Fluid, Electrolytes, and Acid-Base Homeostasis


Fluid and electrolyte and acid–base management are essential components in the care of neonates who are considered high risk. This is particularly true for infants with very low birth weight (VLBW) for several reasons. Premature neonates typically require parenteral fluids, the quantity and composition of which can be highly variable. They also have important developmental limitations in renal homeostatic mechanisms. Finally, immature infants may be particularly susceptible to significant morbidity and mortality related to fluid and electrolyte and acid–base imbalances.

Fluid and Electrolyte Management

In this section, basic renal mechanisms for maintaining fluid and electrolyte homeostasis are reviewed, and factors that govern fluid and electrolyte requirements for term and preterm infants are outlined. Methods for monitoring fluid and electrolyte balance, and potential complications and treatments of fluid and electrolyte disorders, are discussed. Also, several specific situations in high-risk infants that require special consideration are addressed.

Body Fluid Composition in Fetuses and Newborns

Total body water (TBW) encompasses extracellular (interstitial and plasma) and intracellular water. Early in fetal development, TBW is almost 95% of the total body weight. As the fetus grows, there is a decrease in the proportion of body weight represented by water ( Fig. 92.1 ). At birth, TBW represents approximately 75% of body weight in a full-term infant. The progressive decrease in TBW is caused primarily by decreases in the extracellular water compartment. The TBW percentage in premature infants, therefore, is higher than that of term infants and is proportional to gestational age. For instance, at 32 weeks, the infant's TBW is approximately 85% of the body weight, whereas that of a 23-week infant approaches 90%.

Fig. 92.1, Change with age in total body water and its major subdivisions.

During the first week of life, all healthy neonates experience a reduction in body weight. The major cause of this physiologic weight loss is a reduction in extracellular water. In the first 24-48 hours after birth, infants have decreased urine output, followed by a diuresis phase, with urinary losses of water and sodium in the first week of life, resulting in weight loss. Physiologic weight loss in the first few days of life in term and premature infants represents isotonic contraction of body fluids and seems to be part of a normal transitional physiologic process thought to be mediated through release of atrial natriuretic peptide. In term infants, this weight loss can be up to 10%. In very premature infants, weight loss can be up to 15%. Perturbations in this normal transitional physiology can lead to imbalances in sodium and water homeostasis. In ill term infants and premature infants, various factors (discussed subsequently) can lead to increased or decreased urinary or insensible water losses. Similarly, increased or decreased administration of intravenous fluids, with variable amounts of water and sodium, can have a significant impact on overall fluid balance.

Sodium Balance in Newborns

Sodium is the major component of the extracellular fluid (ECF) volume and plasma volume. The total sodium content ( not the serum sodium concentration, which reflects only the relative relationship between salt and water) determines the volume of the ECF. Renal sodium handling is crucial in maintaining sodium balance and protecting against volume depletion or overload. Sodium is freely filtered by the glomerulus, and the bulk of the filtered sodium is reabsorbed in the proximal tubule. Additional sodium reabsorption occurs in the loop of Henle via the Na + -K + -2 Cl cotransporter, the therapeutic target of loop diuretics. In the distal convoluted tubule, sodium is further reabsorbed via the sodium chloride cotransporter, the therapeutic target of thiazide diuretics. The major site of fine regulation of sodium reabsorption is the collecting tubule, wherein aldosterone acts on the principal cells to promote reabsorption through sodium channels located on the luminal membrane.

Healthy term neonates have basal sodium handling similar to that of adults, with a fractional excretion of sodium (FE NA ) of less than 1%, although a transient increase in FE NA occurs during the diuretic phase on the second and third days of life. In premature infants, however, renal sodium losses are inversely proportional to gestational age, with FE NA equaling 5%-6% in infants born at 28 weeks’ gestation ( Fig. 92.2 ). As a result, preterm infants may display negative sodium balance and hyponatremia during the initial 2-3 weeks of life because of high renal sodium losses and inefficient intestinal sodium absorption. The mechanisms responsible for increased urinary sodium losses in preterm infants are multifactorial. The immature kidney exhibits glomerulotubular imbalance, a physiologic state that is present when the glomerular filtration rate (GFR) exceeds the reabsorptive capacity of the renal tubules. This imbalance is attributable to numerous factors, including a preponderance of glomeruli compared with tubular structures, renal tubular immaturity, large extracellular volume, and reduced oxygen availability. Decreased responsiveness to aldosterone is also characteristic of fetal and postnatal kidneys compared with adult kidneys and results in a decrease in sodium reabsorption.

