Fanaroff Liquidos y Electrolitos

44 Fluid, Electrolytes, and
Acid-Base Homeostasis
KATHERINE MACRAE DELL
Fluid and electrolyte and acid-base management are to be part of a normal transitional physiologic process,
essential components in the care of neonates who are although the precise mechanisms underlying this process
considered high risk. This is particularly true for infants are unclear. In term infants, this weight loss can be up to
with very low birth weight for several reasons. Premature 10%. In very premature infants, weight loss can be up to
neonates typically require parenteral fluids, the quantity 15%.60 Perturbations in this normal transitional physiol-
and composition of which can be highly variable. They ogy can lead to imbalances in sodium and water homeo-
also have important developmental limitations in renal stasis. In ill term infants and premature infants, various
homeostatic mechanisms. Finally, immature infants may factors (discussed subsequently) can lead to increased or
be particularly susceptible to significant morbidity and decreased urinary or insensible water losses. Similarly,
mortality related to fluid and electrolyte and acid-base increased or decreased administration of intravenous
imbalances. fluids, with variable amounts of water and sodium, can
have a significant impact on overall fluid balance.
Fluid and Electrolyte Management SODIUM BALANCE IN NEWBORNS
In this section, basic renal mechanisms for maintaining Sodium is the major component of the extracellular fluid
fluid and electrolyte homeostasis are reviewed, and (ECF) volume and plasma volume. The total sodium
factors that govern fluid and electrolyte requirements for content (not the serum sodium concentration) deter-
term and preterm infants are outlined. Methods for mon- mines the volume of the ECF. Renal sodium handling is
itoring fluid and electrolyte balance, and potential com- crucial in maintaining sodium balance and protecting
plications and treatments of fluid and electrolyte disorders against volume depletion or overload. Sodium is freely
are discussed. Also, several specific situations in high-risk filtered by the glomerulus, and the bulk of the filtered
infants that require special consideration are addressed. sodium is reabsorbed in the proximal tubule. Additional
sodium reabsorption occurs in the loop of Henle via the
BODY FLUID COMPOSITION IN FETUSES Na+-K+-2 Cl cotransporter, the therapeutic target of loop
AND NEWBORNS diuretics. In the distal convoluted tubule, sodium is
Total body water (TBW) encompasses extracellular (inter- further reabsorbed via the sodium chloride cotransporter,
stitial and plasma) and intracellular water. Early in fetal the therapeutic target of thiazide diuretics. The major site
development, TBW is almost 95% of the total body of fine regulation of sodium reabsorption is the collecting
weight. As the fetus grows, there is a decrease in the pro- tubule, wherein aldosterone acts on the principal cells to
portion of body weight represented by water (Figure promote reabsorption through sodium channels located
44-1).19 By birth, TBW represents approximately 75% of on the luminal membrane.
body weight in a full-term infant. The progressive decrease Healthy term neonates have basal sodium handling
in TBW is caused primarily by decreases in the extracel- similar to that of adults, with a fractional excretion of
lular water compartment. Premature, particularly very sodium (FENA) of less than 1%, although a transient
premature, infants have a higher TBW content than increase in FENA occurs during the diuretic phase on the
term infants, and that increase is primarily extracellular second and third days of life.37 In premature infants,
water.23 however, renal sodium losses are inversely proportional
During the first week of life, all healthy neonates expe- to gestational age, with FENA equaling 5% to 6% in infants
rience a reduction in body weight. The major cause of born at 28 weeks gestation (Figure 44-2).62 As a result,
this physiologic weight loss is a reduction in extracellular preterm infants may display negative sodium balance and
water.58 In the first 24 to 48 hours after birth, infants have hyponatremia during the initial 2 to 3 weeks of life
decreased urine output, followed by a diuresis phase, because of high renal sodium losses and inefficient intes-
with urinary losses of water and sodium in the first week tinal sodium absorption.67 The mechanisms responsible
of life, resulting in weight loss.37 Physiologic weight loss for increased urinary sodium losses in preterm infants are
in the first few days of life in term and premature infants multifactorial. The immature kidney exhibits glomerulo-
represents isotonic contraction of body fluids and seems tubular imbalance, a physiologic state that is present
613
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614 PART 7 PROVISIONS FOR NEONATAL CARE
100 reduced oxygen availability.51 Decreased responsiveness

90 to aldosterone is also characteristic of fetal and postnatal
kidneys compared with adult kidneys, and results in a
80
Total body water decrease in sodium reabsorption.
70 (TBW) Urinary sodium losses in preterm and term neonates may
% body weight
60 be increased in certain conditions, including hypoxia,

Intracellular fluid respiratory distress, hyperbilirubinemia, acute tubular
50
(ICF) necrosis, and polycythemia. Pharmacologic agents such
40 as dopamine, beta blockers, angiotensin-converting
Extracellular fluid
30 (ECF)
enzyme inhibitors, and diuretics may also increase urinary
sodium losses in neonates. The abnormalities in sodium
20
and water balance seen in premature infants are attenu-
10 ated, to some degree, by prenatal steroid administration.
Prenatal steroid treatment is associated with decreased
2 4 6 8 insensible water loss, a decreased incidence of hyperna-
6 mo
12 mo
3 yr
6 yr
9 yr
12 yr
15 yr
Adult
Birth
tremia, and an earlier diuresis and natriuresis.44 This ben-

eficial effect on water and sodium balance in infants with
Age extremely low birth weight is thought to be mediated by
Figure 44-1 Change with age in total body water and its major maturation of the renal epithelial transport systems con-
subdivisions. (From Friis-Hansen B. Body water compartments in children: trolling fluid and electrolyte homeostasis.
changes during growth and related changes in body composition. Pediatrics.
1961;28:169. Used with permission of American Academy of Pediatrics.) WATER BALANCE IN NEWBORNS
Water balance is controlled primarily by antidiuretic
hormone (ADH), which controls water absorption in
10.0 the collecting duct. ADH secretion is regulated by
hypothalamic osmoreceptors that monitor serum osmo-
larity and baroreceptors of the carotid sinus and left
5.0 atrium that monitor intravascular blood volume. Stimu-
4.0
3.0 r = 0.755 lation of ADH secretion occurs when serum osmolarity
2.0
p < 0.001 increases to greater than 285mOsm/kg or when effective
blood volume is significantly diminished. Increases in
1.0 serum osmolarity also stimulate thirst receptors in the
anterior hypothalamus to promote increased water intake.
Intravascular volume has a greater influence on ADH
0.8
Filtered Na (%)
secretion than serum osmolarity. Patients with hypona-

