Critical Care Medicine

Disorders of water balance

Disorders of Water Balance

1. Description of the problem

Normal water homeostasis

Water homeostasis is tightly regulated in order to maintain plasma osmolality in a narrow normal range of between 280 and 295 mOsm/kg. Disturbances of water homeostasis result in abnormalities in body fluid osmolality. Since sodium is the most abundant cation in the extracellular fluids, disturbances of plasma osmolality are commonly manifested as hypo- or hypernatremia.

Normally, water intake occurs via drinking in response to thirst; however, in hospitalized patients water intake may also be the result of prescribed fluids given enterally and intravenously. Water losses occur across all epithelial surfaces, including the skin, respiratory tract and gastrointestinal tract, but these losses are not physiologically regulated. The kidney is responsible for physiological regulation of water excretion under the control of the peptide hormone vasopressin (also known as antidiuretic hormone, ADH).

Mild abnormalities of water homeostasis are often asymptomatic and are manifested primarily by laboratory abnormalities in the plasma sodium concentration. With more severe disturbances in water homeostasis neurologic manifestations ranging from mild lethargy and confusion to severe depression of sensorium may be present. While the severity of neurologic impairment is variable, the symptoms generally correlate with the magnitude and acuity of onset of hypo- and hypernatremia.


The regulation of water ingestion is complex and poorly understood. Ingestion of water and other beverages is influenced by habit and cultural norms as well as by thirst. Thirst itself is a complex stimulus affected by multiple factors, including both mucosal stimuli and osmotic stimuli. From the perspective of physiologic regulation of water homeostasis, it is the osmotic regulation of thirst that is of importance.

Plasma osmolality is sensed by osmoreceptors in the anterior wall of the third ventricle in the hypothalamus. Impulses from these osmoreceptors are projected through poorly defined pathways to the cerebral cortex, where they trigger the perception of thirst and water-seeking behavior. The osmotic threshold for thirst is usually in the range of 285 to 290 mOsm/kg, with osmotic thirst suppressed below this level and stimulated in proportion to increases in body fluid osmolality above this threshold.


Renal water excretion is regulated by the peptide hormone vasopressin (also known as antidiuretic hormone, ADH). Vasopressin is synthesized in the supraoptic and paraventricular nuclei in the hypothalamus, whose axons terminate in the posterior pituitary gland. Vasopressin secretion is normally regulated in response to two physiologic stimuli: plasma osmolality and effective arterial blood volume.

Vasopressin secretion is normally highly sensitive to changes in plasma osmolality. When plasma osmolality is less than 280 to 285 mOsm/kg, vasopressin secretion is normally suppressed; as plasma osmolality rises above this threshold, vasopressin secretion is stimulated, with changes in plasma osmolality of as little as 1% to 2% resulting in detectable increases in plasma vasopressin levels. The osmoreceptors regulating vasopressin secretion are located in the hypothalamus in the anterior wall of the third ventricle in proximity to, but anatomically distinct from, the osmoreceptors subserving thirst regulation.

Vasopressin is also secreted in response to hypotension and hypovolemia; however, the relationship between hemodynamic changes and vasopressin secretion differs markedly from that of osmotically mediated vasopressin secretion. Unlike the small changes in plasma osmolality that are required to elicit an increase in vasopressin levels, intravascular volume needs to be reduced by more than 10% to stimulate vasopressin secretion.

Hemodynamic status modulates the relationship between osmolality and vasopressin secretion, with hypotension and hypovolemia decreasing the threshold and increasing the sensitivity of the osmotic release of vasopressin and volume loading increasing the threshold and decreasing the sensitivity of the relationship.

Renal water excretion

The kidney is the primary organ for physiologically regulated water excretion. The key steps in renal water homeostasis are:

  • Reabsorption of salt independent of water in the thick ascending limb of the loop of Henle and distal convoluted tubule, creating a concentrated medullary interstitium and a dilute tubular fluid.

  • Variable reabsorption of water along the length of the collecting duct, regulated by plasma vasopressin levels.

In the absence of vasopressin the collecting duct has low water permeability and a dilute urine (urine osmolality less than 100 mOsm/kg). Vasopressin stimulates the insertion of water channels into the apical membrane of collecting duct cells, thereby increasing hydraulic permeability and allowing water to be reabsorbed down the medullary concentration gradient. Thus, in response to increasing plasma vasopressin levels, reabsorption of water along the collecting duct increases as does the osmolality of the final urine, with maximal urinary concentration achieved at vasopressin levels corresponding to a plasma osmolality of approximately 295 mOsm/kg.

