Fluid, Electrolyte, and Acid-Base Balance

Changes During Intrauterine Development

In early gestation, body composition is characterized by a high proportion of total body water (TBW) and a large extracellular compartment. As gestation advances, rapid cellular growth, accretion of body solids, and fat deposition and developmental changes in the production of hormones regulating body water homeostasis result in gradual reductions in TBW content and extracellular fluid (ECF) volume, while the intracellular fluid compartment increases ( Fig. 20.1 ). In the 16-week-old fetus, TBW represents approximately 94% of total body weight; approximately two-thirds and one-third of the TBW are distributed in the extracellular and intracellular compartments, respectively. After delivery, TBW decreases by 1.44% per week in preterm neonates. By term gestation, TBW represents 75% of body weight, and approximately half of this volume is located in the intracellular compartment. Therefore, premature newborns have excess TBW and a larger extracellular volume compared with their term counterparts at birth, with most of the expanded extracellular volume being distributed in the interstitium.

Changes During Labor and Delivery

Greater changes in TBW and its distribution occur during labor and delivery. Arterial blood pressure rises several days before delivery because of increases in plasma catecholamine, vasopressin, and cortisol levels, as well as translocation of blood from the placenta into the fetus. This rise in arterial blood pressure, along with changes in the fetal hormonal milieu and an intrapartum hypoxia-induced increase in capillary permeability, results in a shift of fluid from the intravascular to the interstitial compartment and an associated approximately 25% reduction in circulating plasma volume in the human fetus during labor and delivery. If the cord is not clamped immediately after delivery of the body, placental transfusion tends to restore the circulating blood volume, while the postnatal increase in oxygenation and changes in vasoactive hormone production act to restore capillary membrane integrity and favor absorption of interstitial fluid into the intravascular compartment. The return of interstitial fluid into the bloodstream aids in maintaining intravascular volume during the first 24 to 48 hours postnatally, when oral fluid intake may be limited. The return of interstitial fluid also triggers the release of atrial natriuretic peptide, which is—at least in part—responsible for the physiologic diuresis commencing on postnatal days 2 and 3. However, prematurity, pathologic conditions, or both can disrupt this delicate process and interfere with the physiologic contraction of the ECF compartment in the immediate postnatal period.

In the fetus, body composition and fluid balance depend on the electrolyte and water exchange between the mother, fetus, and amniotic space. Antenatal events can have significant effects on postnatal fluid balance. Maternal indomethacin treatment or excessive administration of intravenous (IV) fluids during labor can result in neonatal hyponatremia with expanded extracellular water content. Placental insufficiency or maternal diuretic therapy can impair fetal extracellular volume, urine output, and amniotic fluid volume.

Effect of Timing of Cord Clamping

The timing of cord clamping after delivery is another important factor significantly affecting total circulating blood volume and extracellular volume in the neonate. Immediate cord clamping does not allow placental transfusion and negatively influences hemodynamic transition, especially in preterm neonates. However, if cord clamping is delayed, up to 25 to 50 mL of blood per kilogram is transfused into the neonate, representing an approximately 25% to 50% increase in the total blood volume. In a metanalysis of term neonates, delayed cord clamping for at least 30 seconds was associated with increased iron stores and higher birth weight but with a higher need for phototherapy. In a metanalysis in preterm neonates, delayed cord clamping was associated with significantly decreased rates of intraventricular hemorrhage (IVH) and necrotizing enterocolitis, and the need for inotropic support and blood transfusion. The use of novel resuscitation trolleys and a better understanding of the cardiorespiratory impact of resuscitating neonates with the cord unclamped have led to a more widespread use of delaying cord clamping in the clinical practice. Animal data and earlier observations in term neonates also suggest that the establishment of an appropriate functional residual capacity is the most relevant factor in determining the volume and rapidity of placental transfusion when cord clamping is delayed. Accordingly, neonates who do not establish effective respirations and who require resuscitation at birth may be at additional risk of lower circulating blood volumes. Although further data are still needed to understand whether increased blood volume at birth is associated with improved long-term outcomes, the American College of Obstetricians and Gynecologists now recommends delaying cord clamping for 30 to 60 seconds after birth in vigorous preterm and term neonates; the World Health Organization recommends it for all newborns.

Changes in the Postnatal Period

In the first few days and weeks after birth, the TBW content and distribution are affected by gestational and postnatal ages, pathologic conditions, the immediate environment (temperature, humidity), and the type of nutrition (enteral vs. parenteral). Normally, in the first few days after birth, an increase in capillary membrane integrity favors absorption of the interstitial fluid into the intravascular compartment. The ensuing rise in circulating blood volume stimulates the release of atrial natriuretic peptide (ANP) from the heart, which in turn enhances renal sodium and water excretion, resulting in an abrupt decrease in TBW and attendant weight loss. Although it is generally accepted that this postnatal weight loss is primarily due to the contraction of the expanded ECF compartment, some water loss from the intracellular compartment can also occur, particularly in infants with extremely low birth weight (ELBW) and increased transepidermal water losses (TEWLs).

