Clinical Nutrition 37 (2018) 2315e2323
`
`Contents lists available at ScienceDirect
`
`Clinical Nutrition
`
`j o u r n a l h o m e p a g e : h t t p : / / w w w . e l s e v i e r . c o m / l o c a t e / c l n u
`
`ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral
`nutrition: Amino acids
`Johannes B. van Goudoever a, *, Virgilio Carnielli b, Dominique Darmaun c,
`Miguel Sainz de Pipaon d, the ESPGHAN/ESPEN/ESPR/CSPEN working group on pediatric
`parenteral nutrition1
`a Amsterdam UMC, University of Amsterdam, Vrije Universiteit Amsterdam, Emma Children's Hospital, Amsterdam, The Netherlands
`b Salesi Hospital and Polytechnic University of Marche, Ancona, Italy
`c IMAD, CHU de Nantes, UMR PHAN, INRA, Universite de Nantes, IMAD, CRNH-Ouest, Nantes, France
`d La Paz University Hospital, Instituto de Salud Carlos III, Red de Salud Materno Infantil y Desarrollo-SAMID, Autonomous University of Madrid, Madrid,
`Spain
`
`a r t i c l e i n f o
`
`Article history:
`Received 29 May 2018
`Accepted 29 May 2018
`
`1. Methods
`
`Search: Searches were performed in three stages. First, all the
`titles with the relevant key words were retrieved by the Cochrane
`Collaboration Department from Budapest, who also performed the
`first reduction. Publications published after the previous guidelines
`[1] (i.e., from 2004eDecember 2014), were considered. Members of
`the Working Group subsequently read all the titles and abstracts,
`and selected potentially relevant ones. These were retrieved and
`full articles were assessed. Some studies published in 2015 or 2016
`
`* Corresponding author.
`E-mail address: h.vangoudoever@amc.nl (J.B. van Goudoever).
`1 ESPGHAN/ESPEN/ESPR/CSPEN working group on Pediatric Parenteral Nutrition: BRAEGGER Christian, University Children's Hospital, Zurich, Switzerland; BRONSKY Jiri,
`University Hospital Motol, Prague, Czech Republic; CAI Wei, Shanghai Jiao Tong University, Shanghai, China; CAMPOY Cristina, Department of Paediatrics, School of Medicine,
`University of Granada, Granada, Spain; CARNIELLI Virgilio, Polytechnic University of Marche, Ancona, Italy; DARMAUN Dominique, Universite de Nantes, Nantes, France;
`DECSI Tamas, Department of Pediatrics, University of Pecs, Pecs, Hungary; DOMELL €OF Magnus, Department of Clinical Sciences, Pediatrics, Umeå University, Sweden;
`EMBLETON Nicholas, Newcastle University, Newcastle upon Tyne, The United Kingdom; FEWTRELL Mary, UCL Great Ormond Street Institute of Child Health, London, UK;
`FIDLER MIS Natasa, University Medical Centre Ljubljana, Ljubljana, Slovenia; FRANZ Axel, University Children's Hospital, Tuebingen, Germany; GOULET Olivier, University
`Sordonne-Paris-Cite; Paris-Descartes Medical School, Paris, France; HARTMAN Corina, Schneider Children's Medical Center of Israel, Petach Tikva, Israel and Carmel Medical
`Center, Haifa Israel; HILL Susan, Great Ormond Street Hospital for Children, NHS Foundation Trust and UCL Institute of Child Health, London, United Kingdom; HOJSAK Iva,
`Children's Hospital Zagreb, University of Zagreb School of Medicine, University of J. J. Strossmayer School of Medicine Osijek, Croatia; IACOBELLI Silvia, CHU La Reunion, Saint
`Pierre, France; JOCHUM Frank, Ev. Waldkrankenhaus Spandau, Berlin, Germany; JOOSTEN, Koen, Department of Pediatrics and Pediatric Surgery, Intensive Care, Erasmus MC-
`Sophia Children's Hospital, Rotterdam, The Netherlands; KOLACEK Sanja, Children's Hospital, University of Zagreb School of Medicine, Zagreb, Croatia; KOLETZKO Berthold, k
`LMU e Ludwig-Maximilians-Universit€at Munich, Dr. von Hauner Children's Hospital, Munich, Germany; KSIAZYK Janusz, Department of Pediatrics, Nutrition and Metabolic
