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Hindawi Publishing CorporationJournal of Nutrition and MetabolismVolume 2011, Article ID 617597, 41 pagesdoi:10.1155/2011/617597
Review Article
Glutamine Supplementation in Sick Children: Is It Beneficial?
Elise Mok1, 2, 3 and Régis Hankard1, 2
1 INSERM Centre D’Investigation Clinique 802, Centre Hospitalier Universitaire de Poitiers, 86021 Poitiers Cedex, France2 Pédiatrie Multidisciplinaire-Nutrition de l’Enfant, Centre Hospitalier Universitaire de Poitiers, 86021 Poitiers Cedex, France3 Child Health Clinical Research Centre, The Montréal Children’s Hospital, McGill University Health Centre,Montréal, QC, Canada H3H 1P3
Correspondence should be addressed to Régis Hankard, [email protected]
Received 1 August 2011; Accepted 28 September 2011
Academic Editor: Johannes B. van Goudoever
Copyright © 2011 E. Mok and R. Hankard. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.
The purpose of this review is to provide a critical appraisal of the literature on Glutamine (Gln) supplementation in variousconditions or illnesses that affect children, from neonates to adolescents. First, a general overview of the proposed mechanisms forthe beneficial effects of Gln is provided, and subsequently clinical studies are discussed. Despite safety, studies are conflicting, partlydue to different effects of enteral and parenteral Gln supplementation. Further insufficient evidence is available on the benefitsof Gln supplementation in pediatric patients. This includes premature infants, infants with gastrointestinal disease, childrenwith Crohn’s disease, short bowel syndrome, malnutrition/diarrhea, cancer, severe burns/trauma, Duchenne muscular dystrophy,sickle cell anemia, cystic fibrosis, and type 1 diabetes. Moreover, methodological issues have been noted in some studies. Furthermechanistic data is needed along with large randomized controlled trials in select populations of sick children, who may eventuallybenefit from supplemental Gln.
1. Introduction
Glutamine (Gln) is the most abundant amino acid in themuscle and plasma of humans [1]. Although Gln is a nones-sential neutral amino acid, it is necessary for optimal growthof mammalian cells in tissue culture [2] and has importantphysiological functions. Apart from providing nitrogen forprotein synthesis, Gln is a precursor for nucleic acids,nucleotides [3], hexosamines [4], the nitric oxide precursor-arginine (Arg) [5], and the major antioxidant-glutathione[4, 6]. Gln is also an important oxidative fuel for rapidlyproliferating cells such as those of the gastrointestinal tract[7] and immune system [3], reticulocytes [8], fibroblasts[9], and so on. It plays a central role in nitrogen transportbetween tissues [10], specifically from muscle to gut, kidney,and liver. In addition to its role as a gluconeogenic substratein the liver, kidney [11], and intestine [12], Gln is involved inthe renal handling of ammonia, serving as a regulator of acid-base homeostasis [13]. Present data also indicate that Glnfunctions as a signalling molecule [14], particularly undercatabolic conditions.
Traditionally Gln is considered a nonessential aminoacid, because it is synthesized by most tissue (skeletalmuscle being the main producer and storage site) [15].Gln synthetase catalyzes the terminal step in Gln de novosynthesis and is a key enzyme in Gln metabolism [16, 17].In mammals, Gln synthetase expression is regulated bytranscriptional and posttranscriptional mechanisms, that is,increasing Gln synthetase mRNA in response to stress (e.g.,glucocorticoids) and regulation of Gln synthetase proteinturnover in response to its product (Gln concentrations)[18]. The importance of Gln at the whole body level ishighlighted by the report of severe brain malformationresulting in multiorgan failure and neonatal death in 2 unre-lated newborns with congenital Gln synthetase deficiency, inwhom Gln was largely absent in plasma, urine, and cerebralspinal fluid [19].
Under normal conditions, Gln is released into circu-lation for consumption by other tissue, whereas duringcatabolic stress the production of Gln may be insufficientto meet the increased requirements by the gut, immunesystem/inflammatory cells, liver, and kidneys. Demands are
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partly met by skeletal muscle proteolysis and release of largeamounts of Gln to maintain normal concentrations in theplasma, resulting in depletion of Gln stores. Based on thisabundant evidence, Lacey and Wilmore [10] suggested thatGln may become a conditionally essential amino acid for thecritically ill.
In paediatrics, several researchers have studied the effi-cacy of supplemental Gln in premature infants of low birthweight (LBW), who are highly stressed and have low energyand protein reserves [20]. Similar to premature neonates, Glnsupplementation may also be beneficial for other childhoodconditions including gastrointestinal disease, malnutrition,cancer, severe burns/trauma as well as chronic diseases ofchildhood. However, less data is available on the effects ofsupplemental Gln in older infants and children with variousdiseases.
In addition to being sick and highly stressed, childrenare also in the process of growth and development. Hence,specific research on the role of Gln in pediatric patients isnecessary. The main purpose of this manuscript is to providea critical review of the literature on Gln supplementationin various conditions/illnesses that affect children (fromneonates to adolescents). First the proposed mechanisms ofGln action are reviewed in a general context, followed by adetailed description and critique of the clinical research onGln supplementation in children.
1.1. Glutamine Mechanisms of Action. While it is well estab-lished that Gln is a protein precursor as well as a major fueland nucleotide substrate for rapidly proliferating cells (e.g.,gut and immune system) [3, 7], additional mechanistic datahas emerged to explain the apparent benefits of Gln. Gln canregulate the expression of many genes related to metabolism,signal transduction, cell defense, and repair and can activateintracellular signaling pathways [14]. In brief, Gln seemsto affect antioxidant capacity, tissue protection, immune,and metabolic function [21] as well as protein synthesisand degradation [14] (Figure 1). The postulated mechanismsremain speculative and are by no means mutually exclusive,since Gln can provoke a number of different effects thatinteract with one another.
1.2. Antioxidant Capacity
1.2.1. Glutathione. Gln is a precursor of the glutamate (Glu),for glutathione (L-γ-glutamyl-L-cysteinyl-glycine) synthesis,an important antioxidant in many cell types [22]. Glu-tathione is present in the cell in reduced (GSH) and oxidized(GSSG) forms. The ratio of reduced-to-oxidized glutathioneis the major regulator of the cellular redox potential thatdetermines the antioxidant capacity of the cell [14, 22, 23].The effectiveness of glutathione protection in individualtissue depends on the tissue concentration of glutathione aswell as the capacity of the tissue to import GSH and to exportGSSG [24].
In vivo experiments in rats demonstrate that adminis-tration of Gln before ischemia/reperfusion injury or surgicalmanipulation can enhance GSH concentrations and provide
Tissue protection
Antioxidant capacity
Protein degradation
Metabolic function
Protein synthesis
Glutamine
Immune function
Figure 1: Schematic representation of the mechanism of glutamineaction.
protection against oxidative stress in various tissues (e.g., car-diac, intestinal, and lung) [25, 26]. Further, the effectivenessof Gln in preventing liver damage in neonatal sepsis appearsto be mediated via glutathione synthesis [27]. In humans,Gln supplementation can attenuate GSH depletion in skeletalmuscle following surgical trauma [28].
During critical illness, muscle concentrations of GSHdecrease and a change in the redox status occurs, indicativeof an elevated GSSG [24]. Moreover, there is a correlationbetween the concentrations of Gln and GSH [24]. Shiftingthe GSH/GSSG redox toward oxidizing conditions acti-vates several signaling pathways, such as c-Jun N-terminalkinase (JNK), apoptosis signal-regulated kinase-1 (ASK-1),mitogen-activated protein kinase (MAPK), and the tran-scription factor nuclear factor-kappaB (NF-κB: a stimulatorof the synthesis of proinflammatory cytokines and adhesionmolecules) [22, 23, 29]. Evidence also implicates oxidativestress as a potential regulator of NF-κB transactivation byMAPKs (in particular extracellular signal-regulated kinase1/2 (ERK1/2) and p38) [30] which could lead to increasedproteolysis in muscle [31]. Moreover, the cellular redoxstatus seems to be related to the degree of muscle proteindegradation [32, 33]. Likewise, there is significant literatureon the role of inflammatory cytokines (interleukin-1, -6,tumour necrosis factor-alpha (TNF-α)) and muscle wasting[34].
Gln metabolism via entry into the citric acid cycle mayallow the activation of malic enzyme which will resultin an increase in NADPH [15] and subsequently increasethe GSH/GSSG ratio [14]. Administration of Gln leads toan increased ratio of GSH/GSSG and reduces the activityof redox sensitive kinases subsequently preventing NF-κBactivation and thus inhibiting the inflammatory response[23].
Experiments from our group in the mdx mouse modelof muscular dystrophy (a condition associated with severemuscle wasting) showed that in vivo Gln administrationcan reduce GSSG in dystrophic skeletal muscle, hence,increasing the ratio of GSH/GSSG [35]. This was associated
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Journal of Nutrition and Metabolism 3
with decreased activation of MAPK (ERK1/2) pathway [35].Similar effects were observed in muscle of control mice;however, the magnitude was less [35]. Thus, in muscle tissue,Gln might affect the cellular redox state involving MAPKpathway.