Fig. 92.2, Scattergram showing the inverse correlation between fractional sodium excretion and gestational age.

Urinary sodium losses in preterm and term neonates may be increased in certain conditions, including hypoxia, respiratory distress, hyperbilirubinemia, acute tubular necrosis, and polycythemia. Pharmacologic agents such as dopamine, beta blockers, angiotensin-converting enzyme inhibitors, and diuretics may also increase urinary sodium losses in neonates. The abnormalities in sodium and water balance seen in premature infants are attenuated, to some degree, by prenatal steroid administration. Prenatal steroid treatment is associated with decreased insensible water loss, a decreased incidence of hypernatremia, and an earlier diuresis and natriuresis. This beneficial effect on water and sodium balance in infants with extremely low birth weight is thought to be mediated by maturation of the renal epithelial transport systems controlling fluid and electrolyte homeostasis.

Water Balance in Newborns

Water balance is controlled primarily by antidiuretic hormone (ADH), which controls water absorption in the collecting duct. ADH secretion is regulated by hypothalamic osmoreceptors that monitor serum osmolarity and baroreceptors of the carotid sinus and left atrium that monitor intravascular blood volume. Stimulation of ADH secretion occurs when serum osmolarity increases to greater than 285 mOsm/kg or when effective blood volume is significantly diminished. Increases in serum osmolarity also stimulate thirst receptors in the anterior hypothalamus to promote increased water intake. Intravascular volume has a greater influence on ADH secretion than serum osmolarity. Patients with hyponatremia and concomitant volume depletion are unable to suppress ADH in response to the decrease in serum osmolarity.

At baseline, when the serum osmolarity and effective blood volume status are normal, the collecting duct is impermeable to water. In response to an increase in serum osmolarity or significant volume contraction, ADH produced in the hypothalamus binds to its receptor, arginine-vasopressin V2 receptor, located on the basolateral membrane of principal and inner medullary collecting duct cells. Receptor activation results in elevated levels of intracellular cyclic adenosine monophosphate. Downstream signaling pathways promote movement of preformed vesicles containing aquaporin 2 (AQ2) water channels to the apical surface. The presence of these water channels on the watertight apical membranes renders them permeable to water. Withdrawal of ADH stimulates endocytosis of AQ2-containing vesicles, which restores the collecting duct cells to a state of water impermeability.

This system may not be as straightforward as previously believed, however, because vasopressin V2 receptors have been shown to be expressed in nephron segments other than the collecting duct, notably the loop of Henle. This study and others support the emerging concept of crosstalk between the ADH/vasopressin V2 receptor system (classically considered a regulator of water homeostasis only) and the renin-angiotensin system (classically considered a sodium regulator only), which may modulate renal handling of salt and water further.

Maximal renal concentration and dilution require structural maturity, well-developed tubular transport mechanisms, and an intact hypothalamic-renal vasopressin axis. In adults and older children, decreased water intake or increased water losses activate a highly efficient renal concentrating mechanism that can produce maximally concentrated urine with an osmolarity of 1500 mOsm/kg, resulting in fluid conservation. Conversely, excessive fluid intake triggers the diluting mechanism of the kidney that can produce maximally dilute urine with an osmolarity of 50 mOsm/kg, resulting in free water excretion.

Urinary concentrating ability is diminished in neonatal kidneys, particularly those of premature infants. When challenged, term newborns can concentrate urine to an osmolarity of 800 mOsm/kg; preterm infants can concentrate urine to an osmolarity of only 600 mOsm/kg. This diminished urinary concentrating ability, particularly in preterm infants, may limit a neonate's ability to adjust to fluid perturbations—notably perturbations that result in increased free water losses (e.g., increased insensible water losses). Multiple factors limit renal concentrating capacity in preterm infants. Structural immaturity of the renal medulla limits sodium, chloride, and urea movement to the interstitium. Preferential blood flow through the vasa recta limits generation of a medullary gradient. Diminished urea-generated osmotic gradient in the renal medulla limits production and maintenance of the countercurrent mechanisms that are essential in producing maximally concentrated urine. Finally, tubular responsiveness to vasopressin is diminished because of decreased transcription and protein synthesis of AQ2 water channels.

