Substrates for Enteral and Parenteral Nutrition Topic 7 · both enteral and parenteral glutamine have been demonstrated to restore the integrity of the GI mucosa and decrease bacterial

Copyright © by ESPEN LLL Programme 2014

Substrates for Enteral

and Parenteral Nutrition Topic 7

Module 7.3

Immunonutrition Substrates for Enteral and Parenteral Nutrition

Stanislaw Klek, MD, PhD, Assist. Prof.

General and Oncology Surgery Unit,

Stanley Dudrick’s Memorial Hospital,

15 Tyniecka Str., 32-050

Skawina, Poland

Tomasz Kowalczyk, MD

Krzysztof Figula, MD

University Hospital,

Dept. of General and Oncologic Surgery

40 Kopernika Str.,

31-501 Krakow, Poland

Learning objectives:

To understand the definition of immunonutrition;

To know about each immunonutrient and understand its mechanisms of action;

To know which substrates may be used in clinical practice;

To know the options for medical interventions with particular immunonutrients;

To know the guidelines for immunonutrition in ICU, surgery and gastroenterology.

Contents:

1. Definition of immunonutrition

2. Amino acids

2.1. Glutamine

2.2. Arginine

2.3. Taurine, cysteine, leucine

3. Nucleotides

4. Omega-3-polyunsaturated fatty acids

5. Vitamins

6. Trace elements

7. Summary of clinical indications for immunonutrition

7.1. Immune response to surgical trauma

7.2. Immunomodulating nutrition in the perioperative period

8. Immunonutrition in gastroenterology

8.1. Crohn’s disease and ulcerative colitis

8.2. Experimental colitis

8.3. Acute pancreatitis

9. Metabolic abnormalities in ICU patients and possibilities of nutritional intervention

9.1. Glutamine

9.2. Arginine

9.3. Nucleotides

9.4. Omega-3-polyunsaturated fatty acids

9.5. Micronutrients


9.6. Execution of immunonutrition in ICU

10. Ambiguities regarding immunonutrition

11. Summary

12. References

Key messages:

Immunonutrition is a special type of nutritional therapy, in which provision of

nutrients covers not only basic needs, but exerts a required clinical effect – it modifies

immune system function;

Glutamine can be beneficial in trauma and burn patients, and may also improve the

outcome of surgery;

Arginine cannot be used in severe sepsis, but is of high value in high-risk elective

surgery patients;

Omega-3-polyunsaturated fatty acids can reverse PN-associated cholestasis in

children, reduce postoperative complications after GI surgery, improve the outcome in

critically ill ARDS and trauma patients, and influence the progression of pancreatic

cancer;

As some of vitamins and trace elements can act as immunomodulators, their dosage

should be significantly increased during catabolic stress;

During enteral and parenteral nutrition micronutrients should be supplemented on a

daily basis, but their dosage must be significantly increased during catabolic stress;

Malnourished patients undergoing extensive surgery form a particular group who

benefit from immunonutrition;

The use of immunonutrition should be approached cautiously in patients with sepsis;

in particular, regimens containing increased amount of arginine are not recommended;

Further studies are needed to fully understand the mechanisms and clinical value of

immunonutrients.


1. Definition of Immunonutrition It is generally accepted that malnutrition alters immunocompetence and increases the risk

of infection. Malnutrition affects both innate and adaptive immune responses. The

consequence of protein energy malnutrition is atrophy of the lymphatic tissue in the

thymus, lymph nodes and spleen. As a result we can find T lymphocyte deficiency in

malnourished patients. The activation of lymphocytes by cytokines and antibodies

production is also affected. Phagocytosis and complement cascade activation are

decreased.

Nutrients, acting not only as a source of protein, energy or micronutrients, but also

capable of modifying the immune system’s response, were called immunonutrients.

Nutritional intervention based on those substrates was initially called immunostimulating

or immunoenhancing nutrition, and then immunomodulating or simply immunonutrition

(1,2). Immunonutrition represents a type of pharmaconutrition. Not every macro- or micronutrient may influence the immune system, but the immunosubstrates include

arginine, glutamine, omega-3-fatty acids, selenium, zinc, vitamins C, E, and nucleotides. They can be administered in the form of enteral nutrition or as intravenous interventions,

depending on the nutrient.

The results of clinical studies of immunonutrients have often been confusing for two major

reasons: 1) authors have usually tried to analyze the impact of immunodiets by using combinations

of substrates: for example, arginine, glutamine and omega-3 fatty acids, as well as vitamins C, E and nucleotides were given altogether. It made the assessment of each

component impossible, and studies performed with only one of those nutrients are

scarce. 2) groups of patients used for those analyses were not homogeneous, even in case of

studies carried out in ICU settings or in surgical patients (in respect of the proportion of well-nourished and malnourished patients or the type of intervention which differed

amongst studies). More ambiguities are presented at the end of section 7, but despite these uncertainties,

all immunonutrients are presented here and their clinical value is discussed.

2. Amino Acids

2.1. Glutamine

Glutamine (GLN) is the most abundant amino acid in humans, contributing to more than 50% of the body’s free amino acid pool (3). It is non-essential and may be synthesised in

vivo, but during catabolic states caused by major surgery, burns, severe trauma or

sepsis, GLN consumption may exceed its endogenous production. For that reason it has

been called a “conditionally essential” amino acid (4). In situations like those, the

skeletal muscle glutamine depletes rapidly and irrevocably.

GLN plays an important role in nitrogen transport, in the maintenance of the cellular

redox state, and the mediation of metabolic processes (5). It acts as a precursor for

glutathione synthesis, and provides substrate for hepatic gluconeogenesis and nucleotide

synthesis in enterocytes, lymphocytes and neutrophils (6-10). It is also the preferred fuel

for macrophages and other cells involved in wound repair – it stimulates proliferation of

these cells via polyamine synthesis and via glutamate conversion to proline (9,10).

Additional functions include participation in acid-base homeostasis, enhancement of the

expression of heat shock proteins and the promotion of lymphocyte proliferation

(8,9,10,11).

As glutamine is relatively unstable in solution unless it is bound to protein, supplemental

glutamine is available in powdered form or in high glutamine hydrolysate formulas.


Parenteral GLN is generally provided as dipeptides such as glycyl-glutamine (GLY-GLN) or

alanyl-glutamine (ALA-GLN) (11).

Experimental data

Glutamine administration reduces GI bacterial translocation and increases synthesis of

nucleic acids; it enhances activation and proliferation of lymphocytes and macrophages,

and the expression of interleukins 1 and 2 (IL-1 and 2) (12). In animals GLN

supplementation protects the GI mucosa in various models of injury via preservation of

intracellular glutathione levels and stimulation of enterocyte proliferation (12). In the

cancer setting, it limits protein breakdown and increases protein synthesis (12). In short

bowel models the administration of GLN reduces the incidence and severity of diarrhoea

and stimulates mucosal growth; it also helps to reduce mucosal permeability in mucosal

atrophy related to total parenteral nutrition and during sepsis (11, 12). A lot of

mechanisms have been identified through which intraluminal glutamine may affect the

gut during and after shock-induced ischaemia/reperfusion (IR) insult. Glutamine is a

preferred fuel source and key player in the intermediary metabolism of the gut mucosa.

