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`Published in final edited form as:
`. 2011 January ; 14(1): 75–82. doi:10.1097/MCO.0b013e328341235a.
`Curr Opin Clin Nutr Metab Care
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`Amino acid composition in parenteral nutrition: what is the
`evidence?
`
`Shadi S. Yarandi8 , Vivian M. Zhaob, Gautam Hebbar8, and Thomas R. Ziegler8,b
`a Department of Medicine, Emory University School of Medicine, Emory University, Atlanta,
`Georgia, USA
`
`b Nutrition and Metabolic Support Service, Emory University Hospital, Emory University, Atlanta,
`Georgia, USA
`
`Abstract
`Purpose of review-Complete parenteral nutrition solutions contain mixed amino acid
`products providing all nine essential amino acids and a varying composition of nonessential amino
`acids. Relatively little rigorous comparative efficacy research on altered parenteral nutrition amino
`acid composition has been published in recent years.
`
`Recent findings-Limited data from randomized, double-blind, adequately powered clinical
`trials to define optimal doses of total or individual amino acids in parenteral nutrition are
`available. An exception is the growing number of studies on the efficacy of glutamine
`supplementation of parenteral nutrition or given as a single parenteral agent. Parenteral glutamine
`appears to confer benefit in selected patients; however, additional data to define optimal glutamine
`dosing and the patient subgroups who may most benefit from this amino acid are needed.
`Although some promising studies have been published, little data are available in the current era of
`nutrition support on the clinical efficacy of altered doses of arginine, branched chain amino acids,
`cysteine, or taurine supplementation of parenteral nutrition.
`
`Summary-Despite routine use of parenteral nutrition, surprisingly little clinical efficacy data
`are available to guide total or specific amino acid dosing in adult and pediatric patients requiring
`this therapy. This warrants increased attention by the research community and funding agencies to
`better define optimal amino acid administration strategies in patient subgroups requiring parenteral
`nutrition.
`
`Keywords
`amino acids; arginine; cysteine; glutamine; taurine
`
`Introduction
`
`Studies over many decades show that the blood amino acid profile is disturbed, lean body
`mass is lost, and body protein requirements are generally increased in a variety of illnesses
`and catabolic conditions warranting amino acid supplementation in all patients who require
`,2
`parenteral nutrition [l 0°
`.. ,3-6]. Mixed amino acid formulations that provide both essential
`and nonessential amino acids are thus a standard component of complete parenteral nutrition
`
`© 2010 Wolters Kluwer Health I Lippincott Williams & Wilkins
`Correspondence to Thomas R. Ziegler, MD, Suite GG-23, Atlanta Clinical and Translational Science Institute, Emory University
`Hospital, 1364 Clifton Road, Atlanta, GA 30322, USA, Tel: + 1 404 727 7351 ; fax: + 1 404 727 5563; tzieg01@emory.edu.
`
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`Y arandi et al.
`
`Page2
`
`prescriptions to support cell, organ and skeletal, cardiac and respiratory muscle functions,
`and wound healing [3,4,6].
`
`All commercially available amino acid formulations for parenteral nutrition provide the nine
`essential amino acids (histidine, isoleucine, leucine, lysine, methionine, phenylalanine,
`threonine, tryptophan, and valine) in amounts varying between 38 and 57% of total amino
`acids (Table 1 ). Commonly used amino acid mixtures also provide nonessential amino acids
`comprising 43-62% of total amino acids. Alanine, arginine, glycine, proline, serine, and
`tyrosine are present in all commonly used products and other nonessential amino acids differ
`by manufacturer ( e.g. glutamate and aspartate are present in some, but not all commercial
`formulations). Commercial amino acid formulations also contain varying amounts of
`classically nonessential amino acids that may become conditionally essential under certain
`circumstances ( e.g. cysteine, as acetyl-cysteine or cysteine HCL, taurine, and, in one
`formulation, glycyl-glutamine and glycyl-tyrosine dipeptide) (Table 1). L-Cysteine HCL (50
`mg/ml as a 5% solution) and L-alanyl-L-glutamine dipeptide (200 mg/ml as a 20% solution;
`of which approximately two-thirds comprises the glutamine moiety) are also commercially
`available in many countries for admixture into cysteine-free or glutamine-free complete
`parenteral nutrition.
