Carol Rees Parrish, M.S., R.D., Series Editor .

Immunonutrition in 2016: Benefit, Harm or Neither?NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #154(continued from page 30)Table 2. Summary Of Meta-Analyses and Systematic Reviews Comparing Use of Immunonutrition (IN) Via Oral or EnteralReferencePopulation & TimingHeyland et al. 200116··N Nutrients StudiedCritical illness and surgical;subgroup analysesDuring but not before criticalillness; pre-operative,perioperative, post-operativefor surgical2419·Enteral IN support with anycombination of arginine, glutamine,n-3 fatty acids, or nucleotidesvs. standard ENWaitzburg et al. 200617··Elective surgical onlyPre-operative, perioperative,post-operative, during criticalillness2305·Enteral IN or oral IN containing anycombination of nutrients vs standardenteral or oral supplementsZheng et al. 200718··Elective mixed GI surgicalPre-operative, perioperative,post-operative1269·Enteral IN or oral IN containingany combination of nutrientsvs. standard dietMarik and Zaloga 201019·Elective surgical only (GI,head/neck cancers, generalabdominal surgery, cardiacsurgery)Pre-operative, perioperative,post-operative1918·Enteral IN with arginine alone,fish oil alone or combinationvs. standard EN·Cerantola et al. 201020··Elective GI surgical onlyPre-operative, perioperative,post-operative2730·Enteral IN with any combinationof IN nutrients vs. standard ENZhang et al. 201221·2331··Elective surgical forGI cancer onlyPerioperativeEnteral IN or oral IN containingany combination of nutrientsvs. standard dietMarimuthu et al. 2012··Open GI surgical onlyPerioperative2496·Enteral IN versus standard dietDrover et al. 201223··Elective surgical onlyPre-operative, perioperative,post-operativeUnspecified·Enteral IN with arginine alone,fish oil alone or combinationvs. standard ENVidal-Casariego et al.201424·Elective surgical head/neckcancer onlyPre-operative, perioperative,post-operative397·Enteral IN with arginine alone,fish oil alone or combinationvs. standard ENElective surgical patientsPreoperative only561·Oral IN with arginine alone,fish oil alone or combinationvs. standard oral supplementor standard oral diet22·Hegazi et al. 201425··IN, immunonutrition; n-3, omega-3; EN, enteral nutrition; RR, relative risk; OR, odds ratio; CI, confidence interval; LOS, length of stay32 PRACTICAL GASTROENTEROLOGY AUGUST 2016

Immunonutrition in 2016: Benefit, Harm or Neither?NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #154Nutrition Support Versus Standard Diet or Standard Enteral Nutrition Support Among Elective Surgical PopulationsOutcomesAuthor AffiliationsOverall significant reduction in infectiouscomplications and hospital LOSHigh-arginine IN resulted in significantly lowerincidence of infection, shorter hospital LOScompared to low-arginine INSurgical patients had significantly fewer infectiouscomplications than the critically illNo effect on mortality·Heyland was a paid site investigator on the Ross(now Nestle) product (Impact)Decreased hospital LOS (3.1 days) and infectiouscomplicationsNo effect on mortality·Hypothesis conceived at workshop sponsoredby Novartis Medical NutritionReduced infectious complications, hospital LOS(weighted mean differenceNo effect on mortality·None disclosed·Post-operative and perioperative IN with both arginine and fish oil reduced risk of acquired infection ,wound, and LOS·Zaloga was a paid employee of Baxter Healthcare, Inc. –though Baxter Healthcare did not manufacture any of theenteral immune-modulating diets mentioned in the article··Reduction in overall complicationsNo effect on mortality·None disclosed·Reduction in hospital LOS, infectious complications,and non-infectious complicationsNo mortality analysis·None disclosedDeceased infectious complications, non-infectiouscomplications, and hospital LOSNo effect on morality·Ljungqvist and Lobo had received research funding fromNutricia Clinical CareVaradhan was supported by research fellowships from theNottingham Digestive Diseases Centre National Institutefor Health Research Biomedical Research Unit, and theEnhanced Recovery After Surgery Society.Reduced infectious complications; with the greatesteffect with pre and post-operative administrationNo effect on �·Heyland received a research grant as the principalinvestigator and a speaker honorarium from Nestle.Ochoa was a paid consultant for Nestle until July 2010,and received a salary as MedicalScientific Director for Nestle for 2 years leading upto publicationReduced incidence of fistulaNo reductions in diarrhea, wound infections or otherinfections were notedNo mortality analysis·None disclosedOral IN vs. standard oral supplement:no difference in wound infection, all infectiouscomplications, non-infectious complications,or LOSOral IN vs standard oral diet: decreasedinfectious complications·Evans was the recipient of educational grants from NestleNutrition and Abbott Laboratories, as well as speakerhonoraria from Abbott LaboratoriesHegazi and Hustead were full-time employees ofAbbott LaboratoriesPRACTICAL GASTROENTEROLOGY AUGUST 2016 ·33

