Chapter 8: Posterior Pituitary and Disorders of Water Metabolism

Maintenance of the tonicity of extracellular fluids within a very narrow range is crucial for proper cell function because extracellular osmolality regulates cell shape, as well as intracellular concentrations of ions and other osmolytes.^1,2 Furthermore, proper extracellular ionic concentrations are necessary for the correct function of ion channels, action potentials, and other modes of intercellular communication. Normal blood tonicity is maintained over a 10-fold variation in water intake by a coordinated interaction among the vasopressin, thirst, and renal systems. Dysfunction in any of these systems can result in abnormal regulation of blood osmolality, which, if not properly recognized and treated, may cause life-threatening hyperosmolality or hypo-osmolality.

Vasopressin

The control of plasma osmolality and intravascular volume involves a complex integration of endocrine, neural, and paracrine pathways. Plasma osmolality is regulated principally via vasopressin release from the posterior pituitary, or neurohypophysis, while volume homeostasis is determined largely through the action of the renin-angiotensin-aldosterone system, with contributions from both vasopressin and the natriuretic peptide family. The nine-amino acid vasopressin (also known as antidiuretic hormone [ADH] and arginine vasopressin [AVP]) molecule consists of a six-amino acid disulfide ring plus a three-amino acid tail, with amidation of the carboxy-terminus (Figure 8-1). Vasopressin has both antidiuretic and pressor activities, actions caused by the hormone binding to different receptors, as discussed subsequently. A synthetic analog of vasopressin, DDAVP (desamino-D-arginine vasopressin, desmopressin) with twice the antidiuretic potency and 100 times the duration of action of vasopressin, and no pressor activity, is routinely used to treat vasopressin-deficient patients (see Figure 8-1).³

Synthesis and secretion

Vasopressin is synthesized in hypothalamic paraventricular and supraoptic magnocellular neurons, whose axons transport the hormone to the posterior pituitary, its primary site of storage and from where it is released into the systemic circulation (Figure 8-2). The bilaterally paired hypothalamic paraventricular and supraoptic nuclei are separated from one another by relatively large distances (∼1 cm). Their axons course caudally and converge at the infundibulum, before terminating at different levels within the pituitary stalk and posterior pituitary gland.⁴ This anatomy has important clinical implications, as will be discussed. Vasopressin is also synthesized in the parvocellular neurons of the paraventricular nucleus (PVN), where it may have a role in regulating the hypothalamic-pituitary-adrenal axis, and in the hypothalamic suprachiasmatic nucleus, where it may participate in the generation of circadian rhythms.

Synthesis.

During its synthesis and perhaps after secretion into the bloodstream, vasopressin is bound to neurophysin, a 10,000-Da (dalton) molecular weight protein, which may function to protect vasopressin against degradation during intracellular storage or to promote more efficient packaging or posttranslational processing of vasopressin within secretory granules (Figure 8-3). Vasopressin and neurophysin are made from a common gene that consists of three exons. Exon 1 encodes the signal and vasopressin peptides and the aminoterminal 9 amino acids of neurophysin, exon 2 encodes the majority of neurophysin, and exon 3 codes for the carboxy-terminal end of neurophysin followed by an additional 39-amino acid-long glycopeptide.

Osmotic regulation.

Water balance is regulated in two ways: Vasopressin secretion stimulates water reabsorption by the kidney, thereby reducing future water losses, and thirst stimulates water ingestion, which restores past water losses (Figure 8-4). Ideally, these two systems work in parallel to efficiently regulate extracellular fluid tonicity. However, each system by itself can maintain plasma osmolality in the near-normal range. For example, in the absence of vasopressin secretion, but with free access to water, thirst drives water ingestion up to the 5 to 10 L/m² of urine output seen with vasopressin deficiency. Conversely, an intact vasopressin secretory system can compensate for some degree of disordered thirst regulation. However, when both vasopressin secretion and thirst are compromised, either by disease or iatrogenic means, there is great risk for the occurrence of life-threatening abnormalities in plasma osmolality. In evaluating any disorder of water balance, the clinician should ask whether abnormalities exist in vasopressin secretion, in thirst, or in both systems.

Vasopressin secretion is stimulated by a rise in the plasma concentrations of osmotically active substances (ie, those that are not freely permeable across cell membranes) principally sodium chloride and glucose (with insulin deficiency). Normal blood osmolality ranges between 280 and 290 mOsm/kg H₂O, with the threshold for vasopressin release being approximately 283 mOsm/kg. Above this threshold, an osmosensor located outside the blood-brain barrier near the anterior hypothalamus, which can detect as little as a 1% to 2% change in blood osmolality, signals for posterior pituitary secretion of vasopressin.⁵ Vasopressin rises in proportion to plasma osmolality, up to a maximum concentration of about 20 pg/mL, when the plasma osmolality is approximately 320 mOsm/kg (Figure 8-5).

Nonosmotic regulation.

