The Atwater’s factors are usually used to calculate the metabolizable energy contents and intakes both in PN and enteral nutrition. However, the energy available from macronutrients is not exactly similar. The gross energy content of 1 g of amino acid (AA, ~ 4.75 kcal/g) is about 10 % lower than that of 1 g of protein (~5.25 kcal/g) . By contrast, the energy provided after oxidation of AA in urea is ~ 3.75 kcal/g, whereas the energy of AA stored in protein is ~ 4.75 kcal/g, a value identical to gross energy. Gross and metabolizable energy content of glucose (~ 3.75 kcal/g) is less than that of more complex carbohydrate (~ 4 kcal/g). For intravenous lipid emulsions (IVLE), metabolizable energy content is also similar to gross energy (~ 10 kcal/g including glycerol energy content) but could be lower in IVLE containing medium-chain triglycerides (MCT) [32, 33]. These differences are not easy to incorporate into practice. This explains why energy requirements in PN are close to that in enteral nutrition when the Atwater’s factors are used.

The energy requirements for premature infants correspond to the sum of total energy expenditure plus the energy stored in the new tissue with growth. Energy expenditure measured by indirect calorimetry increases slightly with postnatal age and varies from 45 to 55 kcal/kg/day. The energy cost of growth implies making allowance for fetal LBM accretion, postnatal fat deposition, and the cost of tissue deposition. The energy cost for a postnatal weight gain of 17–20 g/kg/day with adequate LBM accretion vary from 50 to 70 kcal/kg/day in premature infants. Therefore, metabolizable energy requirements for premature infants on PN are estimated to be between 95 and 125 kcal/kg/day [32, 34, 35]. Taking into account the potential need for a prior energy deficit and for catch-up growth, 120 kcal/kg/day is required for most premature infants .

Current recommendations suggest providing a minimum of 40–60 kcal/kg/day on the first day of life followed by a rapid increase of energy intakes up to 95–125 kcal/kg/day within the first week of life . This needs to be adjusted according to growth and metabolism during the stable growing period (Table 7.1).

Nutritional recommendations include early introduction of enteral feeding in premature infants [36]. However, minimal feeding below 25 mL/kg/day mainly serves as trophic gut feeding. It may not be well absorbed, and therefore, it should not be considered in the total energy intakes. Thereafter, when feeding increases above 40 mL/kg/day, total energy intakes would be calculated as the sum of the parenteral and the enteral intakes taking into account an energy absorption rate of 80 % with human milk and 90 % with preterm formula [16, 33].

Considerable improvements in intravenous AA solutions have been achieved since the 1960s. Specific pediatric AA solutions were designed in the early 1990s with high essential and conditionally essential AA content for use in premature infants [28] . Three different standards of AA profile have been suggested for premature infants: umbilical fetal cord blood AA during last trimester of gestation, healthy breast-fed term infant’s plasma AA, and human milk AA composition. Due to the poor solubility of tyrosine and cystine, current AA solutions have some relative AA imbalance compared to enteral nutrition. The ideal intravenous AA mixture for PN in premature infants is still a matter of debate. Nevertheless, biochemical tolerance and nitrogen utilization in infants do not change significantly despite the different compositions of current pediatric intravenous AA solutions [28, 37, 38].

Fetal protein accretion is estimated around 2–2.5 g/kg/day during the last trimester of gestation [39] . Isotope studies in animals and in human fetuses have demonstrated that fetal AA not only are used for protein synthesis but also serve as an energy source by oxidation [40]. The fetal AA uptake during the last trimester of gestation has been estimated to be between 3.5 and 4.5 g/kg/day up to term [41, 42]. Similarly, Postnatal nitrogen balances in premature infants on PN have shown that an AA intake above 1.5–2.0 g/kg/day from the first day of life allows the infants to avoid a negative nitrogen balance. Thereafter, during the stable growing period, AA intake between 3.5 and 4.5 g/kg/day enables infants to obtain a nitrogen retention between 360 and 400 mg/kg/day, similar to fetal accretion [16, 32, 39, 43, 44]. In addition, an AA intake as high as 2.5–3.5 g/kg/day from the first day of life with current available intravenous AA solutions improves nitrogen retention, protein synthesis, insulin secretion, glucose tolerance, and early postnatal growth without inducing metabolic disturbances and adverse effects [20, 45–50]. In a recent cohort study, Senterre and Rigo demonstrated that providing such AA intakes with a well-balanced PN solution from the first day of life was not only feasible but also improved electrolyte and minerals homeostasis during the first 2 weeks of life, thereby reducing postnatal cumulative nutritional deficits , and may abolish postnatal growth restriction at discharge [17, 21, 47, 51] .