tremia and concomitant volume depletion are unable to
0.6 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
0.4 serum osmolarity or significant volume contraction, ADH
produced in the hypothalamus binds to its receptor,
arginine-vasopressin V2 receptor, located on the basolat-
0.2
eral membrane of principal and inner medullary collect-
ing 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)
26 28 30 32 34 36 38 40 water channels to the apical surface. The presence of these
Gestation (weeks) water channels on the watertight apical membranes
Figure 44-2 Scattergram showing the inverse correlation between renders them permeable to water. Withdrawal of ADH
fractional sodium excretion and gestational age. (From Siegel SR, etal. stimulates endocytosis of AQ2-containing vesicles, which
Renal function as a marker of human renal maturation. Acta Paediatr Scand. restores the collecting duct cells to a state of water
1976;65:481.) impermeability.
This system may not be as straightforward as previ-
ously believed, however, because vasopressin V2 recep-
when the glomerular filtration rate (GFR) exceeds the tors have been shown to be expressed in nephron
reabsorptive capacity of the renal tubules. This imbalance segments other than the collecting duct, notably the loop
is attributable to numerous factors, including a prepon- of Henle.43 This study and others support the emerging
derance of glomeruli compared with tubular structures, concept of crosstalk between the ADH/vasopressin V2
renal tubular immaturity, large extracellular volume, and receptor system (classically considered a regulator of
44 Fluid, Electrolytes, and Acid-Base Homeostasis 615
water homeostasis only) and the renin-angiotensin particularly preterm neonates, at risk for dehydration or
system (classically considered a sodium regulator only), hypernatremia or both. Conversely, generous fluid intake
which may modulate renal handling of salt and water poses the risk of intravascular volume overload or hypo-
further. natremia or both. High fluid intake has also been associ-
Maximal renal concentration and dilution require ated with an increased risk of symptomatic patent ductus
structural maturity, well-developed tubular transport arteriosus (PDA) and necrotizing enterocolitis.10,9 These
mechanisms, and an intact hypothalamic-renal vasopres- facts underscore the importance of careful calculation of
sin axis. In adults and older children, decreased water fluid and electrolyte requirements and close monitoring
intake or increased water losses activate a highly efficient of fluid balance in high-risk neonates.
renal concentrating mechanism that can produce
maximally concentrated urine with an osmolarity of CALCULATION OF FLUID AND
1500mOsm/kg, resulting in fluid conservation. Con- ELECTROLYTE REQUIREMENTS
versely, excessive fluid intake triggers the diluting Calculation of fluid and electrolyte requirements in new-
mechanism of the kidney that can produce maximally borns is based on maintenance needs, deficits, and
dilute urine with an osmolarity of 50mOsm/kg, resulting ongoing losses. Crucial factors that determine these fluid
in free water excretion. requirements include gestational age, renal function,
Urinary concentrating ability is diminished in neona- ambient air temperature and humidity, ventilator depen-
tal kidneys, particularly those of premature infants.14,40 dence, presence of drainage tubes, and gastrointestinal
When challenged, term newborns can concentrate urine losses.11
to an osmolarity of 800mOsm/kg; preterm infants can
concentrate urine to an osmolarity of only 600mOsm/ Maintenance Fluids and Electrolytes
kg.14 This diminished urinary concentrating ability, par- Maintenance fluid requirements represent the water
ticularly in preterm infants, may limit a neonates ability required to maintain a newborn in neutral water balance.
to adjust to fluid perturbationsnotably perturbations The total amount of maintenance fluid required is equal
that result in increased free water losses (e.g., increased to urine production plus insensible losses. Table 44-1
insensible water losses). Multiple factors limit renal con- summarizes maintenance fluid requirements during the
centrating capacity in preterm infants. Structural imma- first month of life for full-term and preterm infants. The
turity of the renal medulla limits sodium, chloride, and numbers presented in Table 44-1 are only guidelines;
urea movement to the interstitium. Preferential blood they are to be used as a starting point for prescribing
flow through the vasa recta limits generation of a medul- maintenance fluid for infants with low birth weight
lary gradient. Diminished urea-generated osmotic gradi- during the first week of life. Further adjustments must be
ent in the renal medulla limits production and based on the clinical situation. In particular, close atten-
maintenance of the countercurrent mechanisms that are tion to the patients volume status and assessment of
essential in producing maximally concentrated urine. factors that may increase or decrease the baseline fluid
Finally, tubular responsiveness to vasopressin is dimin- requirements are essential to the appropriate manage-
ished because of decreased transcription and protein syn- ment of these infants.
thesis of AQ2 water channels.69
Urinary dilution capability, in contrast, is normal in Insensible Losses
term neonates but diminished in preterm neonates. Insensible water losses are primarily evaporative losses
When challenged with a water load, term infants can via the skin and respiratory tract. In newborns, one third
produce dilute urine with an osmolarity of 50mOsm/kg, of insensible water loss occurs through the respiratory
similar to that of an older child or adult. The kidneys of tract, and the remaining two thirds occurs through the
preterm infants, however, may be capable of diluting the skin. Numerous physiologic, environmental, and thera-
urine to an osmolarity of only 70mOsm/kg.40,55 peutic factors can influence insensible water loss, making
The diminished urinary diluting and concentrating it the most variable component of the maintenance fluid
capacities of neonates have important implications for requirements in newborns. Table 44-2 summarizes the
their care. Excessive fluid restriction places newborns, effect of various factors on the degree of insensible water
TABLE 44-1 Maintenance Fluid (Water) Requirements during the First Month of Life
Total Water Requirements by Age (mL/kg/d)
Birthweight (g) Insensible Water Loss (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
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 Averys diseases of the newborn. 6th ed. Philadelphia: Saunders; 1991; and Lorenz J, etal. Phases of fluid and electrolyte homeostasis in the extremely
low birth weight infant. Pediatrics. 1995;96:48.
TABLE 44-2 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 Figure 44-3)
Environmental temperature above neutral thermal zone Increased in proportion to increment in temperature
Elevated body temperature Increased by up to 300% at rectal temperature >37.2C
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%
120 layer of skin, a higher surface areatobody weight ratio,

and increased skin vascularity. Although prenatal gluco-
110 corticoids promote maturation of the renal tubules, they
do not have a similar effect on skin maturation.26 Infants
who have conditions associated with skin breakdown,
100
such as burns or large skin defects such as omphaloceles,
also have increased transepidermal water loss. Photother-
90 apy has been reported to increase insensible water losses
by up to 26%.38 However, with newer phototherapy tech-
Transepidermal water loss (g/m2/hr)
80 niques, this number may be substantially less.39