Integrated Response to Water Loading or Depletion

In response to an acute water load, plasma osmolality will decrease. This fall in plasma osmolality (and the modest degree of volume expansion that accompanies it) will decrease vasopressin secretion by the pituitary gland, leading to a fall in plasma vasopressin levels. The decreased vasopressin levels inhibit the insertion of water channels into the collecting duct, decreasing its hydraulic permeability and leading to the production of a dilute urine. The net result is excretion of the water load by the kidney.

In response to water restriction, plasma osmolality will increase. This rise in plasma osmolality (along with the modest degree of volume contraction that accompanies water deprivation) will stimulate vasopressin secretion by the pituitary gland, raising plasma vasopressin levels. The elevated vasopressin levels stimulate the insertion of water channels into the collecting duct, increasing its hydraulic permeability and permitting water absorption into the hypertonic medullary interstitium and leading to the production of a concentrated urine and minimizing ongoing renal water losses. This renal response is, however, insufficient to correct hypertonicity. The ultimate defense against the development of hypertonicity is the stimulation of thirst, increasing water intake and returning plasma osmolality to normal.

Manifestations of disorders of water balance

The cardinal manifestations of disordered water balance are hypotonic hyponatremia (a serum sodium of < 135 mEq/L) and hypernatremia (a serum sodium > 145 mEq/L) [see the chapter "Dysnatremias"]. Patients with decreased vasopressin secretion (hypothalamic diabetes insipidus) or impaired kidney responsiveness to vasopressin (nephrogenic diabetes insipidus) may manifest profound polyuria without overt hypernatremia due to preservation of thirst [see the chapter "Diabetes Insipidus"]. If, however, thirst is impaired or access to water ingestion is restricted, hypernatremia will rapidly ensue.

Etiologies of hyponatremia

Hyponatremia may occur as the result of disordered water homeostasis (hypotonic hyponatremia) or as the result of accumulation of non-electrolyte solute in the extracellular compartment (hypertonic hyponatremia).

In hypotonic hyponatremia, water intake exceeds water excretion, leading to an increase in total body water relative to total body solute, causing a dilution of body fluids (hypotonicity), which is manifest in the extracellular compartment as hyponatremia. In hypertonic hyponatremia, the accumulation of non-electrolyte solute, such as glucose, in the extracellular fluid causes a hypertonic state, leading to the shift of water from the intracellular compartment into the extracellular compartment.

This shift of water into the intracellular compartment dilutes the extracellular sodium concentration, leading to hyponatremia. Hypertonic hyponatremia is differentiated from hypotonic hyponatremia based on the finding of an elevated plasma osmolality.

In rare circumstances, hyponatremia may be reported as a laboratory artifact as the result of severe hyperlipidemia or paraprotein retention. This "pseudohyponatremia" is of importance primarily as it needs to be distinguished from true hyponatremia requiring medical therapy. Although the frequency of pseudohyponatremia has markedly diminished with improved laboratory methods, it may still occur.

Hypotonic hyponatremia may occur in the setting of extracellular volume depletion; in the setting of heart failure, cirrhosis, nephrotic syndrome or renal failure (edematous disorders); or in the setting of clinically normal extracellular volume (euvolemic hyponatremia) [see section on Hyponatremia in the chapter "Dysnatremia"].

Hypovolemic hyponatremia

Hyponatremia may develop in any setting associated with hypovolemia (e.g., gastroenteritis with severe diarrhea) if water intake exceeds water losses. Hypovolemia stimulates vasopressin secretion independent of plasma osmolality. In addition, intravascular volume depletion stimulates proximal tubular sodium reabsorption, decreasing delivery of tubular fluid to the loop of Henle and distal convoluting tubule (the diluting sites in the nephron), limiting the tubular generation of electrolyte-free water. Characteristically, in hypovolemic hyponatremia the urine sodium is < 30 mEq/L and the urine is concentrated, with a urine osmolality > 300 mOsm/kg.