`
`Amino acid mixtures for parenteral nutrition that are enriched in branched chain amino acids
`and low in aromatic amino acids (intended for use in hepatic encephalopathy) and a variety
`of other 'designer' products are also available for clinical use; examples of these include
`specially designed formulas for individuals with inborn errors of metabolism and the
`addition ofL-glutamine to otherwise glutamine-free parenteral nutrition solutions by
`commercial pharmacies (glutamine dipeptide is not FDA approved in the USA) [4,6]. This
`review will focus on recent evidence from human studies and clinical practice guidelines,
`generally published within the past 5 years, concerning the utility and efficacy of amino acid
`dosing in patients requiring parenteral nutrition and the impact of alteration of specific
`amino acids in this clinical setting.
`
`Total amino acid dosing
`
`Rigorous data on the comparative efficacy of various formulations of parenteral nutrition,
`the optimal timing of administration, and the role of specific clinical factors ( e.g. blood
`glucose control) on clinical outcomes with different parenteral nutrition formulations are
`lacking [7,8] . Unfortunately, few well designed, double-blind, randomized, controlled
`clinical trials (RCTs) have been published, particularly in recent years, on the clinical impact
`of different daily total amino acid doses per kg body weight or different concentrations of
`specific amino acids in parenteral nutrition [7,8]. Further, the relevance of earlier clinical
`studies to guide current parenteral nutrition amino acid dosing is uncertain given the
`significant changes that have occurred in common practices of parenteral nutrition
`administration worldwide over the past decade, including tighter blood glucose control, use
`of lower caloric doses, and commercial availability of alternative lipid emulsions in many
`countries (e.g. medium chain triglycerides, olive oil, fish oil, etc.) [3]. Given the relative
`lack of high-quality RCTs and comparative effectiveness research, current practices of
`amino acid use in parenteral nutrition are largely based on uncontrolled or observational
`,2
`studies, expert opinion, and clinical practice guidelines by academic societies [1..
`··,3,5,6].
`
`Studies performed in the 1980s in nonburned intensive care unit (ICU) patients indicated
`that protein loads of more than approximately 2.0 g/kg/day are not efficiently utilized for
`protein synthesis and the excess is oxidized and contributes to azotemia [3]. Clinical practice
`guidelines published by the American Society for Parenteral and Enteral Nutrition (ASPEN)
`and the Society of Critical Care Medicine, the European Society for Clinical Nutrition and
`
`Curr Opin Clin Nutr Metab Care. Author manuscript; available in PMC 2012 January 1.
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`Eton Ex. 1104
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`Y arandi et al.
`
`Page 3
`
`Metabolism (ESPEN), and the German Association for Nutritional Medicine in 2009
`recommend a parenteral nutrition amino acid dose range of between 1.2 and 1.5 g/kg/day for
`most adult catabolic patients with normal renal and hepatic function ( e.g. 50-100% above
`the RDA of 0.8 g/kg/day). Some guidelines suggest that lower amino acid intake may be
`appropriate for patients without significant catabolic stress [ 41. Administration of adequate
`nonamino acid calories is essential to allow amino acids to be effectively utilized for protein
`synthesis and to minimize the amount that is oxidized as fuel ( e.g. nitrogen to calorie ratio of
`1 : 130 to 1 : 170) [3,4,61.
`
`The optimal dosing of amino acid for patients with acute or chronic renal and/or hepatic
`,10 ,11,12
`failure who require parenteral nutrition is unknown [8,9..
