Nutrition Manuscript Draft Manuscript Number: NUT-D-09-00287R1 Title: Immunonutrition and critical illness: An update Article Type: Review Keywords: immunonutrition; omega-3 fatty acids; fish-oil; gltuamine; arginine; antioxidants; critical illness Abstract: Dietary supplementation with nutrients that have physiologic effects on immune function has been shown to be beneficial in subsets of patients with surgical and medical critical illness. However, several metaanalyses have suggested potential harm when immune nutrients are used inappropriately. This has led to concern among clinicians that in turn has curtailed the more widespread use of immunonutrition as a therapeutic modality. This article will discuss the mechanisms by which immune nutrients can be used to modulate alterations in innate and acquired immunity associated with critical illness. In addition, recent evidence-based clinical practice guidelines for use of immunonutrition in adults will be reviewed as a means to clarify some of the more controversial issues and provide a "roadmap" for the practitioner.

MS reference no: NUT-D-09-00287

October 5, 2009

Dear Dr. Meguid:

Thanks for forwarding the comments by the two reviewers. I would like to

respond to the criticisms from reviewer #2. I felt that a moderately detailed

discussion of the immunologic basis of immunonutrition would be useful to the

reader because it is difficult to logically utilize immunonutrient solutions in various

types of patients (e.g., surgical, trauma, medical) if the major differences in

underlying immune status are not clearly understood. That is, surgical and

trauma patients are mainly immunosuppressed, due to large part to arginine

deficiency, whereas medical patients with sepsis have systemic inflammation,

are not arginine deficient, and may be harmed by supplemental arginine. This is

the key message. The length of the discussion of pathophysiology is 9 pages,

not 13 as mentioned. Nevertheless, I did further shorten the pathophysiology

section.

*Response to Reviewers

2

Second, I affirm that the concept of pharmaconutrition (e.g., administration of

individual immune nutrients) is valid. However, other than supplementing

glutamine or selenium, the clinician is currently limited to commercially-available

enteral formulas containing a mixture of pharmaconutrients and basic nutrients. I

agree that providing pharmaconutrients (e.g., fish-oil) separate from basic

nutrients may facilitate attaining therapeutic dosages. However, this approach is

currently limited to clinical trials. Furthermore, the Canadian, ESPEN and

SCCM/ASPEN guidelines are based on studies that utilized commercial

immunonutrient formulas. Nevertheless, I added a short section on

pharmaconutrition.

Reviewer #2 also mentions my failure to cite the Australian Guidelines. After

spending some time on the Internet, I was able to locate them, but found that

they did not provide specific recommendations regarding the use of immune

nutrients. Table 1 provides an overview of the 3 major sets of practice

guidelines, and is to my knowledge, unique.

The reviewer also commented on my "misuse" of the term "critically-ill". I find

that the use of this term to be confusing when applied to immunonutrition.

Although “critically-ill” is often used to refer to ICU patients, many of the earlier

metaanalyses of immunonutrition “lumped” a wide variety of hospitalized patients

(including elective surgical patients) into this category. This in turn led to

confusion as to the efficacy of immunonutrition in hospitalized patients. As

mentioned by Marik and Zaloga in their excellent metaanalysis, the clinical

response to a given immunonutrient formula varies according to the nature of the

3

patient’s critical illness (e.g., sepsis/SIRS vs. trauma vs. burn), hence the efficacy

of a given formula must be interpreted in the context of the patient population in

which it is studied. I added a short section attempting to clarify this issue.

I deliberately did not discuss the pediatric population, since the guidelines do

not extend to children or infants. I clarified the adult-oriented nature of the review

in my revised draft.

With regard to the comments of reviewer #1, I did not provide metaanalysis

tables due to the need to cite all of the involved references. However, I did add a

figure from the Marik and Zaloga metaanalysis that summarized the important

illness-based outcomes of pharmaconutrient supplementation.

In summary, the revised draft contains a completely rewritten introduction,

shortened pathophysiology section, elaboration on the concept of pharmaco-

nutrition, and addition of an additional figure. Hopefully, these changes will

address the concerns of the reviewers.