`Diseases, The Children's Memorial Health Institute. Warsaw; LAPILLONNE Alexandre, Paris-Descartes University, Paris, France; LOHNER Szimonetta, Department of Pediatrics,
`University of Pecs, Pecs, Hungary; MESOTTEN Dieter, KU Leuven, Leuven, Belgium; MIHALYI Krisztina, Department of Pediatrics, University of Pecs, Pecs, Hungary; MIHATSCH
`Walter A., Ulm University, Ulm, and Helios Hospital, Pforzheim, Germany; MIMOUNI Francis, Department of Pediatrics, Division of Neonatology, The Wilf Children's Hospital,
`the Shaare Zedek Medical Center, Jerusalem, and the Tel Aviv University, Tel Aviv, Israel; MØLGAARD Christian, Department of Nutrition, Exercise and Sports, University of
`Copenhagen, and Paediatric Nutrition Unit, Rigshospitalet, Copenhagen, Denmark; MOLTU Sissel J, Oslo University Hospital, Oslo, Norway; NOMAYO Antonia, Ev. Waldk-
`rankenhaus Spandau, Berlin, Germany; PICAUD Jean Charles, Laboratoire CarMEN, Claude Bernard University Lyon 1, Hopital croix rousse, Lyon, France; PRELL Christine, LMU
`e Ludwig-Maximilians-Universit€at Munich, Dr. von Hauner Children's Hospital, Munich, Germany; PUNTIS John, The General Infirmary at Leeds, Leeds, UK; RISKIN Arieh, Bnai
`Zion Medical Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel; SAENZ DE PIPAON Miguel, Department of Neonatology, La Paz University Hospital, Red de Salud
`Materno Infantil y Desarrollo e SAMID, Universidad Autonoma de Madrid, Madrid, Spain; SENTERRE Thibault, CHU de Liege, CHR de la Citadelle, Universite de Liege, Belgium;
`SHAMIR Raanan, Schneider Children's Medical Center of Israel, Petach Tikva, Israel; Tel Aviv University, Tel Aviv, Israel; SIMCHOWITZ Venetia, Great Ormond Street NHS Trust,
`London, The United Kingdom; SZITANYI Peter, General University Hospital, First Faculty of Medicine, Charles University in Prague, Czech Republic; TABBERS Merit M., Emma
`Children's Hospital, Amsterdam UMC, Amsterdam, The Netherlands; VAN DEN AKKER Chris H.B., Emma Children's Hospital, Amsterdam UMC, Amsterdam, The Netherlands;
`VAN GOUDOEVER Johannes B., Emma Children's Hospital, Amsterdam UMC, Amsterdam, The Netherlands; VAN KEMPEN Anne, OLVG, Amsterdam, the Netherlands; VER-
`BRUGGEN Sascha, Department of Pediatrics and Pediatric Surgery, Intensive Care, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands; WU Jiang, Xin Hua
`Hospital, Shanghai, China; YAN Weihui, Department of Gastroenterology and Nutrition, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
`
`https://doi.org/10.1016/j.clnu.2018.06.945
`0261-5614/© 2018 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.
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`during the revision process have also been considered. The refer-
`ences cited in the previous guidelines are not repeated here, except
`for some relevant publications; only the previous guidelines will be
`cited instead.
`Type of publications: Original papers, meta-analyses and
`overviews.
`Key words: parenteral nutrition, amino acids, requirements,
`toxicity, deficiency.
`Age: Child, infant, preterm.
`Language: English.
`Outcome: Recommendations were developed from a standpoint
`of nutrient adequacy. Depending on age groups, nutrient adequacy
`was based on intrauterine accretion rate, organ development,
`factorial estimates of requirements and amino acid interactions.
`Individual amino acids are discussed. Minimal intakes of specific
`amino acids are those that meet the specific requirement of chil-
`dren in that age group. Maximal intakes are recommended to
`prevent excessive and potentially harmful intakes of amino acids.
