What Is Known
- The quality of parenteral nutrition has major effects on several outcomes in preterm neonates.
- Recent guidelines for the preterm neonate recommend early initiation/high-protein parenteral nutrition.
- These new guidelines may induce adverse effects on neonatal homeostasis.
What Is New
- Revised parenteral nutrition composition may have several effects on ionic homeostasis.
- Clinicians should implement appropriate monitoring to prevent them.
- Future changes in guidelines for neonatal nutrition should be balanced with potential adverse effects.
The quality of parenteral nutrition (PN) in preterm infants has major effects on several outcomes including growth and neurocognitive development, and may induce metabolic and cardiovascular diseases in adulthood (1–3)(1–3)(1–3). Because reports from neonatal intensive care units have shown that nutritional intake in preterm infants could be inadequate (4,5)(4,5), clinical practice guidelines for the nutritional needs of preterm infants have been regularly revised by the Paediatric Parenteral Nutrition of the European Society of Paediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Clinical Nutrition and Metabolism (6). Recent guidelines for the preterm neonate recommend early initiation of PN with high protein and relatively high caloric intake, especially following fetal growth restriction, to prevent extrauterine growth failure (7). The main purpose of the present review was to assess the influence of new guidelines for the parenteral needs of preterm infants on several biological disturbances observed during the first few postnatal weeks.
A systematic search of the published literature (PubMed) up to December 2014 was undertaken by investigators from perinatal centers in France, with an especial emphasis on PN and the implementation of these guidelines in French neonatal intensive care units. No ethical approval from the local institutional research board has been required for this review. This search identified the most recent reports focusing on the impact of revised PN composition on the main indicators of homeostasis in preterm infants. The following terms were used either alone or in combination: “parenteral nutrition,” “preterm,” “neonate,” “guidelines,” “homeostasis,” “fluid and electrolyte intake,” “fluid and electrolyte balance,” “protein intake,” “amino-acid supplementation,” “human,” and “animal.” We focused on articles published in 2005–2014 but included earlier publications when historically relevant or if the topic had not been adequately addressed in recent years. Articles selected were full-text, English-language papers. References cited in target articles were examined separately and were used to identify additional leads.
This review is focused on the impact of early high amino acid, high caloric, and initial mean fluid intakes on biological disturbances frequently observed in preterm infants including hyperchloremic acidosis, metabolic acidosis other than hyperchloremic, elevated aminoacidemia blood urea and ammonia, hypophosphatemia, glucose tolerance, hyperkalemia, water balance and sodium intolerance, and lipid tolerance.
One of the main characteristics of present guidelines for PN in preterm neonates is the introduction as soon as possible of high protein intake (1.5 g · kg−1 · day−1, and up to 4 g · kg−1 · day−1) (6), which could have a substantial impact on protein homeostasis and renal function. These disturbances were summarized in Table 1.
New Guidelines and the Risk of Hyperchloremic Acidosis
The immaturity of the renal tubules observed in the preterm neonate mimics the situation in renal tubular acidosis (8). The substantial loss of sodium, which is therapeutically replaced with sodium chloride (salt) may exacerbate this phenomenon. An increase in the ratio of plasma chloride relative to sodium lowers the plasma strong ion difference and the pH (9). Hyperchloremia with a normal ion gap is also associated with low blood bicarbonate concentrations and the failure of urinary acidification. As a result of the excessive chloride intake, chloremia can reach concentrations >115 mmol/L, which is associated with metabolic acidosis (10). Another source of chloride is the amino acid mixture. Indeed, the metabolism of cationic amino acids (arginine, histidine, and lysine) releases an excess of protons (H+) and may cause hyperchloremic metabolic acidosis. The cation gap (cationic amino acids − [anionic amino acids + acetate]) may help to determine whether the amino acid mixture is well balanced or not. Heird et al (11) have shown that infants and children receiving amino acid mixtures with high titrable acidity do not become acidotic. Peters et al (12) recommend partially replacing chloride salt by acetate in parenteral perfusion. This reduces the incidence of hyperchloremia and leads to beneficial changes in acid-base status. The decrease in the base deficit, however, is accompanied by a rise in blood carbon dioxide tension (PaCO2) because of carbonic anhydrase activity. Phosphate intake also interferes with acid-base homeostasis affecting the renal regulation of plasma bicarbonate. PN-related factors associated with metabolic acidosis are sodium, chloride intakes in preterm infants (13).