1.3. Tissue Protection
1.3.1. Heat Shock Protein (HSP). The HSPs serve as molec-ular chaperones that appear to repair denatured/injuredproteins or promote their degradation following irreparableinjury. Gln has cell-protective effects, as a potent enhancerof the expression of HSP25, HSP70, HSP72, and heme-oxygenase-1 in cell culture [36], in multiple organs of bothstressed and unstressed animal models [37], as well as inhumans [38, 39]. However, Gln depletion during the stressresponse can impair the expression of the major inducibleHSP (HSP70), as shown in human lymphocytes [40]. Andrecent evidence suggests that HSP70 expression is requiredfor Gln’s protection against tissue injury and for attenuationof NF-κB activation and proinflammatory cytokine release[41].
In rats, preoperative administration of Gln inducesHSP70 expression and attenuates the inflammatory responseby regulating nitric oxide synthase (NOS) activity in heart,lung, and liver [42]. Gln is a well-known precursor forArg [5], which can increase nitric oxide formation as aresult of enhanced NOS activity [6]. However, in variousmodels of human intestinal cells, Gln does not furtherincrease nitric oxide production or inducible NOS mRNAfollowing proinflammatory cytokine stimulation [43]. Thus,Gln’s effects on NOS activity might be tissue- or condition-specific.
The survival-promoting effects of HSP70 can also beattributed in part to the suppression of apoptosis, sincereduced HSP expression in Gln-deprived cells together withtheir impaired antioxidant capacity may make them moresusceptible to apoptosis [29].
1.3.2. Apoptosis. Gln starvation has been shown to induceapoptosis in intestinal epithelial cells [44] and also ren-ders human monocytic cells more susceptible to apoptosisinduced by Fas ligand, heat shock, or TNF-α stimulation[45]. In HeLa cells, Gln might also suppress ASK-1 andJNK/stress-activated protein kinase (SAPK) activation byFas ligand [46]. The effect of Gln in delaying spontaneousapoptosis in neutrophils may be mediated by the antioxidanteffects of glutathione [47]. Furthermore, Gln may protectactivated T cells from apoptosis, partially by upregulatingglutathione and Bcl-2 expression and inhibiting Fas [48].
1.3.3. Intestinal Barrier Function. As an important fuel forintestinal tissue and gut-associated lymphoid tissue, Glnmay contribute to gut barrier function [49]. Experimentaldata from neonatal animal models also support the ben-eficial effects of Gln on gastrointestinal development andfunction [50–59]. Gln is also involved in the biosynthesisof hexosamines which are important for maintaining gutwall integrity via surface mucin and glycoprotein-forming
intracellular tight junctions and thus may protect againstbacterial translocation [4, 60].
1.4. Immune Function. As a major fuel for immune cells,Gln is known to modulate immune function. More recently,Gln has also been shown to have anti-inflammatory effects,modulating cytokine production, both in vitro [36, 61–63]and in vivo [41, 51, 64], possibly through decreased NF-κBactivation [41, 62], a major transcription factor regulatingimmune and inflammatory responses. In neonatal mice andrats with experimental NEC, Gln reduces intestinal injury[54, 55], via mechanisms inhibiting inflammatory cytokinerelease [54].
Gln’s anti-inflammatory effects may also be related toenhanced HSP expression [36, 41]. The induction of HSPresponse can attenuate proinflammatory cytokine release,which in turn depends on the cellular redox potential andconsequently is regulated by the intracellular GSH/GSSGratio [14] (as previously described).
1.5. Tissue Metabolic Function. Gln can preserve tissue-meta-bolic function in stress states. For instance, Gln enhan-ces myocardial tissue-metabolic function after ischemia/reperfusion injury in rats [26]. Gln can also enhance ATPlevels in oxidant stressed endothelial cells [65].
1.5.1. Glucose Metabolism. While Gln plays an importantrole in gluconeogenesis [11, 12, 66], evidence also suggeststhat Gln can improve insulin sensitivity and glucose disposalin patients suffering from critical illness [21, 67], a conditionfrequently associated with insulin resistance and subsequenthyperglycemia. Gln also plays a role as a signaling moleculein amino acid- and glucose-stimulated insulin secretion[68]. Interestingly in rats with diet-induced obesity, Glnsupplementation induces insulin resistance in adipose tissueand reduces adipose mass, consequently attenuating insulinresistance and activation of JNK and inhibitory kappaBkinase subunit beta in liver and muscle, thus improvinginsulin signaling [69]. These data suggest that Gln can bene-ficially influence insulin-dependent glucose metabolism.
1.6. Protein Synthesis and Degradation. Gln appears toregulate protein turnover in cultured rat skeletal myotubes,stimulating protein synthesis in stressed myotubes whileinhibiting protein degradation in long-lived proteins. Thismay be related to the increase in HSP70 [70]. There is alsoabundant literature to suggest that amino acids affect proteinturnover via the mammalian target of rapamycin (mTOR)pathway [71, 72].
1.6.1. Protein Synthesis. Amino acids, particularly branchedchain amino acids, for example, leucine (Leu) stimulateskeletal muscle protein synthesis via the activation of mTORwhich in turn activates p70 ribosomal S6 kinase (p70S6K) anddephosphorylates eukaryotic initiation factor 4E-bindingprotein 1 (4E-BP 1), stimulating translation and proteinsynthesis [71, 72]. Gln can induce growth and maturationof neonatal rat cardiomyocytes, which is associated with
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an increase in the mRNAs-encoding contractile proteins andmetabolic enzymes via the activation of protein kinase Aand mTOR [73]. However, the action of Gln seems to becell-type specific. For instance, in C2C12 myogenic cells,Gln and Leu have opposite effects on the mTOR pathway[74]. Whereas Leu activates this pathway, Gln inhibits it bydecreasing the phosphorylation states of mTOR (on serine(Ser)2448), p70S6K, and 4E-BP1, with no effect on proteinsynthesis [74].
1.6.2. Protein Degradation. The major proteolytic pathwaysin organs such as the liver, muscle, and intestine includethe autophagic/lysosomal (cathepsins), the calcium activated(calpains), and the ATP-ubiquitin-proteosome pathway [14,34]. The proteosome system (26S) is a highly selective prote-olytic pathway [71]. In visceral tissues (e.g., liver), autophagyis, however, the major proteolytic pathway and the onlypathway known to be regulated by plasma amino acids (inliver and skeletal muscle) [71, 72]. In autophagic proteolysis,several amino acids have direct regulatory potential, possiblyvia a plasma membrane amino acid receptor/sensor andsubsequent intracellular signaling [71].
Another line of evidence suggests that amino acidsactivate mTOR pathway which in turn suppresses proteinbreakdown by the autophagy/lysosomal pathway [71, 72].Amino acids can also control autophagic lysosomal proteoly-sis by inhibiting MAPK (ERK1/2) phosphorylation [75]. Glnmay cause its antiproteolytic effect through osmotic swelling[76], involving p38 MAPK pathway [77]. An increase incellular hydration acts as an anabolic signal, whereas cellshrinkage is catabolic, and there is a close relation in theregulation of cell volume, Gln, and protein catabolism [23].
On the other hand in the human gut, enteral Gln mayattenuate ubiquitin-dependent proteolysis as demonstratedby decreased ubiquitin mRNA, whereas mRNAs encoding forcathepsins or calpains were not affected [78]. Furthermore,in lung and muscle, Gln can also regulate its own productionthrough a posttranscriptional mechanism in which Glnregulates Gln synthetase protein degradation [16, 17, 79],by facilitating its degradation by the 26S proteosome [18].Thus, the presence of Gln could have a protein-sparing effect,sparing amino acids for protein accretion [80–82].
1.7. Glutamine in the Neonatal Period. Gln is the predomi-nant amino acid supplied to the fetus through the placentaand is specifically suited for its rapid development [83, 84].While normally present in the enteral diet, Gln has beenexcluded from parenteral nutrition (PN) because of lowsolubility and instability in solution. In the first weeks of life,however, premature infants receive most of their nutrientsfrom PN which is Gln-free [85]. The sudden cessation ofGln supply from the mother to premature infants, whoare already stressed and undergoing rapid growth, maybe detrimental [86]. Whereas plasma Gln concentrationsnormally increase during the first days of life in newborninfants breastfed ad libitum [87], selective amino aciddeficiencies have been reported in neonates suffering fromacute illness, including reductions in serum Gln and Arg in
infants who have necrotizing enterocolitis (NEC) that maypredispose them to the illness [88]. It has been suggestedthat in catabolic conditions premature infants are not ableto synthesize sufficient Gln to meet demands, and in theseconditions Gln may become a conditionally essential aminoacid [10].
1.8. Glutamine in Breast Milk. In addition to providing anideal nutritional composition for the neonate, breast milkcontains specific nutrients such as Gln that may influencegastrointestinal development and can modulate immune,metabolic, and inflammatory responses [89]. Deprivationof dietary or endogenously synthesized Gln results in abreakdown in the intestinal epithelium of artificially rearedneonatal rats, whereas Gln supplementation may help tomaintain intestinal integrity [59].