Ambient temperature and relative humidity play an
70 important role in influencing transepidermal water
loss.7,8,20 An increase in ambient temperature results in
increased insensible water loss. A decrease in ambient
60 temperature has no effect on insensible water loss,
however, despite the fact that it increases energy expendi-
50 ture on the basis of cold stress. When ambient tempera-
ture is held constant, a lower ambient humidity increases
40 skin water losses because of increased vapor pressure on
the skin surface compared with the ambient vapor pres-
sure; this is particularly true for very premature infants. A
30
decrease in humidity from 60% to 20% results in an
increased water loss of 100% in infants of less than 26
20 weeks gestation.1 Use of newer humidified incubators
has been reported to result in significant decreases in
10 insensible fluids losses and fluid requirements in prema-
ture infants.33 Alternatively, in the presence of high rela-
0 tive humidity, water evaporation is less. For example,
24 26 28 30 32 34 36 38 40 42
infants on mechanical ventilation, which provides a
humidified oxygen delivery system, have reduced water
Gestation (weeks) evaporation from the respiratory tract.
Figure 44-3 Effects of gestation on transepidermal water loss. Mea- The quantity of water required for the formation of
surements were made from abdominal skin and carried out in the first urine depends on two major factors: the degree of renal
few days of life. (From Hammarlund K, etal. Transepidermal water loss in function and the renal solute load. Under normal condi-
newborn infants, III: relation to gestational age. Acta Paediatr Scand. tions, a major determinant of renal water requirement is
1979;68:795)
renal solute load. Renal solute load is derived from exog-
enous and endogenous sources. During the first 1 to 2
days of life, the exogenous solute load of infants with low
loss in newborns. Transepidermal water loss contributes birth weight may be low. Because these infants are not
significantly to increased insensible losses of premature usually fed enterally, caloric delivery by intravenous
infants (Figure 44-3).20 There is an inverse relationship glucose-containing solutions does not meet basal energy
between body weight and insensible water loss in a needs. In the first 1 to 2 days of life, the basal energy
neutral thermal environment with moderately high rela- requirement for infants with low birth weight is approxi-
tive humidity.68 Factors that contribute to these increased mately 50kcal/kg body weight. Currently, many infants
losses in preterm versus term infants include greater water are started on intravenous hyperalimentation on day 1 to
permeability through a relatively immature epithelial 2. If they are started at 70 to 90mL/kg per day of a 10%
glucose solution, the caloric intake is 35kcal/kg per day. TABLE 44-3 Electrolyte Content of
These infants must derive the remaining mandatory Body Fluids
energy requirement from an endogenous source (i.e.,
catabolism). This catabolic state produces approximately Sodium Potassium Chloride
6mOsm/kg per day of endogenous solute load presented Fluid Source (mmol/L) (mmol/L) (mmol/L)
to the kidney. Assuming the infant can produce a maximal Stomach 20-80 5-20 100-150
urinary concentration of 600mOsm/kg, a minimum of Small intestine 100-140 5-15 90-120
10mL/kg per day of free water is required to excrete this Bile 120-140 5-15 90-120
solute load. Ileostomy 45-135 3-15 20-120
As the infant ages, the exogenous intake from paren- Diarrheal stool 10-90 10-80 10-110
teral or enteral sources increases, resulting in increased
caloric intake. The result is that the exogenous solute load
increases, whereas catabolism decreases, resulting in a Commonly encountered conditions include diarrhea
decreased endogenous solute load. It estimated that by 2 with dehydration, chest tube drainage, surgical wound
or 3 weeks of age, an infant consuming 80 to 120kcal/ drainage, and excessive urinary losses from osmotic
kg per day has a total solute load of approximately 15 to diuresis. The important guiding principle in managing
20mOsm/kg per day. Assuming that the infant can patients with these conditions is to measure the volume
produce a maximal urinary concentration of 800mOsm/ and composition of the pathogenic losses accurately.
kg by this age, 20 to 25mL/kg per day of free water is Electrolyte losses can be calculated by multiplying the
required to excrete the solute load. volume of fluid loss by the electrolyte content of the
respective body fluids (Table 44-3).
Other Fluid Losses Estimating replacement for pathogenic fluid and elec-
Water loss through the gastrointestinal tract from stool trolyte losses can be difficult, particularly in infants who
output is minimal during the first few days of life, particu- accumulate fluid and electrolytes in static body fluid
larly in infants with low birth weight. When enteral feeds compartments. This phenomenon, commonly referred
begin, the water loss in the stool is 5 to 10mL/kg per day. to as third spacing, occurs in several conditions, includ-
In a growing infant, the amount of water required for ing sepsis, hydrops fetalis, hypoalbuminemia, intra-
new tissue formation should be considered in the calcula- abdominal infections, and after abdominal or cardiac
tion of maintenance fluid requirements. Because infants surgery. An infant with necrotizing enterocolitis often
grow at the rate of 10 to 20g/kg per day, and new tissue accumulates fluid in the mucosal and submucosal tissues
contains 70% water, the maintenance fluid required of the small and large intestine and in the peritoneal
should provide a net water balance of 10 to 15mL/kg cavity. Under these circumstances, large amounts of fluid,
per day. electrolytes, and protein may leak into the interstitial
tissue and cannot be accurately quantitated. Because fluid
Electrolyte Requirements lost into these tissue spaces does not contribute to effec-
Maintenance sodium and chloride should not be pro- tive arterial blood volume and circulatory balance in
vided in the first 1 to 2 days of life because of the rela- these patients, they may appear edematous even though
tively volume-expanded state of the newborn. Avoidance their intravascular volume is decreased. The most appro-
of sodium supplementation is particularly important in priate strategic approach in the management of these
very premature infants, who have increased water losses infants is to replenish the extracellular fluid compart-
and for whom early administration of sodium supplements with colloid and crystalloid, as able.
mentation is associated with an increased risk of hyper-
natremia.59 Sodium supplementation from the 4th to the FLUID AND ELECTROLYTE BALANCE
14th day of life in premature infants was associated with Interpretation of key clinical feedback is a crucial part of
improved developmental outcomes at age 10 to 13 years successful fluid and electrolyte management strategies in
compared with a group of premature infants who did not newborns. Fluid and electrolyte balance can be achieved
receive supplementation.2 by using a meticulous and organized system that obtains
Potassium is not provided in parenteral fluid until pertinent data and applies the physiologic principles out-
urinary flow has been established and normal renal func- lined in the beginning of this chapter. A careful assess-
tion is ensured. From postnatal days 3 to 7, maintenance ment of clinical indicators of volume status, including
sodium, potassium, and chloride requirements are heart rate, blood pressure, skin turgor, capillary refill, oral
approximately 1 to 2mEq/kg per day. Beyond the first mucosa integrity, and fullness of the anterior fontanelle,
week of life, 2 to 3mEq/kg per day or more of sodium is essential. Other pertinent data that must be monitored
and chloride is required to maintain the positive electro- include body weight, fluid intake, urine and stool output,
lyte balance that is necessary for the formation of new serum electrolytes, and urine osmolarity or specific
tissue. Because of high urinary sodium losses, premature gravity.
infants may require 4 or 5mEq/kg of sodium per day During the first few days of life, appropriate fluid and
during the first few weeks of life. electrolyte balance is reflected by a urine output of
approximately 1 to 3mL/kg per hour, a urine specific
Pathogenic Losses and Deficit Replacement gravity of approximately 1.008 to 1.012, and an approxi-
Many clinical situations require careful estimates of mate weight loss of 5% in term infants and 15% in pre-
ongoing pathogenic losses and replacement of deficits. mature infants with very low birth weight.60 Microsampling
of serum electrolytes can be done at 8- to 24-hour inter- life) or late onset (occurring in the latter half of the first
vals, depending on illness severity, gestational age, and month of life). Given the broad spectrum of gestational
fluid-electrolyte balance. Extracellular volume depletion ages, underlying diseases, and clinical courses of neonates
is manifest by excessive weight loss, dry oral mucosa, cared for in modern neonatal intensive care units, these
sunken anterior fontanelle, capillary refill greater than 3 distinctions may be less relevant. Assessing the individual
seconds, diminished skin turgor, increased heart rate, low neonates clinical status is more important in determin-
blood pressure, elevated blood urea nitrogen, or meta- ing the causes and appropriate interventions for hypona-
bolic acidosis. Serum sodium, which reflects sodium con- tremia. Increased free water load may be caused by one
centration but not sodium content, may be normal, or more factors, including increased maternal free water
decreased, or increased in states of volume depletion. intake during labor,27 excess free water administration in
Bedside monitoring of weight gain, as an indicator of the postnatal period, or perinatal nonosmotic release of
volume status and growth, is essential for monitoring the vasopressin.48 This latter phenomenon may be seen in
adequacy of fluid and caloric intake in sick neonates. conditions such as perinatal asphyxia, respiratory dis-
Beyond the first week of life, infants should gain approxi- tress, bilateral pneumothoraces, and intraventricular
mately 20 to 30g per day. hemorrhage47 or with various medications, including
morphine, barbiturates, or carbamazepine. Oliguric acute
Hyponatremia and Hypernatremia kidney injury or edematous disorders may also contrib-
Hyponatremia and/or hypernatremia are extremely ute to impaired ability to handle a water load. Alterna-
common in premature infants as well as in term infants tively, hyponatremia may be due to negative sodium
with significant medical issues (such as perinatal asphyxia balance. This condition may occur from either inade-
or septic shock). Hyponatremia, defined as a serum quate sodium intake or excessive renal losses because of
sodium less than 130mmol/L, occurs in up to 30% of a high fractional excretion of sodium, particularly in
very low birth weight infants in the first week of life and preterm infants of less than 28 weeks gestation.62
25% to 65% after the first week.6 Hypernatremia, defined Less common conditions, all of which result in patho-
as a serum sodium greater than 150mmol/L, may occur logic urinary sodium losses, can cause hyponatremia in
in up to 40% of preterm infants born at <29 weeks gesta- neonates and young infants. These conditions may be
tion.22 Both hyponatremia and hypernatremia have been caused by inherited tubulopathies, such as Bartter syn-
associated with significant complications. Large changes drome (see Chapter 99), or disorders of aldosterone pro-
in serum sodium (either an increase or decrease) in the duction or responsiveness. Aldosterone is a steroid
first month of life in premature infants have been associ- hormone produced in the adrenal cortex that has a crucial