New Guidelines and the Risk of Metabolic Acidosis Other Than Hyperchloremic
If serum albumin is low, the anion gap in commonly used to estimate the presence of excess unmeasured inorganic and organic anions such as ketones, and pyruvate or pyroglutamic acid (14). Jadhav et al (15) have shown that the dose or duration of parenteral amino acid and cysteine administration does not seem to affect arterial acidosis. Metabolic acidosis, however, unrelated to the anion gap is commonly seen in premature children between days 3 and 5 after birth. Balancing cysteine hydrochloride with an equimolar amount of base (acetate) could be an option to prevent metabolic acidosis and promote nitrogen accretion in very preterm infants.
Both adults and neonates must excrete acid generated by metabolism in the form of ammonia and titrable acid. In the preterm infant, the activity of glutaminase, the key enzyme leading to ammonia production, in the kidney is lower, and the renal content of glutamine as a substrate is also low (16). Although no significant changes in ammonia concentration have been observed in response to glutamine supplementation (17), Sato et al (18) have suggested that the low urinary excretion rate of ammonium (NH4+) could be a major cause of metabolic acidosis in the neonatal period. Indeed, neonates need to excrete 2 or 3 times more acids than adults (2–3 mEq · kg−1 · j−1) because of their higher protein intake and bone accretion (19).
New recommendations for PN could be associated with metabolic acidosis via the increase in the amino acid ion gap, hyperchloremic acidosis, and ammonia acidosis.
New Guidelines and the Risk of Elevated Aminoacidemia, Blood Urea, and Ammonia
High protein intake soon after birth (3–4 g · kg−1 · day−1) as part of optimal PN is believed to induce metabolic disturbances in preterm infants. This assumption is based on reports from the early 1970s of azotemia and metabolic acidosis in infants who received protein hydrolysate solutions or the first generation of synthetic crystalline amino acid solutions (12). Since the 1990s, multiple studies have demonstrated that high protein intake (1.0–2.5 g · kg−1 · day−1) with more recently developed parenteral amino acid preparations can not only reverse a negative nitrogen balance in preterm infants but is also relatively safe for preterm infants (20).
Elevated blood urea is often interpreted as a sign of an infant's intolerance to amino acids, especially when it exceeds 10 mmol/L. The relation between plasma urea concentrations and amino acid intake, however, in preterm infants is still unclear. Indeed, some clinical trials with early amino acid infusions up to 3.5 g/kg on the first day of life have found no increase in plasma urea levels, and a poor correlation between plasma urea nitrogen and protein intake (21). In contrast, others have reported significantly higher plasma urea concentrations in infants receiving between 2 and 3.6 g · kg−1 · day−1 of amino acids on the first day of life (15,22–25)(15,22–25)(15,22–25)(15,22–25)(15,22–25). Rising blood urea levels, however, do not necessarily mean intolerance to amino acids but rather reflect the oxidation of amino acids, as seen in utero. Moreover, blood urea concentrations depend on hydration status, renal function, gestational age, and acuteness of illness, and there is limited information as to safe blood urea levels in preterm infants. Therefore, using urea levels as a monitoring tool for protein tolerance remains questionable.
In several studies, plasma ammonia concentrations have been shown to remain in the normal range in preterm infants receiving modern amino acid mixtures early in life (20). Blanco et al (23) have reported elevated ammonia concentrations (ranging from 97 to 123 mmol/L), mostly in extremely preterm infants with very high plasma urea concentrations (>20 mmol/L).
