Hyponatremia is uncommon in children and is usually associated with severe systemic disorders.
Hyponatremia is usually seen in the setting of salt loss that is in excess of water loss from the body. It is also seen when there is excessive intake of free water.
Definition and classification of hyponatremia
Hyponatremia (serum sodium < 130 mmol/L) is uncommon in children. It is usually associated with severe systemic disorders. It is most commonly due to either intravascular volume depletion or excessive salt loss, as discussed subsequently, and is also encountered with hypotonic fluid overload, especially in infants. Hyponatremia can be broadly classified as that due to appropriately elevated or inappropriately elevated secretion of vasopressin and that which is associated with decreased secretion of vasopressin. While hyponatremia in conjunction with hypovolemia from any cause is associated with an appropriately elevated secretion of vasopressin, inappropriately elevated secretion of vasopressin is one of the least common causes of hyponatremia in children, except following vasopressin administration for treatment of DI (Figure 8-11).
Diagnostic and therapeutic algorithm for hyponatremia.
Clinical presentation and diagnosis
Because of cerebral edema, signs and symptoms when present are mostly neurological in nature. Headache, nausea, vomiting, and weakness are the most common symptoms. Behavioral changes and altered sensorium can be seen in more severe cases. Cerebral herniation can present with dilated pupils, bradycardia, hypertension, respiratory arrest, and a decorticate posture. In evaluating the cause of hyponatremia, one should first determine whether the patient is dehydrated and hypovolemic.9 This is usually evident from the physical examination (decreased weight, skin turgor, and central venous pressure) and laboratory data (elevated BUN, renin, aldosterone, and uric acid). With a decrease in the GFR, proximal tubular reabsorption of sodium and water will be increased, leading to a urinary sodium concentration less than 20 mmol/L. Patients with decreased “effective” intravascular volume due to congestive heart failure, cirrhosis, nephrotic syndrome, or lung disease will present with similar laboratory data, but they also have obvious signs of their underlying disease, which often includes peripheral edema. Patients with primary salt loss will also appear volume-depleted. When the salt loss is from the kidney (eg, diuretic therapy or polycystic kidney disease), urine sodium will be elevated, as may be urine volume. Salt loss from other regions (eg, the gut in gastroenteritis or the skin in cystic fibrosis) will cause urine sodium to be low, as in other forms of systemic dehydration. Cerebral salt wasting (CSW) is encountered with central nervous system (CNS) insults, and it results in high serum atrial natriuretic peptide (ANH) concentrations leading to high urine sodium and urine excretion.
The syndrome of inappropriate ADH secretion exists when a primary elevation in vasopressin secretion is the cause of hyponatremia. It is characterized by hyponatremia and hypo-osmolality, a urine that is inappropriately concentrated given the degree of hypo-osmolality (> 100 mOsm/kg), a normal or slightly elevated plasma volume, and a normal-to-high urine sodium (because of volume-induced suppression of aldosterone and elevation of ANH). Serum uric acid is low in patients with SIADH, whereas it is high in those withhyponatremia due to systemic dehydration or other causes of decreased intravascular volume. Measurement of plasma vasopressin is not very useful because it is elevated in all causes of hyponatremia except for primary hypersecretion of ANH. Because cortisol and thyroid deficiency cause hyponatremia by several mechanisms discussed subsequently, they should be considered possible etiologies in all hyponatremic patients. Drug-induced hyponatremia should be considered in patients on potentially offending medications, as discussed later in this chapter. In children with SIADH who do not have an obvious cause, a careful search for an ectopic source of vasopressin causing the disease, such as a tumor (thymoma, glioma, or bronchial carcinoid), should be considered.
Most children with hyponatremia develop the disorder gradually, are asymptomatic, and should be treated with water restriction alone. However, the development of acute hyponatremia, or a serum sodium concentration below 120 mmol/L, may be associated with lethargy, psychosis, coma, or generalized seizures, especially in younger children. Acute hyponatremia causes cell swelling due to the entry of water into cells (Figure 8-12). If present for more than 24 hours, cell swelling triggers a compensatory decrease in intracellular organic osmolytes, resulting in the partial restoration of normal cell volume in chronic hyponatremia. The proper emergency treatment of cerebral dysfunction depends on whether the hyponatremia is acute or chronic. In all cases, water restriction should be instituted. If hyponatremia is acute, and therefore probably not associated with a decrease in intracellular organic osmolyte concentration, rapid correction with hypertonic, 3% sodium chloride administered intravenously may be indicated. Infusion of 1 to 2 mL/kg body weight of 3% sodium chloride will raise the serum sodium chloride concentration by approximately 1 to 2 mmol/L. If hyponatremia is chronic, hypertonic saline treatment must be undertaken with caution, because it may result in both cell shrinkage (see Figure 8-12) and the associated syndrome of central pontine myelinolysis. This syndrome, affecting the central portion of the basal pons, is characterized by demyelination with sparing of neurons. It becomes evident within 24 to 48 hours following too rapid correction of hyponatremia, has a characteristic appearance by computed tomographic and MRI, and often causes irreversible brain damage.27 If hypertonic saline treatment is undertaken, the serum sodium should be raised only high enough to cause an improvement in mental status, and in no case faster than 0.5 mmol/L/h or 12 mmol/L/day. In the case of systemic dehydration, the rise in serum sodium may occur especially rapidly using this regimen. The associated hyperaldosteronism will cause avid retention of the administered sodium, leading to rapid restoration of volume and suppression of vasopressin secretion, resulting in a brisk water diuresis and a rise in serum sodium.