In extremely low birth weight (ELBW) infants, thebeneficial effects of breast milk ingested in the neonatalintensive care unit (NICU) on developmental outcomes at18 months of age [90] persist at 30 months [91]. WhilePN is Gln-free, Agostoni et al. [92] reported lower freeGln concentrations in standard infant formulas comparedto breast milk collected from 40 healthy lactating mothersafter delivery of term infants at age 1 month. And similarto previous reports [93], they observed that glutamic acidand Gln accounted for most of the free amino acids inbreast milk [92]. Moreover, heat sterilization of infantformulas can further lower the concentrations of Gln bymore than 60% [94]. Thus, suggesting that enrichmentof infant formulas with nonprotein nitrogen components(particularly Gln and glutamic acid) could be beneficial. Thesame group followed 16 healthy exclusively breastfeedingmothers after delivery of term infants and showed that theconcentrations of free glutamic acid and Gln increased by2.5 and 20 fold, respectively, with progressing lactation,representing >50% of total free amino acids by 3 months[95]. To assess the potential influence of gestational ageand duration of lactation, Jochum et al. [96] measuredthe content of free and protein-bound Gln in transitionaland mature breast milk of 40 healthy mothers after termand preterm delivery. While the time of delivery had noinfluence on the free Gln or total Gln concentration, free Glnconcentrations increased during maturation of lactogenesis,similar to previous reports [95, 97, 98]. In contrast, total Glnand protein-bound Gln concentrations decreased with theduration of lactation, and this correlated with the decrease intotal protein concentration in mature breast milk [96]. Thesedata highlight the need to better define the role of Gln inthe neonatal period and the possible benefit of supplementalGln.
2. Materials and Methods
The following sections describe the clinical studies thatexamined the effects of parenteral and enteral Gln supple-mentation in premature neonates as well as older infantsand children with various diseases. The search methods foridentification of studies consisted of searches of PubMed
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(1966–June 2011). The database was searched using thesearch term: “glutamine.” The search output was limitedwith the search filter for ages: all children 0–18 years. Therewere no language restrictions. References in previous reviewsand studies were examined also. The title and abstract of allstudies identified by the above search strategy were screened,and the full text for all potentially relevant studies publishedin English was obtained. The full text of any potentiallyrelevant studies was assessed by the first author. Studies thatincluded only adult participants were excluded. The sameauthor extracted data from the published studies.
3. Results and Discussion
3.1. Parenteral Glutamine Supplementation in
Premature Neonates
3.1.1. Clinical Outcomes. The first evidence to suggest thatparenteral Gln appears safe and may be considered a con-ditionally essential amino acid in premature infants was putforth more than a decade ago by Lacey et al. [99] (Table 1).Although efficacy was not demonstrated in the entire cohortof very low birth weight (VLBW) infants (N = 44), subgroupanalysis in the infants with birth weight
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Table 1: Glutamine-supplemented parenteral nutrition in premature neonates.
Reference Subjects Design Gln Control Outcomes Results
Lacey et al.1996 [99]
44 VLBWprematureneonates age
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Table 1: Continued.
Reference Subjects Design Gln Control Outcomes Results
Poindexteret al. 2003∗
[103]
141 ELBW (≤72 hafter birth); birthwt: 401–1000 g;GA: 26± 2 wk
Multicentre-randomizeddouble blind
Isonitrogenousstudy AA solutionwith 20% of AAas Gln in PN for∼10 d, AA intake≤3–3.5 g/kg/d(n = 72)
Standard AAsolution withoutGln(TrophAmine) inPN for ∼10 d, AAintake≤3–3.5 g/kg/d(n = 69)
Safety as assessedby plasmaconcentrations ofAA and ammoniaafter infants hadreceived study PN(2.3± 1.0 g/kg/dAA) for ∼10 d
Increased plasma Gln(Gln group only) withno apparentbiochemical risk,increased plasmaessential AA (bothgroups) whereas Pheand Tyr decreased withgreater decrease in Tyr(Gln group), no changein plasma ammonia
Kalhan et al.2005 [80]
20 LBW clinicallystable (24–48 hafter birth); birthwt: 694–1590 g;GA ≤32 wk
Randomizeddouble blind
IsonitrogenousAA mixturesupplementedwith Gln0.6 g/kg/d in PNfor 3–5 d, AAintake∼3.0 g/kg/d(n = 10)
AA mixturewithout Gln inPN for 3–5 d, AAintake∼3.0 g/kg/d(n = 10)
Whole bodyprotein and Glnkinetics (IVinfusions of[2H5]Phe, L-[1–13C,15N]Leu,[15N2]urea,L-[5–15N]Gln)on d6 or d7 of lifewhile receivingAA mixturecontinuouslyafter 3–5 d
Lower endogenousrates of appearance ofPhe and Leu N (indicesof proteolysis), lowerGln de novo synthesis,no differences in rate ofappearance of Leu C,urea turnover orplasma AAconcentrations
Li et al.2007 [101]
53 LBWpremature infants(48–72 h afterbirth); birth wt:2 wk, AA intakestarted at0.5–1.0 g/kg/d to≤3.0 g/kg/d(n = 25)
Growth,biochemicalindices, feedingtolerance, andinfective episodesthroughouthospitalization
Fewer d to regain birthwt, no differences in wtor headcircumferences, fewer don PN, fewer episodesof hospital-acquiredinfection, shorter LOSin hospital, safe
Wang et al.2010 [104]
30 VLBW;median age(interquartilerange) (d):2.5(1.0-2.0) (Gln)and 2.2(1.0-2.0)(control); birthwt: 70% ofrecommendedintake from EN(n = 13)
6% pediatric AAcompoundinjection, averageAA dosage2.0 g/kg/d, PNdecreased whenEN increased andPN withheldwhen >70% ofrecommendedintake from EN(n = 15)
(1) Mortality andchanges inhepatic function(bile acid, ALT,AST, totalbilirubin, directbilirubin,prealbumin,albumin), (2)time to full EN(d), episodes ofgastric residual,total duration ofPN (d), wt gain(g/d), headcircumference(cm), LOS, d onventilator
(1) Decreased AST anddirect bilirubin, nodifferences in bile acid,ALT, total bilirubin,prealbumin, oralbumin, (2) nodifferences in time tofull EN, episodes ofgastric residual, totalduration of PN, wtgain, headcircumference, LOS ord on ventilator
VLBW: very low birth weight; PN: parenteral nutrition; wt: weight; GA: gestational age; AA: amino acid; EN: enteral nutrition; LOS: length of stay; NICU:neonatal intensive care unit; LBW: low birth weight; IV: intravenous; ELBW: extremely low birth weight; NEC: necrotizing enterocolitis; AST: aspartateaminotransferase; ALT: alanine aminotransferase.∗Originating from the same cohort.
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(such as mortality) or multiple endpoints. Furthermore,no deaths occurred and only 28/30 infants randomizedcompleted the study and thus analysis was not by intentionto treat. Interestingly, hepatic function improved as assessedby serum aspartate aminotransferase and direct bilirubin,which both decreased after PN in the Gln-supplementedgroup (P < 0.05). It should be noted, however, that nodifferences were observed for other measures of hepaticfunction (bile acid, alanine aminotransferase, total bilirubin,prealbumin, or albumin) or other secondary outcomes (timeto full EN, episodes of gastric residuals, total duration of PN,weight gain, head circumference, length of stay, or days onventilator).
3.1.2. Protein Metabolism. Two small randomized con-trolled trials in LBW infants examined the effects of Gln-supplemented PN on whole body protein metabolism usingprimed continuous IV infusions of essential amino acidtracers [80, 105] (Table 1). Des Robert et al. [105] studied13 LBW neonates on postnatal d-3, while they receivedexclusive PN that was supplemented with Gln (0.5 g/kg/d)or an isonitrogenous Gln-free amino acid solution for 24 h.Compared to an isonitrogenous amino acid supplement,Gln decreased the rate of plasma Leu appearance, Leurelease from protein breakdown (an index of whole bodyproteolysis; −16%, P < 0.05), and rate of Leu oxidation(−35%, P < 0.05). There was also, however, a decrease innonoxidative Leu disposal (an index of whole body proteinsynthesis; −20%, P < 0.05), and, thus, net Leu balance(protein balance) did not differ between groups. Plasma Glnconcentrations were higher in Gln versus control, whereasplasma ammonia did not differ. Although parenteral Glnfailed to enhance estimates of protein synthesis, Gln maypreserve body protein as it suppressed Leu oxidation andprotein breakdown in LBW infants. In addition to the smallsample size, the failure to enhance protein synthesis mayhave also been due to insufficient amino acid availabilitysince whole body protein kinetics were assessed on d-4 of life(when amino acid intake was 2 g/kg/d in both groups) beforeinfants received an optimal amino acid intake of 3 g/kg/d[106].
Kalhan et al. [80] examined the effect of 0.6 g/kg/dGln-supplemented PN for 3–5 d on whole body proteinand Gln kinetics in a carefully selected population of 20clinically stable LBW infants, between d-1 and -2 after birth.Compared to an isonitrogenous control, Gln-supplementedPN resulted in significantly lower rates of appearance ofphenylalanine (Phe) and Leu nitrogen and a nonsignificantdecrease in the rate of appearance of Leu carbon. Gln alsosuppressed the endogenous rate of Gln synthesis. There wasno significant difference in urea turnover between the 2groups. The results suggest that parenteral Gln supplemen-tation at 0.6 g/kg/d decreases whole body protein breakdownand Gln de novo synthesis in clinically stable LBW infants andmay be beneficial in selected populations of LBW infants.The carefully selected population of clinically stable infantslimits the application of the results to other groups ofpremature neonates. Moreover, the use of a higher dose ofGln makes comparisons with other studies difficult.
