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: [email protected]
-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
*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
References:
1. Beisel WR. History of nutritional immunology: introduction and overview. J
Nut 1992;122:591-596.
2. Gottschlich MM, Jenkins M, Warden GD, et al. Differential effects of three
enteral dietary regimens on selected outcome variables in burn patients. J Parent
Ent Nut 1990;14:225-236.
3. Daly JM, Lieberman MD, Goldfine J, et al. Enteral nutrition with supplemental
arginine, RNA, and omega-3 fatty acids in patients after operation: immunologic,
metabolic, and clinical outcome. Surgery 1992;112:56-67.
4. Jones NE, Heyland DK. Pharmaconutrition: a new emerging paradigm. Curr
Opin Gastroenterol 2008;24:215-222.
5. Ali S, Roberts PR. Nutrients with immune-modulating effects: what role should
they play in the intensive care unit? Curr Opin Anaesthesiol 2006;19:132-139.
6. Kudsk KA. Immunonutrition in surgery and critical care. Ann Rev Nut
2006;26:463-479.
7. Tsoras M, Jacobi J. Immunonutrition as part of the nutritional support of
critically ill patients. Contemp Crit Care 2008;5:1-10.
8. Bansal V, Ochoa JB. Arginine availability, arginase, and the immune response.
Curr Opin Clin Nut Metab Care 2003;6:223-228.
9. Marik PE, Zaloga GP. Immunonutrition in critically ill patients: a systematic
review and analysis of the literature. Intensive Care Med 2008;34:1980-1990..
19
10. Matsuda N, Hattori Y. Systemic inflammatory response syndrome (SIRS):
molecular pathophysiology and gene therapy. J Pharmacol Sci 2006;101:189-
198.
11. Mizock BA. Multiple organ dysfunction syndrome. Disease-a-Month
2009;55:471-526.
12. Bone RC. Sir Isaac Newton, sepsis, SIRS, and CARS. Crit Care Med
1996;24:1125-1128.
13. Munford RS, Pugin J. Normal responses to injury prevent systemic
inflammation and can be immunosuppressive. Am J Resp Crit Care Med
2001;163:316-321.
14. Ward NS, Casserly B, Ayala A. The compensatory anti-inflammatory
response syndrome (CARS) in critically ill patients. Clin Chest Med 2008;29:617-
625.
15. Popovic PJ, Zeh HJ, Ochoa JB. Arginine and immunity. J Nut
2007;137(suppl):1681S-1686S.
16. Ochoa JB, Makarenkova V, Bansal V. A rational use of immune enhancing
diets: when should we use dietary arginine supplementation. Nut Clin Pract
2004;19:216-225.
17. Munder M, Schneider H, Luckner C, Giese T, Langhans CD, Fuentes JM, et
al. Suppression of T-cell functions by human granulocyte arginase. Blood
2006;108:1627-1634.
18. Tshoeke SK, Ertel W. Immunoparalysis after multiple trauma. Injury Int J
Care Injured 2007;38:1346-1357.
20
19. Berger MM, Chiolero RL. Antioxidant supplementation in sepsis and systemic
inflammatory response syndrome. Crit Care Med 2007;35(suppl):S584-S590.
20. Heyland DK, Dhaliwal R, Suchner U, Berger M. Antioxidant nutrients: a
systematic review of trace elements and vitamins in the critically ill patient.
Intensive Care Med 2005;31:327-337.
21. Wischmeyer PE. Glutamine: mode of action in critical illness. Crit Care Med
2007;35(suppl):S541-S544.
22. Novak F, Heyland DK, Avenell A, Droger JW, Su X. Glutamine
supplementation in serious illness: a systematic review of the evidence. Crit Care
Med 2002;30:2022-2029.
23. Boza JJ, Dangin M, Moennoz D, Montigon F, Vuichoud J, Jarret A, et al. Free
and protein-bound glutamine have identical splanchnic extraction in healthy
human volunteers. Am J Physiol 2001;281:G267-G274.
24. Loi C, Zazzo JF, Delpierre E, Niddam C, Neveux N, Curis E, et al. Increasing
plasma glutamine in postoperative patients fed an arginine-rich immune-
enhancing diet – A pharmacokinetic randomized controlled study. Crit Care Med
2009;37:501-509.
25. Bansal V, Syres KM, Makarenkova B, Brannon R, Matta B, Harbrecht BG, et
al. Interactions between fatty acids and arginine metabolism: implications for the
design of immune-enhancing diets. J Parent Ent Nut 2005;29(suppl):S75-S80.
26. Heyland DK, Novak F. Immunonutrition in the critically ill patient: more harm
than good? J Parent Ent Nut 2001;25(2 suppl):S51-S56.
21
27. Bower RH, Cerra FB, Bershadsky B, Licari JJ, Hoyt DB, Jensen GL, et al.
Early enteral administration of a formula (Impact) supplemented with arginine,
nucleotides, and fish oil in intensive care unit patients: results of a multiicenter,
prospective, randomized, clinical trial. Crit Care Med 1995;23:436-449.
28. Bertolini G, Iapichino G, Radrizzani D, Facchini R, Simini B, Bruzzone P, et
al. Early enteral immunonutrition in patients with severe sepsis: results of an
interim analysis of a randomized multicentre clinical trial. Intensive Care Med
2003;29:834-840.
29. Dent D, Heyland D, Levy H. Immunonutrition may increase mortality in
critically ill patients with pneumonia: results of a randomized trial (abstract). Crit
Care Med 2003;30:A17.
30. Suchner U, Heyland DK, Peter K. Immune-modulatory actions of arginine in
the critically ill. Br Journal Nut 2002;87(suppl 1): S121-S132.
27.
31. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and
disease. Physiol Rev 2007;87:315-424.
32. Fink MP, Delude RL. Epithelial barrier dysfunction: a unifying theme to
explain the pathogenesis of multiple organ dysfunction at a cellular level. Crit
Care Clin 2005;21:177-196.
33. Bistrian BR, McCowen KC. Nutritional and metabolic support in the adult
intensive care unit: key controversies. Crit Care Med 2006;34:1525-1531.
22
34. Mizock BA, DeMichele SJ. The acute respiratory distress syndrome: role of
nutritional modulation of inflammation through dietary lipids. Nut Clin Pract
2004;19:563-574.
35. Serhan CN, Arita M, Hong S, Gotlinger G. Resolvins, docosatrienes, and
neuroprotectins, novel omega-3-derived mediators, and their endogenous
aspirin-triggered epimers. Lipids 2004;39:1125-1132.
36. Glatzle J, Kasparek MS, Mueller MH, Binder F,Meile T, Kreis ME, et al.
Enteral immunonutrition during sepsis prevents pulmonary dysfunction in a rat
model. J Gastrointest Surg 2007;11:719-724.
37. Mancuso P, Whelan J, DeMichele SJ, Snider CC, Guszcza JA, Claycombe
KJ, et al. Effects of eicosapentaenoic and gamma-linolenic acid on lung
permeability and alveolar macrophage eicosanoid synthesis in endotoxic rats.
Crit Care Med 1997;25:523-532.
38. Murray MJ, Kumar M, Gregory TJ, Banks PL, Tazelaar HD, DeMichele SJ.
Select dietary fatty acids attenuate cardiopulmonary dysfunction during acute
lung injury in pigs. Am J Physiol Heart Circ Physiol 1995;269:H2090-H2099.
39. Gadek JE, DeMichele SJ, Karlstad MD, Pacht ER, Donahoe M, Albertson TE,
et al. Effect of enteral feeding with eicosapenaenoic acid, -linolenic acid, and
antioxidants in patients with acute respiratory distress syndrome. Crit Care Med
1999;27:1409-1420.
40. Singer P, Theilla M, Fisher H, Gibstein L, Grozovski E, Cohen J. Benefit of an
enteral diet enriched with eicosapentaenoic acid and gamma-linolenic acid in
ventilated patients with acute lung injury. Crit Care Med 2006;34:1033-1038.
23
41. Pontes-Arruda A, Aragao MA, Albuquerque JD. Effect of enteral feeding with
eicosapentaenoic acid, -linolenic acid, and antioxidants in mechanically
ventilated patients with severe sepsis and septic shock. Crit Care Med
2006;34:2325-2333.
42. Pontes-Arruda A, DeMichele S, Seth A, Singer P. The use of an
inflammation-modulating diet in patients with acute lung injury or acute
respiratory distress syndrome: a meta-analysis of outcome data. J Parent Ent
Nut 2008;32:596-605.
43. Heyland DK, Dhaliwal R, Drover JW, Gramlich L, Dodek P. Canadian clinical
practice guidelines for nutrition support in mechanically ventilated, critically ill
adult patients. J Parent Ent Nut 2003;27:355-373.
44. Kreymann KG, Berger MM, Deutz NEP, Hiesmayr M, Jolliet P, Kazandjiev G,
et al. ESPEN guidelines on enteral nutrition: intensive care. Clinical Nutrition
2006;25:210-223.
45. McClave SA, Martindale RG, Vanek VW, McCarthy M, Roberts P, Taylor B,
et al. Guidelines for the provision and assessment of nutrition support therapy in
the adult critically ill patient: Society of Critical Care Medicine (SCCM) and
American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). J Parent
Enteral Nut 2009;33:277-316.
46. Anstwurm MWA, Engelmann L, Zimmermann T, Lehmann C, Spes CH, Abel
P, et al. Selenium in intensive care (SIC): results of a prospective randomized,
placebo-controlled, multiple-center study in patients with severe systemic
24
inflammatory response syndrome, sepsis, and septic shock. Crit Care Med
2007;35:118-126.
47. Forceville X, Laviolle B, Annane D, Vitoux D, Bleichner G, Korach JM, et al.
Effects of high doses of selenium, as sodium selenite, in septic shock: a placebo-
controlled, randomized, double-blind, phase II study. Crit Care 2007;11:R73.
48. Heyland DK. Selenium supplementation in critically ill patients: can too much
of a good thing be a bad thing?(editorial). Crit Care 2007;11:153.
49. Heyland DK, Dhaliwal R, Day A, Drover J, Cote H, Wischmeyer P. Optimizing
the dose of glutamine dipeptides and antioxidants in critically ill patients: a phase
I dose-finding study. J Parent Ent Nut 2007;31:109-118.
50. Berger MM. Antioxidant micronutrients in major trauma and burns: evidence
and practice. Nut Clin Pract 2006;21:438-449.
51. Palombo JD, DeMichele SJ, Lydon EE, Gregory TJ, Banks PL, Forse RA, et
al. Rapid modulation of lung and liver macrophage phospholipid fatty acids in
endotoxemic rats by continuous enteral feeding with n-3 and gamma-linolenic
fatty acids. Am J Clin Nut 1996;63:208-219.
52. Heyland D, Cook DJ, Winder B, Brylowski L, Van deMark H, Guyatt G.
Enteral nutrition in the critically ill patient: a prospective survey. Crit Care Med
1995;23:1055-1080.
53. Rice TL. Energy provided by propofol infusion(letter). Am J Health Syst
Pharm 2008;65:2090-2091.
54. Orsini J, Nadkarni A, Chen J, Cohen N. Propofol infusion syndrome: case
report and literature review. Am J Health Syst Pharm 2009;66:908-915.
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
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.