In a rodent gut IR model Kles and Tappenden demonstrated that glutamine absorption is

preferred over glucose absorption (13). During ischaemia, glucose transport was severely

impaired and not improved by intraluminal glucose infusion, and in contrast to that,

glutamine transport was maintained and further enhanced by intraluminal glutamine

infusion. It was also proved that intraluminal infusion reverses the shock-induced

splanchnic vasoconstriction that persists after effective systemic shock resuscitation, and

that this mesenteric vasodilation occurs under IR conditions because of glutamine

activation of adenosine A2b receptors, which release nitric oxide into the enteroportal

circulation (14). It is also well known that intraluminal glutamine induces a variety of

protective mechanisms against IR insults, such as antioxidant enzymes (glutathione and

haem-oxgenase-1) or the anti-inflammatory transcription factor, peroxisome proliferator

activator receptor gamma (PPAR) (15,16,17). Moreover, glutamine may play a crucial

regulatory role in epithelial growth factor activation of extracellularly-regulated kinases,

which are necessary in enterocyte proliferation (18).

Clinical data

Clinical studies showed a protective effect of GLN on intestinal mucosa trophism and T-

lymphocyte responses (12,19). A meta-analysis has shown that intravenous

administration of 20–40 g/24 h of Gln-dipeptide improves short-term outcome in

abdominal surgery patients (20).

Studies of Houdijk et al, and Jones et al. performed in ICU and in multiple trauma

patients showed positive outcomes after the use of glutamine-supplemented enteral

formulas at a level of 10 g to 14 g glutamine per litre (21,22). Studies in severely burned

patients showed that the addition of glutamine to a standard enteral feeding formula had

a favorable effect on the preservation of intestinal structure (23).

A meta-analysis of 14 clinical trials examined the effects of glutamine supplementation in

mixed populations of critically ill and surgical patients (24). Authors observed that its

supplementation with higher doses (>0.2 g/kg/d) was associated with decreased rates of

mortality, infectious complications, and hospital length of stay (24). Another meta-

analysis recommended using enteral glutamine in burned or trauma patients based on

the impact on mortality and a trend toward reduced infectious comorbidity (25, 26). The

study of McQuiggan et al confirmed that enteral glutamine during active shock

resuscitation is not only safe but also enhances enteral tolerance (21).

In various clinical studies in the ICU setting, intravenous administration of GLN (0.2–0.4

g/kg/day) in the form of dipeptide (0.3–0.6 g/kg/day) contributed to improved glycaemic

control and morbidity, and to reduce the prevalence of infections and mortality (28).

In their vast meta-analysis Marik and Zaloga noted that enteral nutrition with

supplemented glutamine appeared to be beneficial (decreased infections and LOS) in

burns patients, probably because burns are associated with severe gastrointestinal

mucosal injury, leading to increased bacterial translocation, resulting in secondary multi-


system organ dysfunction syndrome (MODS) (29). In experimental and clinical studies,

both enteral and parenteral glutamine have been demonstrated to restore the integrity of

the GI mucosa and decrease bacterial translocation (22). The potentially protective role

of GLN against radiotoxicity and chemotoxicity is less obvious and needs further well-

conducted placebo-controlled studies.

The meta-analysis of clinical trials in surgical patients performed by Wang et al. showed

that parenteral administration of glutamine was related to positive clinical outcomes. The

perioperative administration of glutamine dipeptide was beneficial and resulted in the

reduction of the length of hospital stay (LOS) and had a tendency to reduce infectious

complications (11). Also, randomized controlled studies showed that administration of

enteral immunodiets containing glutamine were beneficial in surgical patients when

administered pre- or postoperatively (1,19). Malnourished surgical patients are the most

likely to benefit from immunodiets (30,31,32,33). Haematopoietic stem cell

transplantation patients may also benefit from intravenous glutamine. Further studies are

needed, however, to determine the underlying mechanism for the observed positive

effect after GLN dipeptide supplementation via the total parenteral route, and its optimal

timing and dose response.

2.2. Arginine

Arginine (ARG) is a non-essential amino acid, which may become essential in stress

conditions, like glutamine. Its effects on the immune system are also similar to those of

GLN, because of analogous pathways (12). ARG is synthesized in the kidneys from

citrulline, which stems from glutamine digested in the intestine. Arginine plays an

important part in the transport, storage, and excretion of nitrogen via the urea cycle. Its

conversion to citrulline by nitric oxide synthase (NOS) leads to nitric oxide (NO)

formation, which is a potent mediator of the inflammatory response. NO induces the

recruitment and migration of leucocytes, and influences the infiltration of the

gastrointestinal mucosa by granulocytes. NO in small amounts positively affects innate

immunity, but the disproportionate production of NO due to NOS induction by

inflammatory cytokines or bacterial endotoxins has pro-inflammatory effects (12).

Arginine promotes the proliferation of rapidly dividing cells such as lymphocytes,

enterocytes and fibroblasts by stimulating the release of growth hormone and polyamine

synthesis from ornithine (12).

Experimental data

Animal models have shown the following effects of arginine supplementation: stimulation

of thymic growth, the mononuclear response to mitogenes, proliferation of lymphokine-

activated natural killer (NK) cells, the release of growth hormone, prolactin, insulin,

glucagon, and polyamines (12). Those models also demonstrated that suppression of NO

production resulted in the increase of gastrointestinal (GI) permeability and splenic

atrophy and decreased haematopoiesis along with the reactivity of mast cells and

worsened overall survival (12). On the other hand, arginine supplementation in severe

sepsis may be deleterious because elevated levels of NO may result in increased GI

vascular permeability (12). In radiation enteritis arginine administration increased

mucosal thickness and villous height, improved barrier function, and diminished bacterial

translocation in short bowel patients. It also helped in wound healing (12). In

experimental studies, L-arginine improved wound healing, restored postoperative

depressed macrophage function and lymphocyte responsiveness, and augmented

resistance to infection (34,35).

Clinical data

Nutrition enriched with arginine proved to be beneficial in high-risk elective surgery

patients, while it failed to improve outcomes in trauma patients and patients with sepsis

(36). The explanation for that observation is unclear; it seems, however, that in the

latter groups conversion of arginine to nitric oxide is increased, moreover, arginine may

augment inflammatory responses in these patients (36). In contrast to ICU, in surgical


patients, arginine levels are decreased and arginine degradation (via arginase) is

increased in patients with surgical trauma. Therefore, in those patients ARG may restore

depressed humoral and cell-mediated immunity and promote wound healing (36). In the

study of Ferreras et al. patients fed with the arginine and ω-3–supplemented formula had

higher local hydroxyproline levels in their surgical wounds and developed fewer surgical

wound complications (38).

