal stimuli due to decreased perfusion pressure or decreased plasma volume (decreased EABV). In these situations, the elevated ADH is inappropriate for the serum osmolality. The syndrome of inappropriate ADH secretion (SIADH) is a research definition that eliminates appropriate physiological ADH responses. The discussion of hyponatremia includes both ‘appropriate’ and SIADH syndromes.

Hyponatremia may be defined as a serum sodium <135 mEq/L, or at a level <130 mEq/L for clinically significant hyponatremia.^1,2 Aside from water intoxication associated with excessive water intake during exercise, most causes of hyponatremia are associated with imbalances in ADH levels.^4,8 Clinical syndromes of hyponatremia (and true hypo‐osmolality) are associated with decreased effective serum osmolality^9,10 where

Serum concentrations of urea, which are included in the calculation of plasma osmolality, are not considered as part of the calculation of effective extracellular osmolality since urea is freely permeable through cell membranes.

Therefore, the major component of extracellular osmolality in the non‐hyperglycemic state is serum sodium with its corresponding anions. Severe clinically significant hyponatremia is usually associated with serum sodium in the range of <120 mEq/L, or with the rapid decline of serum sodium as in water intoxication or post‐anaesthesiology hyponatremia.⁸ The major toxicities are due to changes in neurological functions (defined as hyponatremic encephalopathy).⁸ Symptoms may range from headache, nausea, disorientation, and confusion to more severe symptoms of cerebral oedema with seizures, coma, and, in extreme cases, cerebral tentorial herniation and death. Chronic hyponatremia (which has developed over >48 hours) usually results in central nervous system intracellular adaptation, with the extrusion of intra‐neuronal organic and inorganic osmoles. During the treatment of symptomatic hyponatremia, the concern therefore is that overly rapid correction of hyponatremia (defined as an increase of >8 mEq/L over 24 hours) may result in cerebral dehydration and pontine and extrapontine osmotic demyelination syndromes (ODS).^2,8 These ODS syndromes may be delayed in onset and associated with severe neurological morbidity and mortality.