`..]. Recent guidelines
`have suggested that adult patients with chronic hepatic failure and cirrhosis do not need to
`have protein restriction, but may benefit from amino acid/protein doses of 1.2-1.5 g/kg/day
`,9
`··1. However, these
`given the high rate of protein wasting in this patient population [2° 0
`recommendations have not been based on evidence from rigorous studies in hospital
`patients, who may exhibit acute, severe hepatic decompensation, with or without
`encephalopathy; in such patients, short-term parenteral nutrition amino acid restriction may
`be indicated on an individual basis depending on hepatic function and other clinical factors
`(also not evidence-based) [31. Specific parenteral nutrition amino acid dosing
`recommendations for patients with acute and chronic renal failure (largely based on nitrogen
`balance estimates and data on amino acid losses during renal replacement therapies) have
`,10 ,11,12
`.. 1. Recent
`been recently published by professional societies and others [2""
`European and American clinical practice guidelines suggest that requirements for protein/
`amino acid be provided as a combination of adequate essential amino acids plus non(cid:173)
`essential amino acids in adults with renal failure, combined with adequate nonprotein energy
`..1. Suggested protein/amino acid dosing in adult patients with chronic renal failure
`,12
`[10..
`receiving hemodialysis or peritoneal dialysis is between 1.2 and 1.5 g/kg/day [1 o··
`,12
`Suggested protein/amino acid dosing in adult patients with acute renal failure in the
`European guidelines is from 0.6 to 1.0 g/kg/day in patients with mild catabolism, 1.0-1.5 g/
`kg/day in patients on dialytic therapy with moderate catabolism, to a maximum of I. 7 g/kg/
`day in patients on continuous renal replacement therapy with severe hypercatabolism [10··1.
`The recent American guidelines suggest that standard parenteral nutrition amino acid
`formulations be used in acute kidney injury, while the lack of clinical outcome data does not
`support the use of intradialytic parenteral nutrition as a nutritional supplement in
`malnourished patients with chronic kidney disease [12··1. These guidelines cite metabolic
`studies showing that doses of protein/amino acid between 1.8 and 2.5 g/kg/day may be
`optimal to support lean body mass during continuous renal replacement therapy; those with
`acute kidney injury treated with hemodialysis may require protein/amino acid doses of 1.5-
`,11,12
`2.5 g/kg/day to achieve positive nitrogen balance [2° 0
`. . 1. A common, but not evidence(cid:173)
`based, clinical practice in hospital patients receiving parenteral nutrition is to adjust the total
`amino acid dose downward depending on the degree and tempo of azotemia (in the absence
`ofrenal replacement therapy) [3,61 .
`
`" ] .
`
`0
`
`Recent guidelines for parenteral nutrition support in children, with or without critical illness,
`have been recently published by professional societies from Europe and America [13,14].
`As noted in the American guidelines for critically ill children, there are insufficient data to
`make evidenced-based recommendations for macronutrient intake in this population [14].
`However, based on limited data, estimated protein/amino acid requirements for critically ill
`children are a function of the child's age, as follows: 0-2 years, 2.0-3.0 g/kg/day; 2-13
`years, 1.5-2.0 g/kg/day; and 13-18 years, 1.5 g/kg/day [14].
`
`Curr Opin Clin Nutr Metab Care. Author manuscript; available in PMC 2012 January I.
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`Y arandi et al.