2.3. Taurine, Leucine, Cysteine

Leucine represents the group of branched amino acids and it is the most abundant

essential amino acid. Taurine is the most abundant amino acid in leucocytes (up to 60%

of total amino acids) (39). Cysteine is a precursor for glutathione synthesis. In in vitro

studies leucine was shown to regulate the protein turnover in skeletal muscle and

adipose tissue. Cysteine was able to modulate glutathione metabolism and influence the

interaction between monocytes and lymphocytes. Taurine improved cell membrane

stability and acted as an antioxidative factor. No confirmed data exist, however, on the

clinical value of these potent amino acids. Further human studies are required.

3. Nucleotides

Nucleotides are biologically active substances, which participate in the important

processes of DNA and RNA synthesis, production of adenosine triphosphate (ATP), cyclic

adenosine monophosphate (cAMP)), some coenzymes (e.g. nicotinamide adenine

dinucleotide (NAD+), flavin adenine dinucleotide (FAD), coenzyme A (CoA)) and

biosynthesis intermediates (e.g. uridine diphosphate glucose (UDP-glucose)) (12).

Nucleotides are usually synthesized from endogenous substrates, such as glutamine,

glycine, aspartate, carbon dioxide and tetrahydrofolate, but, like arginine and glutamine,

their synthesis during catabolic stress may be insufficient. The gut and gut-associated

lymphoid tissue are affected the most in such states, and the “salvage pathway” is used

for those tissues. In that mechanism dietary nucleotides are utilized directly (12).

Experimental data

In animal models nucleotides activated macrophages, increased the number of T-helper

cells and the expression of cytokines in the spleen (IL-2). The administration of

nucleotides increased villus height and crypt depth during long-term parenteral nutrition

(PN), reduced diarrhoea in lactose intolerance, helped tissue recovery from ischaemia–

reperfusion injury and GI mucosal trophism in PN-fed rats, increased recovery rates in

cardiac ischaemia and radiation, as well as decreasing bacterial translocation in severe

starvation (12).

Clinical data

Studies in a paediatric population demonstrated that nucleotide supplementation in infant

formula milk positively affects lipid metabolism, resistance to infection, growth and

development (39). The incidence and duration of acute diarrhoea was lowered in infants

fed with a nucleotide-supplemented formula (40). Nucleotide-enriched diets decreased

the prevalence of infectious complications and length of hospital stay in patients with GI

cancer undergoing major elective surgery, but in those studies nucleotides were used in

an admixture together with other immunonutrients. Dietary nucleotides were recently

shown to modestly reduce the feeling of incomplete evacuation and abdominal pain in

irritable bowel syndrome (41).

4. Omega-3-polyunsatturated Fatty Acids

Omega-3 fatty acids are polyunsaturated fatty acids (PUFA) with a terminal double bond

on carbon number 3 (42). The simplest omega-3 fatty acid is alpha-linolenic acid. Fish oil

contains other n-3–PUFAs: eicosapentaenoic acid (EPA, C20:5, n-3) and docosahexaenoic

acid (DHA, C22:6, n-3). Contrary to saturated fatty acids, which exert proinflammatory


effects, EPA and DHA have been considered to be of benefit in patients at risk of

inflammation due to their favourable immunomodulatory and anti-inflammatory

properties (43,44,45). They act directly (by replacing arachidonic acid as an eicosanoid

substrate and by producing anti-inflammatory lipid mediators, including resolvins,

protectins and lipoxins) and indirectly (by altering the expression of inflammatory genes

by influencing the activation of transcription factor). Therefore it has been postulated

that the administration of n-3 LC-PUFA from fish oil (EPA and DHA) leads to a more

balanced immune response which may result in a faster resolution of inflammation and

recovery (44,45).

Mechanisms of action of omega-3-FA include:

- alterations in the physical properties of the cell membrane;

- effects on cell signaling pathways (transcription factors reported to be modified by

the presence of long-chain omega-3 FA include nuclear factor kappa B (NFkB) and

peroxisome proliferator activated receptor (PPAR)-alpha and gamma;

- alterations in the pattern of lipid mediators produced.

Mean intakes of long-chain omega-3 fatty acids among adults in the United Kingdom, in

other Northern European, North American and Australasian countries reach 0.15–0.25

g/d (12). The oil obtained from the flesh of oily fish or the livers of lean fish is named

‘fish oil’ and it has the distinctive characteristic of being rich in long-chain omega-3 fatty

acids (12). It is important to realize that when we discuss effects of the administration of

emulsions containing omega-3-fatty acids or composed of fish oil, we are de facto

discussing the impact of eicosapentaenoic acid (EPA, 20 carbons and 5 double bonds)

and docosahexaenoic acid (DHA, DHA, 22 carbons and 6 double bonds) and in some

cases alpha linolenic acid (ALA, 18 carbons and 3 double bonds). Hence it would be

appropriate to concentrate on EPA and DHA content, and not the amount of fish without

describing the percentage of EPA and DHA in the solution.

Various oily fish contain different amounts of omega-3 fatty acids, and so do fish oils.

EPA and DHA comprise about 30% of the fatty acids in a typical preparation of fish oil.

That is, a 1g capsule of fish oil can provide approx. 0.3 g of EPA plus DHA. Also the

relative proportions of the individual long-chain omega-3 fatty acids vary among fish. For

example, cod liver oil is richer in EPA than DHA, whereas tuna oil is richer in DHA than

EPA. These observations apply also to the content of EPA and DHA in enteral and

parenteral substances, further complicated by the fact that they were constructed using

two different monographs on omega-3 published in European pharmacopiae.

Three lipid emulsions that include fish oil as a component are available for use in

parenteral nutrition: Omegaven, Lipoplus, and SMOFLipid. Omegaven is a pure fish-oil

emulsion (100 g lipid/l) that contains approximately 3 g EPA w 100 ml, Lipoplus (known

also as Lipidem) represents a mix of 50% medium-chain triglycerides, 40% soybean oil

and 10% fish oil. Each 100 ml of Lipoplus will typically contain about 0.8-1.7 g of EPA +

DHA in 100 ml. SMOF Lipid is a mix of 30% medium-chain triglycerides, 30% soybean

oil, 25% olive oil and 15% fish oil. Each 100 ml of SMOFLipid will typically contain about

3 grams of EPA and 0.36 g of DHA.

Experimental data

Animal model studies demonstrated that a diet containing omega-3-PUFAs inhibits the

hepatic synthesis of triglycerides and partially replaces arachidonic acid (AA) with EPA

and DHA in the phospholipid pool of the membrane (12). Their presence improves the

structure of the membrane, ligand/receptor binding, enzyme secretion, antigen

presentation and activates intracellular signaling pathways (12). When released from the

membrane, EPA and DHA depress AA-derived eicosanoid synthesis by cyclooxygenase

and lipoxygenase in platelets, monocytes and macrophages, thereby delaying platelet

aggregation and progression of atherogenesis. In experimental models, omega-3 PUFAs

also show protective effects against the development of tumours, metastases and

cachexia (45).

