The natriuretic peptides are involved in attenuating the renin-angiotensin-aldosterone axis and sympathetic nervous system; suppression of vasopressin release; vasodilatation of the systemic, pulmonary, coronary, and renal circulations; and promotion of natriuresis and diuresis. When compared with older infants and children, neonates in the first few postnatal days have significantly greater circulating levels of natriuretic hormone, perhaps related to the acute increase in ventricular afterload that occurs after birth [3, 4]. Plasma B-type natriuretic peptide (BNP) levels in neonates with respiratory disease, with persistent pulmonary hypertension of the newborn, are significantly greater than in those with normal right ventricular pressure. In children with known congenital heart disease, natriuretic hormone levels vary with the type and severity of the heart defect [5].

Remodelling of the adrenal glands after birth occurs via apoptosis of the fetal zone, by remodelling this zone and the development of other zones [6]. At birth, the concentration of free cortisol is only one-third that of maternal levels, with an inverse relationship between cortisol levels and gestational age. The size of the adrenal glands decreases by 25 % during the first 4 postnatal days. In full-term and late preterm neonates, low cord concentrations of ACTH, cortisol and free triiodothyronine are associated with lung fluid retention and transient tachypnea of the newborn (TTN) [7]. Transient insufficiency of the adrenal cortex has been reported in approximately 27 % of ELBW infants and critically ill neonates (defined as an inability to triple the cortisol production rate in response to stress); these infants mount a poor response to shock with hypotension that is unresponsive to fluids and inotropes [8–10]. Intravenous pulse doses of hydrocortisone have been shown to be effective in treating inotrope-resistant hypotension in critically ill preterm infants that does not suppress the adrenal gland [9, 11]. However, the vast majority of preterm neonates >30 weeks’ gestation demonstrated a positive relationship between their stress response and the urinary cortisol levels [12]. Most neonates with suppressed cortisol levels at birth reach normal plasma cortisol levels within the first 2 weeks after birth [13].

The renin-angiotensin system is very active in the first week of neonatal life resulting in increased vascular tone and increased concentrations of aldosterone [14]. Factors that contribute to increased angiotensinogen and plasma renin activity (PRA) levels include low systemic blood pressure and low renal blood flow, low serum sodium, and a decrease in ECF after birth. The activity of the renin-angiotensin-aldosterone (RAA) system is inversely related to gestational age. The integrity of the renin-angiotensin-aldosterone system at early age contrasts with the inability of the fetal kidney to appropriately control sodium and water reabsorption.

Synthesis of aldosterone in the fetal adrenal gland commences by the 13th gestational week and increases steadily throughout gestation, often exceeding maternal levels at birth. Urinary aldosterone excretion increases significantly in late gestation, between 30 and 41 weeks [2]. In VLBW infants, the adrenal production of aldosterone is reduced compared with that in full-term neonates. This, combined with a partial unresponsiveness of the distal tubule to aldosterone, predisposes these infants to an increased risk of hyponatremia and dehydration. The mechanism of this partial resistance may be explained in part by the reduced expression of renal mineralocorticoid receptors [15]. As aldosterone levels increase with gestational age, distal tubular reabsorption of sodium increases, but even by term, healthy neonates exhibit partial, transient tubular unresponsiveness to aldosterone, resulting in an impaired ability to excrete large or acute sodium loads [2]. In fact at term, plasma levels of aldosterone and renin are increased compared with maternal levels despite the accompanying hyponatremia, hyperkalemia and urinary sodium loss [14]. Aldosterone levels and the distal tubular responses to aldosterone normalize as renal function matures by the end of the first year of life.

Antidiuretic hormone (arginine vasopressin AVP, ADH) increases at birth especially in infants delivered vaginally [16]. ADH secretion is increased in response to stress—during birth, asphyxia or with respiratory distress syndrome (RDS), positive pressure ventilation, pneumothorax, and intracranial hemorrhage. Sensitivity of the volume receptors and osmoreceptors in neonates is similar to the response in adults, but tubular sensitivity to ADH is decreased in preterm infants [17, 18]. The reduced response of the collecting duct’s water permeability response to ADH permits the excretion of hypotonic urine in utero and contributes to the neonate’s inability to concentrate urine postnatally. In utero, prostaglandins E2 signal the prostaglandin EP3 receptor to block AQPs [19]. Postnatally, when ADH binds to its receptor on the basolateral membrane of the collecting duct, a series of events culminate in the insertion of aquaporin-2 (AQP2) water channels into the apical membrane of the renal tubule increasing the tubule’s water permeability in response to ADH [20]. Aquaporins in the apical membranes of collecting ducts are decreased in premature infants at birth, peak on postnatal day 3 and then decrease to birth concentrations by day 7 [21].