Yours truly,

Barry A. Mizock MD, FACP, FCCM

Associate Professor of Medicine

University of Illinois at Chicago

312-413-5449

Fax: 312-413-8283

E-mail: bmizock@earthlink.net

-Re-edited draft (10/5/09)-

Immunonutrition and critical illness:

An update

MS reference no: NUT-D-09-00287

Running head: immunonutrition update

Key words: immunonutrition, omega-3 fatty acids, fish-oil, glutamine,

arginine, antioxidants, critical illness

Word count: 5083

Barry A. Mizock MD, FACP, FCCM

Department of Medicine

University of Illinois at Chicago

840 South Wood Street

Chicago, Illinois 60612

312-413-5449

Fax: 312-413-8283

bmizock@earthlink.net

*Manuscript

2

Abstract

Dietary supplementation with nutrients that have physiologic effects on immune

function has been shown to be beneficial in subsets of patients with surgical and

medical critical illness. However, several metaanalyses have suggested

potential harm when immune nutrients are used inappropriately. This has led to

concern among clinicians that in turn has curtailed the more widespread use of

immunonutrition as a therapeutic modality. This article will discuss the

mechanisms by which immune nutrients can be used to modulate alterations in

innate and acquired immunity associated with critical illness. In addition, recent

evidence-based clinical practice guidelines for use of immunonutrition in adults

will be reviewed as a means to clarify some of the more controversial issues and

provide a “roadmap” for the practitioner.

3

Introduction

The concept of immunonutrition (nutritional immunology) evolved from the

realization that optimal function of the immune system is impaired in the

presence of malnutrition(1). The evolution of immunonutrition as a therapeutic

modality was stimulated by Alexander’s pioneering work in burn injury. His

research led to the development of the Shriners burn formula, an enteral feeding

solution supplemented with immune nutrients (e.g., arginine, omega-3 fatty acids,

vitamins A,C, and zinc). This formula reduced wound infection and length of stay

in burned patients(2). In 1992, Daly and colleagues studied the efficacy of an

immunonutrient formula supplemented with arginine, omega-3 fatty acids, and

nucleotides on clinical outcome in post-operative patients who had undergone

major elective surgery for upper gastrointestinal malignancy(3). When compared

to patients receiving a standard enteral diet, patients who received the immune

formula had a decrease in wound and infectious complications, as well as a more

rapid restoration of lymphocyte mitogenesis. Subsequently, a large number of

clinical trials have been conducted utilizing various proprietary immune formulas

in subgroups of critically-ill patients. Positive effects included: reduced infectious

complications, shorter time on the ventilator, reduced hospital and ICU length of

stay, and reduced mortality. However, not all studies yielded positive results, with

several indicating potential harm, notably in patients with underlying sepsis. In

addition, delivery of immune nutrients as a constituent of a nutritional formula

may be limited in patients with gastrointestinal intolerance who cannot attain

target infusion rates. This in turn stimulated the approach of “pharmaconutrition”

4

which involves administering immune nutrients dissociated from the provision of

calories and protein(4).

This article is not intended to be a comprehensive discussion of clinical

studies of immunonutrition, and the reader is referred to several excellent

reviews(5-7). Instead, this article will utilize recent evidence-based clinical

practice guidelines to provide a “roadmap” by which the clinician can most

effectively utilize immunonutrition to improve outcome in adult critically-ill

patients. This discussion will be preceded by concise summaries of the

characteristic alterations in innate and acquired immune accompanying critical-

illness and the mechanisms by which immune nutrients can favorably impact the

immune response.

Immune alterations in critical illness:

The term “critical illness” can be defined as: “a life-threatening medical or

surgical condition usually requiring ICU-level care that includes, but is not limited

to, trauma, surgery, sepsis, shock, and severe burns”(7). However, the immune

status of critically-ill patients is by no means homogenous, and these patients

have significant differences in underlying immune status that precludes their

being “lumped” together(8,9). This in turn dictates variations in the immune

nutrient profile that is appropriate for each group.

