Electrolyte and Acid-Base Disorders

Body Content and Physiologic Function

Sodium is the dominant cation of the ECF (see Fig. 68.3 ), and it is the principal determinant of extracellular osmolality. Na ⁺ is therefore necessary for the maintenance of intravascular volume. Less than 3% of Na ⁺ is intracellular. More than 40% of total body Na ⁺ is in bone; the remainder is in the interstitial and intravascular spaces. The low intracellular [Na ⁺ ], approximately 10 mEq/L, is maintained by Na ⁺ ,K ⁺ -ATPase, which exchanges intracellular Na ⁺ for extracellular K ⁺ .

Sodium Intake

A child's diet determines the amount of Na ⁺ ingested—a predominantly cultural determination in older children. An occasional child has salt craving because of an underlying salt-wasting renal disease or adrenal insufficiency. Children in the United States tend to have very high salt intakes because their diets include a large amount of “junk” food or fast food. Infants receive sodium from breast milk (approximately 7 mEq/L) and formula (7-13 mEq/L, for 20 calorie/oz formula).

Sodium is readily absorbed throughout the GI tract. Mineralocorticoids increase sodium transport into the body, although this effect has limited clinical significance. The presence of glucose enhances sodium absorption owing to the presence of a co-transport system. This is the rationale for including sodium and glucose in oral rehydration solutions (see Chapter 366 ).

Sodium Excretion

Sodium excretion occurs in stool and sweat, but the kidney regulates Na ⁺ balance and is the principal site of Na ⁺ excretion. There is some Na ⁺ loss in stool, but it is minimal unless diarrhea is present. Normally, sweat has 5-40 mEq/L of sodium. Sweat Na ⁺ concentration is increased in children with cystic fibrosis, aldosterone deficiency, or pseudohypoaldosteronism. The higher sweat losses in these conditions may cause or contribute to Na ⁺ depletion.

Sodium is unique among electrolytes because water balance, not Na ⁺ balance, usually determines its concentration. When the [Na ⁺ ] increases, the resultant higher plasma osmolality causes increased thirst and increased secretion of ADH, which leads to renal conservation of water. Both these mechanisms increase the water content of the body, and the [Na ⁺ ] returns to normal. During hyponatremia, the decrease in plasma osmolality stops ADH secretion, and consequent renal water excretion leads to an increase in the [Na ⁺ ]. Even though water balance is usually regulated by osmolality, volume depletion does stimulate thirst, ADH secretion, and renal conservation of water. Volume depletion takes precedence over osmolality; volume depletion stimulates ADH secretion, even if a patient has hyponatremia.

The excretion of Na ⁺ by the kidney is not regulated by the plasma osmolality. The patient's effective plasma volume determines the amount of sodium in the urine. This is mediated by a variety of regulatory systems, including the renin-angiotensin-aldosterone system and intrarenal mechanisms. In hyponatremia or hypernatremia, the underlying pathophysiology determines the amount of urinary Na ⁺ , not the serum [Na ⁺ ].

Etiology and Pathophysiology

There are 3 basic mechanisms of hypernatremia ( Table 68.1 ). Sodium intoxication is frequently iatrogenic in a hospital setting as a result of correction of metabolic acidosis with sodium bicarbonate. Baking soda, a putative home remedy for upset stomach, is another source of sodium bicarbonate; the hypernatremia is accompanied by a profound metabolic alkalosis. In hyperaldosteronism, there is renal retention of sodium and resultant hypertension; hypernatremia may not be present or is usually mild.

The classic causes of hypernatremia from a water deficit are nephrogenic and central diabetes insipidus (see Chapters 548 and 574 ). Hypernatremia develops in diabetes insipidus only if the patient does not have access to water or cannot drink adequately because of immaturity, neurologic impairment, emesis, or anorexia. Infants are at high risk because of their inability to control their own water intake. Central diabetes insipidus and the genetic forms of nephrogenic diabetes insipidus typically cause massive urinary water losses and very dilute urine. The water losses are less dramatic, and the urine often has the same osmolality as plasma when nephrogenic diabetes insipidus is secondary to intrinsic renal disease (obstructive uropathy, renal dysplasia, sickle cell disease).

The other causes of a water deficit are also secondary to an imbalance between losses and intake. Newborns, especially if premature, have high insensible water losses. Losses are further increased if the infant is placed under a radiant warmer or with the use of phototherapy for hyperbilirubinemia. The renal concentrating mechanisms are not optimal at birth, providing an additional source of water loss. Ineffective breastfeeding, often in a primiparous mother, can cause severe hypernatremic dehydration. Adipsia , the absence of thirst, is usually secondary to damage to the hypothalamus, such as from trauma, tumor, hydrocephalus, or histiocytosis. Primary adipsia is rare.

When hypernatremia occurs in conditions with deficits of sodium and water, the water deficit exceeds the sodium deficit. This occurs only if the patient is unable to ingest adequate water. Diarrhea results in depletion of both Na ⁺ and water. Because diarrhea is hypotonic—typical Na ⁺ concentration of 35-65 mEq/L—water losses exceed Na ⁺ losses, potentially leading to hypernatremia. Most children with gastroenteritis do not have hypernatremia because they drink enough hypotonic fluid to compensate for stool water losses (see Chapter 366 ). Fluids such as water, juice, and formula are more hypotonic than the stool losses, allowing correction of the water deficit and potentially even causing hyponatremia. Hypernatremia is most likely to occur in the child with diarrhea who has inadequate intake because of emesis, lack of access to water, or anorexia.

Osmotic agents, including mannitol, and glucose in diabetes mellitus , cause excessive renal losses of water and Na ⁺ . Because the urine is hypotonic (Na ⁺ concentration of approximately 50 mEq/L) during an osmotic diuresis, water loss exceeds Na ⁺ loss, and hypernatremia may occur if water intake is inadequate. Certain chronic kidney diseases, such as renal dysplasia and obstructive uropathy, are associated with tubular dysfunction, leading to excessive losses of water and Na ⁺ . Many children with such diseases have disproportionate water loss and are at risk for hypernatremic dehydration, especially if gastroenteritis supervenes. Similar mechanisms occur during the polyuric phase of acute kidney injury and after relief of urinary obstruction (postobstructive diuresis). Patients with either condition may have an osmotic diuresis from urinary losses of urea and an inability to conserve water because of tubular dysfunction.

Essential hypernatremia is rare in children and is thought to occur with injury to the hypothalamic-posterior pituitary axis. It is euvolemic, nonhypertensive, and associated with hypodipsia, possibly related to a reset osmol sensor.