Infants tolerate fluid restriction poorly and become dehydrated rapidly as a result of large insensible fluid losses and the inability of the kidneys to concentrate urine. Factors that contribute to this inability to concentrate urine include a decrease in medullary osmotic gradient and a reduced water permeability response of the collecting duct to ADH. The lack of a renal medulla osmotic gradient and the absence of medullary tubules limit the urinary concentrating capacity of the neonatal kidney (600 mOsm/kg in preterm infants and 800 mOsm/kg in full-term neonates) to about half that of the adult value (1,200–1,400 mOsm/kg).

Normal fluid requirements vary markedly in both low birth weight and full-term neonates as well as during infancy (Table 8.1). This variability is caused by differences in caloric expenditures, growth rate, evaporative losses and progress of renal function maturation and proportion of total body water at different ages [26]. Full-term infants require 60 ml/kg/day of fluid on day 1, with increasing incremental requirements that reach 150 ml/kg/day by 1 week postnatally. Premature neonates have larger surface areas relative to their body weights and greater evaporative losses than full-term neonates. As a consequence, premature neonates (≤26 weeks gestational age) require 80 ml/kg/d on day 1 (one-third more than full-term neonates), with increasing incremental requirements that reach 150–180 ml/kg/day by 1 week. In the case of VLBW infants, their surface area-to-weight ratios are approximately three times greater than those in full-term neonates, resulting in greater insensible fluid losses. These losses, combined with the greater urinary excretion of solutes and reduced tubular concentrating ability, further increase the obligatory fluid losses in these infants. Energy expenditure and fluid requirements may also significantly increase during stressful situations such as with surgery (up to 30 % increase), severe sepsis (up to 50 % increase), fever (10 % per degree in excess of 37 °C) and cardiac failure (up to 25 % increase).

Sodium is often not included in the fluids administered to neonates in the first 24–72 h, and the serum sodium can be an accurate marker of the hydration status of the neonate: hyponatremia developing with fluid overload and hypernatremia developing with dehydration.

Careful fluid and electrolyte management is essential for the well-being of the sick surgical neonate. Insufficient administration of fluids can cause hypovolemia, hyperosmolarity, metabolic abnormalities, and renal failure, whereas excess fluid administration can cause generalized edema, congestive heart failure, and pulmonary dysfunction. In the VLBW infant, excess fluid administration may be associated with a patent ductus arteriosus (PDA) because the fluid overload stimulates production of PGE₂, which prevents PDA closure. In the infant with a large PDA, aortic blood is shunted back into the pulmonary artery reducing blood flow down the descending aorta. This reduces intestinal blood flow that may result in hypoperfusion, ischemia and necrotizing enterocolitis (NEC). Excess fluid administration may also result in congestive heart failure, intraventricular hemorrhage, NEC and bronchopulmonary dysplasia (BPD).

Sodium is required for fetal growth, with a normal accretion rate of 1.2 mEq/kg/day between 31 and 38 weeks’ gestation. Immediately after birth, both full-term and preterm infants are in negative sodium balance due to the physiologic natriuresis stimulated by ANP changes with birth [3]. The high fractional excretion of Na⁺ () in premature infants can lead to negative Na⁺ balance, hyponatremia, neurologic disturbances and poor growth unless sodium is administered at a rate of 3–5 mmol/kg/day. Full-term neonates readily conserve sodium with increased responsiveness of the distal tubule to aldosterone and a rapid increase in Na⁺K⁺ ATPase activity in the principal cell of the collecting duct after birth. The principal cell is the final determinant of sodium reabsorption and potassium excretion, the latter dependent on potassium channels [20]. Preterm infants demonstrate negative sodium balance for many weeks post delivery because of decreased Na⁺K⁺ ATPase activity, increased ECF volume and reduced tubular aldosterone sensitivity. Extremely premature infants who become hyponatremic most likely do not have reduced total body sodium, which would permit increasing their sodium intake. These infants require a reduction in total fluid intake. Conversely, the premature infant is unable to rapidly increase sodium excretion in response to an increased concentration of sodium or a large sodium load.