Interestingly, the same group demonstrated that thesuppression of proteolysis and protein oxidation in responseto an acute increase in parenteral amino acids (withoutGln) was not evident when the amino acid infusion wascontinued for a prolonged period in both acutely ill [81] andclinically stable LBW infants [82]. The only exception waswhen amino acids were supplemented with Gln, wherebya prolonged infusion resulted in a sustained inhibition ofwhole body proteolysis and reduced Gln de novo synthesis.Taken together with previous studies [80, 105], Gln supple-mentation may have a protein-sparing effect in prematureinfants decreasing whole body protein breakdown and Glnde novo synthesis thereby “sparing” the increased amino acidsfor protein synthesis.
3.2. Enteral Glutamine Supplementation in
Premature Neonates
3.2.1. Clinical Outcomes. Neu et al. [107] conducted adouble-blind randomized trial to test whether enteral Glnsupplementation for VLBW infants decreases morbidity(Table 2). Sixty-eight premature neonates were assigned toa Gln-supplemented premature formula or a nonsupple-mented standard premature formula between postnatal d-3 to d-30. The Gln supplemented group initially received adose of 0.08 g/kg/d Gln which was increased to a maximumof 0.31 g/kg/d Gln by d-13. The Gln group had bettertolerance to enteral feedings (fewer % of d with no oral intakein Gln: 8.8% versus controls: 23.8%, P < 0.01). Episodesof hospital-acquired sepsis were 4/35 and 10/33 in Gln andcontrol group, respectively. Moreover, when controlling forbirth weight, the estimated odds of developing sepsis was3.8 times higher for control versus Gln (95% CI: 1.01–14.18). Analysis of T cell subsets showed a blunting of therise in HLA-DR+ and CD16/CD56 in the Gln group. Therewere, however, no significant differences between groupsfor cases of NEC, growth, or length of stay. Whereas theplasma concentrations of alanine (Ala), glycine (Gly), Ser,threonine (Thr), Phe, and total nonessential amino acidswere lower in the Gln-supplemented infants after 2-weeksupplementation, there were no differences between groupsfor plasma concentrations of Gln, Glu, or ammonia [108].The authors speculated that the lower plasma amino acidconcentrations in infants fed Gln were the result of enhanceduptake of these amino acids for gluconeogenesis and provideevidence of reduced tissue catabolism. A secondary analysisof the initial trial also provided evidence for decreasedhospital costs [109]. While the control used is comparableto routine clinical practice, the study design cannot ensurethe specific effect of Gln as the differences between feedinggroups might result from higher intakes of nitrogen orenergy with Gln supplementation. The authors, however,chose not to use a third group with an isonitrogenous controldue to recruitment constraints. Although the trial was small,these initial results provided evidence for better toleranceto enteral feedings and lower sepsis rates in VLBW infantsreceiving enteral Gln supplementation.
Barbosa et al. [110] conducted a randomized controlledpilot study to evaluate the tolerance and clinical impact of
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Journal of Nutrition and Metabolism 9T
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emat
ure
form
ula
(Sim
ilac
Spec
ial
Car
eG
rou
p)al
one,
PN
AA
star
ted
at0.
5g/
kg/d
ond3
un
til3
g/kg
/dby
d8(n=
33)
(1)
Hos
pita
l-ac
quir
edse
psis
,to
lera
nce
toen
tera
lfee
din
gs,
and
LOS
inh
ospi
tal;
(2)
anal
ysis
ofT
-cel
lsu
bset
sin
per
iph
eral
bloo
ddu
rin
gw
k-4
oflif
e,N
EC
,gro
wth
,re
spir
ator
yst
atu
s,an
dsa
fety
(1)
Red
uce
dh
ospi
tal-
acqu
ired
seps
is(p
osit
ive
bloo
dcu
ltu
re)
wh
enco
ntr
olle
dfo
rbi
rth
wt,
few
er%
dw
ith
no
oral
inta
ke,a
nd
no
diff
eren
ces
inLO
Sin
hos
pita
l;(2
)bl
un
ted
the
rise
inH
LA-D
R+
and
CD
16/C
D56
subs
ets,
no
diff
eren
ces
inN
EC
,wt,
len
gth
,hea
dci
rcu
mfe
ren
ce,
mec
han
ical
ven
tila
tion
orde
ath
,saf
e
Roi
get
al.
1996
∗[1
08]
68V
LBW
age
<3
dre
ceiv
ing
PN
;bir
thw
t:50
0–12
50g;
GA
:25
–32
wk
Ran
dom
ized
dou
ble-
blin
d
From
d3to
d30
oflif
ere
ceiv
edpr
emat
ure
form
ula
(Sim
ilac
Spec
ial
Car
eG
rou
p)su
pple
men
ted
wit
hG
lnat
0.08
g/kg
/don
d3an
dre
ach
ed0.
31g/
kg/d
byd1
3,P
NA
Ast
arte
dat
0.5
g/kg
/don
d3u
nti
l3
g/kg
/dby
d8(n=
35)
From
d3to
d30
oflif
ere
ceiv
edpr
emat
ure
form
ula
(Sim
ilac
Spec
ial
Car
eG
rou
p)al
one,
PN
AA
star
ted
at0.
5g/
kg/d
ond3
un
til3
g/kg
/dby
d8(n=
33)
Pla
sma
AA
con
cen
trat
ion
sat
3ti
me
poin
ts(p
refe
edin
g,tr
ansi
tion
tofu
llfe
eds
and
full
EN
)
Dec
reas
edpl
asm
aco
nce
ntr
atio
ns
ofA
la,G
ly,
Ser,
Th
r,P
he,
and
tota
ln
ones
sen
tial
AA
afte
r∼2
wk
supp
lem
enta
tion
(i.e
.,at
tran
siti
onto
full
EN
),n
odi
ffer
ence
sbe
twee
ngr
oups
for
plas
ma
con
cen
trat
ion
sof
Gln
,Glu
,or
amm
onia
duri
ng
stu
dy
Dar
mau
net
al.1
997∗
[125
]
11V
LBW
age
<3
dre
ceiv
ing
PN
;bir
thw
t:<
1250
g;G
A:
24–3
2w
k
Ran
dom
ized
dou
ble-
blin
d
Rec
eive
dpr
emat
ure
form
ula
(Sim
ilac
Spec
ial
Car
eG
rou
p)su
pple
men
ted
wit
hG
lnat
0.08
g/kg
/don
d3an
din
crea
sed
to0.
2g/
kg/d
ond1
0,P
NA
Ast
arte
dat
0.5
g/kg
/don
d3u
nti
l3
g/kg
/dby
d8(n=
6)
Rec
eive
dpr
emat
ure
form
ula
(Sim
ilac
Spec
ial
Car
eG
rou
p)al
one
ond3
oflif
eu
nti
ld10
,PN
AA
star
ted
at0.
5g/
kg/d
ond3
un
til3
g/kg
/dby
d8(n=
5)
Wh
ole
body
prot
ein
met
abol
ism
/Leu
kin
etic
san
dG
lnki
net
ics
(IV
infu
sion
sof
L-[2
H]L
euan
dL-
[13C
]Gln
)on
d10
oflif
ein
fed
stat
e,th
atis
,du
rin
gco
nti
nu
ous
EN
(Gln
supp
lem
ente
dor
non
supp
lem
ente
d)an
dP
N
No
diff
eren
ces
inov
eral
lrat
eof
app
eara
nce
ofLe
uan
dG
ln,n
odi
ffer
ence
sin
Leu
and
Gln
rele
ase
from
prot
ein
brea
kdow
n,n
odi
ffer
ence
sin
Gln
deno
vosy
nth
esis
orpl
asm
aG
lnco
nce
ntr
atio
ns
Dal
las
etal
.19
98∗
[109
]
68V
LBW
age
<3
dre
ceiv
ing
PN
;bir
thw
t:50
0–12
50g;
GA
:24
–32
wk
Ran
dom
ized
dou
ble-
blin
d
From
d3to
d30
oflif
ere
ceiv
edpr
emat
ure
form
ula
(Sim
ilac
Spec
ial
Car
eG
rou
p)su
pple
men
ted
wit
hG
lnat
0.08
g/kg
/don
d3an
dre
ach
ed0.
31g/
kg/d
byd1
3,P
NA
Ast
arte
dat
0.5
g/kg
/don
d3u
nti
l3
g/kg
/dby
d8(n=
35)
From
d3to
d30
oflif
ere
ceiv
edpr
emat
ure
form
ula
(Sim
ilac
Spec
ial
Car
eG
rou
p)al
one,
PN
AA
star
ted
at0.
5g/
kg/d
ond3
un
til3
g/kg
/dby
d8(n=
33)
Hos
pita
lcos
tsan
alys
edby
log-
ran
kte
sts
and
Kap
lan
-Mei
erpl
ots
Red
uce
dm
edia
nco
sts
for
hos
pita
lisat
ion
,rad
iolo
gy,
phar
mac
y,la
bora
tory
,an
dN
ICU
,red
uce
dm
edia
nn
um
ber
ofu
tiliz
atio
nu
nit
s
-
10 Journal of Nutrition and Metabolism
Ta
ble
2:C
onti
nu
ed.
Ref
eren
ceSu
bjec
tsD
esig
nG
lnC
ontr
olO
utc
omes
Res
ult
s
Bar
bosa
etal
.19
99[1
10]
9cr
itic
ally
illin
fan
tsag
ed1–
24m
ore
quir
ing
inte
nsi
veca
rean
dto
lera
tin
gE
N
Ran
dom
ized
dou
ble-
blin
d
Gln
supp
lem
ente
d0.