ated with adverse long-term neurologic outcomes.6 role in maintaining sodium and potassium homeostasis
However, whether these poor outcomes are caused by the in the kidney. It is produced in response to either volume
serum sodium changes themselves or, instead, reflect the depletion, via the renin-angiotensin-aldosterone axis, or
severity of the infants clinical situation, has yet to be an increase in serum potassium. Under the influence of
established. aldosterone, apical epithelial sodium channels are
inserted on the luminal (urinary) surface, allowing
Hyponatremia. Hyponatremia is caused by one of three sodium to be reabsorbed down its concentration gradi-
general mechanisms: (1) an inability to excrete a water ent. Potassium, as the primary intracellular cation, is
load, (2) excessive sodium losses, or (3) inadequate excreted in return. This process is facilitated further by
sodium intake. Most commonly, sick newborns are aldosterone-mediated increase in the activity of basolat-
unable to excrete a water load because of a decreased eral Na+,K+-ATPase.54 Aldosterone also has a role in acid-
effective arterial blood volume preventing the suppres- base homeostasis and promotes hydrogen secretion (see
sion of ADH secretion. Hyponatremia may also occur Acid-Base Management) via actions on H+-ATPase located
because of decreased fluid delivery to the distal nephron on the luminal surface of adjacent intercalated cells.
diluting segments. Two common etiologies of this Abnormalities in either the production of, or the renal
decreased delivery are decreased GFR caused by acute responsiveness to, aldosterone can result in variable
kidney injury (AKI) and increased proximal tubular fluid degrees of renal sodium wasting, hyperkalemia, and met-
and sodium reabsorption associated with volume deple- abolic acidosis.
tion. Defects in sodium chloride transport in the cortical Congenital adrenal hyperplasia is an inherited disor-
and medullary ascending limb of the loop of Henle, der of cortisol synthesis that results in diminished aldo-
which is essential in producing an osmotic gradient for sterone production.63 The most common form is complete
distal water absorption via the countercurrent multiplier, absence of 21-hydroxylase activity, a key enzyme in the
also limit the diluting capacity of the nephron. The treat- production of aldosterone. Affected girls have ambiguous
ment for hyponatremia varies depending on the underly- genitalia at birth because of excess adrenal androgens.
ing etiology. A patient with hyponatremia and volume Patients typically present with shock and severe hypona-
depletion should receive increased fluids, whereas a tremia, hyperkalemia, and metabolic acidosis at 1 to 3
patient with oliguric acute kidney injury should have weeks of age as the result of a salt-losing crisis. Additional
fluids restricted. These examples highlight the importance laboratory abnormalities typically seen with this disorder
of assessing the neonates volume status when determin- include elevated plasma levels of renin, adrenocortico-
ing therapy. tropic hormone, 17-hydroxyprogesterone, progesterone,
Hyponatremia in the newborn has historically been androstenedione, and urinary 17-ketosteroids. Serum
delineated as early onset (occurring in the first week of cortisol and aldosterone levels may be undetectable.
Initial treatment is directed at correcting volume and elec- in markedly impaired sodium reabsorption and potas-
trolyte abnormalities. Fluid resuscitation with normal sium secretion.49 Sodium chloride supplementation
saline should be undertaken immediately, particularly in alone often is inadequate in controlling hyperkalemia
patients with unstable vital signs and evidence of shock. and metabolic acidosis in these patients. Dietary restric-
Hyperkalemia (serum potassium values >7mEq/L) tion of potassium intake and the use of rectal sodium
should be treated initially with insulin and glucose as polystyrene sulfonate resin (Kayexalate), a sodium-
well as bicarbonate to promote transcellular shifts of potassium exchange resin, are often required. Indometh-
potassium into the cells and correct metabolic acidosis. acin or hydrochlorothiazide may be necessary to control
Long-term glucocorticoid and mineralocorticoid replace- hyperkalemia and acidosis. These therapies must be con-
ment therapy should be instituted to facilitate normaliza- tinued throughout the childs lifetime because improve-
tion of serum electrolytes and to treat the underlying ment with age usually does not occur.
disease. Sodium supplements may be necessary for a pro- Secondary forms of type I PHA are also seen in the
longed period. newborn period. Partial tubular insensitivity to aldoste-
Pseudohypoaldosteronism (PHA) refers to a group of rone may be seen in patients with unilateral renal vein
disorders characterized by renal tubular unresponsive- thrombosis, neonatal medullary necrosis, urinary tract
ness to aldosterone as evidenced by hyperkalemia, meta- malformations, pyelonephritis, or other tubulointerstitial
bolic acidosis, and variable degrees of renal sodium diseases. Patients with congenital obstructive uropathies,
wasting. There are two major subtypes of PHA. Type I such as posterior urethral valves, may exhibit aldosterone
usually manifests in infancy with hypotension, severe resistance, manifest as a hyperkalemic metabolic acidosis
sodium wasting, and hyperkalemia.49 Type II (Gordon despite relatively intact renal function.
syndrome) typically manifests in late childhood and
adulthood, and is not discussed in detail.46 Hypernatremia. Hypernatremia occurs as the result of
Type I PHA may be primary, inherited as an autosomal increased insensible or urinary water losses, inadequate
recessive or autosomal dominant trait, or secondary, water intake, or excess sodium administration. Hyperna-
resulting from tubular damage from disorders such as tremia occurring in the first week of life is typically caused
obstructive uropathy. Autosomal dominant type I PHA, by increased insensible water losses, often coupled with
previously designated the renal type I, is the most the excess sodium intake that commonly occurs after
common type I PHA. Patients with this form usually resuscitation with sodium bicarbonate. Many other medi-
present during early infancy with failure to thrive, weight cations can contribute to large inadvertent sodium
loss, vomiting, dehydration, or shock. A history of poly- loads, particularly in sick premature infants, including
hydramnios is often present, reflecting excessive fetal calcium gluconate, gentamicin, dopamine, dobutamine,
renal salt wasting and polyuria. Sweat and salivary elec- heparin, and intravenous fluids used to maintain arterial
trolytes are normal in this form of type I PHA. Although or venous vascular lines.11 Onset of hypernatremia later
it is inherited in an autosomal dominant trait, expression in the first month of life usually is attributable to either
may be variable. The disorder is caused by mutations in excess sodium supplementation or inadequate free water
the gene encoding the aldosterone (mineralocorticoid) intake.
receptor. Treatment involves administration of large Excess urinary losses can occur as the result of diabetes
quantities of sodium chloride, 10 to 15mEq/kg per day. insipidus (DI), which is characterized by severe urinary
Although the defect in salt handling seems to be lifelong, water losses reflecting an inability to produce concen-
serum sodium levels typically become easier to control trated urine. Diabetes insipidus results from either low
by 1 to 2 years of age. Increased dietary sodium intake, levels of circulating ADH (central DI) or impaired renal
maturation of proximal tubular transport of sodium, and response to ADH (nephrogenic DI). Newborns with this
improvement in the renal tubular response to mineralo- disorder present with hypernatremia, polyuria, polydip-
corticoids may contribute to the clinical improvement sia, chronic dehydration, irritability, fever, poor feeding,
over time. and growth failure.
Autosomal recessive type I PHA, previously designated Nephrogenic DI can be inherited (congenital) or occur
multiple target organ defects type I PHA, is a severe, as the secondary result of processes that cause renal
life-threatening systemic disease that affects sodium and tubular damage. The most common inherited form of
potassium handling in the kidney, sweat glands, salivary nephrogenic DI is caused by mutations in the gene encod-
glands, nasal mucosa, and colon.21 Patients with this ing the vasopressin receptor V2R and is inherited as an
disorder usually present in the newborn period with X-linked recessive disease.66 Less commonly, autosomal
severe salt wasting and life-threatening hyperkalemia. recessive and autosomal dominant forms have been
They also have increased sweat chloride that may mimic reported, caused by mutations in the AQ2 water channel.36
the presentation of cystic fibrosis. Patients with autoso- Causes of secondary nephrogenic DI include congenital
mal recessive type I PHA have a poorer outcome com- structural disorders such as obstructive uropathy or neph-
pared with patients with the autosomal dominant form ronophthisis, chronic kidney disease, hypercalcemia, and
because of the systemic nature of the disease and com- hypokalemia. Treatment of nephrogenic DI includes
plete unresponsiveness to mineralocorticoid effects in placement on a low sodium formula to reduce solute
multiple organs. intake and resultant obligate water loss associated with
The disease is caused by mutations in one of three solute excretion. Thiazide diuretics are also used to reduce
subunits of the amiloride-sensitive epithelial sodium extracellular sodium content, which enhances sodium
channel of the principal collecting tubule cell, resulting reabsorption in the proximal tubule and diminishes
sodium and water delivery to the distal nephron. sulfonate resin (Kayexalate); sodium bicarbonate, if met-
Amiloride may also be necessary to reduce urinary potas- abolic acidosis is present; and peritoneal dialysis. If a
sium losses that may occur with the use of thiazide significant arrhythmia is present, calcium chloride or
diuretics. Although prostaglandin inhibitors have been calcium gluconate infusion is also indicated to antago-
successfully used to treat nephrogenic DI, long-term use nize the toxic effects of hyperkalemia on the cardiac
of these agents is not recommended because of gastroin- membrane.
testinal, hematopoietic, and renal complications. In addition to acute kidney injury, other factors may
Central DI may be caused by midline central nervous influence fluid management in patients with severe peri-
system malformations, anoxic encephalopathy, cerebral natal asphyxia. Fluid restriction has been advocated by
edema, or trauma.15 Although some ADH secretion may some for infants with perinatal asphyxia even in the
be present in central DI, levels are insufficient to promote absence of acute kidney injury. However, no systematic
appropriate water absorption in the distal nephron. Des- randomized studies have determined whether this prac-
mopressin acetate (DDAVP) is effective therapy for this tice alters the long-term outcome for these patients.30 In
condition, and DDAVP responsiveness can help distin- recent years, hypothermia has emerged as a treatment for
guish central versus nephrogenic causes when the under- preventing mortality and neurologic sequelae of severe
lying etiology is unclear. perinatal asphyxia, although optimal duration and degree
of hypothermia remains a subject of research.25,45,61 To
FLUID AND ELECTROLYTE THERAPY IN date, guidelines for fluid administration during hypother-
COMMON NEONATAL CONDITIONS mia protocols have not been well delineated. However,
given the decreased catabolic rates associated with hypo-
Perinatal Asphyxia thermia, it can be anticipated that treated infants would
Renal parenchymal injury from perinatal asphyxia fre- have less fluid requirements than infants not undergoing