`
`Glutamine
`
`Page4
`
`Over the past 20 years, a large and growing number of clinical investigations have explored
`the clinical and metabolic efficacy of parenteral nutrition supplemented with glutamine,
`either as L-glutamine or as water soluble and heat-stable glycyl-glutamine or alanyl(cid:173)
`glutarnine dipeptide (reviewed in Refs. [ 15-17, 18.]). These clinical trials, supported by
`translational studies in animal models, strongly suggest that glutamine becomes a
`conditionally essential amino acid in severe stress conditions such as critical illness, surgery,
`and trauma, when endogenous utilization exceeds endogenous glutamine production [3,15-
`T Glutamine added to parenteral nutrition at doses up to 0.57 g/kg/day in adults also
`17,18
`appears to be safe. For example, recent studies in head trauma patients show that
`intravenous alanyl-glutamine dipeptide at doses equivalent to 0.34 g/kg/20 h did not alter
`cerebral glutamate (a product of amino acid metabolism and a potential neurotransmitter) or
`brain amino acid exchange [19,20]. In addition to the large number of clinical trials
`summarized in recent reviews [ 15-17, 18.], several additional trials of intravenous glutamine
`have recently been published [21-35]. In these studies, glutamine was either admixed in
`parenteral nutrition formulations or infused as the alanyl-glutamine dipeptide through
`central or peripheral veins. Two relatively small but rigorous RCTs from France [21] and the
`USA [22], respectively, showed that glutamine-supplemented parenteral nutrition (providing
`0.5 g/kg/day of alanyl-glutamine) decreased nosocomial infections in ICU patients [21,22];
`however, in the latter trial, patients admitted to the ICU after pancreatic surgery for severe
`pancreatitis showed no difference in outcomes versus patients who received standard
`glutamine-free parenteral nutrition [22]. In an unblinded study of 109 patients, enterally fed
`patients requiring colorectal cancer resection surgery and given 1.0 g/kg/day alanyl(cid:173)
`n
`glutamine for 11 days perioperatively ( = 57) showed a significant decrease in wound
`infection, intra-abdominal abcess and wound dehiscence [23]. Two recent small, unblinded
`controlled studies suggested that patients with acute pancreatitis may clinically benefit from
`glutamine-supplemented parenteral nutrition in terms of a reduction in total complications
`[24] and infectious morbidity [25], without any effect on length of hospital stay or mortality,
`but rigorous RCTs of glutamine-supplemented parenteral nutrition in this disorder are
`lacking.
`
`Results of studies over the past two decades on the clinical efficacy of glutarnine(cid:173)
`supplemented parenteral nutrition in various forms of cancer and cancer treatment have been
`mixed to date; however, when taken together with results of enteral glutarnine trials and
`animal studies, glutamine administration appears to be safe and potentially efficacious with
`regard to some clinical outcomes in cancer [18"]. A recent Cochrane review concluded that
`bloodstream infections with glutamine-supplemented parenteral nutrition are significantly
`reduced but length of stay is not altered in bone marrow transplant (BMT) recipients [26]. In
`a 2006 pilot double-blind RCT from Argentina, peripherally infused alanyl-glutamine
`dipeptide was given as intermittent daily doses in patients undergoing chemoradiotherapy
`n
`for head and neck malignancy; patients receiving glutamine ( = 14) demonstrated a
`significantly lower incidence of mucositis, less oral pain, and a reduced need for feeding
`n
`tube placement than saline-treated controls ( = 15) [27]. A small unblinded study of
`peripherally infused alanyl-glutamine dipeptide (30 g/day) versus mixed amino acid infusion
`in acute myeloid leukemia patients showed that neutrophil phagocytosis and superoxide
`generation were improved in the glutarnine group [28]. A double-blind trial from Brazil in
`53 patients undergoing allogeneic BMT for hematologic malignancies showed that patients
`receiving parenteral nutrition supplemented with 0.3--0.4 g/kg/day alanyl-glutarnine
`n
`dipeptide ( = 27) had a significantly lower mortality rate at day 100 and 180 post-BMT
`n
`versus glutamine-free parenteral nutrition-treated controls ( = 26), with a nonsignificant
`trend for less infectious complications and no change in intestinal permeability to sugar
`markers [29].
`
`Curr Opin Clin Nutr Metab Care. Author manuscript; available in PMC 2012 January 1.
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`Y arandi et al.
`
`Page 5
`
`Several of the recently conducted trials do not show clinical benefits with parenteral
`glutamine administration [30-35]. A randomized, unblinded, multicenter Italian study in 428
`patients undergoing major abdominal surgery for cancer showed no significant difference in
`surgical complications, morbidity, incidence of infection or length of stay between patients
`who received parenteral alanyl-glutamine supplementation (0.40 g/kg/day of dipeptide
`solution, equal to 0.25 g/kg/day of free glutamine) or no treatment beginning 1 day
`preoperatively and continued for at least 5 days postoperatively (mean =7 days) [30].