Both innate and acquired immunity are involved in the response to acute

severe illness. The innate immune response is characterized by an initial local

inflammatory reaction at the site of infection or injury, which involves activation of

5

macrophages and monocytes, the alternate complement pathway, and the blood

coagulation system. The local inflammatory reaction is amplified through the

release of pro-inflammatory mediators (e.g., tumor-necrosis factor, interleukin-1,

prostaglandins, leukotrienes, thromboxanes) that in turn leads to the systemic

inflammatory response syndrome (SIRS). The initial phase of the SIRS response

is felt to be an adaptive process that facilitates resolution of the acute inciting

process. However, an maladaptive response secondary to overwhelming or

prolonged systemic inflammation (e.g., “excessive SIRS“) may ensue as the

result of factors such as the type of infecting organism, genetic predisposition to

overexpression of inflammatory cytokines, patient age, and comorbidities(10).

Clinical syndromes associated with excessive SIRS include: the acute respiratory

distress syndrome (ARDS), septic shock, disseminated intravascular coagulation,

and the multiple organ dysfunction syndrome(MODS). The mechanism for organ

dysfunction in the setting of systemic inflammation appears to involve extensive

mitochondrial damage resulting from overproduction of nitric oxide and its

metabolite peroxynitrite(11). Provision of supplemental arginine in the setting of

sepsis may be pathogenic in this regard by stimulating nitric oxide

production(8)(see below).

The adaptive immune response develops several days after the initial innate

response and involves the interaction between antigen-presenting cells (e.g.,

macrophages, dendritic cells) and lymphocytes that are responsible for cell-

mediated immunity and antibody production. A transient downregulation of

adaptive immunity is commonly seen in patients with acute critical illness that is

6

termed the “compensatory anti-inflammatory response syndrome” (CARS)(12).

The CARS response may have evolved as a means to prevent downstream

damage to distant organs by locally produced inflammatory mediators(13,14).

The components of the CARS includes both cellular/molecular elements (e.g.,

lymphocyte dysfunction and apoptosis, monocyte/macrophage deactivation,

increased production of interleukin-10) and clinical elements (e.g., cutaneous

anergy, hypothermia, leukopenia)(13,14). In patients who have sustained

significant trauma or following major surgery, upregulated arginase expression in

granulocytes results in a decrease in plasma arginine levels(15-17). The

resultant arginine-deficient state suppresses the acquired immune response by

decreasing translation of the zeta-chain peptide on the T-cell receptor

complex(15). In certain patients (e.g., following major trauma) a maladaptive

state of profound, prolonged immunosuppression (“immunoparalysis”) may

develop that is associated with increased risk of nosocomial infection, organ

dysfunction, and death(18).

In summary, critical illness may be accompanied by various combinations of

systemic inflammation and generalized immunosuppression. Both of these

conditions are amenable to therapy with pharmaconutrients.

Antioxidant vitamins and trace elements

Endogenous antioxidants play an important role in minimizing cellular damage

resulting from enhanced production of reactive oxygen and nitrogen species

(e.g., oxidative stress)(19). The endogenous antioxidants have been collectively

7

termed the antioxidant defense system(AOX)(19). The AOX includes enzymes

(e.g., superoxide dismutase, glutathione peroxidase), trace elements (e.g.,

selenium, zinc), vitamins (e.g., vitamin C, E, beta-carotene), sulfhydryl group

donors (e.g., glutathione), and glutamine. Critical illness is associated with

deficits in circulating antioxidants due to: 1) a SIRS-induced redistribution from

blood to tissues; 2) increased losses (e.g., during burn or trauma); 3) decreased

nutritional intake(19). The resultant reduction in antioxidant potential promotes

increased cellular oxidative injury (esp. lipid peroxidation). A number of clinical

studies have explored the potential benefit of supplementation with antioxidants.

The combinations and doses of antioxidants varied considerably. Heyland et al

performed a metaanalysis of clinical studies of trace element and vitamin

supplementation in critically-ill patients. They concluded that trace-elements and

vitamins that support antioxidant function, particularly high-dose parenteral

selenium (either alone or in combination with other antioxidants) are safe and

may be associated with a reduction in mortality(20). However, the optimal

combination and doses of micronutrients remain to be determined.