Urinary dilution capability, in contrast, is normal in term neonates but diminished in preterm neonates. When challenged with a water load, term infants can produce dilute urine with an osmolarity of 50 mOsm/kg, similar to that of an older child or adult. The kidneys of preterm infants, however, may be capable of diluting the urine to an osmolarity of only 70 mOsm/kg.

The diminished urinary diluting and concentrating capacities of neonates have important implications for their care. Excessive fluid restriction places newborns, particularly preterm neonates, at risk for dehydration or hypernatremia or both. Conversely, generous fluid intake poses the risk of intravascular volume overload or hyponatremia or both. High fluid intake has also been associated with an increased risk of symptomatic patent ductus arteriosus (PDA) and necrotizing enterocolitis.

These facts underscore the importance of careful calculation of fluid and electrolyte requirements and close monitoring of fluid balance in high-risk neonates.

Calculation of Fluid and Electrolyte Requirements

Calculation of fluid and electrolyte requirements in newborns is based on maintenance needs, deficits, and ongoing losses. Crucial factors that determine these fluid requirements include gestational age, renal function, ambient air temperature and humidity, ventilator dependence, presence of drainage tubes, and gastrointestinal losses.

Maintenance Fluids and Electrolytes

Maintenance fluid requirements represent the water required to maintain a newborn in neutral water balance. The total amount of maintenance fluid required is equal to urine production plus insensible losses. Table 92.1 summarizes maintenance fluid requirements during the first month of life for full-term and preterm infants. The numbers presented in Table 92.1 are only guidelines; they are to be used as a starting point for prescribing maintenance fluid for infants with low birth weight during the first week of life. Further adjustments must be based on the clinical situation. In particular, close attention to the patient's volume status and assessment of factors that may increase or decrease the baseline fluid requirements are essential to the appropriate management of these infants.

TABLE 92.1
Maintenance Fluid (Water) Requirements During the First Month of Life
Adapted from data from Veille JC. AGA infants in a thermoneutral environment during the first week of life. Clin Perinatol . 1988;15:863; Taeusch W, Ballard RA, eds. Schaffer and Avery's diseases of the newborn . 6th ed. Philadelphia: Saunders; 1991; and Lorenz J, et al. Phases of fluid and electrolyte homeostasis in the extremely low birth weight infant. Pediatrics . 1995;96:48.
Birth Weight (g) Insensible Water Loss (mL/kg/d) Total Water Requirements by Age (mL/kg/d)
Day 1-2 Day 3-7 Day 8-30
<750 100+ 100-200 120-200 120-180
750-1000 60-70 80-150 100-150 120-180
1001-1500 30-65 60-100 80-150 120-180
>1500 15-30 60-80 100-150 120-180

Insensible Losses

Insensible water losses (see Chapter 35 ) are primarily evaporative losses via the skin and respiratory tract. In newborns, one-third of insensible water loss occurs through the respiratory tract, and the remaining two-thirds occurs through the skin. Numerous physiologic, environmental, and therapeutic factors can influence insensible water loss, making it the most variable component of the maintenance fluid requirements in newborns. Table 92.2 summarizes the effect of various factors on the degree of insensible water loss in newborns. Transepidermal water loss contributes significantly to increased insensible losses of premature infants ( Fig. 92.3 ). There is an inverse relationship between body weight and insensible water loss in a neutral thermal environment with moderately high relative humidity. Factors that contribute to these increased losses in preterm versus term infants include greater water permeability through a relatively immature epithelial layer of skin, a higher surface-area-to-body-weight ratio, and increased skin vascularity. Although prenatal glucocorticoids promote maturation of the renal tubules, they do not have a similar effect on skin maturation. Infants who have conditions associated with skin breakdown, such as burns or large skin defects such as omphaloceles, also have increased transepidermal water loss. Phototherapy has been reported to increase insensible water losses by up to 26%. However, with newer phototherapy techniques, this number may be substantially less.

