Amino acid requirements of total parenteral nutrition (TPN) fed neonates: a narrative review of current knowledge and the basis for a new amino acid solution in neonatal nutrition

Introduction

The global preterm birth rate is 11%, accounting for about 15 million live births (1) annually. Preterm neonates are metabolically immature, born during a period of rapid in utero growth and brain development, when nutrient requirements are high and nutritional imbalances can adversely affect outcome (2-5). Gut immaturity, congenital and acquired gastrointestinal disorders, which all occur frequently in preterm infants, can preclude enteral feeding necessitating the use of parenteral nutrition. Different centers have differing protocols regarding when to commence and how to advance parenteral nutrition; particularly relating to amino acid delivery (6-10). Some maintain that parenteral nutrition should be initiated within the first 24 h after birth with high amino acid intake (3.0–3.5 g.kg⁻¹.d⁻¹) while many argue for a slower, less aggressive introduction and progression (11). More recent data suggest that withholding parenteral nutrition for one week in term neonates was clinically superior to initiation within 24 h (12). However, regardless of the mode of introduction and advancement, many preterm infants require parenteral nutrition for days to months of life. The importance of amino acids for stimulation and maintenance of growth and bodily functions is well understood. Beyond their roles in protein synthesis and growth, amino acids perform functional and regulatory roles, and their intakes, physiological concentrations, as well as concentrations of their metabolites are associated with clinical outcomes in preterm infants (2,13-21). This demonstrates that knowledge of amino acid requirements is necessary in order to provide the ideal amino acid solution for parenterally fed neonates. However, current knowledge of amino acid requirements in total parenteral nutrition (TPN) fed neonates is inadequate and amino acid solutions used in TPN feeding are based on best judgements rather than scientifically derived estimates of requirements in this vulnerable population.

The objective of this review is to summarize current knowledge on amino acid requirements and describe the importance of appropriate composition of amino acids in parenteral nutrition formulas for neonates. The physiological basis for revising current amino acid solutions used in parenteral feeding of neonates is also provided. We present the following article in accordance with the Narrative Review reporting checklist (available at https://pm.amegroups.com/article/view/10.21037/pm-21-27/rc).

Methods

The authors conducted a literature review with a research database search using the following keywords:

“amino acid requirements and neonates”;
“amino acid requirements and parenterally fed neonates”;
“essential amino acid requirements and neonates”.

In addition, personal conversation with the authors of the current manuscript was made to identify publications. Finally, we also review the references list of retrieved publications. A number of publications between 1950 to Aug 2020 were identified and subsequently evaluated to determine if they referred to amino acid requirement in human neonates and neonatal piglets, effect of parenteral nutrition on growth and body composition, splanchnic metabolism of amino acids, neonatal outcomes related to amino acid intake and impact of protein quality on neonatal growth. Papers cited at the back of the manuscript were those agreed upon by all authors to be included in this narrative review.

Discussion

Classification of amino acids and importance of amino acid composition

Classically the α-amino acids, that are the constituents of protein, were divided into essential (indispensable) and non-essential (dispensable) (Table 1). Indispensable amino acids are those which cannot be synthesized in the body and must be obtained exogenously from the diet. Dispensable amino acids on the other hand are those which can be synthesized endogenously. In infants, the classical indispensable amino acids are: the branched chain amino acids (isoleucine, leucine and valine); histidine; lysine; phenylalanine; methionine, threonine; and tryptophan (22). We now recognize that quantitatively important functions of amino acids, which do not involve protein synthesis, must also be considered. These would include the role of cysteine and glycine as components of the major antioxidant, glutathione (23-28), as well as the role of arginine in nitric oxide (NO) synthesis and creatine synthesis (14,29). Hence, as knowledge has accumulated it has been recognized that most of the “dispensable” amino acids are conditionally indispensable (30) (Table 1). That is to say that in illness and in immaturity (both of which apply to premature infants) endogenous synthesis of these amino acids is inadequate. Thus of the 20 constituent amino acids, which make up body proteins, perhaps only alanine, aspartate, serine and glutamate are truly dispensable (22).

Protein quality is a term which refers to a mixture of amino acids in proportions which optimize growth, net protein synthesis (i.e., synthesis minus breakdown) and nitrogen accretion, without supplying any amino acid(s) in an excess, potentially toxic amount. Neonatologists (clinicians) often discuss protein quantity when determining nutritional intake. However, very little attention is paid to protein quality.

Current amino acid solutions used in TPN feeding of neonates

Preterm neonates are at increased risk of poor growth, as well as life-threatening conditions including respiratory distress syndrome, chronic lung disease, persistent pulmonary hypertension, necrotizing enterocolitis (NEC), and neurodevelopmental delay (31-35). While medical advances have increased survival of babies born prematurely, premature infants have poorer outcomes (which extends beyond infancy and childhood) than term infants (36). Optimal nutrition during the early post-natal period is a well-recognized strategy to decrease risk of adverse outcomes in this vulnerable population (16,37-40).

When less than optimal amino acid mixtures are fed parenterally to growing premature infants (41), growth and nitrogen accretion are sub-optimal (42,43). In addition, a variety of aberrations are seen in plasma amino acid profiles (2,20,44,45). However, when the quality of the amino acid mixture is improved, enhanced growth and protein accretion are achieved, largely by a reduction in endogenous protein degradation (46,47).

Current amino acid solutions used in parenteral feeding are patterned after three different approaches. The first approach, patterned the amino acid mixture based on the amino acid composition of egg protein (48), for use in adults. This approach was extrapolated to neonates but instead patterned the amino acids after human milk amino acid composition, the ideal protein source for enterally fed infants. This approach presupposes that the splanchnic bed (gut and liver) absorbs and metabolizes all enterally fed amino acids in the same way and that all enterally consumed amino acids enter the circulation—an assumption that isotope studies have disproved (42,49-55). The second approach was to use the amino acid composition of cord blood. This commercial solution is currently widely used in Neonatal Intensive Care Units (NICU) in North America and Europe (47,56). The third approach was to computer model the plasma amino acid response to parenteral amino acid administration (56). A commercial paediatric amino acid solution was developed based on this approach and is commonly used in NICUs in the USA. This approach cannot account for rates of entry and exit of amino acids from the plasma pool but presupposes that optimal plasma amino acid concentrations are known. Table 2 presents the composition of the two most common commercial amino acid solutions for neonates.

Demonstrating the importance of protein quality, leucine turnover in preterm infants was assessed in response to two of the three amino acid solutions; the one patterned after cord blood (Primene^®) and the other modeled after plasma amino acids (Trophamine^®) (47). Despite a higher intake of leucine in the Trophamine group, leucine breakdown on day 7 was higher in the infants receiving Trophamine than those receiving Primene, indicating that protein quality was affecting leucine metabolism. Whilst this suggests that Primene may have a better protein quality/amino acid profile compared to Trophamine, this does not provide evidence that the amino acid composition is optimal. Another important difference between Primene^® and Trophamine^® is the tyrosine source. While Primene^® contains L-tyrosine, the tyrosine source in Trophamine^® is N-acetyl-L-tyrosine which has a poor bioavailability in neonates (56). Indeed, as an initial step towards assessing parenteral amino acid requirements, others have evaluated available commercial amino acid solutions supplied to critically ill children (57). They found that the concentrations of amino acids in current amino acid solution used for parenteral feeding were either inadequate or excessive and concluded that “amino acid composition of parenteral formulas is variable and lacks scientific support. Parenteral amino acid intakes should be based on measured requirements to maintain nutrition and functional balance and on a knowledge of toxicity” (57). In a more recent review on amino acid intake in parenterally fed newborn infants, the authors concluded that” adequately powered trials in very preterm infants are required to determine the optimal intake of amino acid” (58). Although they were referring to very preterm newborn infants, their observation underlines the lack of adequate information on amino requirements for all parenterally fed neonates.