Macronutrients

Glutamine:

Glutamine is the most abundant free amino acid in the body, with skeletal

muscle glutamine constituting greater than 50% of the total free amino acid pool.

Muscle stores of glutamine become rapidly depleted in catabolic stress states

(e.g., trauma, sepsis, burn), and glutamine can therefore be considered

8

conditionally essential in this setting. Mobilization of glutamine provides substrate

for gut, immune cells, and kidneys. Beneficial effects of glutamine include: anti-

oxidant effects (as a precursor of glutathione), inducing production of heat shock

proteins, maintaining gut barrier function by providing fuel for enterocytes, as an

energy substrate for lymphocytes and neutrophils, and stimulation of nucleotide

synthesis(21). Novak et al performed a metaanalysis of glutamine

supplementation in serious illness(22). They found that in elective surgical

patients, glutamine reduced infectious complications and length of hospital stay,

without adverse effects on mortality. Positive results were also seen in critically-

ill patients, in whom supplemental glutamine reduced complications and mortality

rates. The greatest effects were observed with high-dose (>0.20gm/kg/day)

parenteral glutamine. Unfortunately, the optimal parenteral preparation of

glutamine (L-alanyl-L-glutamine dipeptide) is not available in the US, and

supplementation must therefore be provided enterally (usually with glutamine

powder). Alternately, some immunonutrient formulas contain a glutamine

equivalent (e.g., hydrolyzed wheat protein). A study in healthy human volunteers

indicated that the bioavailability of a glutamine equivalent (oat protein

concentrate) was similar to enteral glutamine given as a free amino acid(23).

However, it is unclear whether the bioavailability of a glutamine equivalent is

similar in patients who are critically-ill. A recent trial in postoperative patients

found that an arginine-supplemented immune-enhancing diet increased plasma

glutamine, possibly by enhancing de novo synthesis from arginine(24).

9

Arginine:

Arginine is also conditionally essential during certain types of critical illness

(e.g., trauma, post-operative). Beneficial effects of arginine supplementation

include: 1) secretegogue for release of anabolic hormones (e.g., growth

hormone, insulin-like growth factor); 2) supporting immune (esp. T-cell) function;

3) detoxification of ammonia; 4) improving wound healing via metabolism to

polyamines and proline(8). An arginine deficiency syndrome commonly develops

following severe trauma or major surgery that is mediated by pathologic release

of arginase from granulocytes(15,17). Arginine deficiency impairs the acquired

immune response by causing T-cell receptor (zeta chain) abnormalities; this in

turn increases predisposition to nosocomial infections, and impairs wound

healing(15,16). In this setting, provision of supplemental arginine helps to

reverse the immunosuppressed state. Concomitant supplementation with fish-oil

is also beneficial in restoring T-cell function by inhibiting arginase, thereby

increasing the available arginine(25).

In 2001, Heyland et al published a metaanalysis of immune-enhancing diets in

critically ill patients(26). Most of the studies included utilized formulas that

contained supplemental arginine. Although no overall adverse effects of these

diets on mortality were seen, there was certain evidence from the data that

suggested adverse effects on outcome. These “signals” were notable in the high-

quality studies and were seen mainly in non-trauma patients who were infected

at the baseline. Although the metaanalysis was not designed to uncover a

precise mechanism for these harmful effects, the authors felt that

10

supplementation of arginine in the setting of sepsis could be responsible. This

hypothesis was based in large part on data from three studies that showed

worsened outcome in septic patients who were administered an arginine-

supplemented immunonutrient solution (compared to those receiving a standard

formula)(27-29). In 2002, a metaanalysis exploring the immunomodulatory

actions of arginine in critical illness concluded that although beneficial effects of

arginine supplementation in surgical patients were consistently seen (e.g.,

reduction in infectious risk, decreased ventilator and ICU days, decreased

hospital stay), critically-ill patients did not benefit and may even have been

harmed(30). A recent metaanalysis by Marik and Zaloga found that the addition

of arginine to fish-oil appeared to counteract the benefits of fish oil on outcome of

ICU and trauma patients with sepsis/SIRS(9) (figure 1). Enhanced cytokine

production during sepsis serves to “turn on” the induced form of nitric oxide

synthase, the key enzyme regulating nitric oxide production. Therefore, when

supplemental arginine is provided during sepsis, large quantities of nitric oxide

are generated and subsequently metabolized to peroxynitrite(31). This molecule

is a potent oxidant and nitrating agent that damages mitochondria, increases gut

barrier permeability, and promotes organ dysfunction(31-33).