TABLE 92.2
Factors Affecting Insensible Water Loss in Newborns
Factor Effect on Insensible Water Loss
Level of maturity Inversely proportional to birth weight and gestational age (see Fig. 92.3 )
Environmental temperature above neutral thermal zone Increased in proportion to increment in temperature
Elevated body temperature Increased by up to 300% at rectal temperature >37.2°C
High ambient or inspired humidity Reduced by 30% if ambient or respiratory vapor pressure equals skin or respiratory tract vapor pressure
Skin breakdown (e.g., burn) Increased; magnitude depends on extent of lesion
Congenital skin defects (e.g., large omphalocele) Increased; magnitude depends on size of defects
Radiant warmer Increased by about 50% above values obtained in incubator setting with moderate relative humidity and neutral thermal environment
Phototherapy Increased by up to 25%, depending on technique
Double-walled incubator or plastic heat shield Reduced by 10%-30%

Fig. 92.3, Effects of gestation on transepidermal water loss. Measurements were made from abdominal skin and carried out in the first few days of life.

Ambient temperature and relative humidity play an important role in influencing transepidermal water loss. An increase in ambient temperature results in increased insensible water loss. A decrease in ambient temperature has no effect on insensible water loss, however, despite the fact that it increases energy expenditure on the basis of cold stress. When ambient temperature is held constant, a lower ambient humidity increases skin water losses because of increased vapor pressure on the skin surface compared with the ambient vapor pressure; this is particularly true for very premature infants. A decrease in humidity from 60%-20% results in an increased water loss of 100% in infants of less than 26 weeks’ gestation. Use of newer humidified incubators has been reported to result in significant decreases in insensible fluid losses and fluid requirements in premature infants. Alternatively, in the presence of high relative humidity, water evaporation is less. For example, infants on mechanical ventilation, which provides a humidified oxygen delivery system, have reduced water evaporation from the respiratory tract.

The quantity of water required for the formation of urine depends on two major factors: the degree of renal function and the renal solute load. Under normal conditions, a major determinant of renal water requirement is renal solute load. Renal solute load is derived from exogenous and endogenous sources. During the first 1-2 days of life, the exogenous solute load of infants with low birth weight may be low. Because these infants may not be fed enterally, caloric delivery by intravenous glucose-containing solutions does not meet basal energy needs. In the first 1-2 days of life, the basal energy requirement for infants with low birth weight is approximately 50 kcal/kg body weight. Currently, many infants are started on total parenteral nutrition (TPN) on day 1-2. If they are started at 70-90 mL/kg per day of a 10% glucose solution, the caloric intake is 35 kcal/kg per day. These infants must derive the remaining mandatory energy requirement from an endogenous source (i.e., catabolism). This catabolic state produces approximately 6 mOsm/kg per day of endogenous solute load presented to the kidney. Assuming the infant can produce a maximal urinary concentration of 600 mOsm/kg, a minimum of 10 mL/kg per day of free water is required to excrete this solute load.

As the infant ages, the exogenous intake from parenteral or enteral sources increases, resulting in increased caloric intake. The result is that the exogenous solute load increases, whereas catabolism decreases, resulting in a decreased endogenous solute load. It estimated that by 2 or 3 weeks of age, an infant consuming 80-120 kcal/kg per day has a total solute load of approximately 15-20 mOsm/kg per day. Assuming that the infant can produce a maximal urinary concentration of 800 mOsm/kg by this age, 20-25 mL/kg per day of free water is required to excrete the solute load.

Other Fluid Losses

Water loss through the gastrointestinal tract from stool output is minimal during the first few days of life, particularly in infants with low birth weight. When enteral feeds begin, the water loss in the stool is 5-10 mL/kg per day. In a growing infant, the amount of water required for new tissue formation should be considered in the calculation of maintenance fluid requirements. Because infants grow at the rate of 10-20 g/kg per day, and new tissue contains 70% water, the maintenance fluid required should provide a net water balance of 10-15 mL/kg per day.

