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REVIEW
CURRENT
PINION Perioperative immunonutrition and gut function
O
Marco Braga
Purpose of review
In the last year, several meta-analyses focused on the potential clinical benefits of perioperative
immunonutrition in surgical patients. Purpose of this review is to summarize their results and to draw
recommendations about the current indication of immunonutrition in surgery.
Recent findings
Standard enteral preparations have been modified by adding specific nutrients, such as arginine, omega-3
fatty acids and others, which have been shown to upregulate immune response, to control inflammatory
response, and to improve gut function after surgery. The majority of the randomized trials found that
perioperative immunonutrition improved short-term outcome in patients, who underwent elective major
gastrointestinal (GI) surgery. Four meta-analyses including a large number of randomized clinical trials
reported that perioperative immunonutrition is associated with a substantial reduction in both infection rate
and length of hospital stay. These results have been found in both upper and lower GI patients, regardless
of their baseline nutritional status. Promising results have been found also in head and neck surgery.
Summary
In the light of these findings the use of perioperative immunonutrition should be implemented in patients
undergoing elective major GI surgery. This should result in a considerable reduction in both postoperative
morbidity and costs for healthcare systems.
Larger trials are required before recommending immunonutrition as a routine practice in head and neck
surgery.
Keywords
arginine, gastrointestinal surgery, immunonutrition, omega-3 fatty acids, postoperative infections
INTRODUCTION benefits of perioperative immunonutrition in surgi-
The causes of postoperative infectious compli- cal patients [2]. The purpose of this review is to
cations are multifactorial and dependent to an summarize their results and to draw recommen-
extent on the primary surgical disease, and the type dationsaboutthecurrentindicationofimmunonu-
and magnitude of operation. Nevertheless, there is trition in surgery.
growingevidencethattraumaticandsurgicalinsult
is associated with a period of relative immune sup- NUTRITION THERAPY
pression, which may expose patients to subsequent
risk of infection. Despite significant changes in elec- Recently, the main focus of clinical nutrition has
tive surgical care and newer antimicrobial agents, moved from the issue to simply cover energy and
postoperativeinfectiouscomplicationsremaincom- nitrogen requirements (nutritional support) to the
mon, adding to length of hospital stay, healthcare newconcept of supplementing selected nutritional
costs and potential excess mortality. Furthermore, substrates because of their specific pharmacological
rates of nosocomial infections are rising in surgical effects (nutritional therapy). Immunonutrition is
and ICUs and the apparent increase in both gram- probablyoneofthebestexamplesoftheapplication
positive and gram-negative resistant bacteria is of of nutritional therapy in the clinical scenario.
particular concern, making the prevention of infec- The main purpose is to modulate postoperative
tion a major surgical issue.
Artificial nutrition still has an important role Professor of Surgery, San Raffaele University, Milan, Italy
amongthecurrent strategy to reduce postoperative CorrespondencetoProfessorMarcoBraga,DepartmentofSurgery,San
morbidity and its related costs, particularly in Raffaele Hospital,Via Olgettina 60, 20132 Milan, Italy. Tel: +39 02 2643
patients undergoing elective major gastrointestinal 2146; fax: +39 02 2643 2871; e-mail: braga.marco@hsr.it
(GI)surgery[1].Inthelastyears,severalrandomized Curr Opin Clin Nutr Metab Care 2012, 15:485–488
clinical trials focused on the potential clinical DOI:10.1097/MCO.0b013e3283567d8f
1363-1950 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-clinicalnutrition.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Nutrition and the gastrointestinal tract
KEYPOINTS cell-mediated immune response, and up-regulation
of gut function parameters early after surgery. In
Immunonutrition upregulates host immune response, particular, perioperative arginine supplementation
modulates inflammatory response, and improves gut wasassociatedwithbetteroperativesmallboweland
oxygenation after surgery. colon microperfusion as measured by laser Doppler
Perioperative immunonutrition reduced both flowmetry system. Moreover, in the first post-
postoperative infection rate and length of hospital stay operative days higher circulating levels of nitric
in patients, who underwent elective major GI surgery. oxide, better intestinal mucosa oxygen metabolism
measured by intestinal tonometry, and lower
Perioperative immunonutrition has been cost-effective as plasma levels of intestinal isoenzyme of alkaline
compared to the standard treatment. phosphatase, which is released in the peritoneal
Patients undergoing elective major GI surgery should fluid and plasma after intestinal hypoxic insult,
receive perioperative immunonutrition, regardless of were found in patients, who were given periopera-
their baseline nutritional status. tive immunonutrition. These findings support the
concept that the better gut microperfusion in
patients receiving immunonutrition translated in
metabolic response by giving perioperatively nutri- a better gut oxygen tension, delivery, and utiliz-
tionalformulassupplementedwithspecificnutrients ation. It should also be stressed that an intra-
such as arginine, glutamine, omega-3 fatty acids, operative deficient blood flow and oxygenation of
nucleotides and others. The main target of these thegutcouldimpairthehealingofanastomosesand
newdiets is not solely to provide energy and nitro- could promote translocation of endotoxins and
gen, but to modulate inflammatory postinjury bacteria from the gut to systemic blood.