Separate from osmotic regulation, vasopressin is secreted in response to a decrease in intravascular volume or pressure. Afferent baroreceptor pathways arising from the right and left atria and aortic arch (carotid sinus) are stimulated by increasing intravascular volume and stretch of vessel walls, and send signals to the hypothalamic PVN and supraoptic nucleus (SON) to inhibit vasopressin secretion. The pattern of vasopressin secretion in response to volume as opposed to osmotic stimuli is markedly different. While minor changes in plasma osmolality above 280 mOsm/kg evoke linear increases in plasma vasopressin, no change in vasopressin secretion is seen until blood volume decreases by approximately 8%. With intravascular volume deficits exceeding 8%, vasopressin concentration rises exponentially, such that when blood volume and/or pressure decrease by approximately 25%, vasopressin concentrations rise to 20- to 30-fold above normal (see Figure 8-5),⁶ vastly exceeding those required for maximal antidiuresis, and high enough to cause vasoconstriction via V1 vascular receptors (see later in this chapter).

Nausea, pain, hypoglycemia, psychological stress, ethanol, and chlorpropamide are also clinically important triggers for vasopressin release (Figure 8-6). On the other hand, vasopressin secretion is inhibited by glucocorticoids and, because of this, loss of negative regulation of vasopressin secretion occurs in the setting of primary and secondary glucocorticoid insufficiency. Cortisol deficiency both enhances hypothalamic vasopressin production as well as directly impairs free water excretion, important considerations in the evaluation of the patient with hyponatremia, as subsequently discussed.

Metabolism

Once in the circulation, vasopressin has a half-life of only 5 to 10 minutes, because of its rapid degradation by a cysteine aminoterminal peptidase, termed vasopressinase. The synthetic analog of vasopressin, DDAVP, is insensitive to aminoterminal degradation, and thus has a much longer half-life of 8 to 24 hours. During pregnancy, the placenta secretes increased amounts of this vasopressinase, resulting in a fourfold increase in the metabolic clearance rate of vasopressin. Normal women compensate with an increase in vasopressin secretion, but women with preexisting deficits in vasopressin secretion or action, or those with increased concentrations of placental vasopressinase associated with liver dysfunction or multiple gestation, may develop diabetes insipidus (DI) in the last trimester, which resolves in the immediate postpartum period. As expected, this form of DI responds to treatment with DDAVP (which is resistant to degradation by vasopressinase), but not with vasopressin.

Action

Vasopressin released from the posterior pituitary and median eminence affects the function of several tissue types by binding to three G-protein–coupled cell surface receptors, designated V1, V2, and V3 (or V1b) (Table 8-1). The major sites of V1 receptor expression are on vascular smooth muscle and hepatocytes, where receptor activation results in vasoconstriction and glycogenolysis, respectively. The concentration of vasopressin needed to significantly increase blood pressure is several-fold higher than that required for maximal antidiuresis. The V3 receptor is present on corticotrophs in the anterior pituitary and acts to increase ACTH secretion.

Modulation of water balance occurs through the action of vasopressin upon V2 receptors located primarily on the blood (basolateral) side of cells in the renal collecting tubule. The human V2 receptor gene is located on the long arm of the X chromosome, at the locus associated with congenital, X-linked vasopressin-resistant nephrogenic DI. Vasopressin-induced increases in intracellular cyclic adenosine monophosphate (cAMP) mediated by the V2 receptor trigger a complex pathway of events, resulting in increased permeability of the collecting duct to water and efficient water transit across an otherwise minimally permeable epithelium (Figure 8-7). Activation of a cAMP-dependent protein kinase causes the insertion of aggregates of a water channel, termed aquaporin-2, into the apical (luminal) membrane. Insertion of ­aquaporin-2 causes up to a 100-fold increase in water permeability of the apical membrane, allowing water movement from the tubule lumen along its osmotic gradient into the hypertonic inner medullary interstitium and excretion of a concentrated urine (see Figure 8-7).⁷

Thirst

The sensation of thirst is determined by hypothalamic neurons anatomically distinct from those that make vasopressin. It makes physiologic sense that the threshold for thirst (∼293 mOsm/kg) is slightly higher than that for vasopressin release (Figure 8-8). Otherwise, during the development of hyperosmolality, the initial activation of thirst and water ingestion would result in polyuria without activation of vasopressin release, causing a persistent diuretic state.⁸

Hypernatremia along with hyponatremia constitutes the commonest electrolyte abnormality in children.

Hypernatremia

Hypernatremia usually occurs when free water loss exceeds salt loss from the body.

Definition and classification of hypernatremia

Hypernatremia is defined as a serum sodium concentration greater than 145 mmol/L. It occurs most often in the setting of dehydration, due to either pure water loss or water loss that exceeds salt loss. Hypernatremia can occur due to either free water loss or excessive intake of sodium. The latter usually causes transient hypernatremia. In the presence of an intact thirst mechanism, the ability to drink water, and intact renal function, it is followed by water intake leading to volume expansion and natriuresis, thus normalizing the serum sodium levels. Similarly, excessive loss of free water is usually compensated by increased intake driven by the intact thirst mechanism. Inability to drink water freely as seen in infants and neurologically impaired children can thus lead to hypernatremia from either excessive ingestion of sodium or from excessive free water loss. Infants in particular also have a limited ability to excrete the osmotic solute load from their kidneys and hence can have persistent hypernatremia from accidental or deliberate inclusion of excessive amounts of salt in their food.