In summary, post-operative and trauma are typically arginine-deficient states,

and these patients consistently benefit from arginine-supplementation. However,

critically-ill medical patients exhibit little if any benefit, and a strong possibility of

increased mortality exists when arginine is supplemented during sepsis(figure 2).

11

Fish-oil and gamma-linoleic acid:

Cold-water fish (e.g. sardines, mackerel, tuna) are rich in eicosapentaenoic

acid (EPA) and docosahexanoic acid (DHA), the active metabolites of alpha-

linolenic acid(ALA). The high EPA/DHA content of fish results from dietary intake

of a food-chain that includes phytoplankton. Whereas marine plankton can

efficiently metabolize ALA to EPA and DHA via desaturase enzymes, humans

possess a limited capacity to synthesize EPA and DHA during basal conditions

(only 8% of dietary ALA is converted)(33). During acute, severe illness these

desaturases are markedly downregulated so that EPA and DHA synthesis from

ALA is negligible. Therefore, supplementation of omega-3 fatty acids in critically-

ill patients requires administration of fish-oil based lipids. Mechanisms for the

anti-inflammatory action of EPA and DHA include: 1) displacing arachidonic acid

(AA) from the phospholipid core of the inflammatory cell (e.g., macrophage,

neutrophil) membrane thereby reducing synthesis of pro-inflammatory

eicosanoids; 2) reduction in synthesis of pro-inflammatory eicosanoids by

competing with AA for metabolism by the enzymes cyclooxygenase and

lipoxygenase; 3) reducing leukocyte and platelet adhesive interaction with the

endothelium; 4) inhibition of inflammatory gene expression; 5) reduction of

oxidative injury by stimulating glutathione production; 6) enhancing synthesis of

anti-inflammatory resolvins; 7) a lung-protective effect mediated by reducing the

release of gut-derived inflammatory mediators into mesenteric lymphatics and

thoracic duct(34-36).

12

Gamma linoleic acid (GLA) is an omega-6 polyunsaturated fatty acid (derived

from borage oil) that has a synergistic effect with EPA and DHA in reducing lung

inflammation(34,37). In addition, GLA is ultimately metabolized to one-series

prostaglandins (e.g., PGE1) that promote pulmonary vasodilation; this in turn

helps to counteract the excessive pulmonary vasoconstriction that occurs in

patients with acute lung injury (ALI) and ARDS(38).

Positive effects of an immunonutrient formula containing fish-oil, borage oil,

and antioxidants on mechanically ventilated patients with ALI or ARDS was

documented in three major randomized clinical trials(39-41). Significant reduction

in duration of ventilation, ICU and hospital stay, and incidence of new organ

failure was seen. Two of the studies also showed a reduction in 28 day mortality

in the treatment group(40,41). A metaanalysis combined the results of the 3

aforementioned trials (411 total patients) and found a 49% reduction in intention-

to-treat mortality, with the number needed to treat to save an additional life at day

28 equal to five(42).

Two additional trials investigating nutritional supplementation in ALI/ARDS are

currently in progress. The “Fish Oil Study” is designed to compare the effects of

enteral administration of pharmaceutical grade fish oil (8 grams/day divided every

6 hours) versus placebo on mortality, ventilator-free days, ICU and hospital

length-of-stay, and infections. The study was completed in December 2008, and

results are pending. The ARDSnet sponsored “EDEN-OMEGA” study was

conducted to compare early versus delayed full calorie feeding on ventilator-free

days and survival rates. This study was also designed to determine the benefit of

13

a twice-daily modular administration of fish-oil, borage-oil, and antioxidants

versus placebo on these clinical outcomes. Unfortunately, the immunonutrient

(“OMEGA”) arm of the study was terminated due an interim statistical analysis

that suggested that the primary endpoint (ventilator-free days) could not be

achieved if the study continued to completion.