`
`2. Introduction
`
`Table 1
`Essential, non-essential and conditionally essential amino acids.
`
`Essential
`
`Histidine
`Isoleucine
`Leucine
`Lysine
`Methionine
`Phenylalanine
`Threonine
`Tryptophan
`Valine
`
`Non-essential
`
`Alanine
`Aspartic Acid
`Asparagine
`Glutamic Acid
`Serine
`
`Semi-essential
`
`Arginine
`Glycine
`Proline
`Tyrosine
`Cysteine
`Glutamine
`
`3. Methods for estimating total and individual amino acid
`needs
`
`Amino acid requirements are mainly determined by the rate of
`net protein synthesis, which depends on the availability of rate
`limiting amino acids. There are several physiological and
`biochemical ways to determine whether the amino acid intake is
`sufficient or in excess of the needs of children. Different measure-
`
`R 3.1
`
`R 3.2
`
`R 3.3
`
`R 3.4
`
`R 3.5
`
`R 3.6
`
`R 3.7
`
`R 3.8
`R 3.9
`
`R 3.10
`
`R 3.11
`
`Table: Recommendations for amino acids in PN
`In preterm infants the amino acid supply should start on the first postnatal day with at least 1.5 g/kg/d to achieve an anabolic state. (LOE 1þþ, RG A,
`strong recommendation)
`In preterm infants the parenteral amino acid intake from postnatal day 2 onwards should be between 2.5 g/kg/d and 3.5 g/kg/d and should be
`accompanied by non-protein intakes >65 kcal/kg/d and adequate micronutrient intakes. (LOE 1þ, RG A, strong recommendation)
`In preterm infants, parenteral amino acid intakes above 3.5 g/kg/d should only be administered as part of clinical trials (LOE 2þ, RG 0, conditional
`recommendation)
`A minimum amino acid intake of 1.5 g/kg/d should be administered to stable term infants to avoid a negative nitrogen balance while the maximum
`amino acid intake should not exceed 3.0 g/kg/d (LOE 1þ, RG B, strong recommendation)
`Withholding parenteral nutrition, including amino acids, for 1 week in critically ill term infants while providing micronutrients can be considered (LOE
`1þ, RG B, conditional recommendation)
`A minimum amino acid intake of 1.0 g/kg/d should be administered in stable infants and children to avoid negative balance (LOE 1, moderate quality,
`RG B, strong recommendation)
`Withholding parenteral nutrition, including amino acids, for 1 week in critically ill infants and children from 1 month to 3 years while providing
`micronutrients can be considered (LOE 1þ, RG B, conditional recommendation)
`In stable children aged 3e12 years an amino acid intake of 1.0e2.0 g/kg per day may be considered. (LOE 4, RG GPP, conditional recommendation)
`Withholding parenteral nutrition, including amino acids, for 1 week in critically ill children aged 3e12 years while providing micronutrients can be
`considered (LOE 1þ, RG B, conditional recommendation)
`An amino acid intake of at least 1.0 with a maximum of 2.0 g/kg/d in stable adolescents may be considered. (LOE 2þþ, RG 0, conditional
`recommendation)
`Withholding parenteral nutrition, including amino acids, for 1 week in critically ill adolescents while providing micronutrients can be considered (LOE
`1þ, RG B, conditional recommendation)
`Bioavailable cysteine (50e75 mg/kg/d) should be administered to preterm neonates. Higher amounts do not improve outcomes (LOE 1þ, RG B,
`conditional recommendation)
`The lower limit of tyrosine intake should be at least 18 mg/kg per day in preterm infants. (LOE 2þþ, RG B, conditional recommendation)
`The advisable tyrosine intake in term infants is 94 mg tyrosine/kg per day. (LOE 1þ, RG B, conditional recommendation)
`Glutamine should not be supplemented additionally in infants and children up to the age of two years. (LOE 1þþ, RG A, strong recommendation)
`Taurine should be part of amino acid solutions for infants and children, although no firm recommendation can be made upon advisable lower or upper
`limits. (LOE 1, RG B, conditional recommendation)
`Arginine supplementation may be used for prevention of NEC in preterm infants (LOE: 1, RG B, conditional recommendation)
`
`R 3.12
`
`R 3.13
`R 3.14
`R 3.15
`R 3.16
`
`R 3.17
`
`Proteins are the major structural and functional components of
`all cells in the body. They consist of chains of amino acid subunits
`joined together by peptide bonds. The chain length ranges from
`two amino acids to thousands, with molecular weights subse-
`quently ranging from hundreds to hundreds of thousands of Dal-
`tons. From a nutritional perspective, an important aspect of a
`protein is its amino acid composition. Some amino acids are clas-
`sified as essential (indispensable). These are amino acids that
`cannot be synthesized by humans and hence must be provided in
`the diet or parenteral solution (Table 1). Non-essential amino acids
`can be synthesized from other amino acids or from other pre-
`cursors. Some amino acids are categorized as semi-essential. These
`amino acids can be synthesized from other amino acids but their
`synthesis is limited under certain circumstances.