Excessive aminoacidemia has been reported in preterm infants receiving early high amino acid intake compared with healthy term newborns (26,27)(26,27). Other reports, however, do not confirm these data (20,24,26)(20,24,26)(20,24,26). In particular, Thureen et al (26) have demonstrated that 3 g · kg−1 · day−1 beginning on the first day of life is safe and associated with plasma amino acid concentrations remarkably similar to those of second and third trimester fetuses.
Altogether, there is increasing evidence that early high-dose amino acid infusions are relatively well tolerated in the preterm infant with regard to metabolism and renal function. Additional studies, however, are warranted to determine markers of protein intolerance and to specify the optimal composition and amount of amino acid solutions, especially in the very immature preterm infant and following fetal growth restriction.
New Guidelines and the Risk of Hypophosphatemia
During the first few days of life, PN in very preterm infants can be associated with important metabolic disturbances, particularly hypophosphatemia and hypercalcemia, simulating a “repeat feeding–like syndrome” observed after intense nutritional deprivation (28,29)(28,29). These disturbances are closely related to the suboptimal availability of nutrients after the disruption of placental feeding. Indeed, amino acid and energy supply through PN maintains the cell in an anabolic state and promotes the uptake of phosphorus, which forms part of the composition of nucleic acids, ATP, and the cell membrane. This high phosphorus consumption by the cell in the growing newborn causes a decrease in its plasma concentrations. If the phosphorus intake is not adequate to cope with these cellular requirements, the bone acts as a mineral reservoir and releases phosphorus into the circulation to maintain its plasma concentrations. It simultaneously releases calcium into the extracellular space, leading to hypercalcemia and hypercalciuria. A formula to calculate phosphorus needs has recently been elaborated from a prospective observational study (29):
Ph needed* = Ca intake*/2.15 + (amino acid intake** − 1.3) × 0.8 × 12.3,
where * indicates mg · kg−1 · day−1 and ** indicates g · kg−1 · day−1.
Repeated measurement of serum phosphate is essential in the first week of life to adjust phosphorus supplementation to optimize mineralization and extrauterine growth. Hypophosphatemia is defined as a serum phosphate level <5 mg/dL (<1.6 mmol//L) and is usually associated with hypophosphaturia and high bone resorption with hypercalcemia and hypercalciuria. High serum alkaline phosphatase levels in preterm infants are strongly associated with phosphorus deficiency and delayed growth but do not predict outcomes such as metabolic bone disease (30).
The early introduction of amino acids through PN soon after birth could be completed by the early intake of phosphorus, especially in preterm infants born following fetal growth restriction because they are the main determinants of cellular growth.
Impact of New Guidelines on Glucose Tolerance
After birth, continuous transplacental transfer of glucose is interrupted. Maintaining normal glucose concentrations that match those of the normally growing fetus is important for neurodevelopment (27). Glucose is the main energy source for the neonate receiving PN. To ensure that preterm infants receive adequate amounts of glucose, especially for brain energy supply, it should initially be delivered at the hepatic glucose production rate of 6 to 8 mg · kg−1 · min−1. Glucose levels need to be monitored regularly with the initiation of PN because preterm infants are at risk of developing hyperglycemia. Indeed, defective islet β cell processing of proinsulin, peripheral resistance to insulin, and persistent hepatic glucose production during parenteral glucose infusion are likely responsible for PN-related hyperglycemia, especially in growth-restricted and very immature infants (31). In addition to careful monitoring of serum glucose level in PN-fed preterm infants, exogenous insulin infusion is efficient and may be used with caution. Paradoxically, low plasma tyrosine levels associated with an increase in insulin-treated hyperglycemia have been recently reported (32). Early higher amino acid intake significantly increases insulin plasma concentration and could therefore decrease glucose intolerance (26).