Methods for determining amino acid requirements

Traditionally, amino acid requirements were studied using nitrogen balance in response to feeding graded intakes of the test amino acids (59). This approach has limitations which have been extensively reviewed (60). One such limitation is the long period required to adapt subjects to each amino acid intake (60). As far as neonates are concerned such studies would require exposing the infant to a deficient intake of the test amino acids for 7 to 10 days, which is unethical. Furthermore, nitrogen balance is not sensitive enough to detect differences in protein quality (61). Hence, alternate methods based on amino acid oxidation (62,63) have been developed. Recent reviews of this topic may be found in (64,65). Indicator oxidation/balance is now recognized as the optimal methods for determining amino acid requirements (66,67). Most applicable to neonates is the minimally invasive indicator amino acid oxidation method, since the infant is exposed to a deficient, or excess intake for only a period of 24 h and only breath and urine are collected (20,68-70).

The development of the indicator amino acid oxidation method provided a major breakthrough for the study of amino acid requirements (62,71). However, it was the development and validation of the neonatal piglet model (72-74) which allowed for a comprehensive assessment of the effect of parenteral nutrition on amino acid requirements and metabolism in neonates. Similarities in anatomy, physiology and metabolism has deemed the neonatal piglet the best model for the human neonate (75,76).

Amino acid requirements of parenterally fed neonates

Using the neonatal piglet model, the group led by Ball and Pencharz worked for almost 30 years to systematically determine parenteral requirements for dietary indispensable and conditionally indispensable amino acids and compared the estimates with enteral requirements (51-54,77-80). They began with an estimate of the phenylalanine requirement (79) using direct amino acid oxidation method and from then used phenylalanine as the indicator amino acid to estimate the requirement for lysine (78), tyrosine (77), threonine (52), methionine in the absence and presence of dietary cysteine (51,81), branched chain amino acids (leucine, isoleucine and valine) (53) and tryptophan (54). The most novel and significant findings are that the parenteral threonine, methionine and total branched chain amino acid requirements are 40%, 69%, and 56% respectively of enteral requirements, while tryptophan requirements are not altered by the route of feeding (51-54) (Table 3). These groundbreaking results demonstrate that the gut is an important site of amino acid metabolism (42,49,85) and when it is bypassed the requirements for most amino acids during parenteral feeding are significantly lower. These findings were independently confirmed by others using different methodologies (73,74). Using the piglet model, Stoll et al. demonstrated that approximately 30% of dietary amino acid intake is utilized on first-pass metabolism. Interestingly approximately 60% of the amino acid taken up on first pass is catabolized by the intestine (73,74). The authors propose that this could be a significant source of energy for the small intestinal mucosa (73,74). Indeed whether used as a source of energy or for incorporation into mucin as in the case of threonine (86), small intestinal metabolism contributes to a significant portion of several amino acid requirements as demonstrated by the number of studies showing lower amino acid requirements of TPN fed compared to enterally fed neonates (51,53,81,86).

These differences in amino acid metabolism between routes of feeding need consideration when designing an amino acid solution for neonates. Additionally the neonate cannot be considered a small adult as immaturity of enzyme pathways and underdeveloped organs may be susceptible to the effects of early nutrition (3-5,87-89). Some have shown that excess protein and amino acid intakes have been linked to permanent damage to the brain (2,90), while more recent systematic review has provided inconclusive results (58). In low-birth-weight infants (42), splanchnic extraction of leucine was observed to be twice as high as in adults (91-93) demonstrating significant differences in amino acid metabolism between the neonate and adult human. The piglet derived estimates also supported the conclusions made by others that current amino acid solutions patterned after cord blood, plasma amino acids or human milk are inadequate (47,57).

Building on knowledge and experience gained from the piglet studies, the minimally invasive indicator amino acid oxidation method (94) was applied in parenterally fed human neonates to determine the requirements for total sulphur amino acid (20) (as methionine only), threonine (68) lysine (69) and tyrosine (82). Since piglets grow at 5 times the rate of the human neonate, it was hypothesized that the requirement in the human neonate will be 1/5^th the estimate obtained from the neonatal piglet model. While it was possible to accurately predict the requirement for methionine and threonine, it was not so for tyrosine and lysine. Thus, is it important that the requirement for each amino acid be derived separately in human neonates. More importantly however, the derived human neonate estimates were up to 90% lower for methionine, threonine and lysine but 70% higher for tyrosine than in current commercial amino acid solutions (Table 4).

In addition, using the indicator amino acid oxidation method, van Goudoever’s group has estimated the requirement for several indispensable amino acids in enterally fed infants (83,84,95-98). When compared to the parenterally derived estimates (68,69), their estimates of threonine (84) and lysine (83) requirements in enterally fed neonates were 100% and 25% higher. This provides support for the data obtained in the piglet model that when the gut is bypassed, amino acid requirements for most amino acids are lower. Furthermore, this provides additional evidence to support the conclusion that current commercial amino acid solutions for parenterally fed neonates are inadequate (99).

Importance of optimal parenteral amino acid therapy for premature infants

Preterm neonates are vulnerable and complex patients and the long-term consequences of providing too little or too much amino acids are not known. Growth is a dynamic process, which from the view of protein metabolism is, a positive balance between whole body protein synthesis and breakdown (100). Accretion of body proteins during growth is dependent on optimal intakes of all indispensable amino acids as well as an adequate supply of dispensable amino acids (or nitrogen for their synthesis), plus non-protein energy (101). If the pattern of amino acids is not ideal, the rate of protein synthesis, and in turn growth, will be determined by the first limiting amino acid. The excess amounts of all other amino acids must be oxidized which could overload immature degradative pathways and increase the risk of toxicity (99). Provision of the correct balance of amino acids is also important because of the roles of specific amino acids in health outcomes, beyond protein synthesis and growth. Data from the piglet model suggest that the ideal amino acid composition (protein quality) of amino acid solutions used for parenteral fed preterm neonates will be different from enterally fed proteins (51-53).