Clinical presentation and diagnosis

Children with significant hypernatremia progress from irritability to lethargy and coma. Neurologic signs such as nuchal rigidity, hypertonia, and hyperreflexia may be present. Seizures and rhabdomyolysis can occur. Shrinkage of cells in the brain in acute hypernatremia can lead to the rupture of bridging veins causing intracranial hemorrhage. Venous infarcts from venous sinus thrombosis can also be seen. A mortality rate of 15% has been reported in children with hypernatremia.⁹

A diagnostic algorithm for hypernatremia (Figure 8-9) in most children with a normal thirst mechanism and a normal ability to drink water is thus most often limited to the identification of the source of the free water loss. The presence of polyuria with dilute urine confirms renal loss of free water. The diagnostic approach for polyuria will be discussed subsequently in this chapter. Free water may be lost relatively in excess to sodium loss through nonrenal routes such as the skin as in burns and excessive sweating, the respiratory tract or the gastrointestinal tract as occurs with diarrhea, or through fistulae. Because hypernatremia causes intracellular dehydration due to osmotic shift of intracellular fluid to the extracellular compartment, the extent of dehydration is often underestimated during physical examination. In addition to other signs of dehydration, the skin has been classically described as having a “doughy” consistency (due to increased turgor) in hypernatremic dehydration. Laboratory investigations should include serum sodium, osmolality, blood urea nitrogen (BUN), and creatinine, along with urine sodium and osmolality.

Treatment

The goals of treating hypernatremia should be to correct the hypovolemia and to normalize the serum sodium level. The management of hypernatremia should involve identification of the underlying cause and the duration of the hypernatremia. Treatment is directed at the underlying cause when one can be identified. An estimation of the free water deficit is made using the formula:

This free water deficit is best corrected slowly with oral or nasogastric free water over a period of 24 to 48 hours. Ongoing losses should be replaced simultaneously while closely monitoring the clinical status and the serum electrolytes. In children who are unable to receive free water through the enteral route, a parenteral solution containing either 5% dextrose (D₅), or 0.45% to 0.225% saline can be used.

The brain cells adapt to hypernatremia over a period of days, by increasing the intracellular osmolyte concentration in order to prevent intracellular dehydration and cell shrinkage (Figure 8-10). They do so by increasing the levels of electrolytes, amino acids such as taurine, and glutamine and other osmotically active substances such as myoinositol, and betaine.¹⁰ While this process is protective during chronic hypernatremia, rapid lowering of the serum sodium can cause swelling of the brain cells. The brain being enclosed within the cranial vault, which is nonexpandable after the closure of the fontanelles, can herniate infratentorially. Seizures, coma, and even death can occur with rapid lowering of chronically elevated serum sodium levels. Hence it is widely accepted that the serum sodium level should be corrected at least over a period of 48 hours. It should not be lowered more rapidly than a rate of 15 mmol/L/day.

Deficiencies of Vasopressin Secretion or Action

Central diabetes insipidus

Causes and clinical presentation.

Central (hypothalamic, neurogenic, or vasopressin-sensitive) DI in children is most often the result of surgical or accidental trauma to vasopressin neurons, congenital anatomical hypothalamic or pituitary defects, or neoplasms. It can also be caused by infiltrative, autoimmune, and infectious diseases affecting vasopressin neurons or fiber tracts, and, least commonly, by disorders of vasopressin gene structure (Table 8-2). In different case series published in the literature, an underlying cause could not be identified in between 9% and 55% of children and young adults affected by central DI.^11,12

The most common cause of central DI is the neurosurgical destruction of vasopressin neurons following pituitary-hypothalamic surgery. It is important to ­distinguish polyuria associated with the onset of acute postsurgical central DI from polyuria due to the normal diuresis of fluids given during surgery. In both cases, the urine may be very dilute and of high volume, exceeding 200 mL/m²/h. However, in the former case, serum osmolality will be high, whereas in the latter case it will be normal. A careful examination of the intraoperative record should also help distinguish between these two possibilities. The axons of vasopressin-containing magnocellular neurons extend uninterrupted to the posterior pituitary over a distance of approximately 10 mm. These axons terminate at various levels within the stalk and gland (see Figure 3-3). Because surgical interruption of these axons can result in retrograde degeneration of hypothalamic neurons, lesions closer to the hypothalamus will affect more neurons and cause greater permanent loss of hormone secretion. Not infrequently, a “triple-phase” response is seen (Table 8-3). Following surgery, an initial phase of transient DI is observed, lasting 1.5 to 2 days, which is possibly due to edema in the area interfering with normal vasopressin secretion. If significant vasopressin cell destruction has occurred, this is often followed by a second phase of syndrome of inappropriate antidiuretic hormone (SIADH), which may last up to 10 days, and is due to the unregulated release of vasopressin, by dying neurons. A third phase of permanent DI may follow if more than 90% of vasopressin cells are destroyed. Usually, a marked degree of SIADH in the second phase portends significant permanent DI in the final phase of this response. In a small study, the “triple-phase response” was observed in one out of three children who underwent surgery for a craniopharyngioma.¹³ In patients with coexisting vasopressin and cortisol deficits (eg, in combined anterior and posterior hypopituitarism following neurosurgical treatment of craniopharyngioma), symptoms of DI may be masked because cortisol deficiency impairs renal free water clearance, as discussed subsequently. In such cases, institution of glucocorticoid therapy alone may precipitate polyuria, leading to the diagnosis of DI.