Hypervolemic hyponatremia

In patients with heart failure, cirrhosis, nephrotic syndrome and other edematous disorders, hypotonic hyponatremia is common. The pathologic mechanisms underlying the development of hyponatremia in these patients is similar to that in hypovolemic hyponatremia - volume-mediated vasopressin secretion resulting from decreased effective arterial blood volume combined with increased proximal tubular sodium reabsorption decreasing delivery of fluid to the distal diluting segments of the nephron. As in hypovolemic hyponatremia, the urine sodium is usually < 30 mEq/L and the urine is concentrated, with a urine osmolality > 300 mOsm/kg.

In patients with advanced chronic kidney disease, hyponatremia may also develop in the setting of volume expansion. In these patients, however, vasopressin secretion and urinary dilution are usually preserved. Hyponatremia develops because renal water excretion is limited by the reduced glomerular filtration rate, leading to a decrease in maximal water excretion by the kidney.

Euvolemic hyponatremia

In patients in whom hyponatremia develops in the absence of volume-stimulated vasopressin secretion, the hyponatremia results from water ingestion exceeding maximal renal water excretion. This may occur as a result of disordered vasopressin secretion or in the setting of normal suppression of vasopressin secretion in the setting of hypotonicity.

Normal osmotic suppression of vasopressin secretion

Hypotonic hyponatremia may develop despite normal suppression of vasopressin secretion by hypotonicity in patients with massive water ingestion (primary or psychogenic polydipsia) or in patients in whom restricted intake of salt and protein (severe malnutrition, beer drinker's potomania) limits total renal solute excretion and, hence, daily renal water excretion.

In primary (psychogenic) polydipsia, water intake exceeds the normal maximal rate of renal water excretion, leading to progressive water intoxication. Normal daily solute load averages 500 to 600 mOsm/day. At a minimal urine osmolality of 40 to 50 mOsm/kg, water homeostasis can be maintained with water intake of up to 10 to 15 liters per day. If intake exceeds this volume, the kidney's ability to maintain water homeostasis is exceeded and hyponatremia will ensue.

In patients with severe malnutrition, daily solute excretion may be markedly decreased, to more than 150 to 200 mOsm/day or less. In these patients, the maximal daily water excretion will be severely limited and water intoxication may develop despite only modest water intake. This situation may be seen in individuals whose caloric intake is limited to beer consumption and who have minimal daily sodium intake (beer drinker's potomania).

Elevated vasopressin secretion

Euvolemic hyponatremia as the result of elevated vasopressin secretion despite prevailing hypotonicity is the hallmark of the syndrome of inappropriate antidiuresis (SIAD, also known as the syndrome of inappropriate antidiuretic hormone, SIADH). In addition, glucocorticoid deficiency and severe hypothyroidism are associated with impaired suppression of vasopressin secretion.

The specific criteria to make a diagnosis of the syndrome of inappropriate antidiuresis (SIAD) are:

  1. Hypotonic hyponatremia (plasma osmolality < 280 mOsm/kg)

  2. An inappropriately concentrated urine relative to plasma osmolality (urine osmolality > 100 mOsm/kg)

  3. An elevated urine sodium concentration (> 30 mEq/L), except during dietary sodium restriction

  4. Absence of hypervolemia (edema) or ECF volume depletion on physical exam

  5. Normal cardiac, hepatic and kidney function

  6. Normal thyroid and adrenal function

SIAD may be the result of a variety of etiologies including pain, nausea, stress, malignancy (most commonly bronchogenic carcinoma, mesothelioma, pancreatic cancer, duodenal cancer, prostate cancer, endometrial carcinoma, thymoma, leukemia and lymphoma), pulmonary disease (tuberculosis, pneumonia, bronchiectasis, cystic fibrosis, asthma, positive pressure ventilation), CNS disease (head trauma, subdural hematoma, subarachnoid hemorrhage, stroke, primary or secondary brain tumors, encephalitis, meningitis) and medications.

Etiologies of hypernatremia

Hypernatremia develops when water ingestion is insufficient to match ongoing water losses. Since normal individuals are able to compensate for even massive water loss though thirst-stimulated drinking, the development of hypernatremia generally implies the presence of impaired thirst or restricted access to water. The etiology of hypernatremia may therefore be broken down into defects in thirst in the absence of increased water losses and states associated with increased water losses. In addition, in a small percentage of patients, hypernatremia may result from the administration of hypertonic sodium solutions or salt ingestion.