quently results in acute tubular necrosis, which is hypothermia.
commonly accompanied by oliguria or anuria. In the
presence of acute kidney injury, fluid restriction to Hyperbilirubinemia
amounts equal to urine output plus insensible losses is Severe hyperbilirubinemia (bilirubin >20mg/dL after 72
crucial to avoid volume excess. In a term infant, insen- hours of life) is not uncommon, occurring in approxi-
sible water losses are approximately 20 to 25mL/kg per mately 1% of term neonates.12 Phototherapy is the
day, and stool loss is minimal. Fluid requirements during mainstay of therapy;39 however, several studies have also
the first day of life in an anuric term infant are approxi- highlighted the importance of fluid therapy as an adjunct
mately 30mL/kg per day. Insensible losses for an anuric to phototherapy. A significant proportion of neonates
premature infant may be as high as 80mL/kg per day, with severe hyperbilirubinemia exhibit dehydration on
depending on gestational age. Fluid restriction is often admission.41 In addition, intravenous fluids have been
difficult to accomplish when relatively large volumes of shown to accelerate the rate of decline in serum bili-
intravenous medications are necessary or when the rubin and decrease the need for exchange transfusion
absence of central venous access limits the concentration in severely affected infants.5,13 The ideal composition
of dextrose-containing fluid that can be delivered. High (specifically the sodium content) of intravenous fluid
caloric density parenteral nutrition, delivered in as small administered in neonates with severe hyperbilirubi-
a volume as possible, is often necessary when fluid restric- nemia was the subject of a recent randomized control
tion is undertaken to avoid fluid overload and water trial.5 In that study, the authors compared the outcomes
intoxication. When urine production normalizes, fluid of neonates treated with isotonic compared with hypo-
intake can be liberalized to reflect urine output and tonic fluid supplementation. They found that both fluids
insensible losses. decreased the rate of exchange transfusion and dura-
If the cause of oliguria or anuria is unclear, and the tion of phototherapy. Patients treated with hypotonic
infant is believed to be intravascularly depleted, a test fluid, however, had a higher incidence of hyponatremia,
dose of 10mL/kg body weight of crystalloid or colloid whereas those treated with isotonic fluid had a higher
can be given. During the oliguric or anuric phase of acute incidence of hypernatremia. The authors hypothesized
tubular necrosis, potassium should not be given to avoid that 0.3% saline, with an intermediate sodium concen-
hyperkalemia. During the recovery phase of acute tubular tration, would be the ideal fluid to administer in these
necrosis, small infants may experience large urinary patients.
sodium and potassium losses, which should be quanti-
tated and replaced. Symptomatic Patent Ductus Arteriosus
In severe perinatal asphyxia, the renal parenchymal Patent ductus arteriosus with left-to-right shunt and pul-
injury may be severe enough to produce acute kidney monary edema is a common cause of morbidity in
injury lasting for several days to weeks, or may be perma- preterm infants, particularly infants with respiratory dis-
nent in cases with cortical necrosis. In the presence of tress syndrome in the first few days of life. Fluid overload
hyperkalemia, defined as serum potassium greater than during this period is associated with an increased inci-
7mEq/L, the cardiac rhythm of the infant should be dence of symptomatic PDA.9 The precise mechanism by
monitored by continuous electrocardiogram to detect any which fluid overload leads to an increased risk of PDA is
cardiac arrhythmia. Treatment options for hyperkalemia unclear, but it may be related to the lack of isotonic con-
include insulin, given with glucose; sodium polystyrene traction of body fluids in this group of infants. Although
the timing of treatment for PDA, especially with respect during the stages of nephron development is discussed.
to prophylaxis of an asymptomatic PDA, and optimal The diagnostic and therapeutic approach to acid-base dis-
dosing regimen remain ongoing issues of debate, intrave- orders is presented, and common acid-base disorders are
nous indomethacin and ibuprofen remain an important discussed.
component of medical management of PDA. Acute
kidney injury is an important potential complication ACID-BASE HOMEOSTASIS IN NEONATES
of indomethacin use and is caused by inhibition of vaso- Normal neonatal metabolism occurs within a tightly con-
dilatory prostaglandins resulting in unopposed renal trolled extracellular pH ranging from 7.35 to 7.43.
vasoconstriction. Risk factors for developing renal insuf- Normal growth and development critically depend on
ficiency after indomethacin treatment include existing this homeostasis, which is threatened in ill term new-
renal or electrolyte abnormalities, maternal exposure to borns or premature infants. The maintenance of serum
indomethacin used as a tocolytic agent, and chorioam- pH (i.e., hydrogen ion concentration) within the physi-
nionitis.24 Urine output and renal function must be mon- ologic range requires two major processes: (1) acute com-
itored closely during the course of intravenous pensation, which is accomplished by rapid acid or base
indomethacin therapy. The lowest possible effective doses buffering by intracellular and extracellular buffers in
of indomethacin should be used, and concomitant response to acute decreases or increases in serum pH, and
administration of other nephrotoxic agents, such as ami- (2) long-term compensation, which is accomplished by
noglycosides, should be avoided. Use of ibuprofen for renal excretion of acid or base, including an obligate daily
ductal closure is associated with a lower risk of AKI (see acid load of approximately 1 to 2mEq/kg per day. Renal
Chapter 83). and extrarenal homeostatic mechanisms contribute to
the maintenance of acid-base balance.
Chronic Lung Disease
Infants with chronic lung disease present complex chal- Acute Compensation: Body Buffer Systems
lenges in fluid and electrolyte management. Because of After an acute change in serum pH caused by losses or
higher basal metabolic rates and increased caloric require- gains of acid or base to the body, intracellular and extra-
ments, the caloric density or volume, or both, of paren- cellular buffering mechanisms respond rapidly to return
teral or enteral feedings needs to be maximized. Care the serum pH to a physiologic level. In response to a
must be taken to provide optimal fluid and nutrient decrease in pH, H+ enters the cell in exchange for K+ by
intake without incurring volume overload and worsening way of an H+/K+ exchanger. H+ is buffered by intracellular
pulmonary disease. In addition, therapies used to treat buffers, including hemoglobin, organic phosphates, and
the underlying lung diseasemost notably, diuretics bone hydroxyapatite. Conversely, when serum pH
may have significant effects on fluid and electrolyte increases, H+ leaves the cell in exchange for K+. Acute
balance.29 acidosis often results in hyperkalemia, whereas alkalosis
Furosemide, a potent loop diuretic, causes a marked is associated with hypokalemia. Intracellular buffering
increase in urinary sodium, potassium, and hydrogen ion accounts for about 47% of an acute acid load, and can
excretion, leading to hypokalemic metabolic alkalosis. reach even higher levels during more prolonged episodes
Long-term use of this diuretic may also result in enhanced of acidosis. Much of this buffering capacity is in bone. In
urinary excretion of calcium leading to osteopenia of disorders characterized by chronic acidosis, increased
prematurity, urolithiasis, or nephrocalcinosis. Furose- bone resorption and loss of bone sodium, potassium,
mide should be used with caution in neonates, particu- calcium, and carbonate occur. These effects on bone par-
larly premature infants with acute kidney injury and tially explain the invariable association of growth failure,
infants receiving concomitant aminoglycoside therapy, to a potentially significant issue for premature infants, with
avoid complications of ototoxicity. Chlorothiazide, a less acidosis.
potent thiazide diuretic that acts at the distal tubule, also The major buffering mechanism in the ECF is medi-
causes a hypokalemic metabolic alkalosis. In contrast to ated by the carbonic anhydrase system, as reflected in the
loop diuretics, thiazides decrease urinary calcium excre- following formula:
tion. Treatment with spironolactone, a potassium-sparing
aldosterone inhibitor, may be associated with hyperkale- CA
CA
mia. Strategies used to avoid complications of diuretic H+ + HCO3
H2 CO3 H2O + CO2
use include minimizing diuretic dosages, obtaining
serum electrolyte measurements to detect electrolyte Regulation of carbon dioxide (CO2) excretion by the
imbalance, monitoring urinary calcium excretion (when respiratory system markedly improves the efficiency of
applicable), and supplementing calcium to prevent osteo- this buffering system at physiologic pH. In the presence
penia of prematurity. Sodium supplementation should of carbonic anhydrase (CA), carbonic acid (H2CO3) is in
be avoided because it may further contribute to hypervol- equilibrium with CO2. Addition or increased production
emia and/or hypertension if present. of acid results in consumption of bicarbonate (HCO3)
and increased H2CO3 and CO2. CO2 then crosses the
Acid-Base Management blood-brain barrier, resulting in a decrease in pH. This
action stimulates central nervous system chemoreceptors,
In this section, normal acid-base homeostasis in neonates leading to increased respiration and resultant decreased
is reviewed, and how these processes are influenced CO2 concentration within 12 to 24 hours. Similar
respiratory compensation occurs in response to an alkali LUMEN Proximal tubule cell BLOOD
load, which leads to increased HCO3 concentration,
H2O+CO2 H2O+CO2
resulting in hypoventilation and accumulation of CO2.
Two formulas are particularly useful in understanding CA CA
H2CO3 Na
+ Na+
and evaluating acid-base disorders. The Henderson- H2CO3
Hasselbach equation expresses the relationship of pH,
PCO2, and HCO3: HCO3 + H+ H+ HCO3
Na+ Glutamine
pH = 6.1 + log [HCO3 /(0.03 PCO2 )]
NH4+ -Ketoglutarate
where 6.1 is the pKa of this equation.
The Winters formula3 can be used to predict the appro- Figure 44-4 Schematic drawing of proximal tubular HCO3- reab-
priate respiratory response (i.e., decrease in PCO2) to a sorption and ammoniagenesis. See text for explanation. CA, carbonic
primary metabolic acidosis: anhydrase.
PCO2 = (1.5 HCO3 ) + 8 2
Respiratory compensation in response to either meta- lactic acidosis related to sepsis or bicarbonate loss
bolic acidosis or metabolic alkalosis does not completely from diarrhea
normalize the pH. The Winters formula predicts that a 3. Compensation for changes in serum pH that result
decrease in HCO3 to 10mmol/L would result in a from primary respiratory disorders
decrease in PCO2 to 21 to 25mmHg. By the Henderson-
Hasselbach equation, the resulting serum pH is 7.22 to Bicarbonate reabsorption occurs primarily in the proxi-
7.29. This is markedly better than the serum pH of 7.02 mal tubule, wherein 60% to 80% of the filtered bicarbon-
that would be seen if no respiratory compensation ate load is reabsorbed. Bicarbonate is not reabsorbed via
occurred, but is still not within the normal range. With a specific transporter. Instead it is reabsorbed via an indi-
simple metabolic acidosis or alkalosis, the respiratory rect mechanism. Bicarbonate present in the lumen is first
compensation does not fully correct the serum pH. If buffered by H+ that is secreted in exchange for sodium via
serum pH is found to be in the normal range (or higher an Na+/H+ exchanger located on the luminal membrane
or lower than predicted), a mixed acid-base disorder, with of proximal tubular cells (Figure 44-4). Through the