Trauma to the base of the brain can cause swelling around or severance of these axons, resulting in either transient or permanent DI. Permanent DI can occur after seemingly minor trauma. Approximately one-half of patients with fractures of the sella turcica will develop permanent DI, which may be delayed by up to 1 month following the trauma, during which time neurons of severed axons may undergo retrograde degeneration. Septic shock and postpartum hemorrhage associated with pituitary infarction (Sheehan syndrome) may involve the posterior pituitary with varying degrees of DI. DI is never associated with cranial irradiation of the hypothalamic-pituitary region.

Midline brain anatomical abnormalities such as septo-optic dysplasia (SOD)/optic nerve hypoplasia (ONH) with agenesis of the corpus callosum, ­holoprosencephaly, and familial pituitary hypoplasia with absent stalk may be associated with central DI, which usually presents in the first month of life, often with signs of anterior pituitary dysfunction, such as jaundice, and, in boys, microphallus. Central DI due to midline brain abnormalities may be accompanied by defects in thirst perception.

Because hypothalamic vasopressin neurons are dis­tributed over a large area within the hypothalamus, tumors that cause DI must either be very large, be infiltrative, or be strategically located at the point of convergence of the hypothalamic-neurohypophyseal axonal tract in the infundibulum. Germinomas and pinealomas typically arise near the base of the hypothalamus where vasopressin axons converge prior to their entry into the posterior pituitary, and for this reason are among the most common primary brain tumors associated with DI. Germinomas causing the disease can be very small and undetectable by magnetic resonance imaging (MRI) for several years following the onset of polyuria. For this reason, serial quantitative measurements of the β-subunit of human chorionic gonadotropin (β-hCG), often secreted by germinomas and pinealomas, and regularly repeated MRI scans should be performed in children with idiopathic or unexplained DI. Long-term surveillance can identify, sometimes after as long as 21 years, an underlying cause that was not apparent at the time of initial diagnosis.¹⁴

Empty sella syndrome, possibly due to unrecognized pituitary infarction, can be associated with DI in children. Craniopharyngiomas and optic gliomas, when very large, can also cause central DI, although this is more often a postoperative complication of the treatment for these tumors. Hematologic malignancies can cause DI. In some cases, such as with acute myelocytic leukemia, the cause is infiltration of the pituitary stalk and sella.

Langerhans cell histiocytosis and lymphocytic hypophysitis are the most common types of infiltrative disorders causing central DI. Approximately 10% of patients with histiocytosis will have DI. These patients tend to have more serious, multisystem disease for longer periods of time than those without DI, and anterior pituitary deficits often accompany posterior pituitary deficiency. MRI characteristically shows thickening of the pituitary stalk. Radiation treatment to the pituitary region within 14 days of onset of symptoms of DI may result in return of vasopressin function. In adults, lymphocytic infundibuloneurohypophysitis may account for over one-half of patients with “idiopathic” central DI. It is a rare cause of DI in children. This entity may be associated with other autoimmune diseases. Image analysis discloses an enlarged pituitary and thickened stalk, and biopsy of the posterior pituitary reveals lymphocytic infiltration of the gland, stalk, and magnocellular hypothalamic nuclei. A necrotizing form of this entity has been described, which also causes anterior pituitary failure and responds to glucocorticoid treatment. DI can also be associated with pulmonary granulomatous diseases including sarcoidosis and granulomatosis with angiitis.

Infections involving the base of the brain, such as meningococcal, cryptococcal, Listeria, and toxoplasmosis meningitis, congenital cytomegalovirus infection, and nonspecific inflammatory disease of the brain can cause central DI. The disease is often transient, suggesting that it is due to inflammation rather than destruction of vasopressin-containing neurons.

Familial, autosomal dominant central DI is manifest within the first half of the first decade of life. Vasopressin secretion, initially normal, gradually declines until DI of variable severity ensues. Patients respond well to vasopressin-replacement therapy. The disease has a high degree of penetrance, but it may be of variable severity within a family. Several different single nucleotide mutations in the vasopressin structural gene have been found to cause the disease, with most occurring in the neurophysin region. Endoplasmic reticulum stress from misfolding of the aberrant protein has been hypothesized to be the possible cause for the premature loss of the magnocellular vasopressin neurons seen in this disease.¹⁵ Vasopressin deficiency is also found in the DIDMOAD syndrome, consisting of Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness. This syndrome complex, also known as Wolfram syndrome, is caused by recessive mutations in the WFS1 gene located on chromosome 4p16. This gene codes for wolframin, a transmembrane protein localizing to the endoplasmic reticulum that is believed to either act as a calcium channel or as a regulator of a calcium channel.¹⁶

Whereas normal children have a nocturnal rise in plasma vasopressin associated with an increase in urine osmolality and a decrease in urine volume, those with primary enuresis have a blunted or absent rise in vasopressin, and excrete a higher urine volume of lower tonicity. This has suggested that enuretic children have a primary deficiency in vasopressin secretion, although the same outcome could be caused solely by excessive water intake in these children. The use of the V2 agonist, DDAVP, is highly effective in abolishing bed-wetting episodes, although relapse is high once therapy is stopped. This therapy must be used with caution, as fluid intake must be limited while a child is exposed to the antidiuretic action of DDAVP to guard against water intoxication.