Defects in thirst

Primary Hypodipsia

Hypothalamic lesions affecting the osmostat

  • Trauma

  • Craniopharyngioma or other primary suprasellar tumor

  • Metastatic tumor

  • Granulomatous disease

  • Vascular lesions

Essential hypernatremia

Geriatric hypodipsia

Secondary Hypodipsia

Cerebrovascular disease



Mental status changes

Increased Water Losses

Pure water losses (normal extracellular volume)

Diabetes insipidus

  • Hypothalamic (decreased vasopressin secretion)

  • Nephrogenic (decreased kidney responsiveness to vasopressin)

Increased insensible losses

  • Hyperpyrexia

  • Mechanical ventilation

Hypotonic fluid losses (decreased extracellular volume)

Renal losses

  • Diuretic administration

  • Osmotic diuresis

  • Post-obstructive diuresis

  • Polyuric phase of acute tubular necrosis

Gastrointestinal losses

  • Vomiting

  • Nasogastric drainage

  • Diarrhea

  • Enterocutaneous fistula

Cutaneous losses

  • Burn injuries

  • Excessive sweating

Hypertonic sodium gain

Salt ingestion (particularly in children)

Iatrogenic hypertonic sodium administration

  • Hypertonic saline

  • Hypertonic sodium bicarbonate

  • Total parenteral nutrition with excessive sodium content.


The prognosis in both hyponatremia and hypernatremia depends on the etiology, initial sodium, and clinical course.

Patients with hyponatremia are generally asymptomatic unless the serum sodium concentration is less than 120 mEq/L, although abnormalities in neurocognitive function may be detected with even mild hyponatremia. Symptoms of hyponatremia may be non-specific, including nausea and vomiting, headache and gait instability, and may be difficult to differentiate from symptoms associated with underlying disease.

Mental status change, seizures, coma and respiratory arrest are associated with more severe hyponatremia, with severity of symptoms correlated with the acuity of onset. The symptoms of hyponatremia, termed hyponatremic encephalopathy, primarily reflect the development of cerebral edema. Cerebral pontine myelinolysis (CPM) is an irreversible neurologic disorder that has been associated with overly rapid correction of the serum sodium concentration.

As with hyponatremia, the symptoms of hypernatremia are non-specific and range from lethargy, nausea and vomiting to impaired mental status, seizures and coma. In severe hypernatremia, particularly in children, intra-cerebral bleeding may occur as the result of traction on bridging veins as the result of osmotic shrinkage of the brain. Although CPM may develop as a result of rapid onset of hypernatremia, it does not appear to be a consequence of treatment. Overly rapid correction of hypernatremia, particularly if there has been a delay in diagnosis and treatment, may be associated with the development of cerebral edema.

Although both hyponatremia and hypernatremia are associated with an increased risk of mortality, it is unclear if this mortality relates to the electrolyte disorder per se, or, more likely, due to the underlying comorbidities that contributed to the development of the disordered water homeostasis.

What's the evidence?

Adrogue, HJ, Madias, NE. "Hyponatremia". NEJM. vol. 342. 2000. pp. 1581.

Adrogue, HJ, Madias, NE. "Hypernatremia". NEJM. vol. 324. 2000. pp. 1493.

Anderson, RJ, Chung, HM, Kluge, R, Schrier, RW. "Hyponatremia: a prospective analysis of its epidemiology and the pathogenetic role of vasopressin". Ann Intern Med. vol. 102. 1985. pp. 164.

Verbalis, JG, Goldsmith, SR, Greenberg, A, Schrier, RW, Sterns, RH. "Hyponatremia treatment guidelines 2007: Expert Panel Recommendations". Am J Med. vol. 120. 2007. pp. S1.

Fried, LF, Palevsky, PM. "Hyponatremia and hypernatremia". Med Clin North Am. vol. 81. 1997. pp. 585.

Rose, BD, Post, TW. Clinical Physiology of Acid-Base and Electrolyte Disorders. New York. 2001. pp. 682-821.

Chawla, A, Sterns, RH, Nigwekar, SU, Cappuccio, JD. "Mortality and serum sodium: Do patients die from or with hyponatremia?". Clin J Am Soc Nephrol. vol. 6. 2011. pp. 960-5.

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