an added primary respiratory abnormality, should be actions of carbonic anhydrase, CO2 and H2O are pro-
considered. duced. CO2 and H2O diffuse into the cell, wherein HCO3
is regenerated and reabsorbed across the basal cell
Long-Term Maintenance of Acid-Base Balance membrane in exchange for chloride. H+ is also regener-
Long-term maintenance of a normal serum pH depends ated, making it available again for buffering of additional
on the balance between the production or intake of acid filtered bicarbonate. The net effect is that for every
and base and their metabolism or excretion. Dietary H+ secreted, one molecule of filtered bicarbonate is
intake accounts for a small amount of preformed acid, reabsorbed.
but most of the daily acid load is a product of obligatory Although proximal tubule bicarbonate reabsorption is
metabolic functions. A large proportion consists of CO2, essential in preventing bicarbonate wasting, no net H+
which is carried to the lung as bicarbonate and carb- excretion occurs in this process. Instead, excretion of the
amino groups bound to hemoglobin and ultimately daily acid load is accomplished by two mechanisms:
excreted through respiration. This is termed volatile acid. ammoniagenesis and production of titratable acids.
Hypoventilation or hyperventilation leads to either reten- Ammoniagenesis occurs in the proximal tubule (see
tion or enhanced excretion of CO2, and results in acidosis Figure 44-4), via the metabolic processing of glutamine
or alkalosis. Metabolic activity also produces an obligate produced in the liver. In the proximal tubule cell, gluta-
nonvolatile acid load of approximately 1 to 2mEq/kg mine is converted to ammonium (NH4+), which is
per day. Most of this acid load is sulfuric acid, which secreted into the lumen in exchange for Na+. Deamina-
results from metabolism of the sulfur-containing amino tion of glutamine also produces a-ketoglutarate, which
acids, methionine and cysteine. The remainder consists buffers H+. Through the actions of the intracellular car-
primarily of incompletely oxidized organic acids, phos- bonic anhydrase system, this process eventually results
phoric acid and hydrochloric acid. Successful mainte- in the production of intracellular HCO3, which can be
nance of acid-base balance depends on renal excretion of reabsorbed across the basal membrane of the cell with
this daily acid load. Na+. NH4+ secretion is the metabolic equivalent to H+
The kidney plays an essential role in maintaining acid- excretion.
base homeostasis by three major mechanisms: The remainder of acid secretion occurs in the cortical
and medullary collecting tubule. H+ is secreted into the
1. Reabsorption of filtered bicarbonate and excretion of collecting tubule against its pH gradient by H+-ATPases
excessive bicarbonate in response to metabolic located on the luminal membrane. This process is influ-
alkalosis enced by the luminal and peritubular pH, distal sodium
2. Excretion of the obligate daily acid load and any addi- delivery, and aldosterone. Secreted H+ titrates filtered
tional acid load from pathogenic processes, such as anions, including phosphates and sulfates, producing
LUMEN Collecting tubule cell BLOOD of older children or adults. Low GFRs, particularly in
premature or stressed neonates, decrease the availability
H2O+CO2 of phosphates and other buffers, decreasing the forma-
HPO4 + H+ CA CI tion and excretion of titratable acids. Tubular immaturity
H2CO3 results in reduced tubular secretory surface for organic
acid secretion, diminished number of organic acid trans-
ATPase
H2PO4 H+ HCO3 port sites per unit area of renal tubular surface, and
diminished energy available for organic acid transport.
Premature infants are also unable to acidify their urine
NH3 + H+ NH3 maximally at birth, exhibiting a minimal urine pH of 6,
in contrast to full-term neonates and adults whose urine
NH4+ pH may reach 4.5. The ability of premature infants to
acidify their urine maximally and to excrete an acid load
Figure 44-5 Schematic drawing of distal urinary acidification mecha- correlates with gestational age. By 6 weeks of age, the
nisms. CA, carbonic anhydrase. capacity of premature and term infants to excrete hydro-
gen ions matures to permit maximal acidification.
Bicarbonate conservation and net acid excretion are
titratable acids (Figure 44-5). The collecting tubule also diminished in neonates because of the immaturity of the
secretes ammonia from the medullary interstitium, where neonatal kidney. This is particularly true for premature
it is buffered by H+ to produce NH4+. Titratable acid for- infants of less than 34 weeks gestation because of incom-
mation and ammonia buffering require an acidic envi- plete nephrogenesis. These limitations not only account
ronment for protonation to occur. In addition to for decreased baseline serum bicarbonate levels, but also
providing a source of H+ for buffering, distal H+ secretion limit the ability of neonates to respond to additional
is important in maintaining acidic urine (pH of 4.5 stresses, particularly acid loading. Renal control of acid-
to 5.0). base homeostasis does not reach adult levels of function
The net acid excretion by the kidney is equal to the until approximately 2 years of age.
sum of titratable acids plus ammonium minus any fil-
tered bicarbonate that is not reabsorbed. During steady- DIAGNOSTIC APPROACH TO DISORDERS
state, total acid secretion equals the production of acid OF ACID-BASE BALANCE
from diet and metabolism. In response to an acid load, In generating a differential diagnosis of an acid-base
ammoniagenesis can increase dramatically because of abnormality, it is helpful to ask the following three
enhanced production of glutamine by the liver. Ammo- questions:
niagenesis is stimulated by hypokalemia and inhibited by 1. What is the primary abnormality?
hyperkalemia. In contrast, titratable acids are relatively
2. What is the secondary compensation?
fixed in their production except in instances of diabetic
ketoacidosis, in which the ketone bodies themselves can 3. Is the compensation appropriate?
form titratable acids. Alternatively, the kidney has the
capacity to alter HCO3 reabsorption in response to The acid-base abnormality alone does not indicate if it is
changes in the filtered load of bicarbonate, further mini- the primary disorder or a response to the primary disor-
mizing changes in pH. der. A low serum bicarbonate level indicating metabolic
acidosis could indicate a primary metabolic acidosis or
DEVELOPMENTAL ASPECTS OF could represent a metabolic compensation for a primary
ACID-BASE PHYSIOLOGY respiratory alkalosis. Conversely, elevated serum bicar-
Although nephron formation is complete by 34 weeks of bonate could be a reflection of a primary metabolic alka-
gestation, maturation and functional changes of the losis or a response to a primary respiratory acidosis. To
nephron continue during the first year of life. The relative distinguish the primary process from the secondary com-
immaturity of the kidney, which is more pronounced in pensation, it is necessary to know the plasma pH, serum
preterm infants, affects basal acid-base status and the bicarbonate level, and CO2 level. In addition to simple
response to additional acid and alkali loads.35 During the respiratory or metabolic acid-base disorders, mixed
initial 24 to 48 hours of life, acid-base balance is influ- (combined) disorders may be seen in which more than
enced by the degree of perinatal stress and environmental one primary process is present. Mixed disorders should
factors such as temperature and diet.64 Between 7 and 21 be considered when the expected compensation falls out
days of life, neonates are in a state of mild metabolic of the expected range.
acidosis. In some infants, blood pH may decrease to less The nomogram presented in Figure 44-6 can aid in the
than 7.25, or base deficit may exceed 8mEq/L.57 diagnosis of simple and mixed acid-base disorders. It
The causes of this metabolic acidosis in neonates are shows the 95% confidence limits of the expected com-
multifactorial. The threshold for bicarbonate reabsorp- pensatory response to a primary metabolic or respiratory
tion in the proximal tubule is lower in neonates, espe- acidosis or alkalosis. If the compensatory change in either
cially premature infants, compared with adults, so that PCO2 or HCO3 falls beyond these limits (i.e., outside of
neonates tend to waste bicarbonate at a lower blood the shaded region for each disorder), a combined disor-
HCO3 concentration (15-21mEq/L). Thus, the normal der is present. Consider a newborn with pH of 7.17, PCO2
bicarbonate level in a healthy neonate is lower than that of 34mmHg, and HCO3 of 12mEq/L. The acidic pH
and low serum HCO3 suggest a primary metabolic aci- of metabolic acidosis in neonates. Calculation of the
dosis. When the values for pH, HCO3, and PCO2 are anion gap allows differentiation into two groups.
plotted on the nomogram, however, the convergence Increased anion gap metabolic acidosis is caused by the
point falls out of the range for a simple metabolic acido- addition of exogenous acids (e.g., salicylates) or increased
sis, suggesting the possibility of a superimposed respira- production of endogenous acids (e.g., lactic acid). In
tory acidosis. To delineate this further, one can estimate neonates, an increased anion gap is usually caused by
the expected compensation (i.e., a respiratory alkalosis) increased production of endogenous acids, such as lactic
based on the values presented in Table 44-4 or, alterna- acidosis in patients with sepsis or toxic metabolites in
tively, the Winters formula (see p. 622). With a decrease patients with inborn errors of metabolism. Increased
in serum HCO3 from 22mEq/L to 12mEq/L, PCO2 anion gap metabolic acidosis is associated with a normal
should decrease by 12.5mmHg. The estimated compen- serum chloride.
sation would result in a PCO2 of 27mmHg. Similarly, the In contrast, a normal anion gap metabolic acidosis is
Winters formula predicts a compensatory PCO2 of 24 to attributable to either bicarbonate loss in the urine (proxi-
28mmHg. The higher-than-expected PCO2 confirms mal renal tubular acidosis [RTA]) or the stool, or the
the presence of a superimposed primary respiratory inability to excrete acid because of a defect in distal
acidosis. nephron function (distal RTA). In this disorder, the serum
chloride is elevated. Correction of the underlying cause
BASIC PRINCIPLES OF THERAPY is the most important therapeutic measure in the man-
agement of metabolic acidosis. The dose of alkali required
Metabolic Acidosis to treat metabolic acidosis in newborns ranges from
Metabolic acidosis is a common problem in critically ill 1mEq/kg per day for mild base deficits to 5 to 8mEq/
neonates that results from either excess acid production kg per day for more severe base deficits, such as seen in
or increased loss of base. Box 44-1 lists common causes proximal RTA. Dialysis may be required when acid
60
120 100 90 80 70 60 50 40
56 110
Arterial plasma bicarbonate (mmol/L)
52
35
48
Metabolic
BOX 44-1 COMMON CAUSES OF
44 Chronic alkalosis 30 METABOLIC ACIDOSIS
40 respiratory
acidosis 25 IN NEONATES
36
32
Acute
INCREASED ANION GAP
20
28 respiratory Lactic Acidosis
24 acidosis Normal Acute
20 respiratory 15 Hypoxemia, shock, sepsis
alkalosis Inborn errors of carbohydrate or pyruvate
16 10
Chronic metabolism
12 Metabolic respiratory PCO2 (mm Hg)
8 acidosis alkalosis Pyruvate dehydrogenase deficiency
4 Pyruvate carboxylase deficiency
0 Mitochondrial respiratory chain defects
7 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 Renal failure
Arterial blood pH
Ketoacidosis
Figure 44-6 Acid-base map showing 95% confidence limits for com-
Glycogen storage disease (type I)
pensatory responses. (From Cogan MG, etal. In: Brenner BM, etal, eds.
The kidney. Philadelphia: Saunders; 1986:462.) Inborn errors of amino acid or organic acid
metabolism