`
`ments for assessing adequacy of amino acid intake include
`anthropometry (weight and length), nitrogen balance, metabolic
`indices (e.g. amino acid concentrations, albumin, pre-albumin, total
`protein concentrations, blood urea nitrogen, metabolic acidosis),
`whole-body nitrogen kinetics, specific amino acid kinetics and the
`indicator amino acid method. The intake of each essential amino
`acid required to maintain nitrogen equilibrium in children and
`infants has been defined as the amount necessary to obtain
`adequate growth and nitrogen balance. The amino acid indicator
`method is an accurate and fast way to determine specific amino
`acid requirements. It has been developed to measure specific amino
`acid requirements [2e4] and has been validated in animal models
`of infancy [5,6]. Such an approach has recently been used in the
`determination of the requirement of several amino acids in
`parenterally fed neonates (Table 2) [7e10].
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`Table 2
`Parenteral requirements in neonates of individual amino acids as determined by
`the gold standard, the indicator amino acid oxidation method [7e10].
`
`Amino acid
`
`Tyrosine
`Methionine þ cysteine
`Threonine
`Lysine
`
`Requirement (mg/kg/d)
`
`74
`47
`38
`105
`
`Most currently used parenteral amino acid mixtures contain
`amino acid amounts that result in a plasma amino acid pattern
`resembling the plasma amino acid patterns of normally growing,
`breast fed infants and children, or cord blood. These paediatric
`parenteral amino acid mixtures provide more essential and less
`non-essential amino acids than normally deposited by the infant or
`child. The utilisation of the amino acid supply depends on a suffi-
`cient energy intake, and often an energy supply of 30e40 kcal per
`1 g amino acids is recommended.
`
`4. Total amino acid needs during parenteral nutrition
`
`4.1. Differences between enterally fed and parenterally fed children
`
`The amino acid requirement is lower in parenterally fed infants
`and children than in enterally fed infants because the supply by-
`passes the intestine. Studies in infants (preceded by studies in
`piglets) and children show that individual amino acids are utilized
`by the intestines at varying rates [11e16]. There is a wide variation
`in the intestinal uptake and utilization of specific amino acids that
`changes with age. First pass (intestinal and liver) leucine utilisation
`in older children is 24% [17], while it accounts for approximately
`50% of the dietary intake in preterm infants [18]. Intestinal uti-
`lisation of lysine accounts for approximately 20% of the intake [12]
`whereas 50% of glutamine is used [18] in preterm infants. Thus, the
`total needs for amino acids in parenterally fed children are lower
`than in enterally fed children, but there are huge differences in
`intestinal utilization of specific amino acids. Besides utilization by
`the intestine, a number of amino acids are also metabolized and
`converted into other amino acids within the intestine and/or liver
`upon first pass. Bypassing the intestine will lower systemic avail-
`ability of these amino acids and thus increase the parenteral re-
`quirements.
`In addition, while ingested phenylalanine and
`methionine appear to be converted to tyrosine and cysteine,
`respectively, it seems that parenterally administered phenylalanine
`and methionine are converted to a lower extent. Systemically active
`peptides are produced within the intestine (e.g. sIgA) and animal
`studies show that the intestine uses predominantly dietary amino
`acids (rather than amino acids that are offered to the intestine from
`the systemic circulation) for specific protein synthesis [19].