`Patients in this study were not given specialized nutritional support unless enteral feeding
`was not possible at day 7 postoperatively [30]. In a double-blind RCT from Germany, Engel
`et al. [31] studied 78 patients undergoing cardiopulmonary bypass and cardiac surgery
`received either alanyl-glutamine dipeptide (0.5 g/kg/day), isonitrogenous glutamine-free
`mixed amino acids or normal saline for the initial 3 postoperative days. Glutamine
`administration did not alter T cell cytokine responses or clinical parameters of recovery
`compared to the other two groups [31 ]. Jo et al. [32], in South Korea, in a double-blind RCT
`of 60 patients requiring pancreati-coduodenectomy for periampullary tumors, randomized
`patients to complete parenteral nutrition supplemented with glycyl-glutamine (Table 1) or
`isonitrogenous parenteral nutrition without glutamine given perioperatively for 7 days (2
`days preoperatively and 5 days postoperatively). No differences in length of hospital stay
`and complication rates were observed between the study groups [32]. An unblinded study of
`perioperative parenteral nutrition with or without glutamine in 70 gastrointestinal surgical
`patients in Taiwan did not show differences between groups in clinical outcomes, although
`indices of inflammation were decreased in the glutamine group [33]. In a double-blind study
`of critically ill patients receiving identical conventional tube feedings, Luo et al. [34] found
`no metabolic differences during 8 days of treatment in the study groups given alanyl(cid:173)
`glutamine dipeptide (0.5 g/kg/day) either enterally or intravenously and when compared
`with a group not receiving glutamine supplementation. Very little information is available
`on the efficacy of glutamine-supplemented parenteral nutrition in home patients. In the first
`such trial, Culkin et al. [35] performed a 12-month cross-over study in 22 home parenteral
`nutrition patients who received 6 months of parenteral nutrition containing glycyl-glutamine
`during either the first or second 6-month study period (0.14-0.15 g/kg/day dipeptide). No
`differences were observed between study periods in nutritional status, intestinal
`permeability, plasma glutamine concentrations, or quality oflife [35].
`
`The mixed results of these clinical trials could be due to the fact that parenteral glutamine
`may be beneficial in only certain patient subgroups ( e.g. those with significant body
`glutamine depletion or increased glutamine needs, or in those with specific medical or
`surgical characteristics or conditions) [22]. Completion of large ongoing RCTs of glutamine
`supplemented parenteral nutrition in postoperative surgical ICU patients (ClinicalTrials.gov
`identifier NCT00248638), combined enteral and parenteral glutamine plus high-dose
`selenium with antioxidants in medical/surgical ICU patients (ClinicalTrials.gov identifier
`NCTO0 133978), and parenteral glutamine as a single agent (ClinicalTrials.gov identifier
`NCT00922714), or in combination with high-dose selenium [36] will better define adult
`patient subgroups who may benefit from parenteral glutamine [16,37,36] . Of interest, the
`2009 clinical practice guidelines ofESPEN and the German Association for Nutritional
`Medicine each recommend that ICU patients requiring parenteral nutrition routinely receive
`glutamine supplementation (ranging from 0.2 to 0.4 g/kg/day) [l 0°,4]. In contrast, the
`American ICU guidelines do not recommend that glutamine be routinely administered in
`ICU patients requiring parenteral nutrition or a specific dose, but that its use should be
`considered if the product is available [2""].
`
`Studies on glutamine-supplemented parenteral nutrition in pediatrics are limited to four
`earlier trials, including one large multicenter American study, in preterm, very low birth
`weight infants requiring ICU care [38]. A recent Cochrane report concluded that glutamine
`
`Curr Opin Clin Nutr Metab Care. Author manuscript; available in PMC 2012 January 1.
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`Y arandi et al.
`
`Page6
`
`supplementation in such infants does not have a statistically significant effect on mortality
`invasive infection, necrotizing enterocolitis, time to achieve full enteral nutrition, or duration
`of hospital stay [38].