Immunonutrition in 2016: Benefit, Harm or Neither?NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #154potentially improving outcomes, if any.To offer fair comparisons between groups wherenutrition is provided to both, allowing IN to be theintervention or treatment, nearly all of the randomizedcontrolled trials (RCTs) that provide the basis for themeta-analyses and systematic reviews described inTable 2 compare administration of IN to standard EN.Similar reductions in LOS have been reported when INwas utilized in the pre- versus post-operative periods.34Hegazi, et al. reported that pre-op oral IN only providedbenefit when compared to those that received nonsupplemented oral diets,25 suggesting that adequatedelivery of basic nutrients results in prevention of postop complications. However, given that the standard ofcare (control) is no nutrition intervention, perhaps thebenefits of preoperative nutrition can be attributed tocarbohydrate loading to maximize glycogen stores asrecommended for Enhanced Recovery After Surgery(ERAS), which has been shown to significantly reducecomplications and hospital LOS.35,36 Though someresearchers have reported that pre-op carbohydrateloading may prevent loss of LBM,37-39 reduce insulinresistance, tissue glycosylation in the operative period,and optimize glycemic control post-op,40-42 directcomparisons have not yet been made. Is it simply theprovision of extra (or adequate) calories above the‘standard’ intake the patient would be able to consumeusually in the pre-op period that is resulting in benefits?More research is needed.Review of Efficacy for Useof IN Among Critically Ill PopulationsGiven the role infectious complications play in thecritically ill population, any intervention that mightdecrease that risk is worthy of investigation. Generally,the outcomes of meta-analyses examining efficacy of INamong the critically ill (Table 3) are similar to those forthe elective surgical population with regards to reducedincidence of infection and decreased hospital LOS, withno difference in mortality; however, some researchers16suggest that provision of IN among the critically ill mayresult in adverse outcomes, and therefore, be a safetyconcern. Like that in the elective surgical population,the research for use of IN in the critical care arena isfull of methodologic and heterogeneity concerns.Much of the debate regarding efficacy of INamong critically ill patients surrounds the safety ofits use – specifically relating to arginine. In a 2001meta-analysis, Heyland et al.,16 concluded that34 arginine-supplemented IN provided no benefit amongthe critically ill, and may potentially result in adverseoutcomes, a conclusion made due to a trend towardincreased mortality among those receiving IN; however,these results were not statistically significant. Since thistime, concerns regarding the safety of IN, specificallyarginine supplementation, among septic patients hasbeen hotly debated; however, research remains limited,and the debate has mainly surrounded three theories(though none confirmed):1. Sepsis results in arginine deficiencyand supplementation may improve septicstate.432. Sepsis is caused by excess nitric oxide(NO) production. Since NO is theend-product of arginine metabolismthat causes vasodilation, argininesupplementation may exacerbate theseptic syndrome.433. Arginine infusion among septic medicaland surgical patients does not causehemodynamic instability.44As many of the IN products available contain a numberof potentially immune-modulating components, andit remains unclear which (if any) nutrient may beproviding the most benefit, researchers have attemptedto scrutinize immune-modulating nutrients independentfrom nutrition delivery.IN, Individual Delivery, Biomarkers andOutcomes Among the Critically IllAs the goal of IN is to enhance the immune response,researchers have examined inflammatory biomarkersconcurrently with clinical outcomes in attempts todemonstrate potential changes in outcomes. However,it is imperative to remember that changes in surrogatemarkers do not necessarily translate to differencesin clinical outcomes, a point that is often missed ininterpretation. One group concluded that deliveryof IN EN containing n-3 fatty acids, glutamineand arginine among those with esophageal cancerundergoing concurrent chemotherapy and radiationresulted in a reduced rise in the inflammatory cytokinesC-reactive protein (CRP) (p 0.001) and tumor-necrosis(continued on page 36)PRACTICAL GASTROENTEROLOGY AUGUST 2016