Healthy term newborns lose approximately 10% of their birth weight during the first 4 to 7 days of age and, thereafter, they establish a pattern of steady weight gain. As preterm neonates have an increased TBW content and extracellular volume, they lose approximately 10% to 15% of their birth weight during this period and, depending on the degree of prematurity and associated pathologic conditions, these neonates only regain their birth weight by 10 to 20 days after birth ( Fig. 20.2 ). Neonates who have intrauterine growth retardation have a smaller initial weight loss and more rapidly regain their birth weight than their normally grown counterparts, whether term or preterm. Although the mechanisms for these differences have not been well studied, they appear to be associated with less diuresis in the infant with intrauterine growth retardation.

In the management of the neonate, it is important that the appropriate weight loss be anticipated and facilitated, if necessary, as the lack of the early postnatal weight loss has been associated with higher rates of persistency of patent ductus arteriosus (PDA), bronchopulmonary dysplasia (BPD), and necrotizing enterocolitis in low birthweight infants.

Regulation of the Intracellular Solute and Water Compartment

The major intracellular solutes include the proteins necessary for cell function, the organic phosphates associated with cellular energy production and storage, and the equivalent cations balancing the phosphate and protein anions. As a consequence of the function of the cell membrane-bound sodium-potassium-ATPase enzyme, potassium is the major intracellular and sodium the major extracellular cation. The energy derived from the concentration differences for sodium and potassium between the intracellular and extracellular compartments is used for cellular work. Because changes in osmolality of the extracellular compartment are reflected as net movements of water into or out of the cell, regulation of ECF osmolality ultimately controls the intracellular compartment. This physiologic principle must be kept in mind when managing sick term and preterm neonates with disturbances of sodium homeostasis. Rapid changes in serum sodium concentration, and thus in extracellular osmolality, directly affect the osmolality and size of the intracellular compartment and can lead to irreversible cell damage, especially in the central nervous system (CNS). Hyponatremia in the neonatal period has been associated with adverse long-term outcomes, especially in preterm neonates, while hypernatremia has been associated with short-term morbidities, including seizures and thrombosis. These associations underscore the importance of maintaining appropriate fluid and electrolyte homeostasis in the neonatal period.

Regulation of the Intracellular–Extracellular Interface: The Interstitial Compartment

In the healthy term neonate, hydrostatic ( P _C , capillary hydrostatic pressure; P _T , tissue/interstitial hydrostatic pressure) and oncotic ( π _P , plasma oncotic pressure; π _T , tissue/interstitial oncotic pressure) pressures are well-balanced, with both being approximately half of those in the adult. Under normal physiologic conditions, movement of fluid across the capillary is determined by the direction of the net driving pressure ([ P _C – P _T ] − [ π _P – π _T ]), the water permeability and the protein permeability, as well as transport characteristics of the capillary wall ( Fig. 20.3 ). At the arterial end of the capillary, intracapillary hydrostatic pressure ( P _C ) is high and plasma oncotic pressure ( π _P ) is relatively low, resulting in a net movement of fluid out of the capillary. As filtration of relatively protein-poor fluid continues along the capillary, plasma oncotic pressure rises and intracapillary hydrostatic pressure drops; therefore on the venous side, fluid moves from the interstitium into the capillary and thus the majority (85% to 90%) of the filtered fluid is reabsorbed at the end of the capillary bed. The fluid remaining in the interstitium (arterial–venous side of the capillary) is drained by the lymphatic system. Interstitial hydrostatic ( P _T ) and oncotic ( π _T ) pressures remain virtually unchanged along the capillary bed. However, pathologic conditions readily disturb the delicate balance between the hydrostatic and oncotic forces, leading to an expansion of the interstitial compartment at the expense of the intravascular compartment. The increased interstitial fluid volume (edema) then further affects tissue perfusion by altering the normal function of the extracellular–intracellular interface. Box 20.1 summarizes the mechanisms for conditions resulting in interstitial edema formation in the neonate. There are also some important developmentally regulated differences between the newborn and the adult relating to the pathogenesis of edema formation. Capillary permeability to proteins is increased during the early stages of development. Because neonatal capillary permeability is further increased under pathologic conditions (see Box 20.1 ), protein concentration in the interstitial compartment may approach that of the intravascular space, favoring further intravascular volume depletion and interstitial volume expansion. The findings of most but not all clinical studies suggest that 0.9% saline administration for suspected hypovolemia is associated with less fluid retention and similar improvements in the cardiovascular status compared with 4.5% or 5% albumin infusion; however, the topic requires further investigation.

Even in the presence of hypoalbuminemia, when sick neonates are treated with frequent albumin boluses, much of the infused albumin rapidly leaks into the interstitium. This creates a vicious cycle of intravascular volume depletion and edema formation, resulting in vasoconstriction and disturbances in tissue perfusion and cellular function, exacerbating impairments in the regulation of extracellular volume distribution. If the cycle is not interrupted, anasarca develops, which is usually associated with an extremely poor prognosis. In summary, the sick neonate has limited capacity to maintain appropriate intravascular volume and to regulate the volume and composition of the interstitium, and high vigilance is thus required by the caretaker in appropriately managing intravascular volume, including avoiding routine use of albumin in the critically ill neonate.