Traditionally, the main focus of nutrition management in preterm infants has been to duplicate in utero growth rates (102) with a “more is better” approach, and little understanding of the metabolic needs of individual nutrients, particularly protein and amino acids. However, there is evidence that premature babies are vulnerable to the neuro-cognitive programming effects of early nutrition (87). For example, the brain of preterm neonates is sensitive to the balance of amino acids in human milk vs. preterm formula (5,89) and older data demonstrate the vulnerability of the brain to excess protein and amino acid intakes affecting school performance (2,90). There is increasing evidence that the amino acid arginine plays a key role in the health of the premature neonate, in addition to its role in protein synthesis, and ammonia clearance, through the urea cycle (13). In the preterm neonate it exerts additional effects as a precursor of NO, which affects lung (14,15) and gut health (16,18). Further, the balance between the dietary sulphur amino acids methionine and cysteine affect plasma homocysteine concentration in preterm neonates (19,20) in whom hyperhomocysteinemia is a risk factor for ischemic and hemorrhagic stroke (21). This emerging body of evidence on the effects of early nutrition and the balance of nutrients on long-term outcomes provides a new lens with which current amino acid solutions for parenterally fed neonates should be evaluated.

The metabolic and physiological basis for a revised amino acid solution for the parenteral fed neonate

In addition to differences in amino acid requirements between enterally and parenterally fed neonates, data from neonatal piglets demonstrate that the amino acid composition (protein quality) of amino acid solutions used for TPN fed preterm neonates should be largely different from enterally fed proteins (51-53). Therefore, the requirements for all indispensable and conditionally indispensable amino acids should be determined as precisely as possible in order to establish an appropriate proportion of amino acids in the amino acid mixtures, used for parenterally fed preterm neonates. In particular, the following amino acids need special consideration.

Arginine

Using the neonatal piglet model, it was demonstrated that arginine is an indispensable amino acid in preterm parenterally fed neonates (55,103). Neonatal piglets receiving arginine-free TPN develop severe hyperammonemia within hours (55). Many authors have reported on hyperammonemia in preterm TPN fed infants (44,104) which can be corrected by arginine supplementation (104). Our group demonstrated in piglets (55,105,106) as well as human neonates (107) that de novo arginine synthesis in neonates is dependent on small intestinal metabolism. Arginine is the only known biological precursor of NO and inadequate arginine has been associated with neonatal necrotizing enterocolits and persistent pulmonary hypertension (14,17,108,109). While arginine supplementation reduced all stage necrotizing enterocolits in a randomized control trial (17), the data was not as clear regarding persistent pulmonary hypertension. More recent data demonstrate that TPN fed preterm infants continue to have low plasma arginine despite adequate essential amino acid and protein intakes (110,111) and that the low plasma arginine was associated with poor glucose control and plasma arginine intake (112). Badurdeen et al. (113) proposed that arginine deficiency is the key factor which increases the susceptibility of neonates to infections. More recent data by Zheng et al. (114), showed that arginine supplementation to the diet of enterally fed low-birth-weight neonatal piglets improved intestinal barrier function and antioxidant capacity as well as weight gain. Arginine content of commercial TPN solution is the most variable of all essential amino acids ranging from 4.7% to 12.3% (99). Premakumar et al. (112) recently suggested that arginine concentration of amino acid solutions for preterm neonates should be 17–20%. In order to prevent deficiency or toxicity, the dietary requirement for arginine should be defined in the parenterally fed neonate.

Methionine and cysteine

Methionine and cysteine are the sulphur containing amino acids. Cysteine is generally considered dispensable because under normal conditions, it can be formed from methionine. Current TPN solutions contain little to no cysteine because cysteine is unstable in solution, oxidized to the insoluble form, cystine (115). Therefore, commercial TPN solutions contain relatively high methionine concentrations to meet the total sulphur amino acid requirement. Despite this practice, many published studies report low plasma cysteine in preterm neonates receiving cysteine-free, high methionine TPN (116-119). Therefore, for many years cysteine was believed to be an essential amino acids in the preterm neonate (120). However, Zlotkin et al. were the first to demonstrate that preterm TPN fed neonates did not need pre- formed cysteine to maintain adequate growth and nitrogen balance (115). Although this was confirmed in neonatal piglet and human studies (20,51,121,122), when the total sulphur amino acids intake was provided as methionine only, hyperhomocysteinemia and high plasma methionine developed in both piglets and human neonates (19,20). This demonstrates that although neonates could synthesize adequate cysteine from methionine for growth, sulphur amino acids would be better provided as a balance between methionine and cysteine to avoid overload of the immature catabolic pathway (123). Methionine is considered one of the most toxic amino acids (124,125) and high plasma methionine has been identified as a contributing factor in the pathogenesis of TPN-associated cholestasis in neonates (126).

In addition to their role in protein synthesis, the sulphur amino acids have been of particular interest because cysteine is a key component of glutathione (127). Glutathione (GSH) is the most prevalent intracellular thiol (24), and the [GSH]:[GSSG] ratio is used as an indicator of cellular redox state. GSH is also the most important endogenous antioxidant (128). In TPN fed neonates, it was shown that when sufficient methionine is given to meet the needs for protein synthesis, additional cysteine did not increase GSH concentration or rates of synthesis (129). This along with data from van Goudoever’s group (130) provide confirmation that cysteine is not a conditionally essential amino acid in neonates.

Although adequate cysteine for growth and GSH synthesis can be provided as methionine only, high plasma methionine and hyperhomocysteinemia observed when the total sulphur amino acids is provided as methionine only suggest that provisions of the sulphur amino acids as a balance between methionine and cysteine are important considerations when designing an amino acid solution for the TPN fed neonate. This is now possible due to the availability of a soluble form of cysteine; N-acetyl cysteine which is highly bioavailable precursor of cysteine (129,131) to meet the needs for nitrogen accretion and growth in the neonate. Currently, no commercial amino acid solution contains this cysteine precursor.

Phenylalanine and tyrosine

Phenylalanine and tyrosine are the aromatic amino acids. Phenylalanine is indispensable and is the precursor for tyrosine which in healthy individuals is dispensable. Tyrosine has low solubility; therefore, excess phenylalanine is added to TPN to meet the needs of the total aromatic acids. However, hyperphenylalaninemia and low plasma tyrosine have been observed in infants receiving high phenylalanine- low tyrosine containing TPN (132-134). This suggests that phenylalanine hydroxylation to tyrosine is limited making tyrosine a conditionally indispensable amino acid in TPN fed neonates. The requirement for tyrosine in TPN fed preterm neonates was estimated using commercial TPN solutions with graded amounts of the soluble form of tyrosine (glycyl-tyrosine) (82). The neonates had high urinary phenylalanine as well as metabolites of phenylalanine catabolism indicating an overload of the catabolic pathway involved in phenylalanine degradation (135). The derived tyrosine requirement was over 70% higher than available in current TPN solutions (Table 3). Data from the neonatal piglet model previously demonstrated that in TPN fed neonatal piglets, there is a limit to which excess phenylalanine can be oxidized and that free phenylalanine accumulates beyond this limit (79). This is very concerning since the long-term effects of high phenylalanine in TPN fed preterm neonates is not known. We do know however, that high phenylalanine in patients with phenylketonuria is associated with significant neurocognitive damage (136-138). It is now possible to provide tyrosine as glycyl-tyrosine, a soluble and highly bioavailable precursor of tyrosine (77,82), and discontinue the practice of providing excessive phenylalanine to meet the needs for tyrosine in parenteral neonatal amino acid solutions.