Clinical Manifestations

Most children with hypernatremia are dehydrated and show the typical clinical signs and symptoms (see Chapter 70 ). Children with hypernatremic dehydration tend to have better preservation of intravascular volume because of the shift of water from the ICS to the ECS. This shift maintains blood pressure and urine output and allows hypernatremic infants to be less symptomatic initially and potentially to become more dehydrated before medical attention is sought. Breastfed infants with hypernatremia are often profoundly dehydrated, with failure to thrive (malnutrition). Probably because of intracellular water loss, the pinched abdominal skin of a dehydrated, hypernatremic infant has a “doughy” feel.

Hypernatremia, even without dehydration, causes central nervous system (CNS) symptoms that tend to parallel the degree of Na ⁺ elevation and the acuity of the increase. Patients are irritable, restless, weak, and lethargic. Some infants have a high-pitched cry and hyperpnea. Alert patients are very thirsty, even though nausea may be present. Hypernatremia may cause fever, although many patients have an underlying process that contributes to the fever. Hypernatremia is associated with hyperglycemia and mild hypocalcemia; the mechanisms are unknown. Beyond the sequelae of dehydration, there is no clear direct effect of hypernatremia on other organs or tissues, except the brain.

Brain hemorrhage is the most devastating consequence of untreated hypernatremia. As the extracellular osmolality increases, water moves out of brain cells, leading to a decrease in brain volume. This decrease can result in tearing of intracerebral veins and bridging blood vessels as the brain moves away from the skull and the meninges. Patients may have subarachnoid, subdural, and parenchymal hemorrhages. Seizures and coma are possible sequelae of the hemorrhage, although seizures are more common during correction of hypernatremia. The cerebrospinal fluid protein is often elevated in infants with significant hypernatremia, probably because of leakage from damaged blood vessels. Neonates, especially if premature, seem especially vulnerable to hypernatremia and excessive sodium intake. There is an association between rapid or hyperosmolar sodium bicarbonate administration and the development of intraventricular hemorrhages in neonates. Even though central pontine myelinolysis is classically associated with overly rapid correction of hyponatremia, both central pontine and extrapontine myelinolysis can occur in children with hypernatremia (see Treatment ). Thrombotic complications occur in severe hypernatremic dehydration, including stroke, dural sinus thrombosis, peripheral thrombosis, and renal vein thrombosis. This is secondary to dehydration and possibly hypercoagulability associated with hypernatremia.

Diagnosis

The etiology of hypernatremia is usually apparent from the history. Hypernatremia resulting from water loss occurs only if the patient does not have access to water or is unable to drink. In the absence of dehydration, it is important to ask about sodium intake. Children with excess salt intake do not have signs of dehydration, unless another process is present. Severe Na ⁺ intoxication causes signs of volume overload, such as pulmonary edema and weight gain. Salt poisoning is associated with an elevated fractional excretion of Na ⁺ , whereas hypernatremic dehydration causes a low fractional excretion of Na ⁺ . Gastric sodium concentrations are often elevated in salt poisoning. In hyperaldosteronism, hypernatremia is usually mild or absent and is associated with edema, hypertension, hypokalemia, and metabolic alkalosis.

When there is isolated water loss, the signs of volume depletion are usually less severe initially because much of the loss is from the ICS. When pure water loss causes signs of dehydration, the hypernatremia and water deficit are usually severe. In the child with renal water loss, either central or nephrogenic diabetes insipidus, the urine is inappropriately dilute and urine volume is not low. The urine is maximally concentrated and urine volume is low if the losses are extrarenal or caused by inadequate intake. With extrarenal causes of loss of water, the urine osmolality should be >1,000 mOsm/kg. When diabetes insipidus is suspected, the evaluation may include measurement of ADH and a water deprivation test, including a trial of desmopressin acetate (synthetic ADH analog) to differentiate between nephrogenic diabetes insipidus and central diabetes insipidus (see Chapters 548 and 574 ). A water-deprivation test is unnecessary if the patient has simultaneous documentation of hypernatremia and poorly concentrated urine (osmolality lower than that of plasma). In children with central diabetes insipidus, administration of desmopressin acetate increases the urine osmolality above the plasma osmolality, although maximum osmolality does not occur immediately because of the decreased osmolality of the renal medulla as a result of the chronic lack of ADH. In children with nephrogenic diabetes insipidus, there is no response to desmopressin acetate. Hypercalcemia or hypokalemia may produce a nephrogenic diabetes insipidus–like syndrome.

With combined Na ⁺ and water deficits, analysis of the urine differentiates between renal and nonrenal etiologies. When the losses are extrarenal, the kidney responds to volume depletion with low urine volume, concentrated urine, and Na ⁺ retention (urine [Na ⁺ ] <20 mEq/L, fractional excretion of Na ⁺ <1%). With renal causes, the urine volume is not appropriately low, the urine is not maximally concentrated, and the urine [Na ⁺ ] may be inappropriately elevated.

Treatment

As hypernatremia develops, the brain generates idiogenic osmoles to increase the intracellular osmolality and prevent the loss of brain water. This mechanism is not instantaneous and is most prominent when hypernatremia has developed gradually. If the serum [Na ⁺ ] is lowered rapidly, there is movement of water from the serum into the brain cells to equalize the osmolality in the 2 compartments. The resultant brain swelling manifests as seizures or coma.

Because of the associated dangers, chronic hypernatremia should not be corrected rapidly. The goal is to decrease the serum [Na ⁺ ] by <10 mEq/L every 24 hr. The most important component of correcting moderate or severe hypernatremia is frequent monitoring of the serum [Na ⁺ ] value so that fluid therapy can be adjusted to provide adequate correction, neither too slow nor too fast. If a child has seizures as a result of brain edema secondary to rapid correction, administration of hypotonic fluid should be stopped. An infusion of 3% saline can acutely increase the serum [Na ⁺ ], reversing the cerebral edema.

Chapter 70 outlines a detailed approach to the child with hypernatremic dehydration. Acute, severe hypernatremia, usually secondary to sodium administration, can be corrected more rapidly with 5% dextrose in water (D5W) because idiogenic osmoles have not had time to accumulate. This fact balances the high morbidity and mortality rates associated with hypernatremia with the dangers of overly rapid correction. When hypernatremia is severe and is caused by sodium intoxication, it may be impossible to administer enough water to correct the hypernatremia rapidly without worsening the volume overload. In this situation, dialysis allows for removal of the excess Na ⁺ , with the precise strategy dependent on the mode of dialysis. In less severe cases, the addition of a loop diuretic increases the removal of excess Na ⁺ and water, decreasing the risk of volume overload. With Na ⁺ overload, hypernatremia is corrected with Na ⁺ -free intravenous (IV) fluid (D5W).