Regulation of the Extracellular Solute and Water Compartment

The osmolality of the extracellular compartment is tightly maintained within 2% of the osmolar set point, which lies between 275 and 290 milliosmoles (mOsm). Blood pressure and serum sodium concentration (i.e., the main contributor to osmolality under homeostatic conditions) are monitored by baroreceptors and osmoreceptors, respectively. The effector limb of the regulatory system consists of the heart, vascular bed, kidneys, and intake of fluid in response to thirst. The inability of critically ill term and preterm neonates to maintain fluid balance by responding to thirst places increased importance on caregiver management of fluid administration. By regulating the function of the effector organs, several hormones play a role in the control of the extracellular compartment, including the renin–angiotensin–aldosterone system (RAAS), vasopressin, ANP, brain (B-type) natriuretic peptide (BNP), bradykinin, prostaglandins, and catecholamines. Effective regulation of the extracellular compartment and intravascular volume also depends on intact cardiovascular function and capillary endothelium integrity. For example, under physiologic conditions, an increase in the extracellular volume is reflected by an increase in the circulating plasma volume, leading to increased blood pressure and renal blood flow. The ensuing increase in glomerular filtration and the hormonally mediated inhibition of renal tubular sodium and water reabsorption result in increased urine output returning the extracellular volume to a normal level. In critically ill neonates, however, the capillary leak and reduced myocardial responsiveness resulting from immaturity and underlying pathologic conditions limit the increase in the circulating blood volume when extracellular volume expands. Thus, especially in sick preterm neonates, blood pressure may rise only transiently, and renal blood flow may remain low after volume boluses as fluid rapidly leaks into the interstitium. Inappropriate central regulation of vascular tone results in vasodilatation, further decreasing effective circulating blood volume and compromising tissue perfusion; this leads to impaired gas exchange in the lungs, resulting in hypoxia with further increases in capillary leak. Unless it is interrupted by appropriate therapeutic measures, a vicious cycle with further deterioration readily occurs in the sick neonate.

Maturation of the Cardiovascular System

There is a direct relationship between gestational maturity and the ability of the neonatal heart to respond to acute volume loading. The blunted Starling response of the immature myocardium primarily results from its lower content of contractile elements, immature intracellular calcium handling, and incomplete sympathetic innervations. Because central vasoregulation and endothelial integrity are also developmentally regulated, an appropriate intravascular volume is seldom maintained in the critically ill preterm neonate. Since regulation of the extracellular volume requires the maintenance of an adequate effective circulating blood volume, the immaturity of the cardiovascular system contributes to the limited capacity of sick preterm neonates to effectively regulate the total volume of their extracellular compartment.

Maturation of Renal Function

The kidney has a crucial role in the physiologic control of fluid and electrolyte balance. It regulates extracellular volume and osmolality through the selective reabsorption of sodium and water, respectively. Immaturity of renal function renders preterm neonates susceptible to excessive sodium and bicarbonate losses. As described earlier, the inability of the preterm neonate to respond promptly to a sodium or volume load also results in a tendency toward extracellular volume expansion with edema formation. Because prenatal steroid administration accelerates maturation of renal function, preterm neonates exposed to steroids in utero have a better capacity to regulate their postnatal ECF contractions. During the first few weeks postnatally, hemodynamically stable but extremely immature infants produce dilute urine and may develop polyuria because of their renal tubular immaturity. As tubular functions mature, their concentrating capacity gradually increases from the second to the fourth postnatal week. However, it takes years for the developing kidney to reach the concentrating capacity of the adult kidney.

Maturation of the Skin

Although the epidermis of term neonates is well developed and cornified, in extremely immature neonates it consists of only two or three cell layers. The absence of an effective barrier to the diffusion of water increases TEWL in the immature neonate. TEWL through immature skin can result in early postnatal hypertonic dehydration, with rapid changes in intracellular volume and osmolality. In many organs, especially the brain, these abrupt changes can result in cellular dysfunction and ultimately cell death. Gestational age, postnatal age, the pattern of intrauterine growth, and environmental factors (e.g., humidity and temperature) affect transepidermal free water loss ( Fig. 20.4 ). Postnatal skin cornification occurs rapidly, but full maturation of the epidermis does not occur until 2 to 3 weeks of age. Chronic intrauterine stress and prenatal steroid treatment also enhance maturation of the skin.

Maturation of End-Organ Responsiveness to Hormones Involved in the Regulation of Fluid and Electrolyte Balance

Several hormones directly regulate the volume and composition of the extracellular compartment by altering renal sodium and water excretion, as well as by inducing changes in systemic vascular resistance and myocardial contractility. These include the RAAS, vasopressin, ANP, and BNP. Other hormones, including the prostaglandins, bradykinin, and prolactin, acting via endocrine, paracrine, or autocrine mechanisms modulate the actions of many of the regulatory hormones.