`
`Despite inconsistant study results across diverse patient groups, parenteral glutamine
`supplementation in adults has been shown to significantly increase plasma glutamine
`concentrations, improve nitrogen retention and upregulate various immune functions [15-
`17]. Also, in catabolic adults, parenteral glutamine also decreased indices of insulin
`resistance [21,39] and upregulated the cytoprotective molecules heat shock protein 70 [40]
`and glutathione in plasma [41] and skeletal muscle [42]. In sum, parenteral glutamine
`appears to confer benefit in selected patients; however, additional data to define optimal
`glutamine dosing strategies in patient subgroups who may most benefit from this amino acid
`are needed.
`
`Arginine is present in relatively high doses in all common amino acid formulations for
`parenteral nutrition used in both children and adults (Table 1 ). Arginine is thought to be a
`conditionally essential amino acid in neonates and infants and possibly in catabolic states.
`Arginine's functions and metabolic roles in health and disease have been comprehensively
`reviewed [43,44.]. Although enteral arginine supplementation in patients requiring
`specialized nutrition support has been extensively studied, little clinical research on clinical
`or metabolic effects of arginine dosing in parenteral nutrition has been performed. A recent
`review speculated on the rationale for combined administration of glutamine and arginine in
`pathologic states [45]. Arginine is the substrate for the production of nitric oxide (a potent
`vasodilator), and there is some speculation that, given the low plasma arginine levels
`observed in preterm neonates, arginine supplementation may serve to prevent necrotizing
`enterocolitis (NEC). In 2002, a double-blind RCT was published in 152 premature infants
`n
`n
`randomized to receive either supplemental L-arginine ( = 75) or placebo ( = 77) with oral
`feeds (as tolerated) and in any required parenteral nutrition during the first 28 days oflife
`[46]. Arginine supplementation was well tolerated and resulted in a significant decrease in
`the incidence of NEC [ 46]. To our knowledge, no further study of arginine efficacy in
`pediatrics has subsequently been published, but further study on the issue of NEC is clearly
`needed.
`
`Arginine
`
`Cysteine
`
`Cysteine is commonly believed to be a conditionally essential amino acid in preterm
`neonates, who have a relative inability to enzymatically convert methionine (the essential
`sulfur amino acid precursor to cysteine), in the liver [47]. As noted in Table 1, small
`amounts of acetyl-cysteine or cysteine HCL are present in some mixed amino acid formulas
`for parenteral nutrition use and larger doses of an approved cysteine HCL product can be
`admixed into parenteral nutrition on the day of administration. Commercial mixed amino
`acid formulas do not contain appreciable cysteine because of instability in solution, but
`methionine, as an essential amino acid, is present in all mixed amino acid formulas (Table
`1).
`
`Cysteine has dynamic effects in metabolism and systemic redox control. The metabolism
`and roles of cysteine (and it's disulfide cystine) in physiologic and pathophysiologic states,
`including as a precursor for the synthesis of glutathione (GSH), have been recently
`summarized [ 48,49]. Cysteine is used in protein synthesis and, in critically ill patients
`receiving conventional parenteral nutrition, GSH levels fall; thus, increased cysteine
`utilization may exceed endogenous production and decreased plasma cysteine. In humans,
`plasma cysteine levels and the redox potential of the cysteine/cystine redox pool have been
`
`Curr Opin Clin Nutr Metab Care. Author manuscript; available in PMC 2012 January I.
`
`Eton Ex. 1104
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`Y arandi et al.
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`Page7
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`recently shown by our group to be dynamically affected by oral dietary intake of cysteine
`and methionine [ 50,51]. In a rat model of short-bowel syndrome, we showed that
`supplementation of enteral diets with cysteine and methionine improved gut mucosal and
`plasma cysteine/cystine redox potential and enhanced adaptive ileal mucosal growth [52].
`Although no studies, to our knowledge, have been published on the clinical or metabolic
`effects of cysteine added to parenteral nutrition in adults, L-cysteine HCL at doses of 500
`mg to 1.5 g/day is empirically added to parenteral nutrition by some clinicians in patients
`with parenteral nutrition-associated liver disease.