EPA and DHA were able to influence the resolution of the inflammatory state by induction

of recently discovered resolving factors, such as resolvins, protectins and lipoxins.

http://en.wikipedia.org/wiki/Eicosapentaenoic_acid

http://en.wikipedia.org/wiki/Docosahexaenoic_acid


In vitro and in vivo studies have shown that omega-3-PUFA may decrease “sprouting

angiogenesis”, suppress endothelial cell proliferation, decrease tumour microvessel

density and even decrease tumour growth (46,47,48).

Clinical data

In heart disease patients the administration of omega-3 PUFAs results in a lower

prevalence of coronary artery disease, which is confirmed by the observation of fish-

based food-consuming populations (e.g. Inuits). A diet rich in omega-3 PUFAs decreases

the incidence of renal and cardiovascular disease (e.g. hypertension, arrhythmia),

probably by inhibiting thrombogenesis and cytokine-dependent inflammation. In patients

with pancreatic cancer, fish-oil supplementation helps to reduce inflammation and to

stabilize energy expenditure. Fish oils improved the quality of life in pancreatic cancer

patients by reducing cachexia, increasing appetite and increasing performance status

(50).

Parenteral infusion of n-3 LC-PUFA from fish oil has repeatedly been shown to be

effective in reversing PN-associated cholestasis in children, when administered alone or

in combination with a soybean oil based lipid emulsion (51, 52). The long-term use of

omega-3 enriched parenteral nutrition in home settings also showed a trend for the

preservation of liver function.

Meta-analyses of clinical trials confirm the reduction of postoperative complications and

the shortening of LOS in surgical patients (53). For those reasons the European Society

of Clinical Nutrition and Metabolisms (ESPEN) has already acknowledged that the optimal

PN regimen for surgical patients should include supplemental n-3 fatty acids (Grade C

(19). Also critically ill patients may benefit from the administration of omega-3 diets. This

kind of therapy should be used in ARDS patients, mild sepsis (Grade B) and trauma

patients (Grade A) (28).

5. Vitamins

Vitamins may improve immune system function by enhancing innate defence

mechanisms as well as via cell-mediated immunity, and the production of antibodies

(54).

In stress conditions vitamin E acts as a free radical scavenger, while vitamin C acts as an

enzyme co-factor and scavenger of lipid peroxidation products.

Vitamins A, B6, B12, C, D and E support the Th1 cytokine-mediated immune response

and the production of cytokines and prostaglandins. Vitamins A and D affect the cell-

mediated and humoral antibody response and support the Th2-mediated anti-

inflammatory cytokine response (12).

In commercially available PN solutions vitamins should ideally be added just before

administration for stability reasons (12). The recommended doses for adult patients are

usually 10 IU/day (9.1 mg/day) of vitamin E, 200 mg/day of vitamin C. In all lipid

emulsions, the concentration of vitamin E should be >0.4 mg/g of PUFAs to avoid lipid

peroxidation (55). It is emphasized that the determination of nutritional requirements

should be based on the monitoring of plasma concentrations together with the

measurement of SIRS.

6. Trace elements

Like the vitamins, trace elements also contribute to the immune defense at various levels

(54). They too form part of the antioxidant defence system. Some of them act as enzyme

cofactors (e.g. selenium for glutathione peroxidase) to eliminate species involved in the

initiation of free-radical chain reactions (12).

Iron, zinc, copper and selenium work synergistically with vitamins to support the Th1

cytokine-mediated immune response and the production of cytokines and prostaglandins,

at least in part through regulation of redox-sensitive transcription factors. Selenium,

copper and zinc improve the function of the skin/mucosa barrier by counteracting cellular

damage caused by reactive oxygen species (54,56). In animal models plasma levels of


selenium and zinc decrease significantly 6 hours after burn injury; this selenium

depletion led to a decrease in the activity of superoxide dismutase and an increase in

oxidative stress and lipid peroxidation (12,57). In parallel clinical situations trace element

supplementation may counteract oxidative damage. In animals it was observed that the

optimal plasma selenium and reactivation of glutathione peroxidase were achieved 24 h

after the injection of sodium selenite (57).

Micronutrient supplementation in artificial nutrition is recommended for all types of

patients with a level of evidence graded C, but level A evidence exists for burns patients,

in whom trace elements should be supplemented at higher than standard doses (30).

Berger et al. confirmed that the prevalence of bronchopneumonia and extended LOS

were reduced by supplementation of trace elements with a daily dose of 40 umol copper,

2.9 umol selenium and 406 umol zinc for 30 days after burn injury (58).The

recommended dose of selenium for adult patients is 60–400 ug/day, it is always,

however, significantly increased during catabolic stress.

During parenteral nutrition both groups of micronutrients should be supplemented on a

daily basis.

7. Summary of Clinical Indications for Immunonutrition

7.1. The Immune Response to Surgical Trauma

A surgical procedure is a specific type of partially controlled trauma that, in addition to

the intended therapeutic effect, causes extensive changes in the functioning of multiple

systems in the patient’s body. Its response to a surgeon’s actions is complex and

integrated, and has as its goal the restoration of overall homeostasis as soon as possible.

Homeostasis is dependent on many factors; those pivotal include the patient’s nutritional

status, the underlying disease and, consequently, the type of surgical intervention and the

immune response to that trauma. These factors affect each other, thereby determining the

final effect of the therapeutic intervention.

In the maintenance of an organism’s homeostasis the immune system plays a crucial role.

Through a number of modulating signals (such as the release of cytokines) it either directly

or indirectly influences whole body metabolism, thus influencing the effect of surgery. It

has long been known that, among other things, chronic inflammation leads to cachexia and

that compromised immunity increases the incidence of postoperative complications.

However, it was not until a few years ago that the mechanisms of the body’s direct

immune response to injury, including surgery, started to be tested. Until then it had been

considered a two-step mechanism: initially with the systemic inflammatory response

syndrome, to be followed by the compensatory anti-inflammatory response syndrome. In

the light of current research it becomes clearly evident that the injury itself causes a

specific immune deficiency by disrupting the immune balance, and changes, inter alia, the

ratio of Th1/Th2 lymphocytes (59).

Following the rupture of natural protective barriers in the form of skin, mucous

membranes, or opening of the gastrointestinal tract, tissues are directly exposed to

pathogens. According to the mechanisms of the innate and adaptive response, at the site

of injury and then within the entire body, a series of characteristic changes occurs that

aims at reducing damage and producing a quick response preventing the spread of

infection. Initially, it is the site of injury that plays an important role in stimulating the

response through the activity of neutrophils and macrophages present at the site. They

produce cytokines and other mediators – such as platelet activating factor, oxygen free

radicals, nitric oxide (arginine) and arachidonic acid metabolites (lipids) – that act both

locally and systemically. They affect the cells directly, but also indirectly, through the

changes in blood flow and activation of the complement system.