response and to counteract postoperative immune Prospective, randomized, double-blind clinical
impairment, which may per se increase patient trials demonstratedthatpatientsfedbeforeandafter
susceptibility to infectious complications. Most of elective major GI surgery with a diet supplemented
the randomized controlled trials performed so far with arginine, omega-3 fatty acids, and nucleotides
in GI elective surgical patients have tested a combi- had a significant reduction of both postoperative
nation of arginine and omega-3 fatty acids given at infections and length of hospital stay when com-
homeorallyfor5–7daysbeforesurgeryand/orafter pared with patients fed with a standard enteral
operationthroughanasojejunaltubefor7days[2,3]. formula[2].Itcouldbesuggestedthatthereduction
Arginineisinvolvedinmultiplemetabolicpath- of postoperative infections found in the supple-
ways. It is a precursor of both nitric oxide and mentedgroupisthetranslationoftheimmunologic
hydroxyproline,whichhasakeyroleforconnective and metabolic advantages previously reported in
tissue repair. In addition, arginine is an essential patients receiving perioperative immunonutrition.
substrate for immune cells, particularly for lympho- Theseresultssupportedtheconceptthatakeypoint
cyte function. in elective surgical GI patients is to anticipate the
Omega-3fattyacidshavepotentanti-inflamma- provision of immunonutrients before operation.
tory properties mediated through incorporation in According to previous studies, European Guide-
membrane structure and function, suppression of lines reported that perioperative immunonutrition
proinflammatory transcription factors, and modu- is effective regardless of the baseline nutritional
lation of eicosanoid production. These effects may status of the patients [1]. In fact, preoperative
play important roles in suppressing the generalized administration of immunoenhancing diets reduced
inflammatory response and subsequent immuno- postoperative infection rate not only in malnour-
suppression and capillary leakage after major ished patients, but also in a series of well nourished
surgery. Moreover, resolvins and protectins are patients with GI cancer, who received immunonu-
novel omega-3 fatty acid products derived from trition only before surgery [3]. In these patients,
eicosapentaenoic acid and docosahexaenoic acid prolongingtheadministrationofimmunonutrients
followingneutrophil-endothelialinteractions.These postoperativelydidnotfurtherimproveclinicalout-
lipid mediators are reported to play a key role in the come.
resolution of inflammation and promotion of The vast majority of randomized clinical trials
woundhealing. carried out so far confirmed the clinical benefits
of immunonutrition in elective surgical patients.
Nevertheless, several trials differed for patient
RESULTS OF CLINICAL TRIALS groups, nutritional formulas and protocols for
Immunonutrition has been associated with modu- immunonutrition administration as well as control
lation of inflammatory response, enhancement of groups that received various treatments such as
486 www.co-clinicalnutrition.com Volume 15 Number 5 September 2012
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Perioperative immunonutrition and gut function Braga
standard enteral formula, parenteral nutrition or consequently to improve short-term postoperative
no nutritional support. Therefore, systematic outcome. Moreover, beneficial effects on clinical
reviews and meta-analyses have been carried out outcome have been found in both malnourished
to further clarify the clinical relevance of peri- and well nourished patients, in accordance with
operative immunonutrition. European Guidelines [1].