3g/
kg/d
EN
for
5d
(n=
5)
Cas
ein
supp
lem
ente
d0.
3g/
kg/d
EN
for
5d
(n=
4)
Sept
icm
orbi
dity
,mor
talit
y,LO
Sin
ICU
,LO
Sin
hos
pita
lan
ddu
rati
onof
mec
han
ical
ven
tila
tion
,an
dto
lera
nce
No
sign
ifica
nt
diff
eren
ces
inse
ptic
com
plic
atio
ns,
mor
talit
y,d
inIC
U,d
inh
ospi
talo
rd
wit
hve
nti
lati
on,w
ellt
oler
ated
,an
dsa
fe
Mer
cier
etal
.20
03[1
12]
25LB
Wpr
emat
ure
neo
nat
esag
e≥1
4d
wit
hou
tac
ute
illn
ess
and
rece
ivin
gex
clu
sive
EN
;bi
rth
wt:
980–
1890
g;G
A:
27–3
5w
k
Ran
dom
ized
dou
ble-
blin
d
Exc
lusi
veen
tera
lpre
term
infa
nt
form
ula
supp
lem
ente
dw
ith
Gln
0.7
g/kg
/d(1
7%of
tota
lpr
otei
nin
take
asG
ln)
for
21d
(n=
12)
Exc
lusi
veen
tera
lpre
term
infa
nt
form
ula
supp
lem
ente
dw
ith
ison
itro
gen
ous
lact
oser
um
extr
acte
dpr
otei
n0.
7g/
kg/d
(17%
ofto
talp
rote
inin
take
asla
ctos
eru
m)
for
21d
(n=
9)
Para
met
ers
ofsu
per
ior
mes
ente
ric
bloo
dfl
owve
loci
ties
mea
sure
din
fed
stat
eby
puls
edD
oppl
eru
ltra
sou
nd
afte
r21
dsu
pple
men
tati
on
No
effec
ton
supe
rior
mes
ente
ric
bloo
dfl
ow
Vau
ghn
etal
.20
03[1
11]
649
VLB
Wag
e<
7d
rece
ivin
gP
N;b
irth
wt:
500–
1250
g
Mu
ltic
entr
era
ndo
miz
eddo
ubl
e-bl
ind
En
tera
lGln
supp
lem
ent
(0.3
g/kg
/d,3
%G
lnin
ster
ilew
ater
)gi
ven
atth
esa
me
tim
ebu
tse
para
tefr
omfe
edin
gsfo
rth
efi
rst
28d
oflif
e;A
Ain
take
∼3–3
.5g/
kg/d
byd7
(n=
314)
En
tera
lpla
cebo
(ste
rile
wat
er)
give
nat
the
sam
eti
me
but
sepa
rate
from
feed
ings
for
the
firs
t28
dof
life;
AA
inta
ke∼3
–3.5
g/kg
/dby
d7(n=
335)
(1)
Nu
mbe
rof
epis
odes
ofbl
ood
cult
ure
-pro
ven
nos
ocom
ials
epsi
sbe
twee
n7
dto
36w
kof
age;
(2)
susp
ecte
dse
psis
,pn
eum
onia
,UT
I,m
enin
giti
s,N
EC
,IV
H,P
VL
,re
tin
opat
hyof
prem
atu
rity
,u
seof
oxyg
enat
36w
k,ga
stro
inte
stin
aldy
sfu
nct
ion
,gr
owth
,age
and
wei
ght
atdi
sch
arge
,an
dde
ath
(1)
No
diff
eren
ces
inn
osoc
omia
lsep
sis;
(2)
decr
ease
dga
stro
inte
stin
aldy
sfu
nct
ion
and
seve
ren
euro
logi
cse
quel
aeam
ong
surv
ivor
s(G
rade
s3
and
4IV
Han
dP
VL
),n
odi
ffer
ence
sin
susp
ecte
dse
psis
,pn
eum
onia
,UT
I,m
enin
giti
s,N
EC
,re
tin
opat
hyof
prem
atu
rity
,u
seof
oxyg
enat
36w
k,gr
owth
,age
and
wt
atdi
sch
arge
,or
deat
h
Pari
mie
tal
.20
04[1
27]
26L
BW
ingo
odh
ealt
han
dga
inin
gw
tag
ed10
–74
d(>
23d
ofag
e);b
irth
wt:
693–
1846
g;G
A<
32w
k
Ran
dom
ized
dou
ble-
blin
dE
nte
ralG
ln0.
6g/
kg/d
for
5d
(n=
9)
(1)
En
tera
lGly
0.6
g/kg
/dfo
r5
d(n=
9)or
(2)
un
supp
lem
ente
den
tera
lfo
rmu
lafo
r5
d(n=
8)
Wh
ole-
body
prot
ein
,Gln
and
ure
aki
net
ics
onst
udy
d-6
(IV
infu
sion
sof
L-[1
–13C
,15N
]Leu
,[2
H5]
Ph
e,[1
5N2]
ure
a,L-
[5–1
5N]G
ln)
afte
r5
dsu
pple
men
tati
ondu
rin
gfa
stin
g(3
haf
ter
the
last
mea
l)an
dfe
dst
ate,
and
plas
ma
AA
con
cen
trat
ion
sdu
rin
gfa
stin
g
Hig
her
rate
ofu
rea
syn
thes
is,
no
diff
eren
ces
inra
tes
ofap
pea
ran
ceof
Ph
e,Le
uC
orLe
uN
,no
diff
eren
ces
inra
teof
app
eara
nce
ofG
lnor
plas
ma
Gln
con
cen
trat
ion
s
-
Journal of Nutrition and Metabolism 11
Ta
ble
2:C
onti
nu
ed.
Ref
eren
ceSu
bjec
tsD
esig
nG
lnC
ontr
olO
utc
omes
Res
ult
s
Kor
kmaz
etal
.200
7[1
23]
69V
LBW
prem
atu
ren
eon
ates
rece
ivin
gP
N;
birt
hw
t:<
1500
g
Pro
spec
tive
inte
rven
tion
From
8d
to12
0d
oflif
ere
ceiv
edG
lnsu
pple
men
t0.
15g/
kg/d
BID
mix
edw
ith
ster
ilew
ater
and
give
nat
the
sam
eti
me
but
sepa
rate
from
feed
ings
byan
orog
astr
ictu
beor
oral
ly(n=
36)
From
8d
to12
0d
oflif
ere
ceiv
edst
erile
wat
er(p
lace
bo)
give
nat
the
sam
eti
me
but
sepa
rate
from
feed
ings
byan
orog
astr
ictu
beor
oral
ly(n=
33)
Gro
wth
para
met
ers
atbi
rth
,1,
2,3,
and
4m
oan
dbi
och
emic
alpa
ram
eter
sat
4m
o
No
diff
eren
ces
ingr
owth
para
met
ers
atbi
rth
and
2m
o,h
igh
erw
t,le
ngt
h,h
ead
circ
um
fere
nce
,MU
AC
and
mid
-th
igh
circ
um
fere
nce
at3
and
4m
o,n
oto
xici
tysi
gns
Van
Den
Ber
get
al.2
005∗
∗
[113
]
102
VLB
W<
48h
afte
rbi
rth
rece
ivin
gP
N;
birt
hw
t:<
1500
g;G
A<
32w
k
Ran
dom
ized
dou
ble-
blin
d
From
3d
to30
dof
life
rece
ived
ente
ralp
rete
rmfo
rmu
laor
brea
stm
ilksu
pple
men
ted
wit
hG
lnin
incr
easi
ng
dose
sto
≤0.3
g/kg
/d(n=
52)
From
3d
to30
dof
life
rece
ived
ente
ralp
rete
rmfo
rmu
laor
brea
stm
ilksu
pple
men
ted
wit
his
onit
roge
nou
sA
lain
incr
easi
ng
dose
sto
≤0.3
g/kg
/d(n=
50)
(1)
Feed
ing
tole
ran
ce;(
2)gr
owth
,in
fect
iou
sm
orbi
dity
,an
dsh
ort-
term
outc
ome
(1)
No
diff
eren
ces
inti
me
tofu
llen
tera
lfee
din
g;(2
)n
odi
ffer
ence
sin
age
PN
disc
onti
nu
ed,d
ofn
oen
tera
lfe
edin
g,N
EC
orw
tz-
scor
es,
decr
ease
din
cide
nce
of≥1
seri
ous
infe
ctio
ns
(sep
sis,
men
ingi
tis,
pyel
onep
hri
tis,
pneu
mon
ia,a
nd
arth
riti
s),
no
diff
eren
ces
inP
DA
trea
ted
wit
hin
dom
eth
acin
orsu
rgic
allig
atio
n,
mec
han
ical
ven
tila
tion
,su
pple
men
talo
xyge
n,
reti
nop
athy
,age
atdi
sch
arge
from
NIC
U,a
geat
disc
har
gefr
omh
ospi
talo
rde
ath
Van
Den
Ber
get
al.2
005∗
∗
[114
]
102
VLB
W<
48h
afte
rbi
rth
rece
ivin
gP
N;
birt
hw
t:<
1500
g;G
A<
32w
k
Ran
dom
ized
dou
ble-
blin
d
From
3d
to30
dof
life
rece
ived
ente
ralp
rete
rmfo
rmu
laor
brea
stm
ilksu
pple
men
ted
wit
hG
lnin
incr
easi
ng
dose
sto
≤0.3
g/kg
/d(n=
52)
From
3d
to30
dof
life
rece
ived
ente
ralp
rete
rmfo
rmu
laor
brea
stm
ilksu
pple
men
ted
wit
his
onit
roge
nou
sA
lain
incr
easi
ng
dose
sto
≤0.3
g/kg
/d(n=
50)
Safe
tyby
dete
rmin
atio
nof
plas
ma
AA
con
cen
trat
ion
sm
easu
red
at4
tim
ep
oin
ts:
<48
h,d
7,d1
4,an
dd3
0of
life
Incr
ease
dpl
asm
aA
Aco
nce
ntr
atio
ns
ofm
ost
esse
nti
alan
dn
ones
sen
tial
AA
incl
udi
ng
Gln
and
Glu
(bot
hgr
oups
),de
crea
sed
Ph
ean
dTy
r(b
oth
grou
ps)
Van
Den
Ber
get
al.2
006∗
∗
[116
]
90V
LBW
<48
haf
ter
birt
hre
ceiv
ing
PN
;bi
rth
wt:<
1500
g;G
A<
32w
k
Ran
dom
ized
dou
ble-
blin
d
From
3d
to30
dof
life
rece
ived
ente
ralp
rete
rmfo
rmu
laor
brea
stm
ilksu
pple
men
ted
wit
hG
lnin
incr
easi
ng
dose
sto
≤0.3
g/kg
/d(n=
45)
From
3d
to30
dof
life
rece
ived
ente
ralp
rete
rmfo
rmu
laor
brea
stm
ilksu
pple
men
ted
wit
his
onit
roge
nou
sA
lain
incr
easi
ng
dose
sto
≤0.3
g/kg
/d(n=
45)
Inte
stin
alp
erm
eabi
lity
(uri
nar
yla
ctu
lose
/man
nit
olra
tio)
asse
ssed
at4
tim
epo
ints
:<48
h,d
7,d1
4,an
dd3
0of
life
Dec
reas
edla
ctu
lose
/man
nit
olra
tio
(bot
hgr
oups
),de
crea
sed
uri
nar
yla
ctu
lose
con
cen
trat
ion
s(b
oth
grou
ps),
incr
ease
du
rin
ary
man
nit
olco
nce
ntr
atio
ns
(bot
hgr
oups
)
-
12 Journal of Nutrition and Metabolism
Ta
ble
2:C
onti
nu
ed.