`
`4.2. Preterm infants
`
`R 3.1 In preterm infants the amino acid supply should start on the
`first postnatal day with at least 1.5 g/kg/d to achieve an anabolic
`state. (LOE 1þþ, RG A, strong recommendation, strong consensus)
`R 3.2 In preterm infants the parenteral amino acid intake from postnatal
`day 2 onwards should be between 2.5 g/kg/d to 3.5 g/kg/d and
`should be accompanied by non-protein intakes >65 kcal/kg/d
`and adequate micronutrient intakes. (LOE 1þ, RG A, strong
`recommendation, strong consensus)
`R 3.3 In preterm infants, parenteral amino acid intakes above 3.5 g/kg/d
`should only be administered as part of clinical trials (LOE 2þ, RG 0,
`conditional recommendation, consensus)
`
`A minimum of 30e40 Kcal per 1 g amino acids is usually rec-
`ommended to guarantee amino acid utilisation. Optimal glucose
`and lipid intakes that maximize protein accretion and growth in
`preterm infants have not been determined at various parenteral
`amino acid intakes [20,21].
`
`4.2.1. Early amino acid intake
`Based on current literature, amino acid intake should be started
`from the first day of life, or, even better, as soon as possible after
`birth so as to avoid the “metabolic shock” caused by the interrup-
`tion of continuous feeding that occurs in utero. Early amino acid
`administration in preterm infants results in increased protein
`synthesis without a decrease in proteolysis [22]. Several studies
`evaluating amino acid administration directly after birth have
`found a positive nitrogen balance, calculated as the difference be-
`tween nitrogen intake and estimated urinary nitrogen loss
`[23e26]. Consistent with these findings were those of a positive
`correlation between an increased amount of amino acid intake and
`an improved nitrogen balance [26e29]. Few studies have looked at
`the effect of early amino acid administration on short-term growth
`[30e33] and in some of the previously mentioned studies growth
`was recorded as a secondary outcome [25e27]. Overall, early amino
`acids, when compared to glucose administration alone, are asso-
`ciated with improved short-term growth. Much less is known
`about the effects on longer-term outcomes such as growth and
`neurodevelopment. Poindexter and colleagues, in a cohort study
`[33] found significant improvement in growth parameters at 36
`weeks postmenstrual age in favour of the infants who received
`early amino acids, but no differences were found in growth or in
`neurodevelopment at 18 months corrected age. Stephens and col-
`leagues [34] reported a retrospective analysis of 150 ELBW infants
`and found a positive association between protein intake in the first
`week of life and scores on the Bayley Mental Developmental Index
`at 18 months corrected age. Van den Akker and co-workers found
`no difference in growth but a neurodevelopmental advantage at 2
`years corrected age for boys that received amino acids from the first
`day of life compared to the ones who received glucose alone [35].
`No detrimental metabolic effects of commencing amino acid
`administration from birth onwards have been reported
`[25,27,28,36]. Some researchers did not find higher urea con-
`centrations in the high amino acid supplemented patients
`[24,29,37,38] while others found a positive correlation between
`amino acid intake and increased blood urea levels [20,25,39,40],
`indicating a greater proportion of amino acids being oxidized.
`This resembles the intrauterine situation in which amino acids
`are also used as an energy source, and higher blood urea levels
`should not be interpreted as a sign of intolerance but rather as a
`reflection of oxidation. Furthermore, the definition of what is a
`safe blood urea level in preterm infants still has to be deter-
`mined and indeed the incidence of metabolic acidosis is not
`related to amino acid intakes [39,41].
`
`4.2.2. High versus low amino acid intakes
`The most commonly used method to estimate amino acid
`requirement is the amount needed to achieve a positive nitrogen
`balance. Studies show that a mean intake of 0.9e2.65 g/kg/day can
`result in a positive nitrogen balance, with an energy intake as low
`as 30 kcal/kg/day. Performing nitrogen balance studies in small,
`often unstable preterm infants during the first days of life is very
`challenging. Most of these infant are not in a steady state and ni-
`trogen balance studies often fail to correct for a rapidly expanding
`urea pool [39].