Impact of New Guidelines on Potassium Balance
Because potassium balance is directly related to cell growth or catabolism, and to the changes in the intracellular water compartment, it could be strongly influenced by the early amino acid supply. Iacobelli et al (13,33)(13,33) have shown that amino acid intake, energy intake, and extremely low gestational age are all factors influencing potassium balance. The potassium balance is positive (94% of cases) when daily amino acid intake is >2 g · kg−1 · day−1 and negative (92%) when amino acid intake is low (<1.5 g · kg−1 · day−1). Nonoliguric hyperkalemia is observed within the first 2 postnatal days and is less frequent in the high amino acid group (>2 g · kg−1 · day−1) compared with the others. This is in contrast to the report by Elstgeest et al (34) who show that the initiation of PN immediately after birth and restricted fluid intake in very preterm infants do not seem to influence serum sodium or potassium levels during the first 3 postnatal days. Standardized PN according to the new guidelines is not associated with hyperkalemia >7 mmol/L in any infant, although hypokalemia <3 mmol/L occurs in 9% of infants, mainly between 1 and 3 days of life (33).
Impact of New Guidelines for PN on Water Balance and Sodium Intolerance
Natremia and water balance are closely related to renal function and insensible water loss in the most immature neonates. The glomerular filtration rate is extremely low in very preterm infants (<10 mL · min−1 · 1.73m−2) and, coupled with a low sodium reabsorption rate in the proximal tubules and a poor response to antidiuretic hormone in the distal tubules, results in high and variable urinary sodium loss in extremely-low-birth-weight infants (35). Elevated urine output observed during the first few postnatal days is usually associated with extremely low urine osmotic pressure. All of these parameters result in poor renal tubule function in very preterm infants. Insensible water loss, defined as fluid loss through the respiratory tract and skin, is closely related to birth weight, postnatal age, and water pressure in the incubator and in the ventilatory support system. Transepidermal water loss is not associated with sodium loss in very preterm infants because efficient sweating does not occur until the third week after birth (36).
Guidelines to decrease postnatal growth restriction have mainly focused on glucose, amino acid, lipid, and total fluid intake, with weight gain as the main criterion of analysis. Initial mean fluid intakes ranged from 55 to 100 mL · kg−1 · day−1 on the first day of life to reach 150 to 180 mL/kg on the seventh day of life. Provision of sodium starting day 1 is also a key point, and recommended sodium intake ranged from 1.22 to 1.80 mmol/kg on the first day of life (37). The level of amino acid intake group was associated with lower weight loss but had no effect on sodium balance, which was mostly influenced by urine output and postnatal age (38).
Impact of New Guidelines on Lipid Tolerance
Lipid intake should usually provide 25% to 40% of nonprotein calories in fully parenterally fed patients (6). In preterm infants, a lipid supply of 3 g · kg−1 · day−1 as continuous infusion was well tolerated based on the measurement of serum triglycerides and cholesterol (39). Limited tolerance to parenteral lipids reported in the 1970s and the 1980s is no longer observed with recent lipid solutions (40). Triglyceride serum levels should be closely monitored in these populations with long-term lipid infusion. Early parenteral lipid administration seems safe and well tolerated and prevents essential fatty acid deficiency (40), but further studies are necessary to determine the optimal type and dose of lipid infusion. The safety of novel lipid emulsions containing a mixture of soybean oil, medium-chain triglycerides, olive oil, and fish oil, enriched in vitamin E was based on short-term results only (adverse events, serum triglycerides, vital signs, and local tolerance); safety data are not currently available for later endpoints) (41).
Optimal PN following new guidelines in very preterm infants, despite their demonstrated benefits on growth, may induce adverse effects on ionic homeostasis. These effects are enhanced in growth-retarded neonates, who are at risk for metabolic disturbances related to renal intolerance, including acid-base and phosphorus imbalances.
Clinicians should be warned of these adverse effects and should implement appropriate monitoring to prevent or correct them. This monitoring should potentiate the positive effects of optimal PN on long-term neurocognitive development in neonates.
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