NORMAL ANION GAP
TABLE 44-4 Expected Compensation in Bicarbonate loss: acute diarrhea; drainage from small
Acid-Base Disorders bowel, biliary, or pancreatic tube; fistula drainage;
bowel augmentation cystoplasty; ureteral diversion
Primary Abnormality Compensation with bowel
Respiratory PCO2 HCO3 Renal tubular acidosis
Mineralocorticoid deficiency
Acute acidosis 1mmHg 0.1mEq/L
Acute alkalosis 1mmHg 0.25mEq/L Administration of Cl-containing compounds: argi-
Chronic acidosis 1mmHg 0.5mEq/L nine HCl, HCl, CaCl2, MgCl2, NH4Cl hyperalimenta-
Chronic alkalosis 1mmHg 0.5mEq/L tion, high-protein formula
Carbonic anhydrase inhibitors
Metabolic HCO3 PCO2 Dilution of extracellular fluid compartment
Acidosis 1mEq/L 1.25mmHg
Alkalosis 1mEq/L 0.2-0.9mmHg Adapted from Brewer E. Disorders of acid-base balance. Pediatr Clin North
Am. 1990;37:429.
BOX 44-2 COMMON CAUSES OF volume depletion typically improves with saline admin-
istration and potassium repletion. Use of agents such as
METABOLIC ALKALOSIS arginine hydrochloride, ammonium hydrochloride, and
IN NEONATES dilute hydrochloric acid may be associated with life-
Acid loss: vomiting (e.g., pyloric stenosis), nasogastric threatening complications, such as severe acidosis or a
suction paradoxical intracellular alkalosis, and is not supported
Diuretics by the literature. Acetazolamide has been used safely in
Chloride deficiency: chronic chloride-losing diarrhea, patients with chronic contraction alkalosis associated
Bartter syndrome, low-chloride formula, loss via skin with congenital heart disease.42 However, no randomized
secondary to cystic fibrosis studies have addressed the use of this agent in neonates
Administration of alkali: bicarbonate, lactate, acetate, or infants with chronic lung disease or other disorders
citrate requiring long-term diuretic therapy. As an alternative,
aggressive repletion of potassium and chloride alone may
facilitate correction of the hypokalemic metabolic alkalo-
sis. Both oral and intravenous potassium supplementa-
tion may be required to correct significant total body
production is severe, such as in lactic acidosis, renal potassium deficits. Although the long-term complica-
failure, or severe inborn errors of metabolism. tions of chronic metabolic alkalosis are unknown, pro-
Administration of alkali, such as bicarbonate, has longed pH greater than 7.6 may increase the risk for
several potential adverse effects, including volume over- sensorineural hearing loss.34
load, hypernatremia, decreased oxygen delivery to the
brain secondary to shifts in the hemoglobin dissociation Respiratory Acidosis and Alkalosis
curve, increased PCO2, and a paradoxical intracellular Respiratory acidosis results from any disorder with
acidosis as CO2 diffuses into cells.50 Bicarbonate admin- decreased alveolar ventilation, resulting in retention of
istration should be used with caution in most neonates.4 CO2. In neonates, this condition is usually caused by
The notable exception is cases of suspected RTA (primary respiratory distress syndrome, meconium aspiration syn-
or secondary to chronic kidney disease), in which drome, pulmonary infections, or congenital diaphrag-
bicarbonate supplementation has an important role matic hernia. Correction of the underlying cause of
in growth and maintenance of bone health and lean respiratory acidosis is essential and frequently requires
muscle mass.18 the use of assisted ventilation to increase excretion of
volatile acid (CO2). Administration of alkali to correct
Metabolic Alkalosis acidemia caused by a primary respiratory acidosis is gen-
Metabolic alkalosis is generated by one of three general erally inappropriate. The resultant increase in serum
mechanisms: (1) loss of acid, such as hydrochloric bicarbonate levels (and serum pH) promotes hypoventi-
acid loss with vomiting; (2) ingestion of base, such as lation and a further increase in PCO2, exacerbating the
sodium bicarbonate administration during resuscitation; respiratory acidosis. In instances in which a mixed acid-
or (3) contraction of the extracellular volume, with loss base disorder is present (i.e., a primary respiratory acido-
of fluid containing more chloride than bicarbonate. Box sis and a primary metabolic acidosis), bicarbonate
44-2 lists common causes of metabolic alkalosis in administration should be used with caution, and assisted
neonates.9 ventilation is typically required.
Although the kidney is usually very effective in excret- Respiratory alkalosis is rare in neonates; however, it
ing excess alkali, several conditions maintain metabolic may occur during excessive assisted ventilation or during
alkalosis when it is generated. Extracellular volume deple- central hyperventilation secondary to serious central
tion limits bicarbonate excretion by several mechanisms. nervous system disease such as intraventricular hemor-
The decrease in GFR reduces the filtered load of bicarbon- rhage. Patients with respiratory alkalosis who are depen-
ate, and the bicarbonate that is filtered is rapidly reab- dent on ventilators are treated easily by adjusting the
sorbed in the proximal tubule as a result of avid sodium assisted ventilation settings. A search for underlying
reabsorption. Volume depletion also stimulates renin- causes of central hyperventilation is necessary in other
angiotensin system-mediated release of aldosterone, patients.
which leads to an increase in distal renal tubular absorp-
tion of sodium and excretion of H+ and potassium. Other SPECIFIC ACID-BASE DISORDERS THAT
states of hyperaldosteronism, such as excess production MAY MANIFEST IN THE NEONATAL PERIOD
of endogenous mineralocorticoids or administration of
exogenous steroids, lead to enhanced distal renal tubular Renal Tubular Acidosis
excretion of H+ and potassium. Potassium depletion also Renal tubular acidosis is a disorder characterized by a
maintains metabolic alkalosis by stimulating renal normal anion gap metabolic acidosis, and is the sequela
ammoniagenesis and inhibiting movement of H+ out of of either impaired reabsorption of bicarbonate or
the cell. Chloride depletion or respiratory acidosis, as impaired urinary acidification/H+ ion excretion.56 It may
evidenced by an elevated PCO2, can also maintain meta- be the result of an inherited defect in the renal handling
bolic alkalosis. of H+ ion or bicarbonate.53
Therapy for metabolic alkalosis consists of correction More commonly, it is secondary to tubular damage
of the underlying disorder. Alkalosis resulting from from various causes, such as medications or obstructive
uropathy. There are three main forms of RTA: type I the distal nephron and result in backleak of H+ from the
(distal), type II (proximal), and type IV (hyperkalemic) lumen. Amphotericin toxicity is a classic example of this
(Box 44-3). Each form of RTA has a distinct pathophysiol- gradient defect form of acquired distal RTA. In addi-
ogy and characteristic serum and urinary laboratory tion, congenital lesions, most notably obstructive uropa-
findings.16 thies, may cause secondary RTA because of tubular
Type I (distal) RTA results from diminished distal H+ damage from obstruction or infections.
secretion. Patients with distal RTA often present in the The diagnosis of suspected distal RTA should be con-
newborn period or during early infancy with lethargy, sidered in any infant with a urinary pH that is greater
polyuria, vomiting, dehydration, and failure to thrive. than 6.5 in the presence of a nonanion gap metabolic
Distal RTA is usually accompanied by hypokalemia acidosis. Conversely, a urine pH of 5.5 or less indicates
because potassium is secreted in lieu of H+ to maintain that distal acidification mechanisms are intact and effec-
electronegativity. Concomitant hypercalciuria and hypo tively rules out distal RTA. If the diagnosis is unclear, two
citraturia predispose patients to the development of different methods have been proposed to assess the distal
nephrocalcinosis and nephrolithiasis. acidification mechanisms formally. Measurement of the
Distal RTA can occur as a sporadic form, although urine-to-blood PCO2 gradient can be used to assess distal
several well-characterized inherited forms have been tubular urinary acidification after bicarbonate loading.
described. In each instance, the genetic defect results in After bicarbonate loading in the presence of normal distal
impairment of a specific component of the distal acidifi- tubular acidification, PCO2 should be at least 20mmHg
cation mechanisms (see Figure 44-5). Autosomal reces- greater than the blood PCO2. With normal function,
sive and autosomal dominant forms have been described.53 secreted H+ combines with bicarbonate to form carbonic
Acquired forms of type I RTA also can occur as the result acid and ultimately CO2, leading to a gradient in PCO2
of tubular injury. Certain medications cause damage to between urine and blood. In distal RTA, this gradient is
diminished because of diminished H+ secretion.24 Alter-
natively, the urine anion gap (= Na+ + K+ Cl) indirectly
assesses the amount of urine ammonium. A positive
BOX 44-3 CLASSIFICATION OF RENAL value suggests a defect in urine ammonium excretion and
TUBULAR ACIDOSIS deficient urinary acidification32
Although primary distal RTA is a permanent defect, the
TYPE I (DISTAL)
prognosis for growth and the prevention of renal insuf-
Primary (autosomal dominant or recessive; sporadic) ficiency is satisfactory when the condition is correctly
Secondary, associated with other renal disorders treated. Therapy for distal RTA in infancy consists of the
Obstructive uropathy administration of alkali, usually in the form of an alkali-
Hypercalciuria/nephrocalcinosis containing liquid such as Bicitra. The typical dose is 2 to
Secondary, associated with acquired or other heredi- 3mEq/kg per day. Maintenance of normal blood pH and
tary diseases serum bicarbonate maximizes the opportunity for normal
Osteopetrosis growth.
Sickle cell anemia
Hereditary elliptocytosis
Type II (proximal) RTA is caused by a decrease in the
Marfan syndrome threshold tubular maximum for HCO3 reabsorption
Primary biliary cirrhosis in the proximal tubule, resulting in HCO3 wastage.
Secondary, associated with drugs or toxins (e.g., The tubular maximum is decreased to approximately
amphotericin B) 15mEq/L, so reabsorption of bicarbonate does not occur
until the serum levels decrease to less than this value. The
TYPE II (PROXIMAL) loss of HCO3 is often large because 60% to 80% of the
Primary (familial or sporadic) filtered HCO3 is normally reabsorbed in the proximal
Fanconi syndrome tubule. Distal urinary acidification is normal, and patients
Primary can appropriately acidify the urine (pH 5.5) when
Cystinosis plasma HCO3 levels are less than 14 to 15mEq/L. An
Tyrosinemia increase in plasma HCO3 beyond the capacity of the
Oculocerebral renal syndrome (Lowe syndrome) proximal tubule results in HCO3 wastage and an alkaline
Hereditary fructose intolerance urine pH of 7.6 or greater. Isolated inherited forms of
Wilson disease
proximal RTA occur rarely and can be inherited as an
TYPE IV (HYPERKALEMIC) autosomal recessive (with ocular abnormalities) or auto-
Pseudohypoaldosteronism somal dominant trait.53 More commonly, proximal RTA
Renal immaturity is a component of Fanconi syndrome, a disorder of global
Obstructive uropathy proximal tubule dysfunction. In addition to bicarbonate
Potassium-sparing diuretics wasting, patients with Fanconi syndrome exhibit tubular
Chloride shunt wasting of sodium, potassium, glucose, phosphorus, and
Hyporenin hypoaldosteronism amino acids. Fanconi syndrome is seen in many inherited
Medications (e.g., cyclosporine) metabolic disorders, including Lowe syndrome, galacto-
semia, tyrosinemia, and hereditary fructose intolerance.16
Adapted from Brewer E. Disorders of acid-base balance. Pediatr Clin North Patients with proximal RTA typically require larger
Am. 1990;37:429. amounts of bicarbonate supplementation than patients
with distal RTA. Dosages of 10mEq/kg or more per day