Hyperglycemia from hypernatremia is not usually a problem and is not treated with insulin because the acute decrease in glucose may precipitate cerebral edema by lowering plasma osmolality. Rarely, the glucose concentration of IV fluids must be reduced (from 5% to 2.5% dextrose in water). The secondary hypocalcemia is treated as needed.

It is important to address the underlying cause of the hypernatremia, if possible. The child with central diabetes insipidus should receive desmopressin acetate. Because this treatment reduces renal excretion of water, excessive intake of water must be avoided to prevent both overly rapid correction of the hypernatremia and the development of hyponatremia. Over the long term, reduced sodium intake and the use of medications can somewhat ameliorate the water losses in nephrogenic diabetes insipidus (see Chapter 548 ). The daily water intake of a child receiving tube feeding may need to be increased to compensate for high losses. The patient with significant ongoing losses, such as through diarrhea, may need supplemental water and electrolytes (see Chapter 69 ). Sodium intake is reduced if it contributed to the hypernatremia.

Etiology and Pathophysiology

Table 68.2 lists the causes of hyponatremia. Pseudohyponatremia is a laboratory artifact present when the plasma contains very high concentrations of protein (multiple myeloma, IVIG infusion) or lipid (hypertriglyceridemia, hypercholesterolemia). It does not occur when a direct ion-selective electrode determines the [Na ⁺ ] in undiluted plasma, a technique that is used by ABG analyzers or POC instruments (see Chapter 68.1 ). In true hyponatremia, the measured osmolality is low, whereas it is normal in pseudohyponatremia. Hyperosmolality, as may occur with hyperglycemia, causes a low [Na ⁺ ] because water moves down its osmotic gradient from the ICS into the ECS, diluting the [Na ⁺ ]. However, because the manifestations of hyponatremia are a result of the low plasma osmolality, patients with hyponatremia resulting from hyperosmolality do not have symptoms of hyponatremia. When the etiology of the hyperosmolality resolves, such as hyperglycemia in diabetes mellitus, water moves back into the cells, and the [Na ⁺ ] rises to its “true” value. Mannitol or sucrose, a component of intravenous immune globulin (IVIG) preparations, may cause hyponatremia because of hyperosmolality.

Classification of hyponatremia is based on the patient's volume status. In hypovolemic hyponatremia the child has lost Na ⁺ from the body. The water balance may be positive or negative, but Na ⁺ loss has been higher than water loss. The pathogenesis of the hyponatremia is usually a combination of Na ⁺ loss and water retention to compensate for the volume depletion. The patient has a pathologic increase in fluid loss, and this fluid contains Na ⁺ . Most fluid that is lost has a lower [Na ⁺ ] than that of plasma. Viral diarrhea fluid has an average [Na ⁺ ] of 50 mEq/L. Replacing diarrhea fluid, which has [Na ⁺ ] of 50 mEq/L, with formula, which has only approximately 10 mEq/L of Na ⁺ , reduces [Na ⁺ ]. Intravascular volume depletion interferes with renal water excretion, the body's usual mechanism for preventing hyponatremia. The volume depletion stimulates ADH synthesis, resulting in renal water retention. Volume depletion also decreases the GFR and enhances water resorption in the proximal tubule, thereby reducing water delivery to the collecting duct.

Diarrhea as a result of gastroenteritis is the most common cause of hypovolemic hyponatremia in children. Emesis causes hyponatremia if the patient takes in hypotonic fluid, either intravenously or enterally, despite the emesis. Most patients with emesis have either a normal [Na ⁺ ] or hypernatremia. Burns may cause massive losses of isotonic fluid and resultant volume depletion. Hyponatremia develops if the patient receives hypotonic fluid. Losses of sodium from sweat are especially high in children with cystic fibrosis, aldosterone deficiency, or pseudohypoaldosteronism, although high losses can also occur in a hot climate. Third space losses are isotonic and can cause significant volume depletion, leading to ADH production and water retention, which can cause hyponatremia if the patient receives hypotonic fluid. In diseases that cause volume depletion through extrarenal Na ⁺ loss, the urine Na ⁺ level should be low (<10 mEq/L) as part of the renal response to maintain the intravascular volume. The only exceptions are diseases that cause both extrarenal and renal Na ⁺ losses: adrenal insufficiency and pseudohypoaldosteronism.

Renal Na ⁺ loss may occur in a variety of situations. In some situations the urine [Na ⁺ ] is >140 mEq/L; thus hyponatremia may occur without any fluid intake. In many cases the urine Na ⁺ level is less than the serum [Na ⁺ ]; thus the intake of hypotonic fluid is necessary for hyponatremia to develop. In diseases associated with urinary Na ⁺ loss, the urine Na ⁺ level is >20 mEq/L despite volume depletion. This may not be true if the urinary Na ⁺ loss is no longer occurring, as is frequently the case if diuretics are discontinued. Because loop diuretics prevent generation of a maximally hypertonic renal medulla, the patient can neither maximally dilute nor concentrate the urine. The inability to maximally retain water provides some protection against severe hyponatremia. The patient receiving thiazide diuretics can concentrate the urine and is at higher risk for severe hyponatremia. Osmotic agents, such as glucose during diabetic ketoacidosis, cause loss of both water and Na ⁺ . Urea accumulates during renal failure and then acts as an osmotic diuretic after relief of urinary tract obstruction and during the polyuric phase of acute tubular necrosis. Transient tubular damage in these conditions further impairs Na ⁺ conservation. The serum [Na ⁺ ] in these conditions depends on [Na ⁺ ] of the fluid used to replace the losses. Hyponatremia develops when the fluid is hypotonic relative to the urinary losses.

Renal salt wasting occurs in hereditary kidney diseases, such as juvenile nephronophthisis and autosomal recessive polycystic kidney disease. Obstructive uropathy, most often a result of posterior urethral valves, produces salt wasting, but patients with the disease may also have hypernatremia as a result of impaired ability to concentrate urine and high-water loss. Acquired tubulointerstitial nephritis, usually secondary to either medications or infections, may cause salt wasting, along with other evidence of tubular dysfunction. CNS injury may produce cerebral salt wasting, which is theoretically caused by the production of a natriuretic peptide that causes renal salt wasting. In type II renal tubular acidosis (RTA) , usually associated with Fanconi syndrome (see Chapter 547.1 ), there is increased excretion of Na ⁺ and bicarbonate in the urine. Patients with Fanconi syndrome also have glycosuria, aminoaciduria, and hypophosphatemia because of renal phosphate wasting.