Despite any evidence, several concerns persist about potential toxicities of such high AA intakes. The association that has been described between PN and metabolic acidosis is not related to early high AA intakes but is mainly due to imbalance in the electrolyte content in PN solutions [49, 52–54]. Uremia, or blood urea nitrogen (BUN), is frequently used to evaluate the adequacy of protein intakes in infants considering that BUN reflects protein degradation and AA oxidation. However, in VLBW infants during the first 2 weeks of life, BUN is poorly related with AA intakes and mainly reflects renal immaturity and hydration status [48, 55]. Indeed, BUN is highly correlated with plasma creatinine concentration and postnatal increase of BUN is inversely related to GA and BW and normalizes progressively during the first month of life [48, 56]. Therefore, high BUN cannot be used as a marker of protein or AA overload during the first week of life in premature infants.

Practical recommendations for premature infants on PN are to provide 2–3 g/kg/day of AA on the first day of life and to rapidly increase AA intake up to 3–4 g/kg/day within 2–3 days in moderately premature infants and to 3.5–4.5 g/kg/day in VLBW infants (Table 7.1).

Glucose is the only intravenous carbohydrate used for nutritional support with the exception of the glycerol content in IVLE. Early provision of carbohydrate supply is required to prevent hypoglycemia in premature infants. Glucose is readily available for brain metabolism and represents its main source of energy during PN.

Early postnatal glucose infusion is essential in VLBW infants and an intake of 6–7 g/kg/day (4.2–4.9 mg/kg/min) is necessary to prevent early postnatal hypoglycemia resulting from the interruption of the materno-foetal glucose transfer and the low glycogen reserves of premature infants [34, 57, 58].

After birth, glucose metabolism is frequently impaired and VLBW infants are not only at risk of early hypoglycemia but are also prone to hyperglycemia, in particular during PN. The incidence of hyperglycemia increases with prematurity and has been associated with insulin resistance, persistence of glucose production, and clinical disorders like sepsis or pain. In VLBW infants, the mechanisms for glucose homeostasis are still immature. The endogenous glucose production is not completely suppressed by glucose intakes and the maximal glucose oxidation rate is generally limited to 17 g/kg/day (11.8 mg/kg/min) or less in critically ill VLBW infants [34, 42, 58, 59].

The definition of hypo- and hyperglycemia, as well as long-term consequences of glucose metabolism disorders, remains controversial in neonates. Reference plasma glucose concentrations are generally defined between 2.6 mmol/L (0.47 g/L) and 6.6 mmol/L (1.2 g/L). In premature infants , hypoglycemia is always a metabolic emergency that needs to be rapidly corrected with 200 mg/kg glucose slow bolus infusion (2 mL/kg of 10 % glucose solution) and by increasing the nutritional intakes.

In contrast, while on PN and due to the continuous glucose infusion rate, the highest reference plasma glucose concentrations needs to be adjusted. A plasma glucose concentration up to 10 mmol/L (1.8 g/L) is usually well tolerated without significant adverse effects. When faced with high plasma glucose concentrations, the first step is to evaluate the various contributing factors and to try to correct them (high glucose and energy intakes, hypophosphatemia, stress, sepsis, pain, dehydration, and steroid treatment). Glycosuria also needs to be ruled out to avoid osmotic diuresis, dehydration, and plasma hyperosmolarity [57, 59].

In the case of persistent hyperglycemia during the early transitional and the stable-growing periods, glucose intakes might be initially reduced by 10–15 % for a transient period of time. Nevertheless, high AA intakes and high protein to energy ratio are important contributing factor to improve glucose tolerance and decrease the incidence of hyperglycemia. Additionally, considering that adequate protein and energy intakes need to be maintained to avoid nutritional deficits and postnatal growth restriction, insulin treatment could be required when hyperglycemia persists above 10 mmol/L (1.8 g/l) or if it occurs with glucose intakes below 12–14 g/kg/day (8.3–9.7 mg/kg/min) during the stable-growing period . The initial dosage should be between 0.02 and 0.05 IU/kg/h and needs to be adjusted to avoid hypoglycemia. To adapt insulin infusion rate, the time necessary to adjust the plasma insulin concentration needs to be factored in during the correction of glycemic perturbations, in particular, to avoid any iatrogenic hypoglycemia [59, 60] .