Leucine, isoleucine, valine

From the neonatal piglet model it was observed that parenteral requirement for the BCAA; leucine, isoleucine and valine were only 56% of the enteral requirement (53). In addition, the plasma amino acid pattern observed in the TPN and enterally fed piglets suggest that the optimum ratio of BCAA differ between routes of feeding (53). The pattern of BCAA in TPN solutions for preterm neonates is similar to human milk but the absolute amount of each BCAA is higher in TPN (99) than in human milk. This suggest, current BCAA composition and ratios of current TPN solutions are inappropriate for TPN fed neonates.

Tryptophan

Beyond its role in protein synthesis tryptophan is important for synthesis of the neurotransmitter serotonin and the hormone melatonin (139). Interestingly in neonatal piglet studies the TPN and enteral requirements for tryptophan were not different (54). Based on extrapolations from that data (54), the tryptophan content of current TPN solutions is likely double the requirement of the preterm TPN fed neonate. However, long-term effects of excessive tryptophan intake in TPN fed preterm neonates is unknown. Therefore, it is important to accurately define its requirement.

Histidine

Histidine is an essential amino acid in preterm infants (22). Beyond its role in protein synthesis it is involved in allergic reactions, and modulation of the immune response in skin. It is also involved in regulation of gut function (140). No data exist on histidine requirement in the TPN fed piglet or human neonate. Hence it is not possible to assess whether current commercial amino acids have an excess or deficiency of this amino acid.

Glutamine

Conclusive evidence on the essentiality of glutamine in neonates is lacking. Conflicting data exist on its efficacy in critically ill patients. While some data suggest that glutamine supplementation reduced mortality in critically ill adults (141), more recent data suggest no effect of glutamine supplementation (142). Glutamine is the most abundant amino acid in the muscle and plasma of humans (143). It is not included in commercial amino acid solutions because it is unstable in solution. Beyond its role in protein synthesis glutamine is involved in many metabolic reactions including the synthesis of glutathione (via glutamate). It is believed that during stress glutamine production may be insufficient to meet increased demands especially in low-birth-weight neonates who have limited reserve (143). Although glutamine supplementation did not result in apparent biochemical risk in TPN fed low-birth-weight infants (144), decreased tyrosine and phenylalanine concentrations were observed in the glutamine supplemented group. Furthermore, glutamine supplementation in parenterally fed neonatal piglets resulted in expansion of the plasma volume; a component of the extracellular fluid and indicated that glutamine is not conditionally indispensable in neonates (145).

Summary & conclusions

Despite the increased need for TPN in premature infants and the recognition that amino acid intake affects clinical outcomes, the scientifically derived requirement estimates for all indispensable and conditionally indispensable amino acids in TPN fed preterm infants have not been derived. Amino acid composition of current commercial solutions are estimates and neonatologists agree that “amino acid composition of parenteral formulas is variable and lacks scientific support”. Preterm neonates are extremely complex and vulnerable patients and uncertainty exists concerning the long-term effects of excess or inadequate amino acid intakes. Randomized clinical trials demonstrate that long-term cognitive performance of preterm infants is adversely affected by suboptimal early nutrition (3).

Using a neonatal piglet model, it was demonstrated that the gut variably utilizes dietary amino acids (ranging from nil for tryptophan to 60% for threonine). It is now confirmed that both tyrosine and arginine are conditionally essential and that the sulphur amino acids are best provided in TPN as a balance between the two to prevent high plasma methionine and homocysteine in the preterm neonate. These observations have been made in human neonates, in whom the requirements for tyrosine, lysine, maximum methionine and threonine have been estimated. The quantitative significance of amino acids beyond their roles in protein synthesis and the impact of prematurity are important consideration when designing an optimal amino acid solution for the parenterally fed neonate. In addition, neonates are not small adults as differences in amino acid metabolism exist between neonates and adults. More research needs to be done so that an amino acid solution with a scientifically derived pattern of amino acid could be designed for neonates requiring parenteral nutrition.

Limitations of the review

A key limitation of this review is that all data on amino acid requirements in the parenterally fed neonates is based on data obtained from carbon oxidation studies using the indicator amino acid oxidation method. This is because data using other methods of which nitrogen balance is the classical method is not available. The adequacy of these data remains to be tested in long-term trials pending the formulation of an amino acid solution designed after all indispensable amino acid requirements have been estimated.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://pm.amegroups.com/article/view/10.21037/pm-21-27/rc

Peer Review File: Available at https://pm.amegroups.com/article/view/10.21037/pm-21-27/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://pm.amegroups.com/article/view/10.21037/pm-21-27/coif). GCM serves as an unpaid editorial board member of Pediatric Medicine from July 2020 to June 2022. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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References