The effects of hyponatremia and its rapid correction on intracellular osmolality and size of the brain cell. The shape and size of cell are normal in the eunatremic state (A) in which the osmolalities within and outside the cell are equal. Acute hyponatremia (B) causes an osmotic fluid shift into the cell (blue arrows) leading to cell swelling. Rapid correction of the acute hyponatremia (C) once again equalizes the intra- and extracellular osmolalities and restores the normal size and shape of the cell. If hyponatremia persists beyond 24 hours (D), the cell tries to regain its original shape and size by extruding some of its osmolytes to equilibrate its osmolality with that of the outside. Rapidly raising the serum sodium and extracellular osmolality at this stage (E) causes cell shrinkage due to osmotic flow of water out of the cell (blue arrows). The cell is unable to generate new osmolytes rapidly enough to once more equilibrate the intra- and extracellular osmolalities.
Hyponatremia with an Appropriate Increase in Vasopressin Secretion
Increased vasopressin secretion causing hyponatremia (serum sodium < 130 mmol/L) may either be an appropriate or an inappropriate response to a pathological state. Inappropriate secretion of vasopressin, also termed SIADH, is the much less common of the two entities. Whatever the cause, hyponatremia is a worrisome sign often associated with increased morbidity and mortality.
Systemic dehydration (water loss in excess of salt depletion) initially results in hypernatremia, hyperosmolality, and activation of vasopressin secretion, as discussed earlier in this chapter. In addition, the associated fall in the renal GFR results in an increase in proximal tubular sodium and water reabsorption, with a concomitant decrease in distal tubular water excretion. This limits the ability to form dilute urine, and, along with the associated stimulation of the renin-angiotensin-aldosterone system and suppression of ANH secretion, results in the excretion of urine with a very low concentration of sodium. As dehydration progresses, hypovolemia and/or hypotension become major stimuli for vasopressin release, much more potent than hyperosmolality (as discussed in a preceding section). This effect, by attempting to preserve volume, decreases free water clearance further and may lead to water retention and hyponatremia, especially if water replacement in excess of salt is given. Often, hyponatremia due to intravascular volume depletion is evident from physical and laboratory signs such as decreased skin turgor, low central venous pressure, hemoconcentration, and elevated BUN.
Congestive heart failure, cirrhosis, nephrotic syndrome, positive-pressure mechanical ventilation, severe burns, and lung disease (bronchopulmonary dysplasia in neonates, cystic fibrosis with obstruction, and severe asthma) are all characterized by a decrease in “effective” intravascular volume. This occurs either because of impaired cardiac output, an inability to keep fluid within the vascular space, or impaired blood flow into the heart, respectively. As with systemic dehydration, in an attempt to preserve intravascular volume, water and salt excretion by the kidney is reduced, and decreased barosensor and volume sensor stimulation results in a compensatory, appropriate increase in vasopressin secretion, leading to an antidiuretic state and hyponatremia. Because of the associated stimulation of the renin-angiotensin-aldosterone system, these patients also have an increase in the total body content of sodium chloride and may have peripheral edema, which distinguishes them from those with systemic dehydration. In patients with impaired cardiac output and elevated atrial volume (such as those with congestive heart failure or lung disease), ANH concentrations are elevated, which contribute to hyponatremia by promoting natriuresis (as discussed subsequently).
Patients with systemic dehydration and hypovolemia should be rehydrated with salt-containing fluids such as normal saline or lactated Ringer solution. Because of activation of the renin-angiotensin-aldosterone system, the administered sodium will be avidly conserved, and a water diuresis will quickly ensue as volume is restored and vasopressin concentrations fall. Under these conditions, caution must be taken to prevent overly rapid correction of hyponatremia, which may itself result in brain damage, as discussed subsequently.