In premature newborns and especially in VLBW infants, 6–7 g/kg/day (4.2–4.9 mg/kg/min) glucose infusion should be started as soon as possible to avoid hypoglycemia. Afterwards, intakes may be gradually increased during the transitional period up to 12–17 g/kg/day (8.5–11.8 mg/kg/min) according to tolerance in order to provide adequate energy intakes (Table 7.1). The maximum glucose intake should not exceed the maximum glucose oxidation rate and more than 60–75 % of the nonprotein energy intakes.

IVLE are important constituents of PN because they are the only source of essential fatty acids: linoleic acid (LA, C18:2n-6) and alpha-linolenic acid (ALA, C18:3n-3). IVLE also represent a high-density energy substrate that can be readily utilized. They are isotonic and can be easily infused in peripheral veins [34].

Initially, IVLE were only based on soybean oil which contained about 45–55 % LA, 6–9 % ALA, and very little saturated or monounsaturated fatty acids. Although apparently safe, experimental reports and clinical studies indicate that these purely soybean-based IVLE could exert an oxidative stress, a negative influence on immunological functions, and a role in PN-associated liver disease . These findings were related to its absolute high polyunsaturated fatty acids (PUFA) content favoring lipid peroxidation and the relative excess of n-6 PUFA favoring pro-inflammatory effects [10].

Newer IVLE have been developed and differ by their fatty acids content and sources: soy, safflower, coconut, olive, and/or fish oil [10, 61, 62]. Composition of IVLE available for clinical use is shown in Table 7.2. These new IVLE have a smaller proportion of soybean oil. MCT are frequently added as they may be preferentially metabolized even if they provide less energy than long-chain triglycerides (LCT). Indeed, structured MCT/LCT emulsions formulated from a random combination of triglycerides synthesized on the same glycerol carbon chain have a less tendency to accumulate in the reticuloendothelial system and are cleared faster from blood in moderately catabolic patients. The addition of olive oil provides derived n-9 monounsaturated fatty acids that are less immunosuppressive and inhibits pro-inflammatory cytokine’s release. Olive oil is also less susceptible to peroxidation and well tolerated in critically ill neonates. Fish oil provides predominantly n-3 PUFA and improves PN-associated liver disease. However, it lacks some essential fatty acids and needs to be used as a supplement or manufactured as physical oils mixture (10 % fish, 40 % soy, and 50 % MCT or 30 % soy, 30 % MCT, 25 % olive oil, and 15 % fish) [10, 61–63].

Direct comparisons between purely soybean-based IVLE to some of the more recent IVLE have shown several disadvantages for purely soybean-based IVLE [10, 62–64]. A recent systematic review suggests that these IVLE are deleterious to VLBW infants by increasing the incidence of sepsis [62]. Therefore, it seems logical that the routine use of purely soy-based IVLE for VLBW infants should be abandoned [62–64]. Recent studies comparing IVLE containing fish oils to exclusive soybean IVLE have demonstrated several benefits from increasing n-3 PUFA intakes, which include a reduction of oxidative stress, liver diseases , and severity of retinopathy of prematurity [63, 65–68]. Although promising, more research is required to determine the advantages of these newer IVLE with fish oil compared to other mixed IVLE and the safety of providing as much eicosapentaenoic acid as docosahexaenoic acid and no arachidonic acid in premature infants [63].

Lipid oxidation depends on lipid intakes, energy intakes, and energy needs for metabolism. During PN, lipid oxidation is inversely related to glucose intakes that promote lipid storage. Carbon dioxide production is lowered when a part of energy intakes is provided by IVLE instead of a high proportion of glucose. Maximum lipid oxidation in neonates usually occurs when IVLE intakes provide 40 % of nonprotein energy intakes, corresponding to 1 g of lipid for 3.6 g of glucose. Additionally, it has been suggested that nitrogen retention could also be improved by adding IVLE to PN [34].