`The 2005 ESPGHAN guidelines on paediatric parenteral nutri-
`tion [42] recommended a minimum amino acid intake of 1.5 g/kg/
`day to prevent a negative nitrogen balance, and a maximum of 4 g/
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`kg/day, according to the evidence that up to 3.3e3.9 g/kg/day
`seemed to be well tolerated. There is still limited evidence that
`increasing amino acid intake above 2.5 g/kg/day is associated with a
`more favourable outcome. The impact on growth of different amino
`acid intakes during parenteral nutrition has been studied in non-
`RCTs [28,31,43] or as secondary analyses of studies designed for
`other purposes [33,44]. Other studies have evaluated different
`protein intake schemes with varying non-protein energy, or at
`different timing of administration [21,27,38,45,46]. To date only a
`few RCTs were conducted to compare solely the effect of increasing
`amino acid in parenteral nutrition on growth and neuro-
`development of small preterm infants. In the study by Clark et al.
`[47], 122 patients were randomised to receive a maximum of 2.5 or
`3.5 g/kg/day amino acid supplementation. Growth at 28 days was
`nearly identical between treatment and controls. In the study by
`Burattini et al. [39] 114 ELBW infants were randomised to receive
`standard (2.5 g/kg/day) versus high (4 g/kg/day) amino acid intake.
`Infants in the intervention group received an extra 8 g/kg of amino
`acids over the first ten days of life without any significant difference
`in short and long term growth. Few other studies have looked at the
`relation between the dose of parenteral amino acids and neuro-
`development. Stephens et al. found [34], in a retrospective study in
`ELBWI, that increasing first-week protein and energy intakes was
`associated with significantly higher mental developmental scores
`at 18 months. Blanco et al. [30,44] in a randomised study found
`lower mental developmental scores at 18 months in infants who
`received the higher amino acid intake but the difference was no
`longer significant at the 2 year follow-up. The study of Blanco et al.
`was a secondary analysis of a study originally designed with the
`aim of reducing hyperkalaemia and it was not powered for neu-
`rodevelopment. Recent, larger studies did not observe short [48] or
`long term beneficial effects of increasing amino acid in the early
`phase [49,50]. Morgan et al. showed an improved head circum-
`ference growth by both increasing parenteral amino acid and
`caloric intake, so no definite conclusion can be drawn on the effect
`of amino acids alone [21].
`It is worth mentioning that some studies reported better glucose
`control in infants who received amino acids/higher amino acid in-
`takes [25,38,39]. These findings come from studies with small
`numbers of patients and should be interpreted with caution. High
`amino acid intakes in small preterm infants have been reported to
`have an effect on electrolytes and mineral metabolism [51,52].
`
`4.3. Term infants
`
`R 3.4 A minimum amino acid intake of 1.5 g/kg/d should be administered
`to stable term infants to avoid a negative nitrogen balance while
`the maximum amino acid intake should not exceed 3.0 g/kg/d
`(LOE 1þ, RG B, strong recommendation, strong consensus)
`R 3.5 Withholding parenteral nutrition, including amino acids, for
`1 week in critically ill term infants while providing micronutrients
`can be considered (LOE 1þ, RG B, conditional recommendation,
`consensus)
`
`At a parenteral supply of 2.4 g amino acids/kg per day, uri-
`nary nitrogen excretion ranges 0.10e0.12 g N/kg per day in
`stable, post-surgical
`term infants
`[53]
`corresponding to
`0.6e0.8 g protein/kg per day. This results in a positive nitrogen
`balance of approximately 1.8 g/kg per day. Stable term neonates
`with a parenteral amino acid intake of 2.5 g/kg per day achieve a
`moderate but positive protein balance (0.27 g/kg per day) [54].
`In a similar age group, Zlotkin recommended a protein intake of
`2.3e2.7 g/kg per day to achieve a similar weight gain rate as in
`full term infants who were fed human milk [55]. Reynolds et al.
`showed improved nitrogen and leucine balance upon delivery of
`
`2.5 versus 1.5 g/kg/d immediately post-operatively in term ne-
`onates [56].