Hyponatremia due to a decrease in effective plasma volume caused by cardiac, hepatic, renal, or pulmonary dysfunction is more difficult to reverse. The most effective therapy is the least easily achieved: treatment of the underlying systemic disorder. Patients weaned from positive-pressure ventilation undergo a prompt water diuresis and resolution of hyponatremia as cardiac output is restored and vasopressin concentrations fall. The only other effective route is to limit water intake to that required for the renal excretion of the obligate daily solute load of approximately 500 mOsm/m2 and to replenish insensible losses. In a partial antidiuretic state with a urine osmolality of 750 mOsm/kg and insensible losses of 500 mL/m2, oral intake would have to be limited to approximately 1200 mL/m2/day. Because of concomitant hyperaldosteronism, the dietary restriction of sodium chloride needed to control peripheral edema in patients with heart failure may reduce the daily solute load and further limit the amount of water that can be ingested without exacerbating hyponatremia. However, hyponatremia in these settings is often slow to develop, it rarely causes symptoms, and usually does not need treatment. If the serum sodium falls below 125 mmol/L, water restriction to 1 L/m2/day is usually effective in preventing a further decline.
Hyponatremia With an Inappropriate Increase in Vasopressin Secretion
SIADH is uncommon in children. It can be seen in association with disorders affecting the CNS such as encephalitis, brain tumor, head trauma, and in the postictal period following generalized seizures, following prolonged nausea, pulmonary and thoracic lesions such as pneumonia, empyema and certain mediastinal tumors that secrete vasopressin, infections such as AIDS, and treatment with drugs, including chlorpropamide, vincristine, imipramine, and phenothiazines (Table 8-7). Newer sulfonylurea agents, including glyburide, are not associated with SIADH. Although SIADH has been believed to be the cause of hyponatremia associated with viral meningitis, volume depletion is more commonly the etiology (see Table 8-7). In the vast majority of children with SIADH, the cause is the excessive administration of vasopressin, whether to treat central DI,17, 18, 19, 20, 21, 22, 23, 24, 25 or less commonly, bleeding disorders, or very rarely following DDAVP therapy for enuresis.
Table 8-7.Causes of SIADH ||Download (.pdf) Table 8-7. Causes of SIADH
|Central nervous system causes |
| Trauma/subdural hematoma/subarachnoid hemorrhage Postoperative (triple-phase response) |
| Meningitis, encephalitis, and brain abscess |
| Brain tumors |
|Pulmonary causes |
| Pneumonia |
| Empyema Neonatal hypoxia |
| Mediastinal: thymoma and bronchogenic carcinoma |
| Other: leukemia |
| Vincristine |
| Chlorpropamide |
| Phenothiazines |
| Imipramine |
Chronic SIADH is best treated by oral fluid restriction to 1000 mL/m2/day to avoid hyponatremia, as discussed in greater detail in a preceding section. In young children, this degree of fluid restriction may not provide adequate calories for growth. In this situation, increasing the urine output by increasing the renal solute load or the creation of nephrogenic DI using demeclocycline may be indicated to allow sufficient fluid intake for normal growth. However, this approach is not suitable in young children and pregnant women because tetracyclines are known to be extensively incorporated into the bones and enamel of children younger than 8 years. The renal solute load is increased by treatment with sodium chloride alone or with a loop diuretic.28 Oral therapy with urea has also been used safely and effectively in children with chronic SIADH.29, 30 Selective V2-receptor antagonists that could be used to treat SIADH and chronic disorders of decreased effective volume associated with hyponatremia are not yet approved for use in children. Acute treatment of hyponatremia due to SIADH is only indicated if cerebral dysfunction is present. In that case, treatment is dictated by the duration of hyponatremia and the extent of cerebral dysfunction, as discussed previously.
Box 8-1 lists the circumstances in which a patient with SIADH should be referred to a pediatric endocrinologist.31
Hyponatremia With No Increase in Vasopressin Secretion
In primary polydipsia, it is the excessive intake of water that drives the polyuria. In older children, with a normal kidney and the ability to suppress vasopressin secretion, hyponatremia does not occur unless water intake exceeds 10 L/m2/day, a feat almost impossible to accomplish. However, neonates cannot dilute their urine as much as older children, and they are prone to develop water intoxication at levels of water ingestion above 4 L/m2/day (∼60 mL/h in a newborn). This may happen when concentrated infant formula is diluted with excess water, either by accident or in a misguided attempt to make it last longer. A primary increase in thirst, without apparent cause, leading to hyponatremia has been reported in infants as young as 5 weeks. Long-standing ingestion of large volumes of water will decrease the hypertonicity within the renal medullary interstitium, which will impair water reabsorption and guard against water intoxication.
Despite the presence of polyuria and polydipsia, this entity should not be confused with DI. Differentiating primary polydipsia from DI is important because treating primary polydipsia with DDAVP will abolish the protective diuresis, leading to potentially fatal fluid overload and profound hyponatremia. In primary polydipsia, although the urinary osmolality may be low, the serum osmolality and serum sodium levels are not elevated. Primary polydipsia may be classified as non–thirst-driven as seen in the setting of psychiatric illnesses (psychogenic) or thirst-driven (dipsogenic).