The next step involves the antigen-presenting cells (monocytes, macrophages and

dendritic cells) which migrate to lymphatic glands and initiate the response which is

mediated by lymphocytes. Helper T lymphocytes play a major role in that process: they

are divided into two groups: Th1 (play an important role in killing intracellular

pathogens), and Th2 (important for antibody production and a defence against


extracellular parasites). Each of these groups mediates the inflammatory response

through specific cytokines: Th1 cells primarily secrete Interferon alpha, IL-2, and TNF-

alpha, which promote cellular immunity, whereas Th2 cells secrete a different set of

cytokines (anti-inflammatory), primarily IL-4, IL-10, and IL-13, which promote humoral

immunity and depress cell-mediated immunity.

As a result of an injury the hypothalamic-pituitary-adrenal axis and the sympathoadrenal

system are activated, and are presumed to be secondarily (the release of cortisol,

catecholamines together with the release of PGE2) responsible for the TH1/TH2

imbalance and the impaired cellular immunity that occurs following tissue damage and

trauma. It is interesting to note that cytokines secreted by Th2 lymphocytes enhance

arginine consumption, (i.a. in bone marrow suppressor cells (myeloid-derived suppressor

cells)), causing an arginine deficient state which further impairs lymphocyte function (1).

That partially justifies the indications for arginine supplementation in patients who have

undergone surgery. Unfortunately, some surgical patients experience complications in the

form of anastomotic leaks, abscess formation or even of sepsis and multiple organ

failure. They constitute a separate group of patients who require special attention (60).

Routine supplementation with arginine is not currently recommended.

7.2. Immunomodulating Nutrition in the Perioperative Period

Nutritional status is a key parameter influencing the potential outcome of surgical

treatment (61,62). Undoubtedly, malnutrition and then trauma in the form of surgery

significantly weaken the organism’s immune response, which results in an increased

number of infectious complications, and impaired wound and anastomotic healing, or in

prolonged hospitalization (63). Therefore, the majority of research carried out so far and

investigating the effects of immunonutrition on the human body pertains to groups of

surgical patients (64-75). In large part, the research deals with the role of glutamine,

arginine, fatty acids (omega-3-PUFA) and diets high in nucleotides. Of central

importance seem to be questions about the indications for immunonutrition (only

malnourished patients or patients with good nutritional status as well), timing of

nutritional intervention (pre-, post-, peri-operatively), and about the route of

administration of nutrient mixtures (enterally, intravenously, or in a mixed way). The

answers vary depending on the composition of the nutrient mixture. Considerations

regarding these aspects of immunonutrition were discussed in the previous chapter.

It is important to realize that, as mentioned above, many authors have now tried to

analyze the clinical impact of the various forms of pharmaconutrition. The most

important studies are presented in Table 1.

Table 1. Studies on immunonutrition in surgical patients

AUTHOR Number of

patients

(n)

Study groups Type of

diet

Patient

characteristics

Results

Senkal

1997

154 IMEN vs

isocaloric

Impact Operated on for

upper GI cancer

17/77 vs 24/77

(p<0.05),

shortening of

hospital stay

Daly 1992 85 IMEN vs

isocaloric


upper GI cancer

11 vs 33%,

shortening of

hospital stay by 5

days


Heslin

1997

195 IMEN vs

isocaloric


upper GI cancer

No differences

Daly 1995 60 Postoperative

IMEN, out-

patient MEN,

standard

postoperative

and outpatients


upper GI cancer

Reduction of

complication rate

(10 vs 43%),

shortening of

hospital stay by 6

days

Braga 2002 150 Pre- and

postoperative

IMEN &

standard EN


upper GI cancer

Reduction of

complication rate

Braga 1996 60 Standard EN,

IMEN, TPN


upper GI cancer

No reduction of

complications

Braga 1999 206 IMEN vs

standard EN


upper GI cancer

Well nourished

and

malnourished

Complications in

14 vs 30%

(p=0.009)

Gianotti

2002

305 Preop- and

postop IMEN


upper GI cancer

Reduction in

infectious

complications if

preop IMEN was

used

Lobo 2006 108 IMEN vs EN

(Nutrison High

Protein)

Stresson Operated on for

upper GI cancer

No effect

Chen 2005 40 IMEN vs

standard EN

Stresson Operated on for

upper GI cancer

Increased serum

Ig, IL-2, CD4 and

CD4/CD8 ratio,

decrease of IL-6

and TNF-alpha

Heys 1999 Metaanalysis

111 RTC,

1009 pts.

IMEN vs

standard EN

Impact

Immun-

Aid

Operated on for

upper GI cancer

Decrease of

complications

and hospital stay,

no differences in

mortality

Heyland

2001

Metaanalysis

22 RTC

2419 pts.

IMEN vs

standard EN

Impact Various, mostly

ICU

Decrease of

complications, no

differences in

mortality


Waitzberg

2006

Metaanalysis

17 RTC

2083 pts.

IMEN vs

standard EN

Impact Various, mostly

operated on for

upper GI cancer

Decrease of

complications

Marik 2010 Metaanalysis

21 RTC,

1918 pts

IMEN: vs

standard EN as

postoperative

feeding

Various,

mostly

Impact

Various, mostly

operated on for

upper GI cancer

Favours

immunodiet

Centarola

2011

Metaanalisis:

21 RTC, 27

pts.

IMEN vs

standard EN

postoperative

Various Various, mostly

operated on for

upper GI cancer

Decrease of

complications

and hospital stay,

no differences in

mortality

Particular benefit from immunonutrition supplemented with glutamine is seen in

malnourished surgical patients (18-20). The administration of glutamine, both before

and after surgery, improves the treatment outcome by reducing the number of

complications (limiting the incidence of infections and shortening hospital length of

stay). On the basis of randomized controlled studies and meta-analyses, it is believed

that intravenous and enteral administrations are equally beneficial (21,22).

ESPEN guidelines (30):

Enteral administration of glutamine is indicated in trauma and burn patients.

If parenteral nutrition is indicated in critically-ill patients (ICU patients with

complications), the glutamine administration should be 0.2 to 0.4 g/kg bw/day (0.3 to

0.6 g/kg bw/day L-alanyl-L-glutamine). In such doses glutamine supplementation has

proven effective in reducing mortality, the number of infectious complications, and length

of hospital stay.

In contrast to glutamine, a proven effect of arginine-enriched nutrition is limited in practice

to high-risk patients undergoing elective surgery. Due to a potential mechanism

responsible for enhanced inflammatory response (overproduction of nitric oxide), that sort

of nutrition is not recommended in sepsis (23). In patients with uncomplicated surgical

infection, however, the level of arginine is usually lowered, therefore such patients can

benefit from its supplementation (it accelerates wound healing and the immune

response). Although the intravenous route of administration is preferred, some reports

about the effectiveness of oral supplementation are also to be found (76).

Nucleotide enriched diets have similar indications, especially for patients with GI cancer

undergoing major elective surgery. Very often nucleotides are one of the

immunomodulating components found in immunonutrition mixtures, but there is a lack of

studies investigating their selective influence on the postoperative course.