`A recent large international multicentre randomised controlled
`trial in 1440 critically ill children, including term infants, (PEPaNIC
`study) compared whether a strategy of withholding parenteral
`nutrition up to day 8 in the PICU (late parenteral nutrition) was
`clinically superior to early initiation of supplemental PN (initiated
`within 24 h after admission) [57]. It was shown that withholding
`parenteral nutrition for 1 week while administering micronutrients
`intravenously was clinically superior to providing early parenteral
`nutrition to supplement insufficient enteral nutrition. No paren-
`teral nutrition for 1 week significantly reduced the number of new
`infections, the time on a ventilator, kidney failure and increased the
`likelihood of earlier live discharge from the PICU and the hospital.
`
`4.4.
`
`Infants and children from 1 month to 3 years
`
`R 3.6 A minimum amino acid intake of 1.0 g/kg/d should be administered
`in stable infants and children from 1 month to 3 years to avoid
`negative balance (LOE 1¡, moderate quality, RG B, strong
`recommendation, strong consensus)
`R 3.7 Withholding parenteral nutrition, including amino acids, for 1 week
`in critically ill children while providing micronutrients can be
`considered (LOE 1þ, RG B, conditional recommendation, consensus)
`
`The administration of 2.4 ± 0.3 g amino acids/kg per day to in-
`fants and children up to an age of 43 months (n ¼ 40, median age
`2.7 months) resulted in a mean positive nitrogen balance of
`242 ± 70 mg/kg per day, with plasma amino acid levels within the
`reference range except for a low level of tyrosine [58]. A positive
`nitrogen balance of 242 mg/kg per day corresponds to a positive
`protein balance of 1.5 g/kg per day. Infants (age 2e12 months) on
`the first day after cardiac surgery excrete 244 ± 86 mg N/kg per day
`corresponding to a negative protein balance of 1.5 ± 0.5 g protein/
`kg per day, whereas the supplementation of 0.8 g amino acids/kg
`per day resulted in a negative protein balance of 114 ± 81 mg N/kg
`per day approx. 0.7 ± 0.5 g protein/kg per day [59]. Based upon
`factorial approach, there is no rational to provide more than 2.5 g/
`kg/d to stable infants and children.
`
`4.5. Children aged 3e12 years
`
`R 3.8 In stable children aged 3e12 years an amino acid intake of
`1.0e2.0 g/kg per day may be considered. (LOE 4, RG GPP,
`conditional recommendation, strong consensus)
`R 3.9 Withholding parenteral nutrition, including amino acids, for 1 week
`in critically ill children while providing micronutrients can be
`considered (LOE 1þ, RG B, conditional recommendation, consensus)
`
`A study by Coss-Bu shows that critically ill children at a mean
`age of 5 years have a negative nitrogen balance at a protein intake
`of 2.1 g/kg per day [60]. The subjects with a positive nitrogen bal-
`ance had a higher protein intake (2.8 ± 0.9 g/kg per day) than
`subjects with a negative nitrogen balance (1.7 ± 0.7 g/kg per day).
`Critically ill children at a mean age of 8 years show a negative
`protein balance at an intake of 1.7 g protein/kg/d. Regression
`analysis showed a protein requirement of 2.8 g/kg per day in this
`study group [61]. However, as discussed previously, a recent trial
`showed adverse clinical outcomes following immediate parenteral
`nutrition in critically ill children [57].
`There is a paucity of data in the age group 3e12 years of age,
`insufficient to draw any firm conclusions on the advisable lower
`and upper limits for protein intake.