`
`As noted, 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 [53]. The authors concluded that growth was not
`significantly affected by cysteine supplementation (evaluated in one quasi-randomized trial),
`but that nitrogen retention was significantly increased by cysteine supplementation (studied
`in four trials); no data were available on clinical outcomes [53]. Riedijk et al. [47] concluded
`that there was no evidence for limited endogenous cysteine synthesis in 4-week-old low
`birth weight infants using exhaled breath methods after oral cystine loads, while Courtney(cid:173)
`Martin et al. [54] 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 (Table 1 ).
`Te Braake et al. [55] found that administration of high-dose cysteine (81 mg/kg/day) via
`parenteral nutrition to preterm infants was safe but did not increase plasma cystine or GSH
`concentrations or synthesis rates. Parenteral cysteine supplementation did not increase
`erythrocyte GSH in a recent study using tracer methodology in five parenteral nutrition-fed
`neonates [56]. Mager et al. [57] report that addition ofN-acetyl-cysteine (NAC) to
`parenteral nutrition or parenteral hydration fluid at doses of20-50 mg/kg/day decreased
`liver enzyme elevations and tended to increase blood GSH levels in children requiring home
`parenteral nutrition. RCTs on the clinical and metabolic efficacy of either L-cysteine or
`NAC added to parenteral nutrition in adults or children requiring this therapy are needed.
`
`Taurine
`
`Taurine, which can be synthesized via its amino acid precursor cysteine, is believed to be
`conditionally essential in premature neonates. As shown in Table l, taurine is present in
`some commercial amino acid formulas for use in parenteral nutrition, particularly in
`formulas designed for infants. Taurine supplementation in enteral nutrition has been studied
`in premature neonates without any conclusive effect on growth rate, morbidity and
`mortality, similar to the one trial oftaurine added to parenteral nutrition in this setting,
`according to a Cochrane report [58]. One observational study suggested that taurine
`supplementation of parenteral nutrition may decrease the occurrence of parenteral nutrition(cid:173)
`associated cholestasis in neonates [59], but a small pilot study failed to reproduce this effect
`in adults requiring long-term parenteral nutrition for short-bowel syndrome [60].
`
`Branched chain amino acids
`
`Earlier studies, primarily in the 1980s, showed that plasma concentrations of the essential
`branched chain amino acids (BCAA) isoleucine, leucine, and valine were decreased in
`patients with severe liver disease and encephalopathy, while levels of aromatic amino acids
`(phenylalanine, histidine, tryptophan, and tyrosine) were elevated in this setting. Given that
`this amino acid pattern was associated with encephalopathy, parenteral nutrition amino acid
`formulas designed to correct this metabolic abnormality became commercially available
`(enriched in BCAA and with decreased amounts of aromatic amino acids). Numerous
`studies of various levels of rigor were conducted (primarily in the 1980s and 1990s) to test
`
`Curr Opin C/in Nutr Metab Care. Author manuscript; available in PMC 2012 January 1.
`
`Eton Ex. 1104
`7 of 14
`
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`Y arandi et al.
`
`Page 8
`
`the clinical and metabolic efficacy of these amino acid solutions. While a review of these
`studies is beyond the scope of this paper, the results on clinical outcomes were overall
`inconclusive and such amino acid formulations are no longer routinely used. However, the
`recent European clinical practice guidelines do suggest that these BCAA-enriched amino
`acid formulations may be useful in selected patients with liver failure-induced
`encephalopathy [9° 0
`] , and these are sometimes used by clinicians in the USA and elsewhere
`in malnourished patients with hepatic encephalopathy who cannot clinically tolerate higher
`doses of parenteral nutrition amino acids. In more recent, relatively small, non blinded
`studies, patients given BCAA-enriched parenteral nutrition after gastrointestinal surgery
`demonstrated improved nitrogen balance compared to patients receiving conventional amino
`acid formulations in parenteral nutrition [61,62], while one of these studies demonstrated a
`decreased overall morbidity rate [62]. Rigorous RCTs on the potential utility ofBCAA
`supplementation in specific catabolic patient groups are needed.
`
`Conclusion
`
`Administration of mixed essential and nonessential amino acids in parenteral nutrition is a
`routine aspect of clinical nutrition support. Although