1. Chawanpaiboon S, Vogel JP, Moller AB, et al. Global, regional, and national estimates of levels of preterm birth in 2014: a systematic review and modelling analysis. Lancet Glob Health 2019;7:e37-e46. [Crossref] [PubMed]
2. Menkes JH, Welcher DW, Levi HS, et al. Relationship of elevated blood tyrosine to the ultimate intellectual performance of premature infants. Pediatrics 1972;49:218-24. [Crossref] [PubMed]
3. Lucas A, Morley R, Cole TJ. Randomised trial of early diet in preterm babies and later intelligence quotient. BMJ 1998;317:1481-7. [Crossref] [PubMed]
4. Lucas A, Morley R, Cole TJ, et al. Early diet in preterm babies and developmental status in infancy. Arch Dis Child 1989;64:1570-8. [Crossref] [PubMed]
5. Lucas A, Morley R, Cole TJ, et al. Early diet in preterm babies and developmental status at 18 months. Lancet 1990;335:1477-81. [Crossref] [PubMed]
6. Thureen PJ, Melara D, Fennessey PV, et al. Effect of low versus high intravenous amino acid intake on very low birth weight infants in the early neonatal period. Pediatr Res 2003;53:24-32. [Crossref] [PubMed]
7. Ziegler EE, Thureen PJ, Carlson SJ. Aggressive nutrition of the very low birthweight infant. Clin Perinatol 2002;29:225-44. [Crossref] [PubMed]
8. Thureen PJ, Hay WW Jr. Early aggressive nutrition in preterm infants. Semin Neonatol 2001;6:403-15. [Crossref] [PubMed]
9. te Braake FW, van den Akker CH, Wattimena DJ, et al. Amino acid administration to premature infants directly after birth. J Pediatr 2005;147:457-61. [Crossref] [PubMed]
10. Porcelli PJ Jr, Sisk PM. Increased parenteral amino acid administration to extremely low-birth-weight infants during early postnatal life. J Pediatr Gastroenterol Nutr 2002;34:174-9. [Crossref] [PubMed]
11. Pillai A, Albersheim S, Elango R. High-dose parenteral amino acid intake in very low birthweight infants: what is the current evidence? Curr Opin Clin Nutr Metab Care 2019;22:236-41. [Crossref] [PubMed]
12. van Puffelen E, Vanhorebeek I, Joosten KFM, et al. Early versus late parenteral nutrition in critically ill, term neonates: a preplanned secondary subgroup analysis of the PEPaNIC multicentre, randomised controlled trial. Lancet Child Adolesc Health 2018;2:505-15. [Crossref] [PubMed]
13. Ball RO, Urschel KL, Pencharz PB. Nutritional consequences of interspecies differences in arginine and lysine metabolism. J Nutr 2007;137:1626S-1641S. [Crossref] [PubMed]
14. Castillo L, DeRojas-Walker T, Yu YM, et al. Whole body arginine metabolism and nitric oxide synthesis in newborns with persistent pulmonary hypertension. Pediatr Res 1995;38:17-24. [Crossref] [PubMed]
15. McCaffrey MJ, Bose CL, Reiter PD, et al. Effect of L-arginine infusion on infants with persistent pulmonary hypertension of the newborn. Biol Neonate 1995;67:240-3. [Crossref] [PubMed]
16. Wu G, Jaeger LA, Bazer FW, et al. Arginine deficiency in preterm infants: biochemical mechanisms and nutritional implications. J Nutr Biochem 2004;15:442-51. [Crossref] [PubMed]
17. Amin HJ, Zamora SA, McMillan DD, et al. Arginine supplementation prevents necrotizing enterocolitis in the premature infant. J Pediatr 2002;140:425-31. [Crossref] [PubMed]
18. Zamora SA, Amin HJ, McMillan DD, et al. Plasma L-arginine concentrations in premature infants with necrotizing enterocolitis. J Pediatr 1997;131:226-32. [Crossref] [PubMed]
19. Shoveller AK, House JD, Brunton JA, et al. The balance of dietary sulfur amino acids and the route of feeding affect plasma homocysteine concentrations in neonatal piglets. J Nutr 2004;134:609-12. [Crossref] [PubMed]
20. Courtney-Martin G, Chapman KP, Moore AM, et al. Total sulfur amino acid requirement and metabolism in parenterally fed postsurgical human neonates. Am J Clin Nutr 2008;88:115-24. [Crossref] [PubMed]
21. Hogeveen M, Blom HJ, Van Amerongen M, et al. Hyperhomocysteinemia as risk factor for ischemic and hemorrhagic stroke in newborn infants. J Pediatr 2002;141:429-31. [Crossref] [PubMed]
22. Pencharz PB, House JD, Wykes LJ, et al. What are the essential amino acids for the preterm and term infant? In: Visser JGBCGKA, editor. Recent Developments in Infant Nutrition. (NUSY, volume 9). doi: 10.1007/978-94-009-1790-3: Springer, Dordrecht; 1996:278-96.10.1007/978-94-009-1790-3
23. Lu SC. Regulation of glutathione synthesis. Curr Top Cell Regul 2000;36:95-116. [Crossref] [PubMed]
24. Meister A, Anderson ME. Glutathione. Annu Rev Biochem 1983;52:711-60. [Crossref] [PubMed]
25. Nguyen D, Hsu JW, Jahoor F, et al. Effect of increasing glutathione with cysteine and glycine supplementation on mitochondrial fuel oxidation, insulin sensitivity, and body composition in older HIV-infected patients. J Clin Endocrinol Metab 2014;99:169-77. [Crossref] [PubMed]
26. Stipanuk MH, Coloso RM, Garcia RA, et al. Cysteine concentration regulates cysteine metabolism to glutathione, sulfate and taurine in rat hepatocytes. J Nutr 1992;122:420-7. [Crossref] [PubMed]
27. Szeinberg A, Ramot B, Sheba C, et al. Glutathione metabolism in cord and newborn infant blood. J Clin Invest 1958;37:1436-41. [Crossref] [PubMed]
28. Wu G, Fang YZ, Yang S, et al. Glutathione metabolism and its implications for health. J Nutr 2004;134:489-92. [Crossref] [PubMed]
29. Wu G, Knabe DA, Kim SW. Arginine nutrition in neonatal pigs. J Nutr 2004;134:2783S-2790S; discussion 2796S-2797S. [Crossref] [PubMed]
30. Millward DJ, Jackson AA, Price G, et al. Human amino acid and protein requirements: current dilemmas and uncertainties. Nutr Res Rev 1989;2:109-32. [Crossref] [PubMed]
31. Kinney HC. The near-term (late preterm) human brain and risk for periventricular leukomalacia: a review. Semin Perinatol 2006;30:81-8. [Crossref] [PubMed]
32. Ramenghi LA. Late preterm babies and the risk of neurological damage. Acta Biomed 2015;86:36-40. [PubMed]
33. Mwaniki MK, Atieno M, Lawn JE, et al. Long-term neurodevelopmental outcomes after intrauterine and neonatal insults: a systematic review. Lancet 2012;379:445-52. [Crossref] [PubMed]
34. Araújo BF, Zatti H, Madi JM, et al. Analysis of neonatal morbidity and mortality in late-preterm newborn infants. J Pediatr (Rio J) 2012;88:259-66. [Crossref] [PubMed]
35. Platt MJ. Outcomes in preterm infants. Public Health 2014;128:399-403. [Crossref] [PubMed]
36. Lim G, Tracey J, Boom N, et al. CIHI survey: Hospital costs for preterm and small-for-gestational age babies in Canada. Healthc Q 2009;12:20-4. [Crossref] [PubMed]
37. Kumar RK, Singhal A, Vaidya U, et al. Optimizing Nutrition in Preterm Low Birth Weight Infants-Consensus Summary. Front Nutr 2017;4:20. [Crossref] [PubMed]
38. Chan SH, Johnson MJ, Leaf AA, et al. Nutrition and neurodevelopmental outcomes in preterm infants: a systematic review. Acta Paediatrica 2016;105:587-99. [Crossref] [PubMed]