Clinical Use of Immunonutrition During Critical Illness

Selection of the most appropriate immunonutrient formula should ideally be

directed by laboratory testing that would enable rapid and accurate assessment

of the patient’s immune status. Since clinicians lack an “immunometer”,

nutritional decision-making is typically guided by the patient’s diagnostic category

in conjunction with relevant practice guidelines. Three evidence-based clinical

practice guidelines for nutritional support of critically-ill patients have recently

been published: 1) the Canadian Clinical Practice Guidelines (CCPG) for

nutritional support in mechanically-ventilated critically-ill adults (updated in 2009);

2) the European Society for Parenteral and Enteral Nutrition (ESPEN) guidelines

on enteral nutrition in intensive care (published in 2006); 3) the Society of Critical

Care Medicine and American Society of Enteral and Parenteral Nutrition

(SCCM/ASPEN) nutritional guidelines for critically-ill adults (published in 2009)

(43-45). These guidelines are organized based on indications for micro- and

macronutrient supplementation in various populations of critically-ill patients (e.g.,

sepsis, burn, trauma, post-operative). The CCPG recommendations are

categorized as: recommended, should be considered, should not be used, and

14

no recommendation due to inadequate data. In contrast, the ESPEN and

SCCM/ASPEN guidelines are graded A through D based on the level of

evidence. A summary of these guidelines is presented in table 1. ICU patients

not meeting criteria for immunonutrition should receive standard enteral

formulations(45).

A number of enteral products containing immunonutrients are currently

available in the US and abroad. These formulas contain varying amounts of

arginine, EPA/DHA, GLA, and antioxidants. Products commonly used in the US

are summarized in table 2. The term “immune-enhancing diet” is used to refer to

enteral formulas containing supplemental arginine along with fish-oil and

antioxidants. As discussed above, these formulas are most appropriate for

patients who are likely to be arginine-deficient (e.g., elective surgery, trauma).

McCowen and Bistrian recommend that immune- enhancing formulas should

ideally contain greater than 12gm arginine/L (>4% of resting energy

expenditure)(33). The optimal duration of administration is at least 3 days,

preferably 5-10 days(33). The ESPEN and SCCM/ASPEN guidelines support

the use of immune-enhancing diets in patients with mild-to-moderate sepsis,

however both advise against the use of immune-enhancing diets in patients with

severe sepsis. The CCPG guidelines maintain that arginine-supplemented

immune-enhancing diets not be used for critically-ill patients (esp. with sepsis).

The optimal formula for septic patients has not been defined at this point in time.

The fish-oil/GLA/antioxidant formula was shown to be beneficial in patients with

severe sepsis or septic shock who had ALI/ARDS(41). A Brazilian trial is

15

currently in progress that is designed to assess the efficacy of this formula in

septic patients without underlying severe lung disease. All three practice

guidelines recommend the use of the fish-oil/GLA/ antioxidant formula in

critically-ill patients with ALI/ARDS.

Enteral immune products contain varying amounts of antioxidant vitamins and

trace elements. Supplementation with additional pharmaconutrients (e.g.,

selenium) may be desirable in certain patients. Positive effects of high-dose

parenteral selenium supplementation were recently documented in patients with

SIRS, sepsis and septic shock(46). In contrast, another trial of selenium

supplementation in septic shock failed to demonstrate beneficial effects(47). It

was suggested that lack of efficacy in this study may have been due to an

excessive dose of selenium(48). Concerns regarding the safety of high doses of

antioxidants (e.g., potential pro-oxidant effects) were addressed in a dose-

optimizing study(49). This trial found that supplementation with 800 g of

selenium in combination with other antioxidants and glutamine appeared to be

safe and had some positive effects on physiologic function. The optimal dose of

selenium during septic critical illness remains to be determined, but doses

ranging between 500-750 g/d and 800 g-1000 g per day for 1-3 weeks have

been suggested(19,48). Somewhat lower doses (e.g., 300-500 g/d) were

recommended for major trauma and burns(50). The REDOX study (currently in

progress) is designed to evaluate the effect of antioxidant and glutamine

supplementation on mortality of critically-ill patients and hopefully will clarify

some of these issues.