Ref
eren
ceSu
bjec
tsD
esig
nG
lnC
ontr
olO
utc
omes
Res
ult
s
Van
Den
Ber
get
al.2
007∗
∗
[115
]
86V
LBW
<48
haf
ter
birt
hre
ceiv
ing
PN
;bi
rth
wt:<
1500
g;G
A<
32w
k
Ran
dom
ized
dou
ble-
blin
d
From
3d
to30
dof
life
rece
ived
ente
ralp
rete
rmfo
rmu
laor
brea
stm
ilksu
pple
men
ted
wit
hG
lnin
incr
easi
ng
dose
sto
≤0.3
g/kg
/d(n=
43)
From
3d
to30
dof
life
rece
ived
ente
ralp
rete
rmfo
rmu
laor
brea
stm
ilksu
pple
men
ted
wit
his
onit
roge
nou
sA
lain
incr
easi
ng
dose
sto
≤0.3
g/kg
/d(n=
43)
Inte
stin
al(f
aeca
l)m
icro
flor
a(b
ifido
bact
eria
,lac
toba
cilli
,E
sch
eria
coli,
stre
ptoc
occi
,cl
ostr
idia
)at<
48h
,at
d7,
d14,
and
d30
oflif
e,as
anal
ysed
byfl
uor
esce
nt
insi
tuhy
brid
izat
ion
No
diff
eren
cein
prev
alen
ceof
inte
stin
alm
icro
flor
a
Van
Den
Ber
get
al.2
007∗
∗
[117
]
77V
LBW
surv
ivin
gin
fan
tsat
the
corr
ecte
dag
eof
1y;
birt
hw
t:<
1500
g;G
A<
32w
k
Follo
wu
pof
alls
urv
ivin
gpa
rtic
ipan
tsof
ara
ndo
miz
eddo
ubl
e-bl
ind
stu
dy
From
3d
to30
dof
life
rece
ived
ente
ralp
rete
rmfo
rmu
laor
brea
stm
ilksu
pple
men
ted
wit
hG
lnin
incr
easi
ng
dose
sto
≤0.3
g/kg
/d(n=
37)
From
3d
to30
dof
life
rece
ived
ente
ralp
rete
rmfo
rmu
laor
brea
stm
ilksu
pple
men
ted
wit
his
onit
roge
nou
sA
lain
incr
easi
ng
dose
sto
≤0.3
g/kg
/d(n=
40)
Inci
den
ceof
alle
rgic
and
infe
ctio
us
dise
ase
duri
ng
the
firs
tye
arof
life
asas
sess
edby
valid
ated
ques
tion
nai
res
Low
erri
skof
atop
icde
rmat
itis
,no
diff
eren
ces
inin
cide
nce
ofbr
onch
ial
hype
ract
ivit
y,in
fect
ion
sof
upp
erre
spir
ator
y,lo
wer
resp
irat
ory,
orga
stro
inte
stin
altr
acts
Van
Zw
olet
al.2
008∗
∗
[122
]
72V
LBW
infa
nts
atth
eco
rrec
ted
age
of2
y;bi
rth
wt:<
1500
g;G
A<
32w
k
Follo
wu
pof
part
icip
ants
ofa
ran
dom
ized
dou
ble-
blin
dst
udy
From
3d
to30
dof
life
rece
ived
ente
ralp
rete
rmfo
rmu
laor
brea
stm
ilksu
pple
men
ted
wit
hG
lnin
incr
easi
ng
dose
sto
≤0.3
g/kg
/d(n=
40)
From
3d
to30
dof
life
rece
ived
ente
ralp
rete
rmfo
rmu
laor
brea
stm
ilksu
pple
men
ted
wit
his
onit
roge
nou
sA
lain
incr
easi
ng
dose
sto
≤0.3
g/kg
/d(n=
32)
Neu
rode
velo
pmen
tal
outc
ome
(neu
rode
velo
pmen
tal
impa
irm
ent,
cere
bral
pals
y,vi
sion
,hea
rin
g,M
DI,
and
PD
Iof
the
Bay
ley
Scal
eof
Infa
nt
Dev
elop
men
tII
)ev
alu
ated
atth
eco
rrec
ted
age
of2
y
No
diff
eren
ces
inth
ein
cide
nce
ofan
MD
In
ora
PD
I≤
85,n
odi
ffer
ence
sin
the
inci
den
ceof
neu
rode
velo
pmen
tal
impa
irm
ent
orce
rebr
alpa
lsy
Van
Den
Ber
get
al.2
009∗
∗
[120
]
63V
LBW
infa
nts
<48
haf
ter
birt
hre
ceiv
ing
PN
;bi
rth
wt:<
1500
g;G
A<
32w
k
Ran
dom
ized
dou
ble-
blin
d
From
3d
to30
dof
life
rece
ived
ente
ralp
rete
rmfo
rmu
laor
brea
stm
ilksu
pple
men
ted
wit
hG
lnin
incr
easi
ng
dose
sto
≤0.3
g/kg
/d(n=
25)
From
3d
to30
dof
life
rece
ived
ente
ralp
rete
rmfo
rmu
laor
brea
stm
ilksu
pple
men
ted
wit
his
onit
roge
nou
sA
lain
incr
easi
ng
dose
sto
≤0.3
g/kg
/d(n=
38)
Th
1(I
F-ga
mm
a,T
NF-
alph
a,IL
-2)
and
Th
2cy
toki
ne
resp
onse
s(I
L-10
,IL-
5,IL
-4)
at48
h,d
7,an
dd1
4of
life
follo
win
gin
vitr
ow
hol
ebl
ood
cell
stim
ula
tion
asan
alyz
edby
cyto
met
ric
bead
arra
y
No
diff
eren
ces
inT
h1
orT
h2
cyto
kin
ere
spon
ses
Van
Zw
olet
al.2
009∗
∗
[119
]
59V
LBW
infa
nts
atag
eof
1y;
birt
hw
t:<
1500
g;G
A<
32w
k
Follo
wu
pof
part
icip
ants
ofa
ran
dom
ized
dou
ble-
blin
dst
udy
From
3d
to30
dof
life
rece
ived
ente
ralp
rete
rmfo
rmu
laor
brea
stm
ilksu
pple
men
ted
wit
hG
lnin
incr
easi
ng
dose
sto
≤0.3
g/kg
/d(n=
28)
From
3d
to30
dof
life
rece
ived
ente
ralp
rete
rmfo
rmu
laor
brea
stm
ilksu
pple
men
ted
wit
his
onit
roge
nou
sA
lain
incr
easi
ng
dose
sto
≤0.3
g/kg
/d(n=
31)
Th
1(I
F-ga
mm
a,T
NF-
alph
a,IL
-2)
and
Th
2cy
toki
ne
profi
les
(IL-
10,I
L-5,
IL-4
)at
1y
ofag
efo
llow
ing
invi
tro
wh
ole
bloo
dst
imu
lati
on
No
diff
eren
ces
inT
h1
orT
h2
cyto
kin
epr
ofile
s
-
Journal of Nutrition and Metabolism 13
Ta
ble
2:C
onti
nu
ed.