Electrolyte Requirements

Maintenance sodium and chloride should not be provided in the first 1-2 days of life because of the relatively volume-expanded state of the newborn. Avoidance of sodium supplementation is particularly important in very premature infants, who have increased water losses and for whom early administration of sodium supplementation is associated with an increased risk of hypernatremia. In contrast, sodium supplementation initiated after the first few days of life in premature infants was associated with improved weight gain in the neonatal period and improved developmental outcomes at age 10-13 years compared with a group of premature infants who did not receive supplementation.

Potassium is not provided in parenteral fluid until urinary flow has been established and normal renal function is ensured and a normal serum potassium is confirmed. From postnatal days 3-7, maintenance sodium, potassium, and chloride requirements are approximately 1-2 mEq/kg per day. Beyond the first week of life, 2-3 mEq/kg per day or more of sodium and chloride is required to maintain the positive electrolyte balance that is necessary for the formation of new tissue. Because of high urinary sodium losses, premature infants may require 4 or 5 mEq/kg of sodium per day during the first few weeks of life.

Pathogenic Losses and Deficit Replacement

Many clinical situations require careful estimates of ongoing pathogenic losses and replacement of deficits. Commonly encountered conditions include diarrhea with dehydration, chest tube drainage, surgical wound drainage, and excessive urinary losses from osmotic diuresis. The important guiding principle in managing patients with these conditions is to measure the volume and composition of the pathogenic losses accurately. Electrolyte losses can be calculated by multiplying the volume of fluid loss by the electrolyte content of the respective body fluids ( Table 92.3 ).

TABLE 92.3
Electrolyte Content of Body Fluids
Fluid Source Sodium (mmol/L) Potassium (mmol/L) Chloride (mmol/L)
Stomach 20-80 5-20 100-150
Small intestine 100-140 5-15 90-120
Bile 120-140 5-15 90-120
Ileostomy 45-135 3-15 20-120
Diarrheal stool 10-90 10-80 10-110

Estimating replacement for pathogenic fluid and electrolyte losses can be difficult, particularly in infants who accumulate fluid and electrolytes in static body fluid compartments. This phenomenon, commonly referred to as “third spacing,” occurs in several conditions, including sepsis, hydrops fetalis, hypoalbuminemia, intra-abdominal infections, and after abdominal or cardiac surgery. An infant with necrotizing enterocolitis often accumulates fluid in the mucosal and submucosal tissues of the small and large intestine and in the peritoneal cavity. Under these circumstances, large amounts of fluid, electrolytes, and protein may leak into the interstitial tissue and cannot be accurately quantitated. Because fluid lost into these tissue spaces does not contribute to effective arterial blood volume and circulatory balance in these patients, they may appear edematous even though their intravascular volume is decreased. The most appropriate strategic approach in the management of these infants is to replenish the extracellular fluid compartments with colloid and crystalloid, as able.

Fluid and Electrolyte Balance

Interpretation of key clinical feedback is a crucial part of successful fluid and electrolyte management strategies in newborns. Fluid and electrolyte balance can be achieved by using a meticulous and organized system that obtains pertinent data and applies the physiologic principles outlined in the beginning of this chapter. A careful assessment of clinical indicators of volume status, including heart rate, blood pressure, skin turgor, capillary refill, oral mucosa integrity, and fullness of the anterior fontanelle, is essential. Other pertinent data that must be monitored include body weight, fluid intake, urine and stool output, serum electrolytes, and urine osmolarity or specific gravity.

During the first few days of life, appropriate fluid and electrolyte balance is reflected by a urine output of approximately 1-3 mL/kg per hour, a urine specific gravity of approximately 1.008-1.012, and an approximate weight loss of 5% in term infants and 15% in premature infants with very low birth weight. Microsampling of serum electrolytes can be done at 8- to 24-hour intervals, depending on illness severity, gestational age, and fluid-electrolyte balance. Extracellular volume depletion is manifest by excessive weight loss, dry oral mucosa, sunken anterior fontanelle, capillary refill greater than 3 seconds, diminished skin turgor, increased heart rate, low blood pressure, elevated blood urea nitrogen, or metabolic acidosis. Serum sodium, which reflects sodium concentration but not sodium content, may be normal, decreased, or increased in states of volume depletion. Bedside monitoring of weight gain, as an indicator of volume status and growth, is essential for monitoring the adequacy of fluid and caloric intake in sick neonates. Beyond the first week of life, infants should gain approximately 20-30 g per day.