The ESPEN guidelines advise as follows (20,21):

Use preoperative enteral nutrition, preferably with immune modulating substrates

(i.a. arginine, nucleotides) for 5–7 d in all patients undergoing major abdominal surgery

independent of their nutritional status.

Use EN, preferably with immuno-modulating substrates (arginine, n-3 fatty acids and

nucleotides) perioperatively independent of the nutritional risk for patients:

- undergoing major neck surgery for cancer (laryngectomy, pharyngectomy)

- undergoing major abdominal cancer surgery (oesophagectomy, gastrectomy, and

pancreatoduodenectomy)

- after severe trauma.

The supply of diets enriched in nucleotides and arginine is indicated in trauma

patients.


Immunomodulating diets (including those enriched with arginine and nucleotides)

may be harmful in severe sepsis, therefore are not recommended.

Apart from that, ESPEN found the use of fatty acids (omega-3-PUFA) optimal for surgical

patients requiring parenteral nutrition. Intravenous infusion of PUFA emulsions is

reasonable to achieve the anti-inflammatory effect much faster than in the case of

enteral diets (19).

On the basis of research conducted so far, it has been expressly demonstrated that the use

of immunomodulating nutrition significantly reduces the risk of acquired infections, wound

complications, and length of hospital stay in the postoperative course. In malnourished

patients enteral immunonutrition shows greater efficacy than using a standard nutritional

formula. Immunonutrition should be used in patients undergoing major surgical

procedures within the abdominal cavity, operated on due to head and neck cancer, and in

severe trauma patients.

Immunonutrition should not constitute a routine treatment in the postoperative period of

all patients undergoing surgery. In patients who show either mild or no signs of

malnutrition, using that sort of nutritional treatment will not bring the hoped-for clinical

benefits, but will instead increase treatment costs. Patients with severe sepsis should be

treated with special care; in accordance with the guidelines of ESPEN, immunonutrition

(especially rich in arginine) should be avoided in that context.

8. Immunonutrition in Gastroenterology

8.1. Crohn’s Disease and Ulcerative Colitis

Despite differences in the clinical picture, the underlying cause of both diseases is chronic

inflammation within the wall of gastrointestinal tract, being the result of immune system

disorders. Therefore, it is natural to direct treatment at fighting inflammation and altering

the immune system response. Pharmacotherapy involves symptomatic treatment (anti-

inflammatory drugs, corticosteroids), but also attempts more targeted therapies

(monoclonal antibodies). It is known, however, that nutrition, enteral in particular, plays

an important role in attempts to attain remission (especially in Crohn's disease in

children). Furthermore dietary treatment is used not only to maintain proper nutritional

status, but also to treat complications of both diseases (fistulas, short bowel syndrome,

etc).

Taking into consideration the aforementioned aspects, it would seem that

immunonutrition should be an additional way of obtaining a therapeutic effect.

Unfortunately, contrary to the expectations, so far there is no satisfactory clinical trial

that expressly confirms the clinical value of immunonutrition. The available research

most often refers solely to experimental attempts.

According to EPSEN guidelines on enteral and parenteral nutrition, in both Crohn’s

disease and ulcerative colitis there is no clear benefit of using an immunomodulating

formula (omega-3-PUFA, glutamine, and/or TGF-beta enriched) (77,78). Although there

are encouraging experimental data, the present clinical studies are insufficient to permit

the recommendation of glutamine, n-3 fatty acids or other pharmaconutrients in CD (79-

81).

8.2. Experimental Colitis

Experimental research with omega-3-PUFA conducted on animal model (rats with

induced colitis) has given emphasis to the benefits of immunonutrition used in

parenteral nutrition (82). It was shown that the association of an MCT/LCT-containing

lipid emulsion with fish oil with a high n-3/n-6 ratio impelled great beneficial impact,

attenuating morphological and inflammatory consequences and decreasing colonic

concentrations of proinflammatory mediators.

The current knowledge based on clinical trials does not however allow a clear formulation

of recommendations for the use of immunonutrition in patients with inflammatory bowel

disease. Nevertheless, taking into account their underlying immune system disorders,


demonstrating a beneficial effects of immunonutrition, with special reference to fatty

acids, seems to be a matter of time.

8.3. Acute Pancreatitis

The mainstay of treatment of acute pancreatitis is appropriate nutritional intervention. If

going back to oral feeding is not possible within 5 days after the onset of the disease,

standard treatment now involves enteral feeding via a nasogastric tube. Apart from

supplying energy and protein, enteral feeding is supposed to minimize the risk of

bacterial translocation and secondary infection of pancreatic necrosis, maintaining

intestinal transit, and providing essential nutrients for the intestinal villi. Nevertheless,

severe acute pancreatitis may require parenteral or mixed nutrition (enteral and

parenteral). In the case of acute pancreatitis, as in inflammatory bowel diseases, there

are few data to support an advantage of immunonutrition (83-92). In accordance with

the guidelines of ESPEN, whenever there is a necessity to use parenteral nutrition,

parenteral glutamine supplementation should also be considered (>0.30 g/kg Ala–Gln

dipeptide) (93). It eventuates from the lack of clear clinical evidence of such enteral

immunonutrition advantage when compared to standard mixtures (both polymeric and

semi-elemental).

Only animal studies suggested that enteric diet enriched with glutamine, arginine, and

probiotics has a positive effect on gut barrier function and immune function (pigs with

severe acute pancreatitis) (94,95). EN maintained gut barrier function and immune

function. It should be taken into consideration, however, that there are conflicting data

regarding probiotics and their potentially harmful effects in impairment of visceral

perfusion.

9. Metabolic Abnormalities in ICU Patients and Possibilities of

Nutritional Intervention

When discussing nutritional issues in the Intensive Care Unit (ICU), it is of utmost

importance to define the ICU patient to get a picture of the scale of metabolic

abnormalities which must be treated. The ESPEN definition is as follows: the ICU patient

is a patient developing an intensive inflammatory response with failure of at least one

organ (SOFA >4) (1). In other words, patients admitted only for monitoring (typical ICU

stay below 3 days) are not representative ICU patients. The latter are those with an

acute illness necessitating support of organ function during an ICU episode expected to

be longer than 3 days (28).

The response to critical illness is a complex one. It involves an increase in glycolysis and

gluconeogenesis and protein turnover with significant protein loss (mostly from muscle,

skin and the gastrointestinal tract) and increased resistance to insulin in liver, muscle

and adipose tissue. Only a small part of available glucose is fully oxidized in stressed

insulin dependent organs even in aerobic conditions, and substantial amounts are

necessary for glycolysis. The latter is essential in erythrocytes which lack a full Krebs

cycle and rely on glycolysis (12). The amino acids derived from protein degradation are

to some degree re-utilized for protein synthesis, but in critically ill individuals a

substantial proportion is irreversibly degraded and the nitrogen component metabolized

to urea (12). All these changes also affect the immune system, its actions dependent on

many factors, such as the severity of disease, the phase of response and concomitant

disease.