Immunonutrition in 2016: Benefit, Harm or Neither?NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #154(continued from page 34)Table 3. Summary of Meta-Analyses and Systematic Reviews Comparing Use of Immunonutrition (IN) Via EnteralReferencePopulation & TimingHeys et al.199926··Beale et al.199927··Heyland et al.200116··Montejo et al.200328··Marik and Zaloga200829··Glenn et al.201430·N Nutrients StudiedMixed critical illness(surgery, trauma, burns,cancer, sepsis)Post-operative only1009·Enteral IN support with anycombination of arginine,glutamine, BCAAs, n-3 fattyacids, RNA vs standard ENMixed critical illness(medical, surgical, trauma)During, but not prior tocritical illness1482·Enteral IN support witharginine alone or arginine incombination with glutamine,nucleotides, n-3 fatty acids vs.standard ENCritical illness and surgical;subgroup analysesDuring critical illnessand pre-operative,perioperative,post-operative for surgical2914·Enteral IN support with anycombination of arginine,glutamine, n-3 fatty acids,or nucleotides vs standard ENMixed critical illness (surgical, trauma, burn, mixed)Post-operative, duringcritical illnessUnspecified·Enteral IN vs standard EN;any combination of IN3013·Enteral IN support with fishoil alone OR arginine alone orarginine in combination withglutamine, nucleotides, n-3fatty acids vs. standard ENUnspecified·Enteral IN with fish oil vs.standard EN9Mixed critical illness(mixed, burn, trauma)During, but not prior tocritical illnessMixed critical illnessIN, immunonutrition; BCAAs, branched chain amino acids; n-3, omega-3; RNA, ribonucleic acid; EN, enteral nutrition;factor-alpha (TNF-α) (p 0.014) compared to thosereceiving standard EN support.45 It is important to notethat although statistically significant change in markersof inflammation were found, these authors failed toconnect their results to clinical outcomes, which isnecessary to drive change in practice.36 To further illustrate this point, researchers of thehighly publicized ARDS Network Omega Trial (n 272), administered n-3, GLA, and antioxidants separatefrom the enteral formulas twice daily.5 Although deliveryof n-3 fatty acid increased plasma EPA concentration8-fold, there were no differences in ventilator-free orPRACTICAL GASTROENTEROLOGY AUGUST 2016

Immunonutrition in 2016: Benefit, Harm or Neither?NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #154Nutrition Support Versus Standard Enteral Nutrition Support Among Critically Ill �Author AffiliationsSignificant reduction in infectious complicationsand hospital LOS (2.5 days)No mortality analysis·None disclosedSignificant reductions in ventilator days, infectionrate, and hospital LOSNo effect on mortality·Partially sponsored by Novartis NutritionOverall significant reduction in infectiouscomplications and hospital LOSHigh-arginine IN resulted in significantly lowerincidence of infection, shorter hospital LOScompared to low-arginine INSurgical patients had significantly fewerinfectious complications than the critically illNo effect on mortality·Heyland was a paid site investigator on the Ross(now Nestle) product (Impact)Lower incidence of abdominal abscesses,nosocomnial pneumonia, bacteremiaReduced mechanical ventilation in traumapatients onlyReduced ICU LOS (mean reduction 1.6 days; andhospital LOS (mean reduction 3.4 days; in traumaand surgical patients onlyNo effect on mortality·Partially sponsored by Novartis Consumer HealthNo effect on LOS or mortality with arginine, with orwithout glutamine of n-3 fatty acidsSignificant reduction in mortality, secondary infections, and LOS with fish oil-only IN·Zaloga was a paid employee of Baxter Healthcare,Inc., which does not manufacture any of the enteral immune modulating formulas mentioned inthe manuscript, does market a glutamine enteralsupplement, but did not sponsor any of the trialsincluded in this reviewReduction in ICU LOS, and reduction in ventilatordays when EN with fish oil was administered, butnot with bolus dosing of IN substance separatefrom ENNo mortality analysis·Wischmeyer served as a consultant for AbbottInc. on the use of fish oil containing enteralformulas in the critical care settingOR, odds ratio; CI, confidence interval; LOS, length of stayICU-free days among those receiving the supplementalimmune-enhancing nutrients.In the Reducing Deaths Due to Oxidative Stress(REDOX) trial comparing the effects of glutamine and/or selenium administered separate from the EN formula,unexpectedly, researchers reported longer time to ICUPRACTICAL GASTROENTEROLOGY AUGUST 2016 and hospital discharge.6 Interestingly, post hoc analysisrevealed that high dose glutamine and/or antioxidantsmay be associated with increased mortality, especially inthose with multiorgan failure. Furthermore, Van Zantenet al.46 found that after adjusting for Acute Physiologyand Chronic Health Evaluation II (APACHE II) scores,37