16

The importance of early initiation of enteral feeding (e.g. within the first 24-48

hours following admission) in critically-ill patients was stressed by all three

practice guidelines as a means to decrease infectious morbidity and hospital

length of stay(43-45). Timely administration of immunutrition is particularly

important in patients with ALI or ARDS. Animal studies have suggested that it

may take as long as 72 hours before significant effects of EPA and GLA on the

polyunsaturated fatty acid profile of inflammatory cell membranes becomes

apparent (e.g., reducing AA content)(51). In elective surgery patients, the

beneficial effects of immunonutrition are most apparent when the formula is given

in the preoperative period(6,45). It is also important to aggressively advance the

infusion rate as tolerated. The SCCM/ASPEN guidelines propose that at least

50%-65% of goal energy requirements should be delivered to receive optimal

therapeutic benefit from immune-modulating formulas(45). Dysfunction of the

gastrointestinal tract is common in acutely-ill patients and can limit the amount of

immunonutrition delivered enterally(52). ESPEN guidelines maintain that

critically-ill ICU patients who do not tolerate more than 700ml of enteral

nutrition/day should not receive immune-enhancing diets(44).

In mechanically-ventilated patients receiving continuous infusion of propofol

for sedation (esp. at higher doses), the associated caloric load can be substantial

(each ml provides 1.1 kcal)(53). For example, an 80 kg patient infused at a rate

of 60 gm/kg/minute receives approximately 760 kcal per day. This in turn could

be counterproductive by promoting overfeeding, as well as by limiting the amount

of fish-oil based lipids that can be administered. Other associated risks of high-

17

dose propofol infusion include: increased potential for developing hyperlipidemia,

adverse effects of parenteral soy-based lipids in ICU patients, and the propofol-

infusion syndrome(43,45,54).

Conclusions

The value of immunonutrient formulas in the management of critically-ill and

postoperative patients is now acknowledged by many medical practitioners.

However, it is important that the clinician be aware that “one size does not fit all”.

This implies that the immune nutrient profile that is appropriate for the trauma or

elective surgery patient may be of minimal benefit for the medical ICU patient,

and could be potentially harmful in the setting of sepsis. Making rational

decisions in choosing the optimal formula will minimize adverse effects that

currently serve to curtail the more widespread use of this valuable therapeutic

modality.

18

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26

Table 1: Immune nutrients for specific patient populations: summary of

clinical practice recommendations

# = Arginine administered in context of immune-enhancing diet that also

contains fish-oil, antioxidants, nucleotides

@ = Enteral glutamine added to enteral nutrition regimen

+ = Fish-oil derived -3 fatty acids (EPA and DHA) administered in context

of immune-enhancing diet that also contains borage oil and antioxidants

^ = antioxidant vitamins (including selenium) and trace elements

No rec = no recommendation

27

Figure 1

29

Figure 2:

30

Figure 1 legend:

Odds ratio (with 95% confidence interval) of the treatment effect (for two or

more studies) of the immunonmodulating diets on mortality

(Arg arginine; A-FO arginine + fish oil, FO fish oil, AFG arginine + fish oil +

glutamine, Gl glutamine).

From reference 9. Used with permission

31

Figure 2 legend:

Benefit vs. harm of arginine-supplemented immune-enhancing diets (IED)

-Patients underlying elective surgery benefit from the use of IED, exhibiting a

significant decrease in infection rates.

-Trauma patients may benefit, but only if they receive adequate amounts of an IED

early after their injury.

-Medical patients appear to exhibit little if any benefit.

-Medical patients with severe sepsis exhibit little benefit; potential for increased

mortality.

From ref 16, used with permission.