It is obvious that the increased metabolic needs related to stress are likely to accelerate

the development of malnutrition, which is always associated with compromised clinical

outcomes. In a randomized study, 300 patients undergoing major surgery received

continuous total parenteral nutrition (PN) or exclusively intravenous glucose (250–300

g/d) for 14 days; the PN patients had 10 times less mortality than those on glucose (94).

It is important to remember that nutritional support can partially compensate for

negative energy and protein balance, but it cannot completely reverse catabolism in

peripheral tissues like muscle, skin and bone until the convalescence phase begins (12).


The above observations confirmed the need to feed critically ill patients. Therefore an

obvious next step was to create an intervention, which should be able not only to cover

basic needs, but also influence the clinical course. Hence the interest in immunonutrition

as a potential treatment option for ICU patients.

Up-to-date studies on glutamine, arginine, omega-3-PUFAs and micronutrients have been

performed, and their biological activities examined. Although some results were

conflicting and sometimes confusing, three of the most important scientific societies

dealing with nutrition and metabolism have been able to formulate guidelines and

recommendations based on some of those experiments.

9.1. Glutamine

Studies performed in multiple trauma ICU patients showed a beneficial impact of

glutamine-supplemented enteral formula with administration of 10 g to 14 g glutamine

per litre (21,22). Studies in severely burned patients showed that the addition of

glutamine to a standard enteral feeding formula had a favorable effect on the

preservation of intestinal structure (36). Another meta-analysis recommended using

enteral glutamine in burned or trauma patients based on the impact on mortality and a

trend toward reduced infectious comorbidity (25). McQuiggan et al demonstrated that

enteral glutamine during resuscitation from acute shock is not only safe but also

enhances enteral tolerance (27).

In various clinical studies in the ICU setting, intravenous administration of glutamine

(0.2–0.4 g/kg/day) in the form of dipeptide (0.3–0.6 g/kg/day) contributed to improve

glycaemic control, and to reduce the prevalence of infections and mortality (28). Marik

and Zaloga proved that enteral nutrition with supplemented glutamine appeared to be

beneficial in burn patients, probably because burns are associated with a severe

gastrointestinal mucosal injury, leading to increased bacterial translocation, resulting in

secondary multi-system organ dysfunction syndrome (MODS) (36).

The above led to the construction of guidelines by leading scientific societies, such as the

European Society for Clinical Nutrition and Metabolism (ESPEN), the Canadian Critical

Care Society together with The Canadian Society for Clinical Nutrition, and the American

Society for Parenteral and Enteral Nutrition (ASPEN), which recommend use of

glutamine-containing formula in the following ICU patients (28,29,30,31):

a) all burn and/ or trauma patients (recommendations of ESPEN and Canadian Societies),

b) all ICU patients in whom parenteral nutrition is needed (ESPEN),

c) in critically ill postoperative or ventilator-dependent patients requiring parenteral

nutrition, due to the positive impact of parenteral glutamine administration, a decrease in

infectious complications, decrease in hospital length of stay, and possible decrease in

mortality (ASPEN),

d) parenteral glutamine may be beneficial in adult burn patients or acute pancreatitis

patients who require PN.

ESPEN and the Canadian Society also described situations, in which glutamine is not

recommended:

a) in patients with severe sepsis: these patients are not only not likely to benefit from

immunomodulating formula, but may also be harmed

b) the routine use of enteral glutamine in all critically ill patients

c) in critically ill patients receiving enteral nutrition - there are insufficient data to

generate recommendations for intravenous glutamine.

According to the ASPEN position there are no absolute contraindications to the use of

parenteral glutamine, but liver function tests should be monitored in all patients and it

should be used with caution in end-stage hepatic failure patients and patients with

hepatic insufficiency (31). ASPEN pointed out that further research is needed on

glutamine supplemented PN in the following areas: specific adult patient populations;

paediatric patients; use of glutamine supplementation in combination with parenteral and

enteral nutrition or enteral/oral nutrition alone; dipeptide vs. free L-glutamine; timing

and dosing; cost-benefit analysis; and further elucidation of parenteral glutamine’s

mechanisms of action (31).


When considering the right dosage: PN glutamine supplementation should probably be

given early and in doses > 0.2 g/kg/day to be effective. [95] ESPEN recommended a

dosage of 0.2–0.4 g/kg/day of L-glutamine (e.g. 0.3–0.6 g/kg/day alanyl-glutamine

dipeptide), but also emphasized the dose-dependency effect of immunodiets; therefore

ICU patients with severe illness who do not tolerate more than 700 ml enteral formula

per day should not receive an immune-modulating formula enriched with arginine,

nucleotides and n-3 fatty acids (28). It is also important to remember that continuous

renal-replacement therapy may increase glutamine loss by 4–7 g/day further enhancing

the case for glutamine supplementation in this context (95).

A new multicentre study of Heyland et al. undermined the position of glutamine in ICU

patients. The study showed higher mortality in ICU patients receiving glutamine along

with antioxidants or alone (96). It must, however, be remembered that these

researchers used the maximum dose of intravenous glutamine and administered oral

amino acid as well. That type of administration could have significantly influenced the

outcome, hence more studies are needed.

9.2. Arginine

Although arginine along with other nutrients was proven to help to reduce postoperative

complications in surgical patients, nutrition enriched with arginine surprisingly failed to

improve outcomes in trauma patients and patients with sepsis (34). The main reason for

that is the increased concentration of nitric oxide in the bodies of those ICU individuals

(in contrast to surgical patients). As Marik and Zaloga summarized, patients with sepsis

and surgical trauma regulate arginine metabolism differently (36). Arginine levels are

lower and arginase activity is higher in patients following surgical trauma than in sepsis,

hence NO is elevated in sepsis and decreased following surgical trauma. It was clearly

shown in the study by Bertolini et al., which compared a formula containing extra L-

arginine, omega-3 fatty acids, vitamin E, beta-carotene, zinc, and selenium with a

standard formula. After recruitment of 237 patients, the study was stopped because an

analysis of 39 of patients with severe sepsis revealed that the immunomodulating

formula was associated with a significantly higher ICU mortality than in those receiving

the standard formula (44.4% versus 14.3%; P=0.039) (97).

Although those observations were contraindicated by other studies, the evidence resulted

in the construction of very strict guidelines and recommendations for the use of arginine.

According to ESPEN, arginine–enriched enteral diets should be used in the case of ARDS

and trauma patients as well as in mild sepsis (<15 APACHE II), while they are

contraindicated in severe sepsis (28). Canadian recommendations even more sturdily

discourage the use of arginine-containing diets in critically ill patients; according to them

diets supplemented with arginine should never be used in this context (29).

9.3. Nucleotides

The administration of nucleotides helped tissue recovery from ischaemia–reperfusion

injury and increased recovery rates in cardiac ischaemia and radiation injury as well as

decreasing bacterial translocation in severe starvation (12). They were clinically effective

in major elective surgery patients (12). Data regarding their role in critically ill patients

are lacking, and more studies are needed.