Earlier meta-analysis found that perioperative Drover et al. [6&&] included 35 randomized
immunonutrition was associated with no change clinical trials with more than 3000 patients, who
in postoperative mortality, however a significant underwent major elective GI or non-GI surgery.
decrease in both infection rate and length of According to meta-analyses by both Cerantola
& &
hospital stay, have been reported [2]. However, et al. [4 ] and Marik and Zaloga [5 ], immunonutri-
selection of trials included in the analyses was sub- tion has been associated with a reduction in both
optimal resulting in data heterogeneity and non- postoperative infectious complications and length
homogeneous control groups. In fact, some of of hospital stay, whereas, no effect on postoperative
the included studies compared enteral immuno- mortality was found. In addition to the whole series
nutrition with total parenteral nutrition, which is analysis, the authors carried out four subgroups
known to be less effective in elective surgical analyses focused on the following topics: first, type
patientswithaworkinggut.Inthesecasesthebetter ofsurgery:25GIstudiesvs.10non-GIstudies(seven
outcome found in the immunonutrition group head and neck surgery, two cardiac surgery, one
could be explained not only by the properties of gynecologysurgery),second,siteofGIdisease(upper
specific substrates given, but also by the different GI vs. lower GI surgery), third, type of immune-
route of nutrients administration. enhancing formula used: arginine–omega-3 fatty
´
acids–nucleotides (Impact Nestle Inc.) vs. other
arginine-supplemented diets, and lastly timing of
RECENTMETA-ANALYSES immunonutrition supplementation. (only before
Recently, four meta-analyses have been published surgery, only after surgery, or both). Significant out-
& & && & &
[4 ,5 ,6 ,7 ]. Cerantola et al. [4 ] included 21 comebenefitsfromimmunonutritionwerefoundin
randomized clinical trials with an overall 2730 both GI and non-GI surgery, in both upper GI and
patients, who underwent elective major surgery lower GI surgery, only when the diet containing.
for either upper GI or lower GI diseases. More than arginine–omega-3fattyacids–nucleotides wasused,
70% of recruited patients were well nourished and particularly when immunonutrition treatment
(median malnutrition rate in the overall series was was started before surgery. Possible explanation for
26%). In all the included randomized clinical trials, the better effect of the diet containing arginine–
control groups received an isoenergetic, isonitroge- omega-3 fatty acids–nucleotides vs. other formulas
nous standard enteral formula. Postoperative is the higher arginine concentration and thespecific
mortality was similar in the immunonutrition and combination of nutrients that can interact to
control groups. The most important finding was produce benefit.
that immunonutritionsignificantly reduced overall Marimuthuetal.[7&]reportedthatperioperative
morbidityrate,particularlypostoperativeinfectious immunonutrition significantly reduced both post-
complications. Moreover, immunonutrition short- operative infectious complications and length of
ened length of hospital stay, probably as a direct hospital stay not only after major abdominal
consequence of lower postoperative complication surgery, but only in a subgroup of patients, who
rate. underwent head and neck surgery.
&
Marik and Zaloga [5 ] included 21 randomized Arginine deficiency after surgical stress was
clinical trials partially overlapping with Cerantola reported more than 30 years ago, although the
meta-analysis, with an overall 1908 patients. mechanisms behind this have remained unknown
According to Cerantola meta-analysis, immuno- for years. An early postoperativeincreaseofmyeloid
nutritionsignificantlyreducedbothinfectiouscom- derived cells expressing arginase 1, which deplete
plications and length of hospital stay. Interestingly, arginine has been recently reported [6&&]. Coupled
studiesweregroupedaccordingtothetypeofimmu- with a poor arginine intake this can lead to an
nonutrition as follows: arginine supplementation arginine-deficiency state and consequently to a
alone, omega-3 fatty acids supplementation alone suppression of T-lymphocyte function. We can
or together. The best results have been obtained speculate that arginine supplementation can over-
when arginine and omega-3 fatty acids were given come this deficiency and omega-3 fatty acids can
together. It could be speculated that they may blunt upregulation of myeloid derived cells and
act synergistically to modulate both immune decrease arginase 1 expression. Further studies
and inflammatory postoperative response and are required to better elucidate other possible
1363-1950 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-clinicalnutrition.com 487
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Nutrition and the gastrointestinal tract
interactions between arginine, omega-3 fatty acids, trials are required before recommending immuno-
and nucleotides. Moreover, dose-response studies nutrition as a routine practice in head and neck
should better clarify which is the optimal dose of surgery.
each substrate to maximize benefits in surgical According to literature data, immunonutrition
patients. should be prescribed to all patients undergoing
elective major GI surgery with a substantial risk of
infectiouscomplications,regardlessoftheirbaseline
COST–BENEFITANALYSIS nutritional status.