This non–thirst-driven excessive intake of water, which is associated with schizophrenia and other psychiatric disorders, has a reported prevalence of 6% to 17% among psychiatric inpatients.32 It may be a form of compulsive behavior, a means of stress reduction, or one of the “positive” symptoms of schizophrenia. Treatment options include controlled fluid intake, behavioral strategies, and pharmacotherapy. Patients do not complain of thirst when their fluid intake is restricted to the normal amount. A Cochrane Database review33 of randomized controlled trials concluded that there was a lack of proper evidence to support the use of any of the medications described in case reports for the treatment of this condition. Therapy with DDAVP is not advised because the patient can have profound hyponatremia with impairment of the renal clearance of free water in the presence of unregulated fluid intake.
Unlike psychogenic polydipsia, the excessive water intake is driven by an altered thirst mechanism. Though this is seen in association with hypothalamic disease, quite often it is idiopathic. Normally, the threshold for the osmotic stimulation of thirst is approximately 10 mOsm/kg higher than that for osmotic stimulation of vasopressin secretion (see Figure 8-8). An individual’s set plasma osmolality lies between these two thresholds.34 If, in the rare patient, thirst is activated below the threshold for vasopressin release, water intake and resulting hypo-osmolality will occur, suppressing vasopressin secretion, thus leading to persistent polydipsia and polyuria. Such individuals will drink copious fluids even as they are unable to concentrate their urine appropriately. However, when their plasma osmolality is allowed to rise to the threshold for vasopressin release by means of water deprivation, they are able to secrete vasopressin appropriately. The renal response to the vasopressin, however, may be blunted by the loss of the intrarenal concentration gradient due to the chronic polyuria. As long as daily fluid intake is less than 10 L/m2, hyponatremia will not occur. Treatment of such patients with DDAVP may lower serum osmolality below the threshold for thirst, suppressing water ingestion and the consequent polyuria.
Decreased renal free water clearance
Adrenal insufficiency, either primary or secondary in nature, has long been known to result in compromised free water excretion.35 Both mineralocorticoids and glucocorticoids are required for normal free water clearance. By restoring the GFR through volume repletion, more free water is delivered to the distal tubule for excretion in the presence of mineralocorticoids. Glucocorticoid deficiency causes upregulation of aquaporin-2 expression in rodent kidney.36 It is possible that glucocorticoids may inhibit the activity of nitric oxide synthase in the collecting duct epithelium, decreasing the local production of nitric oxide that is known to lead to insertion of aquaporin-2 aggregates into the apical membrane.
Thyroid hormone is also required for normal free water clearance, and its deficiency likewise results in decreased renal water clearance and hyponatremia. Additionally, in severe hypothyroidism, hypovolemia is not present, and hyponatremia is accompanied by appropriate suppression of vasopressin.37 This decrease in free water clearance may result from diminished GFR and delivery of free water to the diluting segment of distal nephron as suggested by both animal and human studies.
Given the often subtle clinical findings associated with adrenal and thyroid deficiency, all patients with hyponatremia should be suspected of these disease states and have appropriate diagnostic tests performed if indicated. Moreover, patients with coexisting adrenal failure and DI may have no symptoms of the latter until glucocorticoid therapy unmasks the need for vasopressin replacement.38 Similarly, resolution of DI in chronically polyuric and polydipsic patients may suggest inadequate glucocorticoid supplementation or noncompliance with glucocorticoid replacement.
Some drugs may cause hyponatremia by inhibiting renal water excretion without stimulating secretion of vasopressin, an action that could be called nephrogenic SIADH. In addition to augmenting vasopressin release, both carbamazepine and chlorpropamide increase the cellular response to vasopressin. Acetaminophen also increases the response of the kidney to vasopressin; however, this has not been found to cause hyponatremia. High-dose cyclophosphamide treatment (15-20 mg/kg administered by intravenous bolus) is often associated with hyponatremia, particularly when it is followed by a forced water diuresis to prevent hemorrhagic cystitis. Plasma vasopressin concentrations are normal, suggesting a direct effect of the drug to increase water resorption. Similarly, vinblastine, independent of augmentation of the plasma vasopressin concentration or vasopressin action, and cisplatinum cause hyponatremia. These drugs may damage the collecting duct tubular cells, which are normally highly impermeable to water, or may enhance aquaporin-2 water channel activity and thereby increase water reabsorption down its osmotic gradient into the hypertonic renal interstitium.
Gain-of-function mutations in the V2 receptor have been described to cause hyponatremia in the absence of an elevation in blood vasopressin concentrations.39 These patients may have a clinical presentation during infancy very similar to that of SIADH, except for the lack of elevation in plasma vasopressin levels.
Hyponatremia due to cortisol or thyroid hormone deficiency reverses promptly following institution of hormone replacement. Because the hyponatremia is often chronic, an overly rapid rise in serum sodium should be avoided if possible, as has been discussed. When drugs that impair free water excretion must be used, water intake should be limited, as if the patient has SIADH, to 1 L/m2/24 h, using the regimen discussed. Urea has been used to treat hyponatremia due to gain-of-function mutations in the V2 receptor. V2-receptor antagonists (vaptans) have been approved to treat SIADH in adults, but no pediatric studies have been performed.