Ref
eren
ceSu
bjec
tsD
esig
nG
lnC
ontr
olO
utc
omes
Res
ult
s
Van
Zw
olet
al.2
010∗
∗
[121
]
72V
LBW
infa
nts
atth
eco
rrec
ted
age
of1
y;bi
rth
wt:<
1500
g;G
A<
32w
k
Follo
wu
pof
part
icip
ants
ofa
ran
dom
ized
dou
ble-
blin
dst
udy
From
3d
to30
dof
life
rece
ived
ente
ralp
rete
rmfo
rmu
laor
brea
stm
ilksu
pple
men
ted
wit
hG
lnin
incr
easi
ng
dose
sto
≤0.3
g/kg
/d(n=
34)
From
3d
to30
dof
life
rece
ived
ente
ralp
rete
rmfo
rmu
laor
brea
stm
ilksu
pple
men
ted
wit
his
onit
roge
nou
sA
lain
incr
easi
ng
dose
sto
≤0.3
g/kg
/d(n=
38)
Inte
stin
al(f
aeca
l)m
icro
biot
a(b
ifido
bact
eria
,Ch
is/l
itgr
oup,
Esc
her
iaco
li)at
age
1y
asan
alys
edby
flu
ores
cen
tin
situ
hybr
idiz
atio
n
No
diff
eren
cein
prev
alen
ceof
inte
stin
alm
icro
biot
a
Van
Zw
olet
al.2
011∗
∗
[118
]
76V
LBW
infa
nts
at6
yof
age;
birt
hw
t:<
1500
g;G
A<
32w
k
Follo
wu
pof
part
icip
ants
ofa
ran
dom
ized
dou
ble-
blin
dst
udy
From
3d
to30
dof
life
rece
ived
ente
ralp
rete
rmfo
rmu
laor
brea
stm
ilksu
pple
men
ted
wit
hG
lnin
incr
easi
ng
dose
sto
≤0.3
g/kg
/d(n=
38)
From
3d
to30
dof
life
rece
ived
ente
ralp
rete
rmfo
rmu
laor
brea
stm
ilksu
pple
men
ted
wit
his
onit
roge
nou
sA
lain
incr
easi
ng
dose
sto
≤0.3
g/kg
/d(n=
38)
Alle
rgic
(ato
pic
derm
atit
is,
hay
feve
r,re
curr
ent
wh
eeze
,an
das
thm
a)an
din
fect
iou
sdi
seas
e(u
pper
and
low
erre
spir
ator
ytr
act
infe
ctio
n,
gast
roin
test
inal
trac
tin
fect
ion
,uri
nar
ytr
act
infe
ctio
n)
at6
yof
age
asas
sess
edby
valid
ated
ques
tion
nai
res
Dec
reas
edri
skof
atop
icde
rmat
itis
,no
diff
eren
ces
inh
ayfe
ver,
recu
rren
tw
hee
zeor
asth
ma,
decr
ease
dri
skof
gast
roin
test
inal
trac
tin
fect
ion
,no
diff
eren
ces
inu
pper
orlo
wer
resp
irat
ory
trac
tin
fect
ion
oru
rin
ary
trac
tin
fect
ion
VLB
W:v
ery
low
birt
hw
eigh
t;P
N:p
aren
tera
lnu
trit
ion
;wt:
wei
ght;
GA
:ges
tati
onal
age;
AA
:am
ino
acid
;EN
:en
tera
lnu
trit
ion
;IV
:in
trav
enou
s;LO
S:le
ngt
hof
stay
;NE
C:n
ecro
tizi
ng
ente
roco
litis
;IC
U:i
nte
nsi
veca
reu
nit
;LB
W:l
owbi
rth
wei
ght;
UT
I:u
rin
ary
trac
tin
fect
ion
;IV
H:i
ntr
aven
tric
ula
rh
emor
rhag
e;P
VL:
peri
ven
tric
ula
rle
uko
mal
acia
;PD
A:p
aten
tdu
ctu
sar
teri
osu
s;N
ICU
:neo
nat
alin
ten
sive
care
un
it;B
ID:t
wic
ea
day;
MU
AC
:mid
upp
erar
mci
rcu
mfe
ren
ce;M
DI:
Men
talD
evel
opm
enta
lIn
dex;
PD
I:Ps
ych
omot
orD
evel
opm
enta
lIn
dex;
Th
1:T
hel
per
typ
e1;
Th
2:T
hel
per
typ
e2;
IF:i
nte
rfer
on;T
NF:
tum
orn
ecro
sis
fact
or;
IL:i
nte
rleu
kin
.∗ ,∗∗
Ori
gin
atin
gfr
omth
esa
me
coh
ort.
-
14 Journal of Nutrition and Metabolism
enteral formula supplemented with 0.3 g/kg/d Gln for 5 daysversus an equal dose of casein in 9 critically ill infants aged 1–24 months. Although Gln was well tolerated, the study wasunderpowered to detect differences in septic complications(control: 3/4 versus Gln: 1/5, P = 0.10), mortality (control:2/4 versus Gln: 0/5, P = 0.10) or other outcomes (ventilatoruse, length of stay in intensive care unit (ICU) or in hospital).It was also not reported in the inclusion criteria whether thestudy population of infants were premature or term.
Vaughn et al. [111] conducted a large multicentre trial totest whether enteral Gln supplement decreases the incidenceof hospital-acquired infection and other morbidities in 649VLBW infants. Within the first 7 d of age, infants wererandomly assigned to enteral Gln supplement (0.3 g/kg/d,3% Gln in sterile water) or placebo (sterile water) given atthe same time but separate from feedings for the first 28 d.There were no differences between groups for the primaryoutcome (nosocomial sepsis between 7 d and 36 weeks post-menstrual age; Gln: 30.9% versus control: 33.7%). However,gastrointestinal dysfunction (2.5 versus 7.5%, P < 0.01)and severe neurological sequelae among survivors (Grades3 and 4 intraventricular hemorrhage and paraventricularleukomalacia; 10.4 versus 15.1%, P = 0.08) were lessfrequent in Gln versus control, respectively. There were nodifferences in the occurrence of suspected sepsis, pneumonia,urinary tract infection, meningitis, NEC, retinopathy ofprematurity, oxygen use at 36 weeks, or mortality. Growth,age, and weight at discharge were also similar. Whereasenteral Gln does not appear to decrease nosocomial sepsisin VLBW infants, the study may have been underpoweredto detect a significant difference, as dropout rate was higherthan anticipated (i.e., 105 infants exited the study beforecompletion). Also the centre-to-centre variation in this andother multicentre trials [102] may have blunted differences inoutcomes (e.g., sepsis), since nutrition and infection controlpractices may differ among centres and may mask some ofthe differences that might be apparent in a single facility.While the study provides further evidence to suggest thatenteral Gln improves feeding tolerance and may preventcentral nervous system (CNS) morbidity, these positiveresults are based on secondary endpoints and subgroupanalyses. Furthermore, the Gln dose was based on birthweight and was not adjusted for interval changes in weight.Therefore, the dose administered may have been inadequatedue to rapid growth during the early neonatal period.
The apparent improved feeding tolerance in VLBWinfants receiving enteral Gln in previous studies [107, 111]cannot be explained by enhanced mesenteric blood flow[112]. It seems that, in premature infants without acuteillness and tolerating exclusive EN, mesenteric blood flowremains stable after 14 d of age and does not appear to beinfluenced by enteral Gln.