Clinically important disturbances in acid–base status are unusual in full-term neonates, unless protein intake is excessive. Plasma bicarbonate (HCO₃ ⁻) concentrations depend on the renal HCO₃ ⁻ threshold, which is reduced in the full-term neonate (19–23 mEq/l) and even less in the premature (18–22 mEq/l) and very low birth weight (<1,300 g) infants (14–18 mEq/l) [19, 20]. The reduced renal HCO₃ ⁻ threshold (physiological renal tubular acidosis—RTA) may be caused by the physiologic volume expansion in the premature neonate and the relative immaturity of the tubular transport mechanisms. Sodium bicarbonate or more commonly sodium or potassium acetate supplements of 1–2 mmol/kg/day are generally recommended for very small premature infants. Infants with normal anion gap metabolic acidosis secondary to renal immaturity may have a greater requirement for alkali (acetate) in their parenteral nutrition.

The fetal pancreas is able to release insulin in response to the presence of increased glucose and amino acids by the 20th week of gestation, although insulin remains inactive until the onset of corticosteroid action in the second trimester. Insulin then regulates the expression of enzymes related to glycogen and lipid synthesis. As a result, glycogen storage does not begin until the 27th week gestation and increases slowly thereafter until 36 weeks. Hepatic glycogen content then increases quickly until full-term is reached at a rate of 50 mg/g of tissue. This reserve, less than 5 % of the body weight, is rapidly depleted if a source of energy is needed suddenly, explaining why an infant is prone to developing hypoglycemia during the fasting period. The placenta is permeable to triglycerides, free fatty acids, and glycerol, and under the influence of insulin, fatty acid synthesis in the liver and glucose uptake in adipose tissue occur leading to triglyceride synthesis. During the third trimester, fat is stored in adipose tissue, which comprises 16 % of body weight at term, corresponding to an energy reserve of approximately 5,000 kcal.

Birth is associated with an endocrine stress response that is characterized by a massive increase in plasma catecholamine, glucagon and cortisol concentrations. Decreased plasma insulin concentrations as glucagon concentrations increase induce hepatic glycogenolysis, lipolysis, and gluconeogenesis, effects that are also stimulated by increased concentrations of circulating catecholamines at birth. A physiological decrease in blood glucose concentration occurs during the first 2 h after delivery, although the above mechanisms correct this physiologic aberration and initiate homeostasis. Hepatic synthesis through glycogenolysis and gluconeogenesis is the only source of glucose until feeding is established. Estimates of glucose kinetics in full-term neonates suggest that healthy neonates produce glucose at the rate of 5–8 mg kg/min (or 28–45 μmoles kg/min), of which 50–70 % is contributed by gluconeogenesis. Liver glycogen stores are depleted from 50 to 5 mg/g tissue within 12 h of birth, after which energy requirements are supported by oxidative fat metabolism until enteral feeding is established. The rate of lipolysis, as estimated by the rate of appearance of glycerol or fatty acid, corresponds to 6–12 μmoles kg/min.

There is no consensus on the precise definition of hypoglycemia in neonates (although many use a concentration <47 mg/dL as hypoglycemia, rounding to 50 mg/dl) [27], and there are no uniform standards for euglycemia. The physiologically optimal range for plasma glucose concentrations is 70–100 mg/dl (3.9–5.6 mmol/l) with a minimal optimal concentration of glucose, 60 mg/dl (3.3 mmol/l). Infants who are very immature (ELBW or VLBW) or ill (hypoxia, ischemia, or sepsis) may have greater glucose requirements and are more vulnerable to the consequences of hypoglycemia. Other infants at risk of postnatal hypoglycemia include infants of diabetic mothers, large for gestational age (LGA > 90 ‰) or small for gestational age infants (SGA), infants with Beckwith-Wiedemann syndrome or intrauterine growth retardation (IUGR <10 ‰), post-asphyxiated infants (APGAR <5 at 5 min) and infants ≤36 weeks’ gestation. A glucose infusion rate of 3–4 mg/kg/min should prevent hypoglycemia in full-term infants, whereas an infusion rate of 6–10 mg/kg/min should prevent hypoglycemia in ELBW infants.