Immunonutrition in 2016: Benefit, Harm or Neither?NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #154patients requiring mechanical ventilation that receivedan IN formula containing glutamine, n-3 fatty acids andantioxidants were found to have significantly higher6-month mortality than those receiving an isocaloric,high protein formula (54% vs 35% in the controlEN group, p 0.04). Conversely, a systematic reviewconcluded that use of fish oil/antioxidant containingenteral formulas or supplements were associated witha reduction in ICU LOS and ventilator days; However,after excluding the Omega trials5 where fish oil wasadministered as a twice daily bolus outside of the EN,use of continuously administered EN containing fish oilwas associated with a significant reduction in mortality(P 0.004).30The influence of IN nutrients glutamine and seleniumamong patients requiring both enteral and parenteralsupport remains inconclusive. Although most haveconcluded that glutamine and selenium supplementationmay result in reduction of nosocomial infections amongthe critically ill, researchers of one meta-analysisconcluded that glutamine supplementation via enteral,parenteral, or a combination of these routes posed nobenefit in overall mortality or hospital LOS, but didresult in lower incidence of noscocomial infectionsamong the critically ill.47 Furthermore, these researchers,as well as a separate group48 concluded that high-dosesupplementation ( 0.5 g/kg/day) significantly increasedmortality among the critically ill, resulting in higherrates of infection, and longer ICU and hospital LOS.Appropriately, the A.S.P.E.N./SCCM 2016 guidelinessuggest that supplemental enteral glutamine (abovewhat is standard in EN formulas) NOT be supplementedin critically ill adults.31cost-benefit analyses complicated. Differences incoverage may depend on route of administration (oral,enteral or parenteral).51 Therefore, clinicians must becognizant of coverage to prevent a cost burden not onlyto the patient, but also the healthcare system as a whole.CostReferencesThe potential ability to reduce the cost of medicalcare was one of the driving forces behind initialefforts to study the impact effect(s) of IN on post-opmorbidity, and continues to influence the decision touse IN. Researchers have suggested that IN enteralformulas may be cost-effective when used in specificpopulations and healthcare settings;49,50 However, thisis only if they work, which remains unclear. Productswith IN properties are significantly more expensivethan standard preparations (Table 1) with some IN ENformulations costing up to 6 times that of a standardformula. Although nutrition support is widely acceptedas a life-sustaining therapy, insurance coverage differsamong payers and administration settings, making38 CONCLUSIONDespite the large volume of research conducted onefficacy of IN products over the past three decades,there is still no consensus on whether or not they providebenefit. More concerning, some suggest potential risk tothe critically ill. Researchers have attempted to find apattern of potential benefit by conducting meta-analysesand systematic reviews. However, overall, these haverevealed no difference in the ultimate outcome ofmortality in a variety of populations with enteral INwas compared to standard EN support, in either thesurgical and critically ill populations. The literatureis riddled with limitations, including research design,heterogeneity, and possible bias from conflicts ofinterest, thereby preventing the ability to draw solidconclusions and make specific recommendations forclinical practice.Guidelines and recommendations for use arederived from research conducted by a relatively smallgroup of individuals, many of which receive financialgain/funding from the makers of IN formulas. Giventhe lack of consensus and exorbitant cost associatedwith IN, clinicians must demand a well constructed,multi-center, non-biased robust study that addressesthe limitations of previous research, and is designed totest the true efficacy of these formulas among criticallyill patients.1.2.3.4.5.Richards MJ, Edwards JR, Culver DH, et al. Nosocomial infections in combined medical-surgical intensive care units in theUnit

surgery, and are therefore elemental or semi-elemental as a presumed necessary criteria. 28 PRACTICAL GASTROENTEROLOGY AUGUST 2016 NUTRITION ISSUES IN GASTROENTEROLOG, SERIES 1 . semi-elemental or elemental formulas Peptamen* 1.0 Yes 0 0 0 0 0 -- 28.33 14 Vital 1.0** 1.0 Yes 4.2 0 0 0