In contrast to previous reports on Gln-enriched EN inVLBW infants [107, 111], Van Den Berg et al. [113] found noimprovement in feeding tolerance, as assessed by the mediand to reach full enteral feeds (Gln: 13 d versus control: 13 d;hazard ratio [95% CI]: 1.19 [0.79–1.79]). In this randomizedcontrolled trial, 102 VLBW infants received either enteral Glnsupplementation or an isonitrogenous control (Ala) added to
breast milk or preterm formula in increasing doses from d-3to d-30 of life to a maximum dose of 0.3 g/kg/d Gln. Therewere also no differences between groups for other variablesof feeding tolerance (age at which PN was discontinued, dof no enteral feeding), NEC, or growth. However, the Gln-supplemented group had a lower incidence of ≥1 seriousinfections (sepsis, meningitis, pyelonephritis, pneumonia,and arthritis) compared with the isonitrogenous controlgroup (Gln: 50% versus control: 76%; OR [95% CI]: 0.32[0.14–0.74]. Other short-term outcomes (patent ductusarteriosus treated with indomethacin or surgical ligation,mechanical ventilation, supplemental oxygen, retinopathy,age at discharge from NICU, age at discharge from hospital,or death) were not significantly different. Gln did not alterplasma concentrations of Gln, Glu, or other amino acids[114]. Although safe at the dose provided, Gln-enrichedEN did not improve feeding tolerance or other short-term outcomes in VLBW infants. However, because Glnreduced infectious morbidity, the use of Gln-enriched EN inVLBW infants deserves further consideration. Comparison,however, with other studies is made difficult because of theuse of different feeding guidelines for the introduction orwithholding enteral feeds. Whereas the choice of isonitroge-nous control prevented the removal of amino acids fromthe Gln supplement in the present study, groups were madeisonitrogenous by adding more amino acid (Ala) to thecontrol group. The control group then received additionalamino acid/nitrogen, which is not representative of dailypractice. However, given the limited sample size, a thirdcomparison group (enteral formula routinely used in anNICU) was not feasible. The beneficial effect of enteral Glnon infection rate could not be explained by an increasednumber of bifidobacteria or lactobacilli in the intestinalmicroflora as demonstrated by a secondary analysis in asubset of 86 VLBW infants [115]. Furthermore, Gln did notenhance the postnatal decrease in intestinal permeability,as assessed by the urinary lactulose/mannitol ratio in asubset of 90 VLBW infants. Specifically, supplementationwith Gln or isonitrogenous control equally decreased urinaryconcentrations of lactulose and increased urinary mannitol[116]. More recently, followup of all surviving participants(n = 77) revealed that Gln-enriched EN in VLBW infantsmay lower the incidence of atopic dermatitis (OR [95%CI]: 0.13 [0.02–0.97]) during the first year of life but hasno effect on the incidence of bronchial hyperactivity orinfectious diseases [117]. Further followup of this cohortof VLBW infants (n = 76) at 6 y of age also found adecreased risk of atopic dermatitis (adjusted OR [95% CI]:0.23 [0.06–0.95]) and gastrointestinal infections (adjustedOR [95% CI]: 0.10 [0.01–0.93]) in the Gln-supplementedgroup [118]. Although outcomes were assessed by validatedquestionnaires in these 2 followup studies, parental reportof physician diagnosis of disease could be subject to report-ing/information bias. Furthermore, the lower incidence ofatopic dermatitis and infection rates with Gln were notrelated to changes in cytokine profiles [119]/responses [120]or to changes in intestinal bacterial species at age 1 y[121]. Finally, the same group studied neurodevelopmentaloutcome at 2 y corrected age in a subgroup of 72 VLBW
-
Journal of Nutrition and Metabolism 15
infants and found no beneficial effect of Gln-enriched ENduring the neonatal period [122].
The effect of Gln supplementation on long-term out-come of VLBW infants has also been reported by Korkmazet al. [123] who studied the effect of 4-month enteral Glnsupplementation on growth. From d-8 through d-120 of life,69 VLBW infants were assigned to enteral Gln (0.3 g/kg/d)supplement or placebo (sterile water) according to the orderof admission to the NICU. Whereas growth parameters didnot differ during the first 2 months of life, by the end ofthe third and fourth month, infants treated with Gln showedhigher weight, length, head circumference, mid-upper-armcircumference, and midthigh circumference compared tocontrols. The authors concluded that long-term enteral Glnin VLBW infants may lead to improvements in growth in atime-dependent manner without any signs of Gln toxicity.Although this was a prospective interventional study, a com-plete description of masking, blinding, or randomizationprocedures was not provided. Also, because the placebo(sterile water) was neither isocaloric nor isonitrogenous tothe Gln treatment, the enhanced growth could have resultedfrom the effect of increased amino acid/nitrogen, since earlyprovision of parenteral amino acids (without Gln) has beenshown to improve growth parameters in VLBW infants[124].
3.2.2. Protein Metabolism. Darmaun et al. [125] determinedthe effect of enteral Gln on Leu and Gln metabolism ina subset of 11 VLBW neonates from the larger trial [107](Table 2). Enteral Gln supplementation provided at lowdoses (≤0.2 g/kg/d) from d-3 to d-10 of life did not inhibitwhole-body protein breakdown in VLBW infants. Leu releasefrom protein breakdown (an index of whole-body proteinbreakdown) was slightly but not significantly lower in theGln group versus controls. Plasma Gln concentration, Glnrelease from protein breakdown, or Gln de novo synthesis didnot significantly differ between groups. However, there was atrend toward lower rates of Gln de novo synthesis in infantsreceiving Gln supplement. Although the number of patientswas small, the failure to detect a significant effect of Gln on itsown metabolism or on whole-body protein breakdown couldalso be due to the different effects of enteral and parenteralGln supplementation. Importantly, the majority of enteralGln is used in first pass in premature infants [126]. This islikely a significant factor in the different effects of enteral andparenteral Gln. Moreover, the dose of Gln used in the currentstudy was lower than that (0.5 g/kg/d Gln) previously shownto inhibit proteolysis in LBW infants [105].
Parimi et al. [127] examined the effect of enteralGln on whole-body Gln and nitrogen kinetics in healthygrowing LBW infants during the fasting (3 h after the lastmeal) and fed state. This study was the only to have 3groups, where Gln-supplemented group was compared withan isonitrogenous control and enteral formula routinelyused in the NICU. Between 10 and 74 d of age, infantswere randomly assigned to formula supplemented with Gln(0.6 g/kg/d; n = 9), isonitrogenous amounts of Gly (n =9), or unsupplemented formula (n = 8) for 5 d. During
fasting, the rate of appearance of Phe, Leu carbon, andLeu nitrogen (measures of proteolysis) were not significantlydifferent between groups. Compared with controls, enteralGln resulted in an increased rate of urea synthesis, no changein Gln rate of appearance, or plasma Gln concentrations.Similar effects were observed with Gly supplement, but themagnitude was less. The authors concluded that enteral Glndoes not affect Gln rate of appearance or whole-body proteinturnover in a specific group of healthy growing LBW infants,thus, suggesting that Gln is primarily metabolized in the gut(and liver) [126] and is associated with an increased rate ofurea synthesis. Alternatively, because, in healthy prematurenewborns, there is already a high rate of Gln turnover (85%of which is contributed by de novo synthesis) [128], thisspecific population of neonates could have been less sensitiveto enteral Gln. This is in contrast to premature neonates withacute illness, whereby catabolic stress may provoke a greaterneed for exogenous Gln.
In summary, although methodologically sound random-ized trials consistently demonstrate safety in VLBW infants[80, 99, 100, 102, 105, 107, 111, 113, 127], parenteralor enteral Gln supplementation does not appear to affectmortality [100, 102, 104, 107, 111, 113], NEC [100, 102, 107,111, 113], length of stay [99, 100, 102, 104, 107, 111, 113],or growth [100, 102, 104, 107, 111, 113]. Moreover, theresults are conflicting for other short-term clinical outcomessuch as feeding tolerance [99, 100, 102, 104, 107, 111, 113],serious infections/sepsis [100, 102, 107, 111, 113], ventilatoruse [99, 102, 104, 107, 113], and severe neurological sequelae[111]. Few data have been reported for the effects of Glnsupplementation in VLBW infants on long-term clinicaloutcomes such as growth at 4 months [123], allergic andinfectious morbidity at 1 y [117] and 6 y [118], and neu-rodevelopmental outcomes at 2 y corrected age [122]. Largerwell-controlled studies are needed. A systematic review of7 randomized controlled trials showed that parenteral orenteral Gln supplementation in premature infants of VLBWdoes not affect mortality (RR [95% CI]: 0.98 [0.80–1.20])or other clinical outcomes including invasive infection, NEC,time to achieve full EN, duration of hospital stay, growth, orneurodevelopmental outcomes at 18 months corrected age[129].
In contrast, studies on protein metabolism showed thatparenteral Gln may have a protein-sparing effect decreasingwhole body proteolysis and Gln de novo synthesis inpremature infants of LBW [80, 105]. However, the beneficialeffects on whole-body protein metabolism have not beenreproduced for enteral Gln [125, 127]. Hence, the routeof administration (enteral versus parenteral) should beconsidered in interpreting the effect of Gln on outcome inpremature infants [126].
Parenteral and enteral Gln supplementation is apparentlysafe in premature neonates; however, the lack of anyconsistent benefit(s) does not support its routine use in thispopulation as a whole. It is possible that any beneficial effectsof Gln are limited to specific subgroups of premature infantssuffering from acute stress (e.g., NEC, who are perhaps Glnor Arg deficient [88]) whereby increased Gln utilizationexceeds the body’s synthetic capacity [10]. Future studies
-
16 Journal of Nutrition and Metabolism
are needed to better define the role of Gln in the neonatalperiod and its mechanism of action. Large prospectivelystratified trials are needed to identify the specific subgroupsof premature neonates, who may have a greater need for Glnand who may eventually benefit from Gln supplementation.
3.3. Glutamine Supplementation in Pediatric Patients with
Gastrointestinal Disease
3.3.1. Glutamine Supplementation in Infants with SurgicalGastrointestinal Disease. While several trials have been con-ducted in VLBW infants, only 2 small double-blindedrandomized trials tested whether supplemental Gln might beof benefit in critically ill infants with surgical gastrointestinaldisease [130, 131] (Table 3). Duggan et al. [130] comparedenteral Gln to an isonitrogenous mix of nonessential aminoacids in 20 neonates and infants younger than 12 monthsreceiving PN after gastrointestinal surgery and found noapparent effect on the duration of PN (Gln: 39 d versuscontrol: 21 d, NS) or days to achieve 80% energy requirementby EN (Gln: 24 d versus control: 13 d, NS). Secondaryoutcomes (energy absorption, clinical infections, or growth)were also not affected by enteral Gln. Albers et al. [131]compared standard PN to isonitrogenous Gln-supplementedPN in 80 newborns and infants (
-
Journal of Nutrition and Metabolism 17
Ta
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