Treatment.

Patients with otherwise untreated DI crave cold fluids, especially water. With complete central DI, maximum urine concentrating ability is approximately 200 mOsm/kg. An average 10-year-old child with a body surface area of 1 m² would then require a urine output of 2.5 L of urine to excrete an average daily solute load of 500 mOsm/m². Insensible (nonrenal) fluid losses in this example would amount to 500 mL/day (500 mL/m²/day). In order to maintain normal plasma tonicity, this child’s fluid intake must match his/her fluid loss of 3 L/day. With an intact thirst mechanism and free access to oral fluids, a person with complete DI can maintain plasma osmolality and sodium in the high-normal range, although at great inconvenience. Furthermore, long-standing intake of these volumes of fluid in children can lead to hydroureter, and even hyperfluorosis in communities that provide fluoridated water.

There are two situations in which central DI is sometimes treated solely with high levels of fluid intake, without vasopressin. Vasopressin therapy coupled with excessive fluid intake (usually > 1 L/m²/day as discussed subsequently) can result in unwanted hyponatremia. Because neonates and young infants receive all of their nutrition in liquid form, the obligatory high oral fluid requirements for this age (3 L/m²/day), combined with vasopressin treatment, are likely to lead to this dangerous complication.¹⁷ Thus, neonates may be better managed with fluid therapy alone. The use of breast milk or Similac 60/40 formula reduces the renal solute load by 20% to 30%. This in turn reduces the urine volume in infants with DI by 20% to 30%. Chlorothiazide (oral dose 5 mg/kg twice daily) is a diuretic that increases the urine osmolality and decreases the urine output through mechanisms that are unclear. The latter two therapeutic options significantly reduce the amount of free water supplementation needed in infants with both forms of DI. However, supplementation with 20 to 30 mL of free water for every 120 to 160 mL of formula might still be required.¹⁸ Infants with central DI have also been successfully treated with subcutaneous injections of DDAVP (initial dose 0.002-0.1 μg/kg once daily, titrated upward and given twice daily if needed) until they are eating solid food. Therapy in infants with subcutaneous injections of DDAVP has been associated with far fewer episodes of hyponatremia and hypernatremia than with either intranasal or oral DDAVP.¹⁹

In the acute postoperative management of central DI occurring after neurosurgery in young children, vasopressin therapy may be successfully used, but extreme caution must be exerted with its use. While under the full antidiuretic effect of vasopressin, a patient will have a urine osmolality of approximately 1000 mOsm/kg and become hyponatremic if she/he receives an excessive amount of fluids, depending on the solute load and nonrenal water losses. With a solute excretion of 500 mOsm/m²/day, normal renal function, and nonrenal fluid losses of 500 mL/m²/day, fluid intake of greater than 1 L/m²/day will result in hyponatremia. In addition, vasopressin therapy will mask the emergence of the SIADH phase of the “triple-phase” neurohypophyseal response to ­neurosurgical injury (as discussed earlier). For these reasons, it is often best to manage acute postoperative DI in young children with fluids alone, avoiding the use of vasopressin. This method consists of matching input and output hourly using between 1 and 3 L/m²/day (40-120 mL/m²/h). If intravenous therapy is used, a basal 40 mL/m²/h should be given as D₅ in 1/4 normal saline (normal saline = 0.9% sodium chloride) and the remainder, depending on the urine output, as 5% dextrose inwater (D₅W). Potassium chloride (40 mmol/L) may be added if oral intake is to be delayed for several days. No additional fluid should be administered for hourly urine volumes under 40 mL/m²/h. For hourly urine volumes above 40 mL/m²/h, the additional volume should be replaced with D₅W up to a total maximum of 120 mL/m²/h. For example, in a child with a surface area of 1 m² (∼30 kg), the basal infusion rate would be 40 mL/h of D₅ in 1/4 normal saline. For an hourly urine output of 60 mL, an additional 20 mL/h D₅W would be given, for a total infusion rate of 60 mL/h. For urine outputs above 120 mL/h, the total infusion rate would be 120 mL/h. In the presence of DI, this will result in a serum sodium in the 150 mmol/L range and a mildly volume contracted state, which will allow one to assess both thirst sensation as well as the return of normal vasopressin function or the emergence of SIADH. Patients may become mildly hyperglycemic with this regimen, particularly if they are also receiving postoperative glucocorticoids. However, this fluid management protocol, because it does not use vasopressin, prevents any chance of hyponatremia.