Hyponatremia and Hypernatremia

Hyponatremia and/or hypernatremia are extremely common in premature infants as well as in term infants with significant medical issues (such as perinatal asphyxia or septic shock). Hyponatremia, defined as a serum sodium less than 130 mmol/L, occurs in up to 30% of very low birth weight infants in the first week of life and 25%-65% after the first week. Hypernatremia, defined as a serum sodium greater than 150 mmol/L, may occur in up to 40% of preterm infants born at <29 weeks’ gestation. Both hyponatremia and hypernatremia have been associated with significant complications. Large changes in serum sodium (either an increase or decrease) in the first month of life in premature infants have been associated with adverse long-term neurologic outcomes. Alternatively, the presence of hypernatremia itself rather than rapid changes in sodium (up to 15 mmol/liter/day) has been identified as a risk factor for intraventricular hemorrhage. Whether these long- and short-term poor outcomes are caused by the serum sodium changes themselves or, instead, reflect the severity of the infant's clinical situation, has yet to be established. However, given the potential risks, it is prudent to try attempt to maintain serum sodium levels within the normal range and avoid large fluctuations.

Hyponatremia

Hyponatremia is caused by one of three general mechanisms: (1) an inability to excrete a water load, (2) excessive sodium losses, or (3) inadequate sodium intake. Most commonly, sick newborns are unable to excrete a water load because of a decreased effective arterial blood volume preventing the suppression of ADH secretion. Hyponatremia may also occur because of decreased fluid delivery to the distal nephron diluting segments. Two common etiologies of this decreased delivery are decreased GFR caused by acute kidney injury (AKI) and increased proximal tubular fluid and sodium reabsorption associated with volume depletion. Defects in sodium chloride transport in the cortical and medullary ascending limb of the loop of Henle, which is essential in producing an osmotic gradient for distal water absorption via the countercurrent multiplier, also limit the diluting capacity of the nephron. The treatment for hyponatremia varies depending on the underlying etiology. A patient with hyponatremia and volume depletion should receive increased fluids, whereas a patient with oliguric acute kidney injury should have fluids restricted. These examples highlight the importance of assessing the neonate's volume status when determining therapy.

Hyponatremia in the newborn has historically been delineated as early onset (occurring in the first week of life) or late onset (occurring in the latter half of the first month of life). Given the broad spectrum of gestational ages, underlying diseases, and clinical courses of neonates cared for in modern neonatal intensive care units, these distinctions may be less relevant. Assessing the individual neonate's clinical status is more important in determining the causes and appropriate interventions for hyponatremia. Increased free water load may be caused by one or more factors, including increased maternal free water intake during labor, excess free water administration in the postnatal period, or perinatal nonosmotic release of vasopressin. This latter phenomenon may be seen in conditions such as perinatal asphyxia, respiratory distress, bilateral pneumothoraces, and intraventricular hemorrhage or with various medications, including morphine, barbiturates, or carbamazepine. Impaired free water clearance attributed to excessive vasopressin release has been reported in very low birth weight (VLBW) infants and may contribute to the development of chronic lung disease in those children. Oliguric acute kidney injury or edematous disorders may also contribute to impaired ability to handle a water load. Alternatively, hyponatremia may be due to negative sodium balance. This condition may occur from either inadequate sodium intake or excessive renal losses because of a high fractional excretion of sodium, particularly in preterm infants of less than 28 weeks’ gestation.