Aldosterone is necessary for renal Na ⁺ retention and for the excretion of K ⁺ and acid. In congenital adrenal hyperplasia caused by 21-hydroxylase deficiency, the block of aldosterone production results in hyponatremia, hyperkalemia, and metabolic acidosis. Decreased aldosterone secretion may be seen in Addison disease (adrenal insufficiency). In pseudohypoaldosteronism, aldosterone levels are elevated, but there is no response because of either a defective Na ⁺ channel or a deficiency of aldosterone receptors. A lack of tubular response to aldosterone may occur in children with urinary tract obstruction, especially during an acute urinary tract infection.

In hypervolemic hyponatremia there is an excess of TBW and Na ⁺ , although the increase in water is greater than the increase in Na ⁺ . In most conditions that cause hypervolemic hyponatremia, there is a decrease in the effective blood volume , resulting from third space fluid loss, vasodilation, or poor cardiac output. The regulatory systems sense a decrease in effective blood volume and attempt to retain water and Na ⁺ to correct the problem. ADH causes renal water retention, and the kidney, under the influence of aldosterone and other intrarenal mechanisms, retains sodium. The patient's sodium concentration decreases because water intake exceeds sodium intake and ADH prevents the normal loss of excess water.

In these disorders, there is low urine [Na ⁺ ] (<10 mEq/L) and an excess of both TBW and Na ⁺ . The only exception is in patients with renal failure and hyponatremia. These patients have an expanded intravascular volume, and hyponatremia can therefore appropriately suppress ADH production. Water cannot be excreted because very little urine is being made. Serum Na ⁺ is diluted through ingestion of water. Because of renal dysfunction, the urine [Na ⁺ ] may be elevated, but urine volume is so low that urine Na ⁺ excretion has not kept up with Na ⁺ intake, leading to sodium overload. The urine [Na ⁺ ] in renal failure varies. In patients with acute glomerulonephritis, because it does not affect the tubules, the urine Na ⁺ level is usually low, whereas in patients with acute tubular necrosis, it is elevated because of tubular dysfunction.

Patients with hyponatremia and no evidence of volume overload or volume depletion have euvolemic hyponatremia. These patients typically have an excess of TBW and a slight decrease in total body Na ⁺ . Some of these patients have an increase in weight, implying that they are volume-overloaded. Nevertheless, from a clinical standpoint, they usually appear normal or have subtle signs of fluid overload. In SIADH the secretion of ADH is not inhibited by either low serum osmolality or expanded intravascular volume (see Chapter 575 ). The result is that the child with SIADH is unable to excrete water. This results in dilution of the serum Na ⁺ and hyponatremia. The expansion of the extracellular volume because of the retained water causes a mild increase in intravascular volume. The kidney increases Na ⁺ excretion to decrease intravascular volume to normal; thus the patient has a mild decrease in body Na ⁺ . SIADH typically occurs with disorders of the CNS (infection, hemorrhage, trauma, tumor, thrombosis, Guillain-Barré syndrome), but lung disease (infection, asthma, positive pressure ventilation) and malignant tumors (producing ADH) are other potential causes. A variety of medications may cause SIADH, including recreational use of 3,4-methylenedioxymethylamphetamine (MDMA, or “Ecstasy”), opiates, antiepileptic drugs (carbamazepine, oxcarbazepine, valproate), tricyclic antidepressants, vincristine, cyclophosphamide, and selective serotonin reuptake inhibitors (SSRIs). The diagnosis of SIADH is one of exclusion, because other causes of hyponatremia must be eliminated ( Table 68.3 ). Because SIADH is a state of intravascular volume expansion, low serum uric acid and BUN levels are supportive of the diagnosis. A rare gain-of-function mutation in the renal ADH receptor causes nephrogenic syndrome of inappropriate antidiuresis . Patients with this X-linked disorder appear to have SIADH but have undetectable levels of ADH.

Hyponatremia in hospitalized patients is frequently caused by inappropriate production of ADH and administration of hypotonic IV fluids (see Chapter 69 ). Causes of inappropriate ADH production include stress, medications such as narcotics or anesthetics, nausea, and respiratory illness. The synthetic analog of ADH, desmopressin acetate, causes water retention and may cause hyponatremia if fluid intake is not appropriately limited. The main uses of desmopressin acetate in children are for the management of central diabetes insipidus and nocturnal enuresis.

Excess water ingestion can produce hyponatremia. In these cases, [Na ⁺ ] decreases as a result of dilution. This decrease suppresses ADH secretion, and there is a marked water diuresis by the kidney. Hyponatremia develops only because the intake of water exceeds the kidney's ability to eliminate water. This condition is more likely to occur in infants because their lower GFR limits their ability to excrete water.

Hyponatremia may develop in infants <6 mo of age when caregivers offer water to their infant as a supplement, during hot weather, or when they run out of formula. Hyponatremia may result in transient seizures, hypothermia, and poor tone. With cessation of water intake, the hyponatremia rapidly corrects. Infants <6 mo of age should not be given water to drink; infants 6-12 mo of age should not receive >1-2 ounces. If the infant appears thirsty, the parent should offer formula or breastfeed the child.

In some situations the water intoxication causes acute hyponatremia and is caused by a massive acute water load . Causes include infant swimming lessons, inappropriate use of hypotonic IV fluids, water enemas, and forced water intake as a form of child abuse. Chronic hyponatremia occurs in children who receive water but limited sodium and protein. The minimum urine osmolality is approximately 50 mOsm/kg, the kidney can excrete 1 L of water only if there is enough solute ingested to produce 50 mOsm for urinary excretion. Because Na ⁺ and urea (a breakdown product of protein) are the principal urinary solutes, a lack of intake of Na ⁺ and protein prevents adequate water excretion. This occurs with the use of diluted formula or other inappropriate diets. Subsistence on beer, a poor source of Na ⁺ and protein, causes hyponatremia because of the inability to excrete the high water load (“beer potomania”). Exercise-induced hyponatremia , reported frequently during marathons, is caused by excessive water intake, salt losses from sweat, and secretion of ADH.