Miscellaneous Causes of True and Factitious Hyponatremia
Primary salt-losing disorders can cause hyponatremia. Salt can be lost from the kidney, such as in patients with congenital polycystic kidney disease, acute interstitial nephritis, and chronic renal failure. Mineralocorticoid deficiency, pseudohypoaldosteronism (sometimes seen in children with urinary tract obstruction or infection), diuretic use, and gastrointestinal disease (usually gastroenteritis with diarrhea and/or vomiting) can also result in excess loss of sodium chloride (for more detail, see Chapter 5). Hyponatremia can also result from salt loss in sweat in cystic fibrosis, although obstructive lung disease with elevation of plasma vasopressin probably plays a more prominent role, as discussed previously. With the onset of salt loss, any tendency toward hyponatremia will initially be countered by suppression of vasopressin and increased water excretion. However, with continuing salt loss, hypovolemia and/or hypotension ensue, causing nonosmotic stimulation of vasopressin. This, along with increased thirst, leads to ingestion of hypotonic fluids with low solute content, resulting in hyponatremia. Weight loss is usually evident, as is the source of sodium wasting.
Although ANH does not usually play a primary role in the pathogenesis of disorders of water metabolism, it may have an important secondary role. Patients with SIADH have elevated ANH concentrations, probably due to hypervolemia, which may contribute to the elevated natriuresis of SIADH and which decrease as water intake is restricted. However, hyponatremia in some patients, primarily those with CNS disorders, including brain tumor, head trauma, and brain death, may be due to the primary hypersecretion of ANH. This syndrome, termed CSW (discussed subsequently in greater detail), is defined by hyponatremia accompanied by hypovolemia, elevated urinary sodium excretion (often exceeding 150 mmol/L), excessive urine output, suppressed vasopressin, and elevated ANH concentrations (> 20 pmol/L).40 Thus, it is distinguished from SIADH, in which euvolemia, normal or decreased urine output, only modestly elevated urine sodium concentration, and elevated vasopressin concentration occur. The distinction is important because the therapies of the two disorders are markedly different as shown is Table 8-13.
True hyponatremia is also associated with hyperglycemia, which causes the influx of water into the intravascular space. Serum sodium will decrease by 1.6 mmol/L for every 100 mg/dL increment in plasma glucose above 100 mg/dL. Glucose is not ordinarily an osmotically active agent, and it does not stimulate vasopressin release, probably because it is able to equilibrate freely across plasma membranes. However, in the presence of insulin deficiency and hyperglycemia, glucose becomes osmotically active and can stimulate vasopressin release. Rapid correction of hyponatremia may follow soon after the institution of fluid and insulin therapy. That this contributes to the pathogenesis of cerebral edema occasionally seen following treatment of diabetic ketoacidosis has been suggested, but it is not proven. Elevated concentrations of triglycerides may cause factitious hyponatremia, as can obtaining a blood sample downstream from an intravenous infusion of hypotonic fluid.
In general, patients with hyponatremia due to salt loss require ongoing supplementation with sodium chloride and fluids. Initially, intravenous replacement of urine volume with fluid containing sodium chloride, 150 to 450 mmol/L depending on the degree of salt loss, may be necessary. Oral salt supplementation may be required subsequently. This treatment contrasts with that of SIADH, where water restriction without sodium supplementation is the mainstay.
Cerebral salt wasting (CSW) is a condition of profound salt wasting (natriuresis) that follows CNS insults, for example, infection, trauma, or tumor, and is thought to be due to an inappropriate secretion of atrial natriuretic hormone (ANH) following these insults.40
ANH is a highly significant product of atrial tissue, as 2% to 3% of all atrial messenger RNA (mRNA) codes for it. ANH and brain natriuretic peptide (BNP) are synthesized in the hypothalamus and other regions of the CNS involved in cardiovascular regulation, as well as in many other tissues, suggesting paracrine functions for ANH and BNP.41 The majority of circulating ANH is derived from the atria, and its plasma concentration is highly dependent on and directly proportional to plasma volume. Some studies suggest, however, that brain-derived ANH could account for significant amounts of the total circulating ANH under some circumstances.42
High-affinity receptors for ANH are found in a wide variety of tissues, including general vascular smooth muscle, renal glomerular arterioles, juxtaglomerular (JG) cells and tubules, the adrenal gland, heart, lung, and others. This explains the wide-ranging effects of ANH in the regulation of salt and water metabolism, plasma volume, and blood pressure.