39. Hortensius LM, van Elburg RM, Nijboer CH, et al. Postnatal Nutrition to Improve Brain Development in the Preterm Infant: A Systematic Review From Bench to Bedside. Front Physiol 2019;10:961. [Crossref] [PubMed]
40. Gidi NW, Mekasha A, Nigussie AK, et al. Preterm Nutrition and Clinical Outcomes. Glob Pediatr Health 2020;7:2333794X20937851.
41. Pencharz P, Beesley J, Sauer P, et al. Total-body protein turnover in parenterally fed neonates: effects of energy source studied by using [15N]glycine and [1-13C]leucine. Am J Clin Nutr 1989;50:1395-400. [Crossref] [PubMed]
42. Beaufrère B, Fournier V, Salle B, et al. Leucine kinetics in fed low-birth-weight infants: importance of splanchnic tissues. Am J Physiol 1992;263:E214-20. [PubMed]
43. Pencharz PB. Nutrition of the low birth weight infant. In: Grand RJ, Sutphen JL, Deitz WH. editors. Pediatric Nutrition; Theory and Practice. Butterworth 1987:313-26.
44. Heird WC, Nicholson JF, Driscoll JM Jr, et al. Hyperammonemia resulting from intravenous alimentation using a mixture of synthetic l-amino acids: a preliminary report. J Pediatr 1972;81:162-5. [Crossref] [PubMed]
45. Kashyap S, Okamoto E, Kanaya S, et al. Protein quality in feeding low birth weight infants: a comparison of whey-predominant versus casein-predominant formulas. Pediatrics 1987;79:748-55. [PubMed]
46. Wykes LJ, House JD, Ball RO, et al. Amino acid profile and aromatic amino acid concentration in total parenteral nutrition: effect on growth, protein metabolism and aromatic amino acid metabolism in the neonatal piglet. Clin Sci (Lond) 1994;87:75-84. [Crossref] [PubMed]
47. Sáenz de Pipaón M, Quero J, Wattimena DJ, et al. Effect of two amino acid solutions on leucine turnover in preterm infants. Biol Neonate 2005;87:236-41. [Crossref] [PubMed]
48. Wretlind A. Complete intravenous nutrition. Theoretical and experimental background. Nutr Metab 1972;14:1-57. [Crossref] [PubMed]
49. Matthews DE, Marano MA, Campbell RG. Splanchnic bed utilization of leucine and phenylalanine in humans. Am J Physiol 1993;264:E109-18. [PubMed]
50. Biolo G, Tessari P, Inchiostro S, et al. Leucine and phenylalanine kinetics during mixed meal ingestion: a multiple tracer approach. Am J Physiol 1992;262:E455-63. [PubMed]
51. Shoveller AK, Brunton JA, Pencharz PB, et al. The methionine requirement is lower in neonatal piglets fed parenterally than in those fed enterally. J Nutr 2003;133:1390-7. [Crossref] [PubMed]
52. Bertolo RF, Chen CZ, Law G, et al. Threonine requirement of neonatal piglets receiving total parenteral nutrition is considerably lower than that of piglets receiving an identical diet intragastrically. J Nutr 1998;128:1752-9. [Crossref] [PubMed]
53. Elango R, Pencharz PB, Ball RO. The branched-chain amino acid requirement of parenterally fed neonatal piglets is less than the enteral requirement. J Nutr 2002;132:3123-9. [Crossref] [PubMed]
54. Cvitkovic S, Bertolo RF, Brunton JA, et al. Enteral tryptophan requirement determined by oxidation of gastrically or intravenously infused phenylalanine is not different from the parenteral requirement in neonatal piglets. Pediatr Res 2004;55:630-6. [Crossref] [PubMed]
55. Brunton JA, Bertolo RF, Pencharz PB, et al. Proline ameliorates arginine deficiency during enteral but not parenteral feeding in neonatal piglets. Am J Physiol 1999;277:E223-31. [PubMed]
56. Heird WC, Dell RB, Helms RA, et al. Amino acid mixture designed to maintain normal plasma amino acid patterns in infants and children requiring parenteral nutrition. Pediatrics 1987;80:401-8. [PubMed]
57. Verbruggen S, Sy J, Arrivillaga A, et al. Parenteral amino acid intakes in critically ill children: a matter of convenience. JPEN J Parenter Enteral Nutr 2010;34:329-40. [Crossref] [PubMed]
58. Osborn DA, Schindler T, Jones LJ, et al. Higher versus lower amino acid intake in parenteral nutrition for newborn infants. Cochrane Database Syst Rev 2018;3:CD005949. [Crossref] [PubMed]
59. Holt LE, Snyderman SE. The amino acid requirements of children. In: Nyhan WL. editor. Amino Acid Metabolism and Genetic Variation McGraw-Hill; 1967:381-90.
60. Fuller MF, Garlick PJ. Human amino acid requirements: can the controversy be resolved? Annu Rev Nutr 1994;14:217-41. [Crossref] [PubMed]
61. Barness LA, Omans WB, Rose CS, et al. Progress of premature infants fed a formula containing demineralized whey. Pediatrics 1963;32:52-3. [Crossref] [PubMed]
62. Ball RO, Bayley HS. Tryptophan requirement of the 2.5-kg piglet determined by the oxidation of an indicator amino acid. J Nutr 1984;114:1741-6. [Crossref] [PubMed]
63. Brookes IM, Owens FN, Garrigus US. Influence of amino acid level in the diet upon amino acid oxidation by the rat. J Nutr 1972;102:27-35. [Crossref] [PubMed]
64. Elango R, Ball RO, Pencharz PB. Indicator amino acid oxidation: concept and application. The Journal of nutrition 2008;138:243-6. [Crossref] [PubMed]
65. Zello GA, Wykes LJ, Ball RO, et al. Recent advances in methods of assessing dietary amino acid requirements for adult humans. J Nutr 1995;125:2907-15. [PubMed]
66. DRI. The Institute of Medicine, Food and Nutrition Board, Dietary Reference Intakes: Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein and Amino Acids. Washington DC: The National Academy Press; 2005.
67. FAO/WHO/UNU. Protein and amino acid requirements in human nutrition: World Health Organization, Geneva, Switzerland; 2007:1-265.
68. Chapman KP, Courtney-Martin G, Moore AM, et al. Threonine requirement of parenterally fed postsurgical human neonates. Am J Clin Nutr 2009;89:134-41. [Crossref] [PubMed]
69. Chapman KP, Courtney-Martin G, Moore AM, et al. Lysine requirement in parenterally fed postsurgical human neonates. Am J Clin Nutr 2010;91:958-65. [Crossref] [PubMed]
70. de Groof F, Huang L, Twisk JW, et al. New insights into the methodological issues of the indicator amino acid oxidation method in preterm neonates. Pediatr Res 2013;73:679-84. [Crossref] [PubMed]
71. Kim KI, McMillan I, Bayley HS. Determination of amino acid requirements of young pigs using an indicator amino acid. Br J Nutr 1983;50:369-82. [Crossref] [PubMed]
72. Wykes LJ, Ball RO, Pencharz PB. Development and validation of a total parenteral nutrition model in the neonatal piglet. J Nutr 1993;123:1248-59. [Crossref] [PubMed]
73. Stoll B, Burrin DG, Henry J, et al. Dietary amino acids are the preferential source of hepatic protein synthesis in piglets. J Nutr 1998;128:1517-24. [Crossref] [PubMed]
74. Stoll B, Henry J, Reeds PJ, et al. Catabolism dominates the first-pass intestinal metabolism of dietary essential amino acids in milk protein-fed piglets. J Nutr 1998;128:606-14. [Crossref] [PubMed]