Intravenous therapy with synthetic aqueous vasopressin (Pitressin) is useful in the management of central DI of acute onset. If continuous vasopressin is administered, fluid intake must be limited to 1 L/m²/day (assuming normal solute intake and nonrenal water losses as described previously). The potency of synthetic vasopressin is still measured using a bioassay and is expressed in bioactive units, with 1 milliunit (mU) equivalent to approximately 2.5 ng of vasopressin. For intravenous vasopressin therapy, 1.5 mU/kg/h results in a plasma ADH (vasopressin) concentration of approximately 10 pg/mL, twice that needed for full antidiuretic activity. The effect of vasopressin is maximal within 2 hours of the start of infusion. Patients treated with vasopressin for postneurosurgical DI should be switched from intravenous to oral fluids at the earliest opportunity, because thirst sensation, if intact, will help regulate blood osmolality, as discussed previously. Intravenous DDAVP (desmopressin) should not be used in the acute management of postoperative central DI, for it offers no advantage over vasopressin, and its long half-life (8-12 hours) compared with that of vasopressin (5-10 minutes) is a distinct disadvantage, because it may increase the chance of causing water intoxication.

In the outpatient setting, treatment of central DI in children beyond infancy should begin with oral DDAVP tablets (Table 8-4).²⁰ Young children may respond to 25 or 50 μg at bedtime. If the dose is effective but has too short a duration, it should be increased further or a second, morning dose should be added. Patients should escape from the antidiuretic effect for at least 1 hour before the next dose, to ensure that any excessive water will be excreted. Otherwise, water intoxication may occur. DDAVP is also available for intranasal administration via a rhinal tube (10 μg/0.1 mL) or as a nasal spray (10 μg/spray). The initial dose is 0.025 mL (2.5 μg) given by the rhinal tube at bedtime. When switching patients from intranasal to oral DDAVP, the equivalent oral dose is 10- to 20-fold greater. (Dose equivalence of DDAVP:1 μg subcutaneously = 10 μg intranasally = 100 to 200 μg orally.)

A special problem arises when a patient with central DI on chronic DDAVP treatment is to undergo an elective surgical procedure requiring general anesthesia (Table 8-5). Two options are possible. The patient can receive their usual regimen of DDAVP on the morning of surgery; alternatively DDAVP can be held the evening before and the morning of surgery. In either case, intraoperative and postoperative intravenous fluids must be limited to 1 L/m²/24 h as described previously, until the antidiuretic effect of DDAVP wanes, and the patient should be switched to oral fluid intake as soon as possible, to allow thirst to guide replacement. Another special situation arises when a patient with established central DI must receive a high volume of fluid for therapeutic reasons, for example, accompanying cancer chemotherapy. Such patients can either be managed by discontinuing antidiuretic therapy and increasing fluid intake to 3 to 5 L/m²/day (rendering the patient moderately hypernatremic), or by using a low dose of intravenous vasopressin (0.1 mU/kg/h, approximately one-eighth of the full antidiuretic dose), with which the partial antidiuretic effect allows the administration of higher amounts of fluid without causing hyponatremia.²¹

Box 8-1 lists the circumstances in which a patient with DI should be referred to a pediatric endocrinologist.

Nephrogenic diabetes insipidus

Causes and clinical presentation.

Nephrogenic (vasopressin-resistant) DI can be due to genetic or acquired causes (Table 8-6). Genetic causes are less common but more severe than acquired forms of the disease, although genetic etiologies are more common in children than in adults.²²

Congenital, X-linked nephrogenic DI is caused by inactivating mutations of the vasopressin V2 receptor. Because of its mode of transmission, it is a disease of males. Because of vasopressin resistance in congenital nephrogenic DI, the kidney elaborates large volumes of hypotonic urine with osmolality ranging between 50 and 100 mOsm/kg. Manifestations of the disease are usually present within the first several weeks of life but may only become apparent after weaning from the breast. The predominant symptoms are polyuria and polydipsia. Thirst may be more difficult to satisfy than in central DI. Many infants initially present with fever, vomiting, and dehydration, often leading to an evaluation for infection. Growth failure in the untreated child may be secondary to the ingestion of large amounts of water, which the child may prefer over milk and other higher caloric substances. Mental retardation of variable severity may result from repeated episodes of dehydration. Intracerebral calcification of the frontal lobes and basal ganglia is not uncommon in children with X-linked nephrogenic DI. Older children may present with enuresis or nocturia. They may learn to reduce food intake (and therefore solute load) to decrease polyuria, which may contribute to growth failure. After long-standing ingestion and excretion of large volumes of water, patients may develop nonobstructive hydronephrosis, hydroureter, and megabladder.

More than 30 mutations in the V2 receptor have been found to cause X-linked nephrogenic DI. In a family with a known mutation, prenatal or early postnatal DNA screening can unambiguously identify affected males, allowing the prompt institution of appropriate therapy. Several patients with autosomal recessive nephrogenic DI have been reported recently, who have mutations in the gene encoding the renal water channel, aquaporin-2. Aside from the mode of transmission (affecting both males and females), these patients have a clinical presentation similar to those with the X-linked disease.