Cardiovascular effects of ANH43—ANH acts on the heart and vascular smooth muscle and endothelium to produce significant decreases in heart rate, stroke volume, and mean arterial blood pressure (Table 8-8). Furthermore, ANH inhibits and reverses vasoconstriction mediated by angiotensin-II or norepinephrine. The net effect of ANH on the cardiovascular system, therefore, is hypotension, and (potentially) a reversal of essential and other forms of hypertension. Effects of intravenously administered BNP on the hemodynamics are similar.44
Renal effects of ANH43—ANH binds primarily to receptors in the glomerulus and JG cells, and, to a lesser extent, in the tubules and collecting ducts. The main effects of ANH in the glomerulus are dilation of the afferent arterioles and constriction of the efferent arterioles, leading to greatly increased GFR and sodium excretion. ANH also inhibits sodium resorption in the tubules, primarily that which is due to the effects of the angiotensin-II/aldosterone axis. In addition, ANH inhibits vasopressin-mediated resorption of free water. The effects of BNP in the kidney are similar to those of ANH.44
The net result of the actions of the natriuretic peptides in the kidney, therefore, is profound natriuresis and diuresis (see Table 8-8; Figure 8-13), which result in clinically significant hyponatremia and hypovolemia.
CNS effects of ANH—When administered intraventricularly in pharmacological amounts, ANH and BNP cause reductions in water intake. ANH in physiological amounts also decreases salt intake and inhibits secretion of vasopressin. Thus, the net local (paracrine) CNS effects of the natriuretic peptides complement their peripheral endocrine effects (see the following section Endocrine Effects of ANH) by inhibiting the conservation of water and salt, and thereby potentiating hyponatremia and hypovolemia. Insults to the CNS (eg, trauma, tumor, infection), therefore, could potentiate an “inappropriate” local secretion of ANH as well as a peripheral (cardiac) oversecretion of ANH to produce CSW seen in adults and children under these circumstances.
Endocrine effects of ANH43 (Table 8-9)—ANH inhibits renin secretion, its enzymatic action on angiotensinogen, and basal and angiotensin-II–mediated aldosterone synthesis and secretion. BNP is as effective in causing these changes as is ANH.44 ANH is also a potent inhibitor of the secretion and action of ADH.
Inhibitory effects of ANH and BNP on the renal and endocrine regulation of salt and water metabolism/conservation are summarized in Figures 8-13 and 8-14, respectively. It is apparent that these peptides provide a counterbalancing influence to the renin-angiotensin-aldosterone axis in the regulation of blood pressure and blood volume. Thus, oversecretion of ANH and/or BNP could account for the observed natriuresis and diuresis seen in patients with CNS injury, infection, or tumor.
ANH in disease states—ANH secretion is stimulated by atrial stretch and is, therefore, increased in conditions characterized by increased plasma volume, whereas its secretion is suppressed by plasma volume contraction (Table 8-10). Disease states characterized by plasma volume depletion, such as dehydration from any cause, including DI (see Figure 8-15) 46 and diabetic ketoacidosis, are associated with decreased plasma concentrations of ANH.
Conditions associated with increased plasma concentrations of ANH are usually characterized by increased plasma volume (eg, hypertension47[Figure 8-16A] and SIADH46 [Figure 8-16B]). The increase in ANH concentrations in SIADH is most likely due to the increase in plasma volume, and there is speculation that CSW may be an inappropriate response to SIADH in acute CNS insults (see the following section Etiologic Role of ANH in CSW).
Etiological role of ANH in CSW—Inappropriate SIADH secretion was for many years thought to be responsible for most occurrences of hyponatremia developing after CNS insult. It has become evident, however, that SIADH cannot account for all cases, particularly when the patient exhibits polyuria and dehydration. A true “salt wasting” associated with cerebral disease is now recognized as a distinct clinical entity. Because the treatments of CSW and SIADH are very distinct and potentially harmful if incorrectly applied, proper understanding of the cause of hyponatremia in a CNS-injured child is essential.
The salt-wasting syndrome associated with CNS pathology was first defined in 1950 as the inability to prevent salt loss in the urine despite hyponatremia in individuals with cerebral disease, that is, a “cerebral” salt wasting.48, 49 This concept was abandoned after the discovery of ADH; however, it was “rediscovered” over 30 years later.50 An etiological role for ANH in CSW was proposed, and its plasma concentration is elevated in some children and adults with various types of CNS injury.51, 52, 53, 54, 55, and 56 In the acute period (eg, 1-4 days after subarachnoid hemorrhage), plasma vasopressin concentrations can be elevated and cause water retention and transient hyponatremia. In patients with persistent hyponatremia, plasma ANH levels are usually elevated. This suggests that CSW may follow SIADH in some patients if ANH secretion remains high after their CNS insult.