In neonates <28 weeks gestational age, hypoglycemia is almost unavoidable in the first few hours after birth if exogenous glucose is not administrated. These infants have limited glycogen stores, decreased availability of amino acids for gluconeogenesis and inadequate lipid stores for the release of fatty acids and fat stores to maintain glucose balance. Ketogenesis is severely limited in preterm infants because they lack fat stores in adipose tissue (fat represents <2 % of total body weight). Depending on its severity, hypoglycemia can produce devastating effects on the central nervous system, especially in neonates [28]. Reduced blood concentrations of glucose invoke a stress response and alter cerebral blood flow and metabolism. During hypoglycemia, brain glucose metabolism decreases by up to 50 % with increased reliance on ketones and lactate as sources for energy. Preterm infants appear less able to counterbalance these developments and to provide alternative fuels for the brain unlike full-term infants. Even moderate hypoglycemia can lead to an adverse neurodevelopmental outcome including an increased risk of motor and developmental delay. Cerebral injury is caused not only by severe prolonged hypoglycemia but also by mild hypoglycemia when it is combined with mild hypoxia or ischemia. MRI detected white matter abnormalities in more than 90 % of full-term neonates with symptomatic hypoglycemia (blood glucose level <45 mg/dL or 2.6 mmol/l) [29, 30].

Feeding is less efficient in some late preterm infants than in full-term neonates because they fatigue quickly and have immature feeding skills prompting oral gavage (tube) feeding until effective oral feeding is achieved [31]. Suck and swallow coordination is often poor in infants born at <34 weeks’ gestation. Furthermore, some infants require a longer-than-normal interval between feedings because of delayed gastrointestinal motility and gastric emptying. Furthermore, premature infants <34 weeks’ gestation often have intestinal dysmotility that contributes to feeding intolerance with associated anesthetic implications.

Minimal enteral nutrition refers to the practice of early enteral feeding of premature infants. Starting volumes vary from 5 to 25 ml/kg/day with benefits noted at less than 1 ml/kg/day (priming). Minimal trophic feeds (either by bolus or continuous infusion of 10 ml/kg/day) in the first week of life stimulate the gut by increasing the activity of various enzymes, inducing mucosal growth, promoting motility and preventing translocation of bacteria across the gut wall—a significant concern in VLBW infants [32]. Maternal breast milk (colostrum) is preferred; however, positive results have been reported with donor milk and formula feeding. Feeding volumes are kept small, regardless of the size of gastric residuals, with volumes usually less than 20 ml/kg/day. Minimal enteral nutrition is used with caution in any situation associated with gut hypoxia or decreased intestinal blood flow (asphyxia, hypoxemia, hypotension) and/or marked diastolic steal (a patent ductus arteriosus). Continuing feeds during indomethacin treatment is still a controversial issue and clinical practice differs among hospitals.

Maturation of the gastrointestinal tract with increases in the intestinal length and surface area including villus and microvillus growth occur during the last trimester. Human milk is the first choice for preterm and term infants as it provides substantial benefits to premature infants’ health including reduced infectious and inflammatory disease and enhanced neurodevelopmental outcome. If unfortified however, human milk may not provide adequate nutrients to meet the demands of premature infants particularly in light of the large variations in the protein and fat content of human milk. Human milk from mothers of preterm infants contains more protein than does the milk from mothers of term infants; initially, it has a protein content of approximately 2.5–3 g/100 mL (colostrum), which decreases to approximately 1.5–2 g/100 mL soon after birth (transitional milk), and finally stabilizes at 0.9–1.4 g/100 mL (mature milk). In general, increased concentration levels of protein persist for the first month of lactation. Thereafter, the protein content of preterm milk decreases and approaches the composition of term human milk. Preterm infants receiving 150 ml/kg per day of fortified human milk receive approximately 3.5 g/kg per day of protein.

The smaller the infant, the greater the need for parenteral nutrition and the greater the urgency to initiate it. Thus, for infants with birth weights <1,500 g, total parenteral nutrition (TPN) is started at 2–3 days of life when the fluid and sodium status has stabilized. Infants require 90–100 cals/kg of TPN or 110–130 cals/kg of enteral nutrition to optimize growth. When supplementing orogastric feeds, the TPN is increased to 150–160 ml/kg/day as tolerated in order to provide adequate calories for growth. Current practice in many NICUs is to initiate TPN with 3 g/kg of protein soon after birth using “starter” or “vanilla” TPN solutions that are stocked in the NICU. In both human milk and formulae, lipids comprise about 50 % of the total energy and contain the essential fatty acids, linolenic acid and linoleic acid. The primary reason for including parenteral lipids is to provide the essential fatty acids, which are important determinants of membrane lipid composition and central nervous system development. ELBW infants usually receive their dietary fat via parenteral lipid emulsions. There are concerns that lipid infusions in premature neonates may have adverse effects such as impaired oxygenation, increased risk of lung disease, impaired immune function and increased free bilirubin levels. In addition, while there are good reasons for using lipids, a good proportion of these lipids are stored rather than oxidized as fuel.