Acquired causes of nephrogenic DI are more common and less severe than genetic causes. Nephrogenic DI may be caused by drugs such as lithium and demeclocycline. Approximately 50% of patients receiving lithium have impaired urinary concentrating ability, although only 10% to 20% of them develop symptomatic nephrogenic DI, which is almost always accompanied by a reduction in the glomerular filtration rate (GFR). The risk increases with duration of therapy. Treatment with demeclocycline, amphotericin, or rifampin can cause nephrogenic DI, as can hypercalcemia or hypokalemia. Osmotic diuresis due to glycosuria in diabetes mellitus, or to sodium excretion with diuretic therapy, will interfere with renal water conservation. Primary polydipsia can result in secondary nephrogenic DI because the chronic excretion of dilute urine lowers the osmolality of the hypertonic renal interstitium, thus decreasing renal concentrating ability.

Treatment.

The treatment of acquired nephrogenic DI focuses on elimination, if possible, of the underlying disorder, such as offending drugs, hypercalcemia, or hypokalemia. Congenital nephrogenic DI is often difficult to treat. The main goals should be to ensure the intake of adequate calories for growth and to avoid severe dehydration. Foods with the highest ratio of caloric content to osmotic load should be ingested, to maximize growth and minimize the urine volume required to excrete urine solute. However, even with the early institution of therapy, growth and mental retardation are not uncommon. Thiazide diuretics in combination with amiloride or indomethacin are the most useful pharmacologic agents in the treatment of nephrogenic DI. The combination of thiazide and amiloride diuretics is the most commonly used regimen because amiloride counteracts thiazide-induced hypokalemia, avoids the nephrotoxicity associated with indomethacin therapy, and is well tolerated, even in infants.²³ In addition, amiloride decreases the uptake of lithium by renal epithelial cells, and for this additional reason it has been proposed in combination with thiazide as treatment for lithium-induced nephrogenic DI.

Differential Diagnosis of Polyuria and Polydipsia

In children, one must first determine if pathologic polyuria or polydipsia, exceeding 2 L/m²/day, is present, by asking the following questions: Is there a psychosocial reason for either polyuria or polydipsia? Can either be quantitated? Has either polyuria or polydipsia interfered with normal activities? Is nocturia or enuresis present? If so, does the patient also drink following nocturnal awakening? Does the history (including longitudinal growth data) or physical examination suggest other deficient or excessive endocrine secretion or an intracranial neoplasm?

If pathologic polyuria or polydipsia is present, the following should be obtained in the outpatient setting: serum osmolality and concentrations of sodium, potassium, glucose, calcium, and BUN; and urinalysis, including specific gravity and glucose concentration, and measurement of urine osmolality. A serum osmolality greater than 300 mOsm/kg, with urine osmolality less than 300 mOsm/kg, establishes the diagnosis of DI (see Figure 8-9). If serum osmolality is less than 270 mOsm/kg, or urine osmolality is greater than 600 mOsm/kg, the diagnosis of DI is unlikely. If, upon initial screening, the patient has a serum osmolality less than 300 mOsm/kg, but the intake/output record at home suggests significant polyuria and polydipsia which cannot be attributed to primary polydipsia (ie, the serum osmolality is > 270 mOsm/kg), the patient should undergo a water deprivation test to establish a diagnosis of DI and to differentiate central from nephrogenic causes.

After a maximally tolerated overnight fast (based on the outpatient history and age), the child is admitted to the outpatient testing center in the early morning of a day when a water deprivation test (which may require 8-10 hours to complete) can be carried out.²⁴ Physical signs (weight, pulse, and blood pressure) and biochemical parameters (serum sodium and osmolality, and urine volume, osmolality, and specific gravity) are measured during the test. If at any time during the test, the urine osmolality exceeds 1000 mOsm/kg, or 600 mOsm/kg and is stable over 1 hour, the patient does not have DI. If at any time the serum osmolality exceeds 300 mOsm/kg and the urine osmolality is less than 600 mOsm/kg, the patient has DI. If the serum osmolality is less than 300 mOsm/kg and the urine osmolality is less than 600 mOsm/kg, the test should be continued unless vital signs disclose hypovolemia. A common error is to stop a test too soon (especially in patients with primary polydipsia who are volume-overloaded) based on the amount of body weight lost, before either urine osmolality has plateaued above 600 mOsm/kg or a serum osmolality above 300 mOsm/kg has been achieved. Unless the serum osmolality rises above the threshold for vasopressin release, a lack of vasopressin action (as inferred by nonconcentrated urine) cannot be deemed pathological. If the diagnosis of DI is made, short-acting aqueous vasopressin (Pitressin), 1 U/m² subcutaneously, rather than long-acting DDAVP, should be given. If the patient has central DI, urine volume should fall and osmolality should at least double during the next hour, compared with the value just prior to vasopressin therapy. If there is less than a twofold rise in urine osmolality following vasopressin administration, the patient probably has nephrogenic DI. DDAVP should not be used for this test, as it has been associated with water intoxication in small children in this setting.²⁵ Patients with long-standing primary polydipsia may have mild nephrogenic DI because of dilution of their renal medullary interstitium. This should not be confused with primary nephrogenic DI, because patients with primary polydipsia should have a tendency toward hyponatremia, rather than hypernatremia, in the basal state. Patients with a family history of X-linked nephrogenic DI can be evaluated for the disorder in the pre- or perinatal period by DNA sequence analysis, thus allowing therapy to be initiated without delay.