The pathogenesis of the hyponatremia in glucocorticoid deficiency (adrenal insufficiency) is multifactorial and includes increased ADH secretion. In hypothyroidism there is an inappropriate retention of water by the kidney, but the precise mechanisms are not clearly elucidated.

Cerebral salt wasting , an uncommon disorder in children, may be confused with SIADH and is often associated with CNS injury or lesions. Cerebral salt wasting produces renal salt losses and hypovolemia (orthostatic hypotension and elevated hematocrit, BUN, or creatinine).

Clinical Manifestations

Hyponatremia causes a decrease in the osmolality of the ECS. Because the ICS then has a higher osmolality, water moves from the ECS to the ICS to maintain osmotic equilibrium. The increase in intracellular water causes cells to swell. Although cell swelling is not problematic in most tissues, it is dangerous for the brain, which is confined by the skull. As brain cells swell, there is an increase in intracranial pressure, which impairs cerebral blood flow. Acute, severe hyponatremia can cause brainstem herniation and apnea; respiratory support is often necessary. Brain cell swelling is responsible for most of the symptoms of hyponatremia. Neurologic symptoms of hyponatremia include anorexia, nausea, emesis, malaise, lethargy, confusion, agitation, headache, seizures, coma, and decreased reflexes. Patients may have hypothermia and Cheyne-Stokes respirations. Hyponatremia can cause muscle cramps and weakness; rhabdomyolysis can occur with water intoxication.

The symptoms of hyponatremia are mostly a result of the decrease in extracellular osmolality and the resulting movement of water down its osmotic gradient into the ICS. Brain swelling can be significantly obviated if the hyponatremia develops gradually, because brain cells adapt to the decreased extracellular osmolality by reducing intracellular osmolality. This reduction is achieved by extrusion of the main intracellular ions (K ⁺ , Cl ⁻ ) and a variety of small organic molecules. This process explains why the range of symptoms in hyponatremia is related to both the serum [Na ⁺ ] and its rate of decrease. A patient with chronic hyponatremia may have only subtle neurologic abnormalities with a serum [Na ⁺ ] of 110 mEq/L, but another patient may have seizures because of an acute decline in serum [Na ⁺ ] from 140 to 125 mEq/L.

Diagnosis

The history usually points to a likely etiology of the hyponatremia. Most patients with hyponatremia have a history of volume depletion. Diarrhea and diuretic use are common causes of hyponatremia in children. A history of polyuria, perhaps with enuresis, and/or salt craving is present in children with primary kidney diseases or absence of aldosterone effect. Children may have signs or symptoms suggesting a diagnosis of hypothyroidism or adrenal insufficiency (see Chapters 581 and 593 ). Brain injury raises the possibility of SIADH or cerebral salt wasting, with the caveat that SIADH is much more likely. Liver disease, nephrotic syndrome, renal failure, or congestive heart failure may be acute or chronic. The history should include a review of the patient's intake, both intravenous and enteral, with careful attention to the amounts of water, Na ⁺ , and protein.

The traditional first step in the diagnostic process is determination of the plasma osmolality. This is done because some patients with a low serum [Na ⁺ ] do not have low osmolality. The clinical effects of hyponatremia are secondary to the associated low osmolality. Without a low osmolality, there is no movement of water into the intracellular space.

A patient with hyponatremia can have a low, normal, or high osmolality. A normal osmolality in combination with hyponatremia occurs in pseudohyponatremia. Children with elevation of serum glucose concentration or of another effective osmole (mannitol) have a high plasma osmolality and hyponatremia. The presence of a low osmolality indicates “true” hyponatremia. Patients with low osmolality are at risk for neurologic symptoms and require further evaluation to determine the etiology of the hyponatremia.

In some situations, true hyponatremia is present despite a normal or elevated plasma osmolality. The presence of an ineffective osmole, usually urea, increases the plasma osmolality, but because the osmole has the same concentration in the ICS, it does not cause fluid to move into the ECS. There is no dilution of the serum Na ⁺ by water, and the [Na ⁺ ] remains unchanged if the ineffective osmole is eliminated. Most importantly, the ineffective osmole does not protect the brain from edema caused by hyponatremia. Therefore, a patient may have symptoms of hyponatremia despite having a normal or increased osmolality because of uremia.

In patients with true hyponatremia, the next step in the diagnostic process is to clinically evaluate the volume status. Patients with hyponatremia can be hypovolemic, hypervolemic, or euvolemic. The diagnosis of volume depletion relies on the usual findings with dehydration (see Chapter 70 ), although subtle volume depletion may not be clinically apparent. Children with hypervolemia are edematous on physical examination. They may have ascites, pulmonary edema, pleural effusion, or hypertension.

Hypovolemic hyponatremia can have renal or nonrenal causes. The urine [Na ⁺ ] is very useful in differentiating between renal and nonrenal causes. When the losses are nonrenal and the kidney is working properly, there is renal retention of Na ⁺ , a normal homeostatic response to volume depletion. Thus the urinary [Na ⁺ ] is low, typically <10 mEq/L, although Na ⁺ conservation in neonates is less avid. When the kidney is the cause of the Na ⁺ loss, the urine [Na ⁺ ] is >20 mEq/L, reflecting the defect in renal Na ⁺ retention. The interpretation of the urine Na ⁺ level is challenging with diuretic therapy because it is high when diuretics are being used but low after the diuretic effect is gone. This becomes an issue only when diuretic use is surreptitious. The urine [Na ⁺ ] is not useful if a metabolic alkalosis is present; the urine [Cl ⁻ ] must be used instead (see Chapter 68.7 ).

Differentiating among the nonrenal causes of hypovolemic hyponatremia is usually facilitated by the history. Although the renal causes are more challenging to distinguish, a high serum [K ⁺ ] is associated with disorders in which the Na ⁺ wasting is caused by absence of or ineffectiveness of aldosterone.

In the patient with hypervolemic hyponatremia, the urine [Na ⁺ ] is a helpful parameter. It is usually <10 mEq/L, except in the patient with renal failure.

Treatment

The management of hyponatremia is based on the pathophysiology of the specific etiology. The management of all causes requires judicious monitoring and avoidance of an overly quick normalization of the serum [Na ⁺ ]. A patient with severe symptoms (seizures), no matter the etiology, should be given a bolus of hypertonic saline to produce a small, rapid increase in serum sodium. Hypoxia worsens cerebral edema, and hyponatremia may exacerbate hypoxic cell swelling. Therefore, pulse oximetry should be monitored and hypoxia aggressively corrected.