In the past, many pediatricians have expressed concerns about IVLE in neonates due to perceived potential adverse effects. However, recent studies do not support these concerns, especially with the most recent IVLE, which can be used from the first days of life [18, 34, 62, 69]. Continuous lipid infusion is generally preferred in neonates, and plasma triglyceride levels need to be monitored to avoid hyperlipidemia, particularly in VLBW infants, in small for gestational age (SGA) infants, and in neonates with high lipid intakes, hyperglycemia, sepsis, hypoxemia, or severe hyperbilirubinemia. Even if there are some controversies about the level of maximal plasma triglycerides tolerance in premature infants because high concentration may be deleterious, there is general consensus that lipid intakes should be reduced when plasma triglycerides concentrations exceed 2.85 mmol/L (250 mg/dL) during continuous IVLE infusion [34].

The use of carnitine supplementation during PN in premature infants is still controversial. Carnitine is necessary for the transportation of long-chain fatty acids through the mitochondrial membranes and the lipids metabolism. Its synthesis and storage are insufficiently developed at birth particularly in premature infants and carnitine is not available through commercial intravenous solutions. In parenterally fed infants, plasma and tissue carnitine levels decline with postnatal age suggesting that carnitine supplementation could be necessary [70]. However, a meta-analysis based on 14 randomized controlled studies showed no effect of carnitine supplementation on lipid metabolism, lipogenesis, or weight gain suggesting that up to now, there is no evidence to support the systematic addition of carnitine supplementation during short-term (< 3 weeks) PN in preterm infants. In newborns who require prolonged PN of more than 2 weeks, carnitine supplementation at a dose of 10–20 mg/kg/day could be suggested [63, 71].

Lipid intakes during PN should represent 25–40 % of nonprotein energy intakes in order to promote lipid oxidation and to reduce lipid deposition in fat mass. Current recommendations encourage the provision of IVLE as soon as possible after birth in all premature infants at dosage of 1–2 g/kg/day. Thereafter, IVLE need to increase by 0.5–1 g/kg/day up to 3–4 g/kg/day during the transitional postnatal period according to metabolic tolerance (Table 7.1).

Birth is associated with major changes in fluid and electrolytes homeostasis. Water as part of the body composition significantly decreases. This is due to physiological contraction of the extracellular compartment. It leads to the so-called postnatal physiological weight loss of the newborn [72].

Compared to term infants, premature infants are characterized by higher transcutaneous and insensible water losses. Due to their renal immaturity, urine output and fractional sodium excretion might also be deregulated. Therefore, fluid and electrolytes disturbances are frequently observed and are associated with increased morbidity, mortality, and adverse developmental outcomes, especially in VLBW infants [54, 73–75]. In particular, dehydration (weight loss above 10 %) combined with or without inadvertent increase sodium intake frequently induces severe hypernatremia above 150 mmol/L and brain injuries [54, 74, 76–78]. On the other hand, excessive water intake and relative hyponatriemia below 130 mmol/L might also compromise cardio-respiratory functions and induce brain injuries in premature infants. Fluid overload is associated with patent ductus arterisosus, bronchopulmonary dysplasia, necrotizing enterocolitis, and long-term adverse outcomes [34, 79].

Catabolic state induced by insufficient protein and energy intakes during the first week of life can also induce non-oliguric hyperkalemia. Hyperkalemia can also be potentiated by dehydration, renal failure, and postnatal use of nonsteroidal anti-inflammatory drugs (indomethacin, ibuprofen) to treat patent ductus arteriosus [80, 81].

In order to reduce the occurrence of fluid and electrolytes disorders, previous recommendations were to provide 90–120 mL/kg/day of water on the first day of life and to progressively increase intakes up to 140–180 mL during the stable-growing period [34, 58, 74]. In addition, it was also advised to postpone sodium and potassium supplementation until after 48 h of life or after the increase of urinary output over 1.5 mL/kg/h [34, 58, 74].

Recent studies, however, suggest that optimizing early PN intakes from the first hour of life positively influences postnatal fluid and electrolytes homeostasis [47, 82, 83]. By optimizing early AA and energy intakes combined with early electrolytes supplies from the first day of life with a reduction of insensible water losses, it is possible to limit postnatal weight loss to 6–7 % and to regain BW after 7 days on average in both VLBW and extremely low birth-weight (ELBW, < 1000 g) infants, [21, 51]. Such strategy also improves the electrolyte homeostasis during the first 2 weeks of life decreasing dramatically the incidence of hypernatremia and non-oliguric hyperkalemia in VLBW infants [47, 82, 83]. As a result of early induction of an anabolic status, the new strategy could induce a “new” metabolic disorder during the first days of life, especially in SGA and VLBW infants, in the form of hypophosphatemia and hypokalemia and sometimes hyponatremia and hypercalcemia [19, 47, 84–88]. These studies suggest that actual optimized PN strategy needs to be accompanied by an increase in early electrolyte and mineral intakes during the first days of life to ensure a complete balanced PN solution from the first day of life in VLBW infants [16, 21, 47, 89].