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`J.B. van Goudoever et al. / Clinical Nutrition 37 (2018) 2315e2323
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`4.6. Adolescents
`
`R 3.10 An amino acid intake of at least 1.0 with a maximum of 2.0 g/kg/d
`in stable adolescents may be considered. (LOE 2þþ, RG 0,
`conditional recommendation, strong consensus)
`R 3.11 Withholding parenteral nutrition, including amino acids, for
`1 week in critically ill adolescents while providing micronutrients
`can be considered (LOE 1þ, RG B, conditional recommendation,
`consensus)
`
`Young men, receiving an essentially protein free diet, excrete
`approximately 24e38 mg N/kg per day which corresponds to
`0.15e0.24 g protein/kg per day [62,63]. Goulet et al. administered
`different amino acid intakes to patients with a compromised gut
`function [64]. The response of protein turnover to graded levels of
`amino acid intakes was assessed by using stable isotope technology
`(leucine kinetics) in approximately 13 years old children in a stable
`nutritional status receiving home parenteral nutrition. Since the
`body fat content of adolescents changes very rapidly during this
`period, the estimates were based on lean body mass rather than
`body weight alone. Intakes ranged from 0.7 to 2.5 g amino acids/kg
`lean body mass per day. Positive nitrogen balance was achieved in
`these children at an intake of 1.5 g amino acids/kg lean body mass
`per day, whereas this was not the case at an intake 0.7 g amino
`acids/kg lean body mass per day. There was a significant positive
`difference in protein balance when the intake increased from 1.5 to
`2.5 g/kg lean body mass per day. More recently, Verbruggen et al.
`showed that critically ill children and adolescents require higher
`amino acid intakes (3 g/kg/d) to circumvent a catabolic state,
`although albumin synthesis rates were not affected [65,66]. How-
`ever, as discussed previously, a recent trial showed adverse clinical
`outcomes following immediate parenteral nutrition in critically ill
`children [57].
`The recommendations are summarized in Table 3.
`
`5. Specific amino acid requirements during total parenteral
`nutrition
`
`5.1. Cysteine
`
`R 3.12
`
`Bioavailable cysteine (50e75 mg/kg/d) should be administered
`to preterm neonates. Higher amounts do not improve outcomes
`(LOE 1þ, RG B, conditional recommendation, strong consensus)
`
`Cysteine used to be considered a semi-essential amino acid in
`the newborn period, indicating that cysteine needed to be admin-
`istered to circumvent low cysteine synthesis with subsequently low
`plasma levels and impaired protein synthesis in certain circum-
`stances. It is normally synthesized from methionine (S-donor) and
`
`Table 3
`Parenteral amino acid supply considered adequate for stable
`patients (g/kg/d).
`
`Preterm infants
`First day of life
`From day 2 onwards
`Term infantsa
`2nd monthe3rd yeara
`3rde18th yeara
`
`1.5e2.5
`2.5e3.5
`1.5e3.0
`2.5
`2.0
`a Critically ill patients may benefit from withholding paren-
`teral nutrition while providing micronutrients during the first
`week of hospital admission.
`
`serine (C-donor). The stability of cysteine is low in solution, making
`it hard to supply enough to the infant. However, it is possible to add
`cysteine-HCL to the amino acid solution just before the adminis-
`tration to the infant. Cystine (the oxidation product of two cysteine
`molecules combined) is stable but has a low solubility making it
`unsuitable as alternative to cysteine. Cysteine is approved for
`addition to parenteral nutrition in preterm infants.
`A 2006 Cochrane review evaluated five small trials of short-term
`cysteine supplementation of cysteine-free parenteral nutrition
`[67]. The authors concluded that growth was not significantly
`affected by cysteine supplementation (evaluated in one quasi-
`randomised trial), but that nitrogen retention was significantly
`increased by cysteine supplementation (studied in four trials); no
`data were available on clinical outcomes [67]. Riedijk et al. [68]
`concluded that there was no evidence for limited endogenous
`cysteine synthesis in 4-week-old low birth weight infants using the
`indicator amino acid oxidation method, while Courtney-Martin
`et al. [8] found that the methionine requirement to achieve
`adequate cysteine plasma levels in postsurgical human neonates
`requiring parenteral nutrition is lower than the methionine dose
`currently provided in commercial parenteral nutrition solutions.
`Indeed, Thomas et al. concluded as well that transsulfuration of
`methionine is evident in the human newborn in the immediate
`neonatal period, again suggesting that cysteine may not be
`considered a “conditionally” essential amino acid for the neonate
`[69].
`Cysteine is a major substrate for glutathione, a tripeptide (glu-
`tamic acid/cysteine/glycine) with important antioxidant properties,
`but also important in maintaining redox potential and calcium
`homeostasis. Appropriate levels of cysteine are therefore war-
`ranted. An intake of 170 mmol/kg per day (approx. 27 mg Cysteine-
`HCl/kg per day) result