With all causes of hyponatremia, it is important to avoid overly rapid correction, which may cause central pontine myelinolysis (CPM) . This syndrome, which occurs within several days of rapid correction of hyponatremia, produces neurologic symptoms, including confusion, agitation, flaccid or spastic quadriparesis, and death. There are usually characteristic pathologic and radiologic changes in the brain, especially in the pons, but extrapontine lesions are quite common and may cause additional symptoms. Despite severe symptoms, full recovery does occur in some patients.

CPM is more common in patients who are treated for chronic hyponatremia than for acute hyponatremia. Presumably, this difference is based on the adaptation of brain cells to the hyponatremia. The reduced intracellular osmolality, an adaptive mechanism for chronic hyponatremia, makes brain cells susceptible to dehydration during rapid correction of the hyponatremia, which may be the mechanism of CPM. Even though CPM is rare in pediatric patients, it is advisable to avoid correcting the serum [Na ⁺ ] by >10 mEq/L/24 hr or >18 mEq/L/48 hr. Desmopressin is a potential option if the serum [Na ⁺ ] is increasing too rapidly. This guideline does not apply to acute hyponatremia, as may occur with water intoxication, because the hyponatremia is more often symptomatic, and the adaptive decrease in brain osmolality has not had time to occur. The consequences of brain edema in acute hyponatremia exceed the small risk of CPM.

Patients with hyponatremia can have severe neurologic symptoms, such as seizures and coma. The seizures associated with hyponatremia generally are poorly responsive to anticonvulsants. The child with hyponatremia and severe symptoms needs treatment that will quickly reduce cerebral edema. This goal is best accomplished by increasing the extracellular osmolality so that water moves down its osmolar gradient from the ICS to the ECS.

Intravenous hypertonic saline rapidly increases serum [Na ⁺ ], and the effect on serum osmolality leads to a decrease in brain edema. Each mL/kg of 3% NaCl increases the serum [Na ⁺ ] by approximately 1 mEq/L. A child with active symptoms often improves after receiving 4-6 mL/kg of 3% NaCl.

The child with hypovolemic hyponatremia has a deficiency in Na ⁺ and may have a deficiency in water. The cornerstone of therapy is to replace the Na ⁺ deficit and any water deficit present. The first step in treating any dehydrated patient is to restore the intravascular volume with isotonic saline. Ultimately, complete restoration of intravascular volume suppresses ADH production, thereby permitting excretion of the excess water. Chapter 70 discusses the management of hyponatremic dehydration.

The management of hypervolemic hyponatremia is difficult; patients have an excess of both water and Na ⁺ . Administration of Na ⁺ leads to worsening volume overload and edema. In addition, patients are retaining water and Na ⁺ because of their ineffective intravascular volume or renal insufficiency. The cornerstone of therapy is water and Na ⁺ restriction, because patients have volume overload. Diuretics may help by causing excretion of both Na ⁺ and water. Vasopressin antagonists ( vaptans ), by blocking the action of ADH and causing a water diuresis, are effective in correcting the hypervolemic hyponatremia caused by heart failure. Vaptans are contraindicated if there are moderate to severe CNS symptoms.

Hyponatremic patients with low albumin from nephrotic syndrome have a better response to diuretics after an infusion of 25% albumin; the [Na ⁺ ] often normalizes as a result of expansion of the intravascular volume. A child with heart failure may have an increase in renal water and Na ⁺ excretion if there is an improvement in cardiac output. This improvement will “turn off” the regulatory hormones causing renal water (ADH) and Na ⁺ (aldosterone) retention. The patient with renal failure cannot respond to any of these therapies except fluid restriction. Insensible fluid losses eventually result in an increase in the [Na ⁺ ] as long as insensible and urinary losses are greater than intake. A more definitive approach in children with renal failure is to perform dialysis, which removes water and Na ⁺ .

In isovolumic hyponatremia there is usually an excess of water and a mild Na ⁺ deficit. Therapy is directed at eliminating the excess water. The child with acute excessive water intake loses water in the urine because ADH production is turned off as a result of the low plasma osmolality. Children may correct their hyponatremia spontaneously over 3-6 hr. For acute, symptomatic hyponatremia as a result of water intoxication, hypertonic saline may be needed to reverse cerebral edema. For chronic hyponatremia from poor solute intake, the child needs an appropriate formula, and excess water intake should be eliminated.

Children with iatrogenic hyponatremia caused by the administration of hypotonic IV fluids should receive 3% saline if symptomatic. Subsequent management is dictated by the patient's volume status. The hypovolemic child should receive isotonic IV fluids. The child with nonphysiologic stimuli for ADH production should undergo fluid restriction. Prevention of this iatrogenic complication requires judicious use of IV fluids (see Chapter 69 ).

Specific hormone replacement is the cornerstone of therapy for the hyponatremia of hypothyroidism or cortisol deficiency. Correction of the underlying defect permits appropriate elimination of the excess water.

SIADH is a condition of excess water, with limited ability of the kidney to excrete water. The mainstay of its therapy is fluid restriction with normal sodium intake. Furosemide and NaCl supplementation are effective in the patient with SIADH and severe hyponatremia. Even in a patient with SIADH, furosemide causes an increase in water and Na ⁺ excretion. The loss of Na ⁺ is somewhat counterproductive, but this Na ⁺ can be replaced with hypertonic saline. Because the patient has a net loss of water and the urinary losses of Na ⁺ have been replaced, there is an increase in the [Na ⁺ ], but no significant increase in blood pressure. Vaptans, which block the action of ADH and cause a water diuresis, are effective at correcting euvolemic hyponatremia , but overly rapid correction is a potential complication. Vaptans are not appropriate for treating symptomatic hyponatremia because it can take a few hours before the water diuresis occurs.

Treatment of chronic SIADH is challenging. Fluid restriction in children is difficult for nutritional and behavioral reasons. Other options are long-term furosemide therapy with Na ⁺ supplementation, an oral vaptan (tolvaptan), or oral urea.

Body Content and Physiologic Function

The intracellular [K ⁺ ], approximately 150 mEq/L, is much higher than the plasma [K ⁺ ] (see Fig. 68.3 ). The majority of body K ⁺ is contained in muscle. As muscle mass increases, there is an increase in body K ⁺ . Thus an increase in body K ⁺ occurs during puberty, and it is more significant in males. The majority of extracellular K ⁺ is in bone; <1% of total body K ⁺ is in plasma.