Table 8-8.Systemic Effects of ANH ||Download (.pdf) Table 8-8. Systemic Effects of ANH
|Cardiovascular effects |
| Relaxation of arterial smooth muscle |
| Inhibition and reversal of vasoconstriction due to angiotensin-II and norepinephrine |
| Negative chronotropic and inotropic effects |
| Net effects: Hypotension/reversal of hypertension |
|Renal effects |
| Dilatation of afferent arterioles |
| Constriction of efferent arterioles: Increase in glomerular filtration rate |
| Decrease in juxtaglomerular cell renin secretion |
| Inhibition of angiotensin-II–induced, aldosterone-mediated sodium resorption: Decrease in tubular sodium resorption |
| Inhibition of vasopressin-induced water resorption |
| Net effects: Increased urine and sodium excretion (true natriuresis) and diuresis/hypovolemia |
|Central nervous system effects |
| Inhibition of vasopressin secretion |
| Inhibition of water and salt intake |
| Net effects: Diuresis/hyponatremia |
Table 8-9.Endocrine Effects of ANH on Water and Salt Balance ||Download (.pdf) Table 8-9. Endocrine Effects of ANH on Water and Salt Balance
|Inhibition of renin secretion |
|Inhibition of renin on angiotensin-I generation |
|Inhibition of angiotensin-II–mediated aldosterone secretion |
|Inhibition of vasopressin secretion and action |
| Net effects: Increased sodium and water excretion (natriuresis/diuresis) |
Table 8-10.Clinical Conditions Associated With Abnormal Plasma Concentrations of ANH ||Download (.pdf) Table 8-10. Clinical Conditions Associated With Abnormal Plasma Concentrations of ANH
|Conditions (Hypovolemic) with decreased plasma concentrations of ANH |
| DI |
| Diabetic ketoacidosis with dehydration |
|Conditions (Hypervolemic) with increased plasma concentrations of ANH |
| CSW |
| SIADH |
| Cushing syndrome/hyperaldosteronism |
| Hypertension |
| Congestive heart failure |
Renal effects of atrial natriuretic hormone (ANH).41 (The horizontal hash mark indicates inhibitory actions of ANH.)
Effects of ANH on the endocrine control of salt and water metabolism. (The horizontal hash marks indicate inhibitory actions of ANH.)
Plasma ANH concentrations before and after treatment in patients with diabetes insipidus.42 The horizontal lines represent the 95% confidence limits of plasma ANH concentrations in 108 normal subjects.
Plasma ANH concentrations in normotensive versus hypertensive adults. (Modified from Sagnella et al.47 With permission.)
Plasma ANH concentrations before and after treatment in patients with SIADH. The horizontal lines represent the 95% confidence limits of plasma ANH concentrations in 108 normal subjects.
Clinical presentation in CSW
CSW can occur in adults and children after CNS insults, including trauma, infection, tumor, and surgery. The diagnosis is suggested by hypovolemia, marked salt wasting, as evidenced by hyponatremia accompanied by high urine volumes and excessive urine sodium concentrations (80-480 mEq/L). Renal salt loss up to 10 to 20 times predicted basal requirements can occur. Plasma ANH concentrations when measured are usually inappropriately elevated, given the hypovolemic state. CSW usually develops in the first week after surgery, but the range in presentation can be from 1 to 28 days. Its duration is usually between 3 and 11 days, but rarely it can persist much longer when the causative CNS insult cannot be corrected. Key diagnostic components include evidence of net salt wasting (hyponatremia, high urine volumes with excessive urine sodium concentrations), elevated plasma ANH concentrations, and (inappropriately) suppressed plasma renin activity and aldosterone concentrations (Tables 8-11 and 8-12). General characteristics of adults and children with CSW are shown in Table 8-11. While an occurrence rate of approximately 1% after CNS injury has been reported,56 a more recent study estimated its prevalence at 6% to 25%.57
Table 8-11.Characteristics of Cerebral Salt Wasting ||Download (.pdf) Table 8-11. Characteristics of Cerebral Salt Wasting
|Prevalence: 1%-25% post–CNS-related abnormalities |
|Onset within the first week after a general CNS insult |
|Laboratory findings |
| Plasma sodium concentration: 95-130 mEq/L |
| Urine osmolality: 280-1100 mOsm/kg |
| Urine sodium concentration (maximum): 100-310 mEq/L |
| Urinary excretion rate: 3-15 mL/kg/h (average 6 mL/kg/h) |
|Acute, intermittent excessive fluid and salt loss 10-20 times maintenance |
|Duration variable: Usually 1-3 weeks, but may be months |
Table 8-12.Characteristics of CSW and SIADH ||Download (.pdf) Table 8-12. Characteristics of CSW and SIADH
| ||CSW ||SIADH |
|Plasma volume ||Decreased ||Increased |
|Clinical evidence of volume depletion ||Yes ||No |
|Plasma sodium concentration ||Low ||Low |
|Urine sodium concentration ||High ||High |
|Urine output ||Very high ||Low |
|Plasma renin activity ||Suppressed ||Suppressed |
|Net sodium loss (urine Na+ × urine volume) ||Very high ||Normal |
|Plasma aldosterone concentration ||Suppressed ||Normal/high |
|Plasma vasopressin concentration ||Suppressed ||High |
Laboratory tests and other means of monitoring the overall plasma volume and electrolyte status in children who present with a CNS insult (pre- or postoperatively) are shown in Box 8-2. Clinical and simple, readily available laboratory assessments provide the cornerstone of diagnosis, because other entities such as plasma renin activity and hormones such as ANH, aldosterone, and vasopressin that can help distinguish between CSW and SIADH usually require “send-outs” to regional reference laboratories and are not immediately available to aid the practicing physician.