9.4. Omega-3-polyunsatturated Fatty Acids

A review of the effect of including fish oils in PN in ICU patients concluded that there was

a significant reduction in the length of stay, but no differences in mortality were noted

(98). A multi-centre study, which enrolled 661 patients (SAPS II score >32) showed that

intravenous fish oil supplementation had favorable effects on survival, infection rate,

antibiotic requirements and length of stay when administered in doses between 0.1 and

0.2 g/kg/day (99). The greatest influences were observed in patients wth abdominal

sepsis. In the study of Wichmann et al., the mixed soybean LCT/MCT/fish oil emulsion


significantly increased EPA, LTB5 production and antioxidant levels, as well as yielding a

significantly shorter length of hospital stay (17.2 vs. 21.9 days, p=0.006) (100).

For those reasons ESPEN recommends its use in ARDS patients (Grade A), mild sepsis

(Grade B) and trauma patients (Grade A) (28). Canadian recommendations endorse the

use of an enteral formula with fish oils, borage oils and antioxidants in patients with

Acute Lung Injury (ALI) and acute respiratory distress syndrome (ARDS) (28).

9.5. Micronutrients

In animal models, plasma levels of selenium and zinc significantly decreased 6 hours

after burn injury, which led to a decrease in the activity of superoxide dismutase and an

increase in oxidative stress and lipid peroxidation (2,31,32). In situation like that trace

element supplementation may counteract oxidative damages.

ESPEN recommends micronutrient supplementation for ICU patients at standard doses in

all types of patient receiving artificial nutrition (28).

In burn patients trace elements should be supplemented at higher than regular dosage

(16). The reason for this is explained by the example of selenium. Its turnover is always

significantly increased during catabolic stress. Generally speaking, antioxidant vitamins

(including vitamin E and ascorbic acid) and trace elements (including selenium, zinc, and

copper) are believed to improve patient outcome, especially in burns, trauma, and critical

illness requiring mechanical ventilation (101, 102).

9.6. Execution of Immunonutrition in ICU

The selection of the right ICU patient for immunonutrition and the proper choice of diet

are not the only problems regarding this type of intervention. Another very important

issue lies in the dosage of nutrients, so also the question of tolerance and compliance.

According to ESPEN guidelines, ICU patients who cannot tolerate at least 700 ml per day

of enteral diet should not receive immunomodulating (enriched with arginine, nucleotides

and omega-3-PUFAs) formulas, because that type of intervention is of no clinical value

(30).

During parenteral intervention, the dosage of immunonutrients also matters. Glutamine

should be administered at the dose of 0.2 to 0.4 g/kg bw/day (0.3 to 0.6 g/kg bw/ day L-

alanyl-L-glutamine – the intravenous form of glutamine). The administration of fish oil

should at least reach the level of 0.1 g/kg bw/day. The recommended dose of selenium

for adult patients is 60–400 ug/ day.

The selection of efficient enteral diet may be difficult. Impact® (Nestle), as in the

surgical studies, was the diet most often used in the studies which indicated the clinical

value of immunonutrition, as presented in Table 1. It does not mean that the other diets

do not work or should not be used, it just indicates the need for more clinical studies.

Table 2 presents the largest clinical analyses on ICU immunonutrition.


Table 2. Studies on immunonutrition in ICU patients

10. Ambiguities Regarding Immunonutrition

Studies on immunonutrition sometimes give puzzling results, mostly due to discrepancies

between in vitro and in vivo research. In many cases preclinical studies prove beneficial

impact of immunodiets on the immune system, but the outcome of clinical observations

is then different. Some other reasons for these ambiguities are as listed:

- Heterogeneity of study groups in the various studies (the ratio of malnourished

patients to well-nourished patients was different in each study, and it is obvious that

nutrition helps malnourished patients even without an immunomodulating component)

- Heterogeneity of nutritional interventions (intervention took place pre-, peri- or

postoperatively or even in other phases of the clinical course)

- Various formulas were used (Impact, Stresson, Reconvan – their nutrient content

varies considerably; for example Impact® does not contain glutamine)

- Various caloric loads were used during nutritional support (authors used hypercaloric,

iso- or hypocaloric diets, and the compliance with treatment was also flawed in almost

50% of studies)

- Heterogeneity of definitions (definitions for complications differed or were unknown,

various definitions describing nutritional status were used)

- poor methodology: small number of ITT analyses, lack of well-designed, randomized

studies

The above factors are probably the main reasons for the conflicting results from the

clinical studies, and which have made the assessment of the real clinical value of

immunonutrition difficult even in meta-analyses. In future, study designs should consider

these factors more carefully in the planning phase to avoid further disappointment. Those

ambiguities, however, indicate the need for careful use of the guidelines, which are based

AUTHOR(S) Number of

patients (n)

Study groups Type of

diet

Results

Bower et al.

1995 (103)

326 IMEN vs

isocaloric

Impact Decreased complication

rate in IMEN, but higher

mortality

Atkinson et al.

1998 (104)

398 IMEN vs

isocaloric

Impact Mechanical ventilation and

ICU stay reduced

Caparros et al.

2001 (105)

235 Experimental

formula vs

sntadard

Experimental

formula

Standard formula better

results

Kieft et al,

2005 (106)

597 IMEN vs

standard

Stresson ICU stay similar, shorter

ventilator days in

immunogroup

Dent et al,

2003 (107)

170 IMEN vs

standard

Optimental

vs Osomolite

HN

Mechanical ventilation and

ICU stay reduced

Heyland et al.

2001 (108)

Meta-analysis

22 RTC

2419 pts.

IMEN vs

standard EN

Impact Decrease of complications,

no differences in mortality

Montejo et al.

2003 (109)

Meta-analysis

1270

IMEN vs

standard EN

Various

(Impact,

Stresson)

Decrease of complications,

no differences in mortality


on EBM, and clearly signpost the requirement for more clinical studies. Nonetheless,

immunodiets, when used wisely, can improve the outcomes of therapy.

11. Summary

Immunonutrition represents a form of nutritional support, which covers not only basic

nutritional demands, but also modifies functions of the immune system.

Immunosubstrates include arginine, glutamine, omega-3-fatty acids, selenium, zinc,

vitamins A, C and E, and nucleotides. They can be administered in the form of enteral

nutrition or intravenously. Glutamine can be beneficial in trauma and burn patients, and

may also improve the outcome of surgery. Arginine cannot be used in severe sepsis

patients, but is of value in high-risk elective surgery patients. The latter group may also

benefit from nucleotides. Omega-3-unsaturated fatty acids can reverse PN associated

cholestasis in children, reduce postoperative complications after GI surgery, improve the

outcome in critically ill ARDS and trauma patients, and favourably influence pancreatic

cancer growth. During enteral and parenteral nutrition micronutrients should be

supplemented on a daily basis, and their dosage must be significantly increased during

catabolic stress. Further in vitro and in vivo studies are needed to fully understand the

mechanisms and clinical value of immunonutrients.

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Documents

Substrates for Enteral and Parenteral Nutrition Topic 7 · both enteral and parenteral glutamine have been demonstrated to restore the integrity of the GI mucosa and decrease bacterial