Because most K ⁺ is intracellular, the plasma concentration does not always reflect the total body K ⁺ content. A variety of conditions alter the distribution of K ⁺ between the intracellular and extracellular compartments. Na ⁺ ,K ⁺ -ATPase maintains the high intracellular [K ⁺ ] by pumping Na ⁺ out of the cell and K ⁺ into the cell. This activity balances the normal leak of K ⁺ out of cells via potassium channels that is driven by the favorable chemical gradient. Insulin increases K ⁺ movement into cells by activating Na ⁺ ,K ⁺ -ATPase. Hyperkalemia stimulates insulin secretion, which helps mitigate the hyperkalemia. Acid-base status affects K ⁺ distribution, probably via K ⁺ channels and the Na ⁺ ,K ⁺ -ATPase. A decrease in pH drives potassium extracellularly; an increase in pH has the opposite effect. β-Adrenergic agonists stimulate the Na ⁺ ,K ⁺ -ATPase, increasing cellular uptake of K ⁺ . This increase is protective, in that hyperkalemia stimulates adrenal release of catecholamines. α-Adrenergic agonists and exercise cause a net movement of K ⁺ out of the ICS. An increase in plasma osmolality, as with mannitol infusion, leads to water movement out of the cells, and K ⁺ follows as a result of solvent drag. The serum [K ⁺ ] increases by approximately 0.6 mEq/L with each 10 mOsm rise in plasma osmolality.

The high intracellular concentration of K ⁺ , the principal intracellular cation, is maintained through Na ⁺ ,K ⁺ -ATPase. The resulting chemical gradient is used to produce the resting membrane potential of cells. K ⁺ is necessary for the electrical responsiveness of nerve and muscle cells and for the contractility of cardiac, skeletal, and smooth muscle. The changes in membrane polarization that occur during muscle contraction or nerve conduction make these cells susceptible to changes in serum [K ⁺ ]. The ratio of intracellular to extracellular K ⁺ determines the threshold for a cell to generate an action potential and the rate of cellular repolarization. The intracellular [K ⁺ ] affects cellular enzymes. K ⁺ is necessary for maintaining cell volume because of its important contribution to intracellular osmolality.

Potassium Intake

Potassium is plentiful in food. Dietary consumption varies considerably, even though 1-2 mEq/kg is the recommended intake. The intestines normally absorb approximately 90% of ingested K ⁺ . Most absorption occurs in the small intestine, whereas the colon exchanges body K ⁺ for luminal Na ⁺ . Regulation of intestinal losses normally has a minimal role in maintaining potassium homeostasis, although renal failure, aldosterone, and glucocorticoids increase colonic secretion of K ⁺ . The increase in intestinal losses in the setting of renal failure and hyperkalemia, which stimulates aldosterone production, is clinically significant, helping to protect against hyperkalemia.

Potassium Excretion

Some loss of K ⁺ occurs in sweat but is normally minimal. The colon has the ability to eliminate some K ⁺ . In addition, after an acute K ⁺ load, much of the K ⁺ , >40%, moves intracellularly, through the actions of epinephrine and insulin, which are produced in response to hyperkalemia. This process provides transient protection from hyperkalemia, but most ingested K ⁺ is eventually excreted in the urine. The kidneys principally regulate long-term K ⁺ balance, and they alter excretion in response to a variety of signals. K ⁺ is freely filtered at the glomerulus, but 90% is resorbed before reaching the distal tubule and collecting duct, the principal sites of K ⁺ regulation that have the ability to absorb and secrete K ⁺ . The amount of tubular secretion regulates the amount of K ⁺ that appears in the urine. The plasma [K ⁺ ] directly influences secretion in the distal nephron. As the [K ⁺ ] increases, secretion increases.

The principal hormone regulating potassium secretion is aldosterone , which is released by the adrenal cortex in response to increased plasma K ⁺ . Its main site of action is the cortical collecting duct, where aldosterone stimulates Na ⁺ movement from the tubule into the cells. This movement creates a negative charge in the tubular lumen, facilitating K ⁺ excretion. In addition, the increased intracellular Na ⁺ stimulates the basolateral Na ⁺ ,K ⁺ -ATPase, causing more K ⁺ to move into the cells lining the cortical collecting duct. Glucocorticoids, ADH, a high urinary flow rate, and high Na ⁺ delivery to the distal nephron also increase urinary K ⁺ excretion. Insulin, catecholamines, and urinary ammonia decrease K ⁺ excretion. Whereas ADH increases K ⁺ secretion, it also causes water resorption, decreasing urinary flow. The net effect is that ADH has little overall impact on K ⁺ balance. Alkalosis causes potassium to move into cells, including the cells lining the collecting duct. This movement increases K ⁺ secretion, and because acidosis has the opposite effect, it decreases K ⁺ secretion.

The kidney can dramatically vary K ⁺ excretion in response to changes in intake. Normally, approximately 10–15% of the filtered load is excreted. In an adult, excretion of K ⁺ can vary from 5-1,000 mEq/day.

Etiology and Pathophysiology

Three basic mechanisms cause hyperkalemia ( Table 68.4 ). In the individual patient, the etiology is sometimes multifactorial.

Spurious hyperkalemia or pseudohyperkalemia is very common in children because of the difficulties in obtaining blood specimens. This laboratory result is usually caused by hemolysis during a heelstick or phlebotomy, but it can be the result of prolonged tourniquet application or fist clenching, either of which causes local potassium release from muscle.

The serum [K ⁺ ] is normally 0.4 mEq/L higher than the plasma value, secondary to K ⁺ release from cells during clot formation. This phenomenon is exaggerated with thrombocytosis because of K ⁺ release from platelets. For every 100,000/m ³ increase in the platelet count, the serum [K ⁺ ] rises by approximately 0.15 mEq/L. This phenomenon also occurs with the marked white blood cell (WBC) count elevations sometimes seen with leukemia. Elevated WBC counts, typically >200,000/m ³ , can cause a dramatic elevation in the serum [K ⁺ ]. Analysis of a plasma sample usually provides an accurate result. It is important to analyze the sample promptly to avoid K ⁺ release from cells, which occurs if the sample is stored in the cold, or cellular uptake of K ⁺ and spurious hypokalemia, which occurs with storage at high temperatures. Pneumatic tube transport can cause pseudohyperkalemia if cell membranes are fragile (leukemia). Occasionally, heparin causes lysis of leukemic cells and a false elevation of the plasma sample; a blood gas syringe has less heparin and may provide a more accurate reading than a standard tube. There are rare genetic disorders causing in vitro leakage of K ⁺ from red blood cells (RBCs) that may causes familial pseudohyperkalemia.