Measurements that distinguish between CSW, SIADH, and DI:
Plasma volume status
Plasma sodium concentration
Urine output (mL/kg/h) compared to fluid input
Urine sodium concentration
Net urinary sodium loss: urine sodium concentration × urine volume
The similarities and differences between CSW and SIADH are shown in Table 8-12. Hyponatremia is usually detected during the course of routine monitoring of serum electrolytes in CNS “at-risk” patients, and the urine sodium concentration may be found to be inappropriately high for the observed low serum sodium concentration in both CSW and SIADH. In CSW, however, there is a net negative water and sodium balance, as estimated by multiplying urine sodium concentration by urine volume. Thus, a true and sustained net natriuresis is characteristic of CSW in contrast to SIADH. Furthermore, there is usually evidence of plasma volume depletion (eg, hypotension) in patients with CSW, while patients with SIADH may have at least a modest plasma volume expansion initially.
Plasma renin activity may be suppressed in both CSW and SIADH, but plasma vasopressin concentrations are usually suppressed in CSW in contrast to SIADH, by definition. Plasma ANH concentrations may be increased in both CSW and SIADH, but water restriction results in a return of plasma ANH concentrations to normal in SIADH despite little change in vasopressin. Thus, although vasopressin is known to stimulate ANH secretion, the initial plasma volume expansion in SIADH is a more likely stimulus for ANH release and is possibly etiologic in CSW, if ANH oversecretion persists “inappropriately” after SIADH resolves.
In summary, last year, Hannon et al stated, “where hyponatremia coincides with a progressive increase in urine volume, a fall in blood pressure, and a rise in blood urea, …cerebral salt wasting should be considered. In contrast, falling plasma sodium concentration in a patient who is euvolemic and has a falling blood urea and low urine output would suggest…SIADH.”57
The differentiation of DI from CSW and/or SIADH is not usually difficult, as the polyuria in DI most often results in hypernatremia, and the urine sodium concentration and urine osmolality are low. It is imperative that the distinctions be made, however, because the treatment of each of these conditions is quite different, and the potential for increased morbidity/mortality exists if inappropriate treatment is given.58,59
Treatments of CSW and SIADH are outlined in Table 8-13. It is critical to distinguish between SIADH and CSW as the cause of hyponatremia, because fluid restriction (indicated in SIADH) could be potentially disastrous in CSW.
Table 8-13.Treatment of CSW and SIADH ||Download (.pdf) Table 8-13. Treatment of CSW and SIADH
| ||CSW ||SIADH |
|Fluids ||Replacement ||Restriction |
|Sodium ||Replacement with 0.9% or 3% saline ||Maintenance |
|Other ||Fludrocortisone ||Demeclocycline, lithium |
Aggressive replacement of urine salt and water losses using 0.9% NaCl (or 3% NaCl if necessary) is the cornerstone of treatment of CSW. Administration of parenteral vasopressin (as aqueous Pitressin or DDAVP) does not usually provide any beneficial effect on urine output in CSW. Similarly, because CSW is characterized by a functional mineralocorticoid deficiency and resistance (hyporeninemic hypoaldosteronism), mineralocorticoid supplementation in the form of fludrocortisone has only been shown to be of benefit in a few patients.52, 60
CSW is a clinical entity distinct from SIADH, although both may present with hyponatremia after an insult to the CNS. It is critical to distinguish between CSW and SIADH, because the treatment of the former would be deleterious to patients with the latter, and vice versa. A large body of evidence suggests that the oversecretion of brain- or cardiac-derived ANH is etiologic in CSW. Insults to the CNS could result in a direct oversecretion of ANH with resultant natriuresis and diuresis leading to hyponatremia and hypovolemia, that is, CSW. Alternatively, the CNS insult could lead to SIADH, which, in turn, could stimulate ANH secretion directly by vasopressin or indirectly by plasma volume expansion. The heightened secretion of ANH does not abate when plasma volume has returned to normal, and CSW results. It is also possible that the mechanism of the development of CSW varies between patients, and that a direct CNS insult and/or a secondary response to SIADH are possible antecedents in different patients. CSW is a potentially serious entity, which may result in life-threatening hyponatremia and severe plasma volume depletion, and must be distinguished from SIADH for optimal patient care.