75. Book SA, Bustad LK. The fetal and neonatal pig in biomedical research. J Anim Sci 1974;38:997-1002. [Crossref] [PubMed]
76. Miller ER, Ullrey DE. The pig as a model for human nutrition. Annu Rev Nutr 1987;7:361-82. [Crossref] [PubMed]
77. House JD, Pencharz PB, Ball RO. Tyrosine kinetics and requirements during total parenteral nutrition in the neonatal piglet: the effect of glycyl-L-tyrosine supplementation. Pediatr Res 1997;41:575-83. [Crossref] [PubMed]
78. House JD, Pencharz PB, Ball RO. Lysine requirement of neonatal piglets receiving total parenteral nutrition as determined by oxidation of the indicator amino acid L-[1-14C]phenylalanine. Am J Clin Nutr 1998;67:67-73. [Crossref] [PubMed]
79. House JD, Pencharz PB, Ball RO. Phenylalanine requirements determined by using L-[1-14C]phenylalanine in neonatal piglets receiving total parenteral nutrition supplemented with tyrosine. Am J Clin Nutr 1997;65:984-93. [Crossref] [PubMed]
80. Elango R, Humayun MA, Ball RO, et al. Indicator amino acid oxidation is not affected by period of adaptation to a wide range of lysine intake in healthy young men. J Nutr 2009;139:1082-7. [Crossref] [PubMed]
81. Shoveller AK, Brunton JA, House JD, et al. Dietary cysteine reduces the methionine requirement by an equal proportion in both parenterally and enterally fed piglets. J Nutr 2003;133:4215-24. [Crossref] [PubMed]
82. Roberts SA, Ball RO, Moore AM, et al. The effect of graded intake of glycyl-L-tyrosine on phenylalanine and tyrosine metabolism in parenterally fed neonates with an estimation of tyrosine requirement. Pediatr Res 2001;49:111-9. [Crossref] [PubMed]
83. Huang L, Hogewind-Schoonenboom JE, de Groof F, et al. Lysine requirement of the enterally fed term infant in the first month of life. Am J Clin Nutr 2011;94:1496-503. [Crossref] [PubMed]
84. Hogewind-Schoonenboom JE, Huang L, de Groof F, et al. Threonine Requirement of the Enterally Fed Term Infant in the First Month of Life. J Pediatr Gastroenterol Nutr 2015;61:373-9. [Crossref] [PubMed]
85. Bertolo RF, Chen CZ, Pencharz PB, et al. Intestinal atrophy has a greater impact on nitrogen metabolism than liver by-pass in piglets fed identical diets via gastric, central venous or portal venous routes. J Nutr 1999;129:1045-52. [Crossref] [PubMed]
86. Law GK, Bertolo RF, Adjiri-Awere A, et al. Adequate oral threonine is critical for mucin production and gut function in neonatal piglets. Am J Physiol Gastrointest Liver Physiol 2007;292:G1293-301. [Crossref] [PubMed]
87. Lucas A. Long-term programming effects of early nutrition -- implications for the preterm infant. J Perinatol 2005;25:S2-6. [Crossref] [PubMed]
88. Isaacs EB, Fischl BR, Quinn BT, et al. Impact of breast milk on intelligence quotient, brain size, and white matter development. Pediatr Res 2010;67:357-62. [Crossref] [PubMed]
89. Lucas A, Morley R, Cole TJ, et al. Breast milk and subsequent intelligence quotient in children born preterm. Lancet 1992;339:261-4. [Crossref] [PubMed]
90. Goldman HI, Goldman J, Kaufman I, et al. Late effects of early dietary protein intake on low-birth-weight infants. J Pediatr 1974;85:764-9. [Crossref] [PubMed]
91. Cortiella J, Matthews DE, Hoerr RA, et al. Leucine kinetics at graded intakes in young men: quantitative fate of dietary leucine. Am J Clin Nutr 1988;48:998-1009. [Crossref] [PubMed]
92. Hoerr RA, Matthews DE, Bier DM, et al. Leucine kinetics from [2H3]- and [13C]leucine infused simultaneously by gut and vein. Am J Physiol 1991;260:E111-7. [PubMed]
93. Hoffer LJ, Yang RD, Matthews DE, et al. Effects of meal consumption on whole body leucine and alanine kinetics in young adult men. Br J Nutr 1985;53:31-8. [Crossref] [PubMed]
94. Bross R, Ball RO, Pencharz PB. Development of a minimally invasive protocol for the determination of phenylalanine and lysine kinetics in humans during the fed state. J Nutr 1998;128:1913-9. [Crossref] [PubMed]
95. de Groof F, Huang L, van Vliet I, et al. Branched-chain amino acid requirements for enterally fed term neonates in the first month of life. Am J Clin Nutr 2014;99:62-70. [Crossref] [PubMed]
96. Hogewind-Schoonenboom JE, Zhu L, Zhu L, et al. Phenylalanine requirements of enterally fed term and preterm neonates. Am J Clin Nutr 2015;101:1155-62. [Crossref] [PubMed]
97. Huang L, Hogewind-Schoonenboom JE, van Dongen MJ, et al. Methionine requirement of the enterally fed term infant in the first month of life in the presence of cysteine. Am J Clin Nutr 2012;95:1048-54. [Crossref] [PubMed]
98. Huang L, Hogewind-Schoonenboom JE, Zhu L, et al. Tryptophan requirement of the enterally fed term infant in the first month of life. J Pediatr Gastroenterol Nutr 2014;59:374-9. [Crossref] [PubMed]
99. Brunton JA, Ball RO, Pencharz PB. Current total parenteral nutrition solutions for the neonate are inadequate. Curr Opin Clin Nutr Metab Care 2000;3:299-304. [Crossref] [PubMed]
100. Pencharz PB. The 1987 Borden Award lecture. Protein metabolism in premature human infants. Can J Physiol Pharmacol 1988;66:1247-52. [Crossref] [PubMed]
101. Duffy B, Gunn T, Collinge J, et al. The effect of varying protein quality and energy intake on the nitrogen metabolism of parenterally fed very low birthweight (less than 1600 g) infants. Pediatr Res 1981;15:1040-4. [Crossref] [PubMed]
102. American Academy of Pediatrics Committee on Nutrition. Nutritional Needs of Preterm Infants. In: Kleinman R, editor. Pediatric Nutrition Handbook. Elk Grove Village, IL: American Acadamy of Pediatrics; 1998:55-87.
103. Wilkinson DL, Bertolo RF, Brunton JA, et al. Arginine synthesis is regulated by dietary arginine intake in the enterally fed neonatal piglet. Am J Physiol Endocrinol Metab 2004;287:E454-62. [Crossref] [PubMed]
104. Batshaw ML, Wachtel RC, Thomas GH, et al. Arginine-responsive asymptomatic hyperammonemia in the premature infant. J Pediatr 1984;105:86-91. [Crossref] [PubMed]
105. Urschel KL, Shoveller AK, Pencharz PB, et al. Arginine synthesis does not occur during first-pass hepatic metabolism in the neonatal piglet. Am J Physiol Endocrinol Metab 2005;288:E1244-51. [Crossref] [PubMed]
106. Urschel KL, Evans AR, Wilkinson CW, et al. Parenterally fed neonatal piglets have a low rate of endogenous arginine synthesis from circulating proline. J Nutr 2007;137:601-6. [Crossref] [PubMed]
107. Tomlinson C, Rafii M, Sgro M, et al. Arginine is synthesized from proline, not glutamate, in enterally fed human preterm neonates. Pediatr Res 2011;69:46-50. [Crossref] [PubMed]
108. Vosatka RJ, Kashyap S, Trifiletti RR. Arginine deficiency accompanies persistent pulmonary hypertension of the newborn. Biol Neonate 1994;66:65-70. [Crossref] [PubMed]