Despite good results from both randomized clinical Future trials should investigate the efficacy of
trials and meta-analyses, the high cost of these new immunonutrition in patients undergoing mini-
nutritional products could be considered a major invasive GI surgery and/or receiving early after
drawbackfortheirroutineuse.Inviewoftheworld- surgery recovery programmes, both associated with
wide increasing concerns over exploding costs in a reduction of postoperative complications and
medical care, the decision process for adopting the length of hospital stay. Another interesting field
use of new products for routine treatment should ofresearchcouldbetestingtheefficacyoflong-term
not only weigh clinical benefits and risks, but also treatment with immune-enhancing diets in cancer
consider whether these benefits are worth the patients receiving neoadjuvant therapy.
healthcare resources used. This decision-making
process should be informed by cost-effectiveness Acknowledgements
analyses of clinical trials. In such economic studies No funding was received for this work.
the following costs should be calculated: the mean
in-hospital-related costs of routine surgical care per Conflicts of interest
patient, the costs of treating postoperative infec- There are no conflicts of interest.
tious and noninfectious complications, the costs
of nutrition, and the overall costs for all patients.
Economicanalysiscarriedoutbyblindeconom- REFERENCESANDRECOMMENDED
ists on datagatheredfromaprospectiverandomised READING
clinical trial showed that perioperative immuno- Papers of particular interest, published within the annual period of review, have
nutrition led to a substantial saving in healthcare been highlighted as:
& of special interest
resources consumed [8]. In fact, the saving due to a && of outstanding interest
significant reduction in postoperative infectious Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 518–519).
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surgery including organ transplantation. Clin Nutr 2006; 25:224–244.
mented diet. Some general limitations of such an 2. Waitzberg DL, Saito H, Plank LD, et al. Postsurgical infections are
economic analysis should be noticed on the trans- reduced with specialized nutrition support: World J Surg 2006; 30:
1592–1604.
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which may also influence their reproducibility. preoperative oral supplementation with a specialized diet in patients with
gastrointestinal cancer. Gastroenterology 2002; 122:1763–1770.
Comparable cost saving by the routine use of peri- 4. Cerantola Y, Hubner M, Grass F, et al. Immunonutrition in gastrointestinal
operative immunonutrition might be achieved in & surgery. Br J Surg 2011; 98:37–48.
This is the first large meta-analysis showing the clinical benefits of perioperative
hospitals where the same type of operations are immunonutrition in either upper or lower GI surgery.
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& tematic review and analysis of the literature. J Parenter Enteral Nutr 2010;
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when arginine and omega-3 fatty acids have been given together.
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&& supplemented diets: a systematic review of the evidence. J Am Coll Surg
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This is the largest meta-analysis published on perioperative immunonutrition so far
CONCLUSION in either GI or non-GI surgery. A subanalysis found that the best clinical benefits
have been obtained when a high-arginine diet was given.
Perioperative immunonutrition improved gut 7. Marimuthu K, Varadhan KK, Ljungqvist O, Lobo DN. A meta-analysis of the
oxygenation andmetabolicpostoperative response, & impact of enteral immune modulating nutrition cocktails on postoperative
outcomes after major abdominal and head and neck surgery. Abstract
and significantly reduced both postoperative infec- presented at the ESPEN Meeting 2011 (Goteborg, Sweden). Clinical Nutri-
tion rate and length of hospital stay in patients tion Suppl 2011; 30:13–14.
This is the first meta-analysis showing significant clinical benefits from periopera-
undergoing elective major GI surgery. Promising tive immunonutrition in head and neck surgery.
results have been obtained also in non-GI surgery, 8. BragaM,GianottiL,VignaliA,etal.Hospitalresourcesconsumedforsurgical
morbidity: effects of preoperative arginine and omega-3 fatty acid supple-
especially in head and neck surgery, however larger mentation on costs. Nutrition 2005; 21:1078–1086.
488 www.co-clinicalnutrition.com Volume 15 Number 5 September 2012
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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