The water deprivation test should be sufficient in most patients to establish the diagnosis of DI and to differentiate central from nephrogenic causes. Measurements of plasma vasopressin (ADH or AVP) concentration may be obtained during the procedure, although they are rarely needed for diagnostic purposes in children. They are particularly helpful in differentiating between partial central and nephrogenic DI, in that they are low in the former and high in the latter situation. If urine osmolality concentrates normally, but only after serum osmolality is well above 300 mOsm/kg, the patient may have an altered threshold for vasopressin release, also termed a reset osmostat. This may occur after head trauma, neurosurgery, or with brain tumors. MRI is not very helpful in distinguishing central from nephrogenic DI. Normally, the posterior pituitary is seen as an area of enhanced brightness on T1-weighted images following administration of gadolinium. The posterior pituitary “bright spot” is diminished or absent in both forms of DI, presumably because of decreased vasopressin synthesis in central and increased vasopressin release in nephrogenic disease. In primary polydipsia, the bright spot is normal, probably because vasopressin accumulates in the posterior pituitary during chronic water ingestion, whereas it is decreased in SIADH, presumably because of increased vasopressin secretion.

In the inpatient, postneurosurgical setting, central DI is likely if hyperosmolality (serum osmolality > 300 mOsm/kg) is associated with urine osmolality less than serum osmolality. One must beware of intraoperative fluid expansion with subsequent hypo-osmolar polyuria masquerading as DI.

Adipsic Hypernatremia

Causes and clinical presentation

Lesions in the anterior hypothalamus can affect the thirst mechanism causing adipsia. Hypernatremia with adipsia can occur even in the absence of associated DI because the free water intake maybe inadequate to match the obligatory renal and nonrenal losses. On the other hand, the lack of vasopressin, despite causing significant polyuria, rarely causes significant hypernatremia when the osmosensor-thirst mechanism is intact. A disordered thirst mechanism is seen in about 10% of patients with DI. The vasopressin response to osmotic stimulation is often partially or completely deficient in this condition. However, the vasopressin response to nonosmotic stimuli, for example, hypotension, may be intact.

Adipsic hypernatremia can potentially occur with a malformation of or any injury to the osmosensor for thirst. Malformations of the brain such as holoprosencephaly, hypoplasia of the corpus callosum including SOD/ONH, vascular lesions such as anterior communicating artery aneurysms, neoplasms such as craniopharyngioma, suprasellar germinoma, and pinealoma have been associated with adipsia. Other associations include granulomatous diseases such as histiocytosis and sarcoidosis and miscellaneous conditions such as hydrocephalus, arachnoidal cysts, and idiopathic hypothalamic dysfunction.

Patients with adipsic hypernatremia do not feel the urge to drink fluids even in the presence of hyperosmolar dehydration due to a disruption in the regulation of thirst by the osmosensor. The condition is characterized by chronic or recurrent hypernatremic dehydration usually accompanied by a deficient response of vasopressin to osmotic stimulation. The hypernatremia develops over time and is uncovered or accelerated by events such as gastroenteritis, fever, or excessive sweating, which increase renal or nonrenal fluid losses. Clinical manifestations of dehydration and hypernatremia may be seen. Laboratory manifestations include hypernatremia, azotemia, hypokalemia, and alkalosis. Complications such as acute renal failure, deep vein thrombosis, and rhabdomyolysis have been observed in this group of patients.

Treatment

In the presence of normal osmoregulation of vasopressin release, patients with adipsic hypernatremia are managed with controlled intake of daily fluids along with close monitoring of body weight, urine output, clinical symptoms, and serum sodium levels. While the patients should consume a minimum amount of fluids calculated from the renal and nonrenal losses, this amount may vary with events that increase these losses. The intact vasopressin response to osmotic stimulus should accommodate for variations in the fluid balance by regulating renal free water excretion. However, caution must be exercised in order to avoid fluid overloading, even in patients without significant polyuria because some of these individuals may be unable to fully suppress vasopressin release when faced with lower serum osmolalities.

Fluid management of adipsic hypernatremia is more difficult when it is associated with DI. There is the additional danger of hypo-osmolar overhydration with fluid intake in the presence of DDAVP. A practical method of managing these patients is to maintain antidiuresis with a fixed dose of DDAVP and then adjusting the controlled fluid intake based on changes in body weight, urine output, and the presence or absence of events associated with increased renal or nonrenal fluid losses. A target body weight with the patient in a euvolemic state is identified. The intake of fluids for a particular day then could be adjusted to keep the daily weight close to this target weight.²⁶ Frequent revision of the target weight would be required for a growing child. Education of the family is vital in the management of this condition. Frequent monitoring of serum sodium levels using portable home analyzers may be helpful in the management of children with this problem.

Hyponatremia is uncommon in children and is usually associated with severe systemic disorders.

Hyponatremia

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).

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.

Treatment

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.

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.

Causes

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).

Treatment

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

Causes

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.

Treatment

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

Primary polydipsia

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).

Psychogenic polydipsia.

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.

Dipsogenic polydipsia.

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

Causes.

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.

Treatment.

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

Causes

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.

Treatment

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

Definition

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

Pathophysiology

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.

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

Differential diagnosis

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.

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.

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

Treatment of CSW

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.

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}

Summary

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.