Chloride homeostasis is also important in premature infants because imbalance between sodium , potassium, and chloride intakes may promote metabolic acidosis or alkalosis [49, 47, 72]. Chloride requirements are generally considered similar to sodium requirements and pediatricians frequently do not control chloride intakes transferring chloride content in PN to the authority of the pharmacist. Hidden chloride intakes are frequent and combined with many other intakes like sodium, potassium, calcium, AA, and also in some drugs like dopamine and dobutamine. Therefore, as a result of the poor ability of the premature kidney to eliminate acid load, an excessive chloride intake frequently induces metabolic acidosis . Thus, limiting chloride intakes and providing sodium and potassium intakes as organic phosphate or as sodium or potassium acetate/citrate in PN preparation might prevent hyperchloridemic metabolic acidosis [49, 47, 54, 72, 90–94].

Rigorous monitoring of fluid and electrolyte homeostasis is required during the first week of life for all premature infants, especially VLBW and ELBW infants with high insensible water losses. The idea is the close assessment of fluid and electrolyte balance every 6–12 h during the first days of life to monitor intakes, urinary output, and body weight. Prevention of excessive insensible water losses is essential to maintaining fluid and electrolyte homeostasis. Insensible water losses can be easily estimated by subtracting from the total fluid intakes the weight change and the urinary output in order to adapt fluid intakes. Additionally, excessive urine output above 5 mL/kg/h needs to be rapidly compensated volume for volume with 0.45 % sodium chloride infusion to balance water and sodium losses. Excessive sodium intakes from medications should be controlled to avoid any sodium overload and hypernatremia [54, 76–78]. In VLBW infants, urine sodium fractional excretion is high due to immature kidney functions. Regular determination of plasma and urine electrolyte concentrations may also be helpful to adjust intakes.

Current recommendations advocating for revisions are based on the most recent publications. Our suggestion is to provide an initial fluid supply on the first day of life at 60–80 mL/kg/day in VLBW infants and 80–100 mL/kg/day in ELBW infants combined with double wall incubator and high-humidity environment . Then, fluid supply should be increased progressively with careful monitoring of hydration, allowing for a weight loss of 5–10 % during the first 3 days of life. A target fluid intake of between 120 and 160 mL/kg/day is estimated to maintain adequate fluid and electrolyte homeostasis and an appropriate weight gain (Table 7.1).

For sodium and potassium, an initial intake of around 1 mmol/kg/day is currently recommended on the first day of life to match an optimized high protein and energy intake from birth. Thereafter, intakes should be increased up to 3–5 mmol/kg/day for sodium (up to 7 mmol/kg/day in VLBW infants) and 2–3 mmol/kg/day for potassium in order to meet requirements for growth (Table 7.1).

For chloride , an intake of around 1 mmol/kg/day is recommended on the first day of life, then 3–5 mmol/kg/day afterwards assuming the maintenance of a positive difference of 1–2 mmol/kg/day between the sum of sodium and potassium intakes and chloride intakes (Na + K–Cl = 1–2 mmol/kg/day). The use of acetate or lactate (1–2 mmol/kg/day) instead of chloride in PN could be helpful to prevent hyperchloridemia and metabolic acidosis (Table 7.1) .

In contrast to enteral nutrition , calcium and phosphorus in PN are directly available for metabolism. Calcium may be provided in the form of calcium gluconate, calcium chloride, or calcium glycerophosphate. Due to aluminum contamination, calcium gluconate is now being progressively faced out by the industry to meet the rule of < 5 µg/kg/day of aluminum exposure in infants but it still remains frequently used in homemade hospital pharmacy preparations [95, 96]. Calcium chloride is easy to use but its high chloride content needs to be considered in the electrolytes balance of the PN solution. Calcium glycerophosphate with one to one calcium to phosphorus ratio (mmol/mmol) is an adequate source but is not registered for use in PN and need to be prescribed from powdered anhydrous calcium glycerophosphate.