109. Di Lorenzo M, Bass J, Krantis A. Use of L-arginine in the treatment of experimental necrotizing enterocolitis. J Pediatr Surg 1995;30:235-40; discussion 240-1. [Crossref] [PubMed]
110. Burgess L, Morgan C, Mayes K, et al. Plasma arginine levels and blood glucose control in very preterm infants receiving 2 different parenteral nutrition regimens. JPEN J Parenter Enteral Nutr 2014;38:243-53. [Crossref] [PubMed]
111. Morgan C, Burgess L. High Protein Intake Does Not Prevent Low Plasma Levels of Conditionally Essential Amino Acids in Very Preterm Infants Receiving Parenteral Nutrition. JPEN J Parenter Enteral Nutr 2017;41:455-62. [Crossref] [PubMed]
112. Premakumar CM, Turner MA, Morgan C. Relationship between arginine intake in parenteral nutrition and preterm neonatal population plasma arginine concentrations: a systematic review. Nutr Rev 2019;77:878-89. [Crossref] [PubMed]
113. Badurdeen S, Mulongo M, Berkley JA. Arginine depletion increases susceptibility to serious infections in preterm newborns. Pediatr Res 2015;77:290-7. [Crossref] [PubMed]
114. Zheng P, Song Y, Tian Y, et al. Dietary Arginine Supplementation Affects Intestinal Function by Enhancing Antioxidant Capacity of a Nitric Oxide-Independent Pathway in Low-Birth-Weight Piglets. J Nutr 2018;148:1751-9. [Crossref] [PubMed]
115. Zlotkin SH, Bryan MH, Anderson GH. Cysteine supplementation to cysteine-free intravenous feeding regimens in newborn infants. Am J Clin Nutr 1981;34:914-23. [Crossref] [PubMed]
116. Kanaya S, Nose O, Harada T, et al. Total parenteral nutrition with a new amino acid solution for infants. J Pediatr Gastroenterol Nutr 1984;3:440-5. [Crossref] [PubMed]
117. Pohlandt F. Cystine: a semi-essential amino acid in the newborn infant. Acta Paediatr Scand 1974;63:801-4. [Crossref] [PubMed]
118. Winters RW, Heird WC, Dell RB, et al. Plasma amino acids in infants receiving parenteral nutrition. In: Greene HL, Holliday MA, Munro MA. editors. Clinical Nutrition Update: Amino Acids. Chicago: American Medical Association; 1977:147-57.
119. Heird WC, Gomez MR. Parenteral nutrition in low-birth-weight infants. Annu Rev Nutr 1996;16:471-99. [Crossref] [PubMed]
120. Sturman JA, Gaull G, Raiha NC. Absence of cystathionase in human fetal liver: is cystine essential? Science 1970;169:74-6. [Crossref] [PubMed]
121. Thomas B, Gruca LL, Bennett C, et al. Metabolism of methionine in the newborn infant: response to the parenteral and enteral administration of nutrients. Pediatr Res 2008;64:381-6. [Crossref] [PubMed]
122. Miller RG, Jahoor F, Reeds PJ, et al. A new stable isotope tracer technique to assess human neonatal amino acid synthesis. J Pediatr Surg 1995;30:1325-9. [Crossref] [PubMed]
123. Zlotkin SH, Anderson GH. The development of cystathionase activity during the first year of life. Pediatr Res 1982;16:65-8. [Crossref] [PubMed]
124. Hardwick DF, Applegarth DA, Cockcroft DM, et al. Pathogenesis of methionine-induced toxicity. Metabolism 1970;19:381-91. [Crossref] [PubMed]
125. Benevenga NJ. Toxicities of methionine and other amino acids. J Agric Food Chem 1974;22:2-9. [Crossref] [PubMed]
126. Moss RL, Haynes AL, Pastuszyn A, et al. Methionine infusion reproduces liver injury of parenteral nutrition cholestasis. Pediatr Res 1999;45:664-8. [Crossref] [PubMed]
127. Lyons J, Rauh-Pfeiffer A, Yu YM, et al. Blood glutathione synthesis rates in healthy adults receiving a sulfur amino acid-free diet. Proc Natl Acad Sci U S A 2000;97:5071-6. [Crossref] [PubMed]
128. Wernerman J, Hammarqvist F. Modulation of endogenous glutathione availability. Curr Opin Clin Nutr Metab Care 1999;2:487-92. [Crossref] [PubMed]
129. Courtney-Martin G, Moore AM, Ball RO, et al. The addition of cysteine to the total sulphur amino acid requirement as methionine does not increase erythrocytes glutathione synthesis in the parenterally fed human neonate. Pediatr Res 2010;67:320-4. [Crossref] [PubMed]
130. Riedijk MA, van Beek RH, Voortman G, et al. Cysteine: a conditionally essential amino acid in low-birth-weight preterm infants? Am J Clin Nutr 2007;86:1120-5. [Crossref] [PubMed]
131. Shoveller AK, Brunton JA, Brand O, et al. N-acetylcysteine is a highly available precursor for cysteine in the neonatal piglet receiving parenteral nutrition. JPEN J Parenter Enteral Nutr 2006;30:133-42. [Crossref] [PubMed]
132. Lucas A, Baker BA, Morley RM. Hyperphenylalaninaemia and outcome in intravenously fed preterm neonates. Arch Dis Child 1993;68:579-83. [Crossref] [PubMed]
133. Puntis JW, Edwards MA, Green A, et al. Hyperphenylalaninaemia in parenterally fed newborn babies. Lancet 1986;2:1105-6. [Crossref] [PubMed]
134. Walker V, Hall MA, Bulusu S, et al. Hyperphenylalaninaemia in parenterally fed newborn babies. Lancet 1986;2:1284. [Crossref] [PubMed]
135. Roberts SA, Ball RO, Filler RM, et al. Phenylalanine and tyrosine metabolism in neonates receiving parenteral nutrition differing in pattern of amino acids. Pediatr Res 1998;44:907-14. [Crossref] [PubMed]
136. Thompson AJ, Smith I, Brenton D, et al. Neurological deterioration in young adults with phenylketonuria. Lancet 1990;336:602-5. [Crossref] [PubMed]
137. Thompson AJ, Smith I, Kendall BE, et al. Magnetic resonance imaging changes in early treated patients with phenylketonuria. Lancet 1991;337:1224. [Crossref] [PubMed]
138. Thompson AJ, Tillotson S, Smith I, et al. Brain MRI changes in phenylketonuria. Associations with dietary status. Brain 1993;116:811-21. [Crossref] [PubMed]
139. Friedman M. Analysis, Nutrition, and Health Benefits of Tryptophan. Int J Tryptophan Res 2018;11:1178646918802282. [Crossref] [PubMed]
140. Wu G. Amino acids: metabolism, functions, and nutrition. Amino Acids 2009;37:1-17. [Crossref] [PubMed]
141. Griffiths RD, Jones C, Palmer TE. Six-month outcome of critically ill patients given glutamine-supplemented parenteral nutrition. Nutrition 1997;13:295-302. [PubMed]
142. Ziegler TR, May AK, Hebbar G, et al. Efficacy and Safety of Glutamine-supplemented Parenteral Nutrition in Surgical ICU Patients: An American Multicenter Randomized Controlled Trial. Ann Surg 2016;263:646-55. [Crossref] [PubMed]
143. Mok E, Hankard R. Glutamine supplementation in sick children: is it beneficial? J Nutr Metab 2011;2011:617597. [Crossref] [PubMed]
144. Poindexter BB, Ehrenkranz RA, Stoll BJ, et al. Effect of parenteral glutamine supplementation on plasma amino acid concentrations in extremely low-birth-weight infants. Am J Clin Nutr 2003;77:737-43. [Crossref] [PubMed]
145. House JD, Pencharz PB, Ball RO. Glutamine supplementation to total parenteral nutrition promotes extracellular fluid expansion in piglets. J Nutr 1994;124:396-405. [Crossref] [PubMed]