Less common conditions, all of which result in pathologic urinary sodium losses, can cause hyponatremia in neonates and young infants. These conditions may be caused by inherited tubulopathies such as Bartter syndrome, or disorders of aldosterone production or responsiveness, respectively, including congenital adrenal hyperplasia (CAH) and pseudohypoaldosteronism. Aldosterone is a steroid hormone produced in the adrenal cortex that has a crucial role in maintaining sodium and potassium homeostasis in the kidney. It is produced in response to either volume depletion, via the renin-angiotensin-aldosterone axis, or an increase in serum potassium. Under the influence of aldosterone, apical epithelial sodium channels are inserted on the luminal (urinary) surface, allowing sodium to be reabsorbed down its concentration gradient. Potassium, as the primary intracellular cation, is excreted in return. This process is facilitated further by aldosterone-mediated increase in the activity of basolateral Na + ,K + -ATPase. Aldosterone also has a role in acid–base homeostasis and promotes hydrogen secretion (see Acid–Base Management ) via actions on H + -ATPase located on the luminal surface of adjacent intercalated cells. Abnormalities in either the production of, or the renal responsiveness to, aldosterone can result in variable degrees of renal sodium wasting, hyperkalemia, and metabolic acidosis.

Congenital adrenal hyperplasia (CAH) is an inherited disorder of cortisol synthesis that results in diminished aldosterone production (See also Chapter 89 ). The most common form is complete absence of 21-hydroxylase activity, a key enzyme in the production of aldosterone. Affected girls have ambiguous genitalia at birth because of excess adrenal androgens. Patients typically present with shock and severe hyponatremia, hyperkalemia, and metabolic acidosis at 1-3 weeks of age as the result of a salt-losing crisis. Additional laboratory abnormalities typically seen with this disorder include elevated plasma levels of renin, adrenocorticotropic hormone, 17-hydroxyprogesterone, progesterone, androstenedione, and urinary 17-ketosteroids. Serum cortisol and aldosterone levels may be undetectable. Initial treatment is directed at correcting volume and electrolyte abnormalities, including fluid resuscitation and management of life-threatening hyperkalemia. Long-term glucocorticoid and mineralocorticoid replacement therapy should be instituted to facilitate normalization of serum electrolytes and to treat the underlying disease. Sodium supplements may be necessary for a prolonged period.

Pseudohypoaldosteronism (PHA) refers to a group of disorders characterized by renal tubular unresponsiveness to aldosterone as evidenced by hyperkalemia, metabolic acidosis, and variable degrees of renal sodium wasting. PHA can be primary (genetic) or secondary (acquired). The two subtypes of primary PHA include type I, which usually manifests in infancy with hypotension, severe sodium wasting, and hyperkalemia, and type II (Gordon syndrome), which typically presents later in childhood. Autosomal dominant type I PHA, previously designated the “renal” type I, is the most common type I PHA. Patients with this form usually present during early infancy with failure to thrive, weight loss, vomiting, dehydration, or shock. Sweat and salivary electrolytes are normal in this form of type I PHA. Although it is inherited in an autosomal dominant trait, expression may be variable. Treatment involves administration of large quantities of sodium chloride, 10 to 15 mEq/kg per day. Autosomal recessive type I PHA, previously designated “multiple target organ defects” type I PHA, is a severe, life-threatening systemic disease that affects sodium and potassium handling in the kidney, sweat glands, salivary glands, nasal mucosa, and colon. Patients with this disorder usually present in the newborn period with severe salt wasting and life-threatening hyperkalemia. They also have increased sweat chloride that may mimic the presentation of cystic fibrosis. Sodium chloride supplementation alone often is inadequate in controlling hyperkalemia and metabolic acidosis in these patients. Dietary restriction of potassium intake and the use of rectal sodium polystyrene sulfonate resin (kayexalate), a sodium-potassium exchange resin, are often required. Indomethacin or hydrochlorothiazide may be necessary to control hyperkalemia and acidosis. Mutations in multiple different genes have been implicated in the pathogenesis of PHA type 1, including those encoding components or regulators of the mineralocorticoid receptor, epithelial sodium channels, and thiazide-sensitive sodium chloride co-transporter. Secondary forms of PHA occur more commonly than primary forms and are typically caused by injury to the collecting tubules, the primary segment responsible for potassium balance. Causes of secondary PHA in the newborn period include unilateral renal vein thrombosis, neonatal medullary necrosis, urinary tract malformations, pyelonephritis, or other tubulointerstitial diseases. Patients with congenital obstructive uropathies such as posterior urethral valves are particularly prone to exhibiting aldosterone resistance, manifest as a hyperkalemic metabolic acidosis, even in the face of relatively intact renal function.

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