Because of the kidney's ability to excrete K ⁺ , it is unusual for excessive intake, by itself, to cause hyperkalemia. This condition can occur in a patient who is receiving large quantities of IV or oral K ⁺ for excessive losses that are no longer present. Frequent or rapid blood transfusions can acutely increase the [K ⁺ ] because of the K ⁺ content of blood, which is variably elevated. Increased intake may precipitate hyperkalemia if there is an underlying defect in K ⁺ excretion.

The ICS has a very high [K ⁺ ], so a shift of K ⁺ from the ICS to the ECS can have a significant effect on the plasma [K ⁺ ]. This shift occurs with metabolic acidosis, but the effect is minimal with an organic acid (lactic acidosis, ketoacidosis). A respiratory acidosis has less impact than a metabolic acidosis. Cell destruction, as seen with rhabdomyolysis, tumor lysis syndrome, tissue necrosis, or hemolysis, releases K ⁺ into the extracellular milieu. The K ⁺ released from RBCs in internal bleeding, such as hematomas, is resorbed and enters the ECS.

Normal doses of succinylcholine or β-blockers and fluoride or digitalis intoxication all cause a shift of K ⁺ out of the intracellular compartment. Succinylcholine should not be used during anesthesia in patients at risk for hyperkalemia. β-Blockers prevent the normal cellular uptake of K ⁺ mediated by binding of β-agonists to the β ₂ -adrenergic receptors. K ⁺ release from muscle cells occurs during exercise, and levels can increase by 1-2 mEq/L with high activity. With an increased plasma osmolality, water moves from the ICS, and K ⁺ follows. This process occurs with hyperglycemia, although in nondiabetic patients the resultant increase in insulin causes K ⁺ to move intracellularly. In diabetic ketoacidosis (DKA) , the absence of insulin causes potassium to leave the ICS, and the problem is compounded by the hyperosmolality. The effect of hyperosmolality causes a transcellular shift of K ⁺ into the ECS after mannitol or hypertonic saline infusions. Malignant hyperthermia , which is triggered by some inhaled anesthetics, causes muscle release of potassium (see Chapter 629.2 ). Hyperkalemic periodic paralysis is an autosomal dominant disorder caused by a mutated Na ⁺ channel. It results in episodic cellular release of K ⁺ and attacks of paralysis (see Chapter 629.1 ).

The kidneys excrete most of the daily K ⁺ intake, so a decrease in kidney function can cause hyperkalemia. Newborn infants in general, and especially premature infants, have decreased kidney function at birth and thus are at increased risk for hyperkalemia despite an absence of intrinsic renal disease. Neonates also have decreased expression of K ⁺ channels, further limiting K ⁺ excretion.

A wide range of primary adrenal disorders , both hereditary and acquired, can cause decreased production of aldosterone, with secondary hyperkalemia (see Chapters 593 and 594 ). Patients with these disorders typically have metabolic acidosis and salt wasting with hyponatremia. Children with subtle adrenal insufficiency may have electrolyte problems only during acute illnesses. The most common form of congenital adrenal hyperplasia , 21-hydroxylase deficiency, typically manifests in male infants as hyperkalemia, metabolic acidosis, hyponatremia, and volume depletion. Females with this disorder usually are diagnosed as newborns because of their ambiguous genitalia; treatment prevents the development of electrolyte problems.

Renin, via angiotensin II, stimulates aldosterone production. A deficiency in renin, a result of kidney damage, can lead to decreased aldosterone production. Hyporeninemia occurs in many kidney diseases, with some of the more common pediatric causes listed in Table 68.4 . These patients typically have hyperkalemia and a metabolic acidosis, without hyponatremia. Some of these patients have impaired renal function, partially accounting for the hyperkalemia, but the impairment in K ⁺ excretion is more extreme than expected for the degree of renal insufficiency.

A variety of renal tubular disorders impair renal excretion of K ⁺ . Children with pseudohypoaldosteronism type 1 have hyperkalemia, metabolic acidosis, and salt wasting (kidney, colon, sweat) leading to hyponatremia and volume depletion; aldosterone values are elevated. In the autosomal recessive variant, there is a defect in the renal Na ⁺ channel that is normally activated by aldosterone. Patients with this variant have severe symptoms (failure to thrive, diarrhea, recurrent respiratory infections, miliaria-rubra like rash), beginning in infancy. Patients with the autosomal dominant form have a defect in the aldosterone receptor, and the disease is milder, often remitting in adulthood. Pseudohypoaldosteronism type 2 (familial hyperkalemic hypertension), also called Gordon syndrome, is an autosomal dominant disorder characterized by hypertension caused by salt retention and impaired excretion of K ⁺ and acid, leading to hyperkalemia and hyperchloremic metabolic acidosis. Activating mutations in either WNK1 or WNK4 , both serine-threonine kinases located in the distal nephron, cause Gordon syndrome. Patients may respond well to thiazide diuretics. In Bartter syndrome , caused by mutations in the potassium channel ROMK (type 2 Bartter syndrome), there can be transient hyperkalemia in neonates, but hypokalemia subsequently develops (see Chapter 549.1 ).

Acquired renal tubular dysfunction, with an impaired ability to excrete K ⁺ , occurs in a number of conditions. These disorders, all characterized by tubulointerstitial disease, are often associated with impaired acid secretion and a secondary metabolic acidosis. In some affected children, the metabolic acidosis is the dominant feature, although a high K ⁺ intake may unmask the defect in K ⁺ handling. The tubular dysfunction can cause renal salt wasting, potentially leading to hyponatremia. Because of the tubulointerstitial damage, these conditions may also cause hyperkalemia as a result of hyporeninemic hypoaldosteronism.

The risk of hyperkalemia resulting from medications is greatest in patients with underlying renal insufficiency. The predominant mechanism of medication-induced hyperkalemia is impaired renal excretion, although ACE inhibitors may worsen hyperkalemia in anuric patients, probably by inhibiting GI potassium loss, which is normally upregulated in renal insufficiency. The hyperkalemia caused by trimethoprim generally occurs only at the very high doses used to treat Pneumocystis jiroveci pneumonia. Potassium-sparing diuretics may easily cause hyperkalemia, especially because they are often used in patients receiving oral K ⁺ supplements. Oral contraceptives containing drospirenone, which blocks the action of aldosterone, may cause hyperkalemia and should not be used in patients with decreased renal function.