may be required because of excessive HCO3 wastage. Neonatal Bartter Syndrome
As previously discussed, neonates display a mild Bartter syndrome is an inherited disorder characterized
degree of proximal RTA because of an altered threshold by hypokalemia, hypochloremia, and metabolic alkalosis
for proximal tubular HCO3 reabsorption, with mainte- that is often associated with failure to thrive and recurrent
nance of plasma HCO3 of 20 to 24mEq/L in full-term episodes of dehydration. It is caused by obligate and
neonates and 15 to 24mEq/L in preterm infants. Over uncontrolled renal losses of sodium, potassium, and
the first year of life, the tubular maximum for HCO3 chloride. Currently there are three clinically and geneti-
increases to adult levels as the proximal tubule elongates cally distinct variants of this syndrome, including antena-
and transport function matures. Some infants show tal Bartter syndrome, classic Bartter syndrome, and
delayed maturation that results in a persistent proximal Gitelman syndrome.17
RTA, which usually resolves by 5 or 6 years of age. The antenatal variant is the most severe form and man-
Type IV (hyperkalemic) RTA is characterized by ifests in the neonatal period with dehydration, a history
impaired ammoniagenesis as the result of hyperkalemia. of polyhydramnios, and dysmorphic facies characterized
Hyperkalemia results from abnormalities in aldoste- by triangular facies, protruding ears, strabismus, and a
rone production or from altered tubular sensitivity to drooping mouth. Patients typically have elevated urinary
aldosterone. Disorders associated with abnormalities in calcium excretion, elevated urinary prostaglandin E levels,
mineralocorticoid production (e.g., congenital adrenal nephrocalcinosis, and normal serum magnesium levels.
hyperplasia) or responsiveness (i.e., inherited or acquired This form of Bartter syndrome is inherited as an autoso-
pseudohypoaldosteronism) have been discussed earlier mal recessive trait and is caused by mutations in genes
in this chapter. The symptoms of type IV RTA in infancy encoding the rectifying potassium channel or the Na+-
include dehydration and symptoms related to hyperkale- K+-2 Cl cotransporter. Both of these transporter proteins
mia. Laboratory abnormalities include a nonanion gap are located in the thick ascending loop of Henle and are
metabolic acidosis, hyperkalemia, elevated urine sodium, required for sodium and chloride reabsorption in that
and diminished urine potassium. Therapy for type IV nephron segment. Treatment includes the use of indo-
RTA consists of mineralocorticoid supplementation in methacin to inhibit prostaglandin and aldosterone pro-
conditions characterized by a deficiency of aldosterone. duction, potassium supplementation, and maintenance
Treatment of hyperkalemia may reverse many of the of adequate intravascular volume. Persistent hypokalemia
abnormalities; however, alkali supplementation is gen- and nephrocalcinosis rarely lead to chronic renal insuf-
erally required in patients with end-organ resistance to ficiency as a result of progressive tubulointerstitial
aldosterone. The need for such supplementation seems to disease.52
diminish by age 5, possibly because of further maturation
of the kidney.
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44 Fluid, Electrolytes, and

100 reduced oxygen availability.51 Decreased responsiveness

60 be increased in certain conditions, including hypoxia,

tremia, and an earlier diuresis and natriuresis.44 This ben-

secretion than serum osmolarity. Patients with hypona-

TABLE 44-2 Factors Affecting Insensible Water Loss in Newborns

120 layer of skin, a higher surface areatobody weight ratio,

80 niques, this number may be substantially less.39

PCO2 = (1.5 HCO3 ) + 8 2

with distal RTA. Dosages of 10mEq/kg or more per day

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