Nutrition 26 (2010) 701–707

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Nutrition
journal homepage: www.nutritionjrnl.com

Review

Immunonutrition and critical illness: An update

Barry A. Mizock M.D., F.A.C.P., F.C.C.M. *
Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA

a r t i c l e i n f o a b s t r a c t

Article history: Dietary supplementation with nutrients that have physiologic effects on immune function has
Received 17 June 2009 been shown to be beneficial in subsets of patients with surgical and medical critical illness.
Accepted 5 November 2009 However, several meta-analyses have suggested potential harm when immune nutrients are used
inappropriately. This has led to concern among clinicians that in turn has curtailed the more
Keywords: widespread use of immunonutrition as a therapeutic modality. This article discusses the mecha-
Immunonutrition
nisms by which immune nutrients can be used to modulate alterations in innate and acquired
Omega-3 fatty acids
immunity associated with critical illness. In addition, recent evidence-based clinical practice
Fish-oil
Glutamine guidelines for use of immunonutrition in adults is reviewed as a means to clarify some of the more
Arginine controversial issues and provide a ‘‘roadmap’’ for the practitioner.
Antioxidants Ó 2010 Elsevier Inc. All rights reserved.
Critical illness

Introduction potential harm, notably in patients with underlying sepsis. In

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
postoperative 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 clin-
ical trials have been conducted utilizing various proprietary
immune formulas in subgroups of critically ill patients. Positive
effects included the following: reduced infectious complications,
shorter time on the ventilator, reduced hospital and intensive
care unit (ICU) length of stay, and reduced mortality. However,
not all studies yielded positive results, with several indicating
* Corresponding author. Tel.: þ312-413-5449; fax: þ312-413-8283.
E-mail address: bmizock@earthlink.net (B. A. Mizock)
0899-9007/$ – see front matter Ó 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.nut.2009.11.010
addition, delivery of immune nutrients as a constituent of
a nutritional formula may be limited in patients with gastroin-
testinal intolerance who cannot attain target infusion rates. This
in turn stimulated the approach of ‘‘pharmaconutrition,’’ 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 utilizes
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 is 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.
702 B. A. Mizock / Nutrition 26 (2010) 701–707
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 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, a 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 predis-
position to overexpression of inflammatory cytokines, patient
age, and comorbidities [10]. Clinical syndromes associated with
excessive SIRS include the following: the acute respiratory
distress syndrome (ARDS), septic shock, disseminated intravas-
cular coagulation, and the multiple organ dysfunction syndrome.
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 argi-
nine in the setting of severe sepsis (especially with multiple
organ dysfunction) may be deleterious in this regard by further
augmenting production of nitric oxide [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 adap-
tive immunity is commonly seen in patients with acute critical
illness that is 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 include both cellular/molecular
elements (e.g., lymphocyte dysfunction and apoptosis, mono-
cyte/macrophage deactivation, increased production of inter-
leukin-10) and clinical elements (e.g., cutaneous anergy,
hypothermia, leukopenia) [13,14]. In patients who have sus-
tained significant trauma or following major surgery, upregu-
lated 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 immu-
nosuppression. Both of these conditions are amenable to therapy
with pharmaconutrients.
Antioxidant vitamins and trace elements
Endogenous antioxidants play an important role in mini-
mizing cellular damage resulting from enhanced production of
reactive oxygen and nitrogen species (e.g., oxidative stress) [19].
The endogenous antioxidants have been collectively termed the
antioxidant defense system [19]. The antioxidant defense system
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 the following: 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 (especially 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 meta-analysis 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 antioxi-
dants), 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
conditionally essential in this setting. Mobilization of glutamine
provides substrate for gut, immune cells, and kidneys. Beneficial
effects of glutamine include the following: 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 meta-analysis 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 supple-
mental glutamine reduced complications and mortality rates.
The greatest effects were observed with high-dose (>0.20 g/kg/
d) 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].
Arginine
Arginine is also conditionally essential during certain types of
critical illness (e.g., trauma, postoperative). Beneficial effects of
arginine supplementation include the following: 1) secretegogue
 B. A. Mizock / Nutrition 26 (2010) 701–707 703

for release of anabolic hormones (e.g., growth hormone, insulin-

like growth factor); 2) supporting immune (especially T-cell)
function; 3) detoxification of ammonia; 4) improving wound
healing via metabolism to polyamines and proline [8]. An argi-
nine 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 argi-
nine 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 Fig. 1. Odds ratio (with 95% confidence interval) of the treatment effect (for two or
arginine [25]. Plasma levels of arginine during sepsis are variable more studies) of the immunonmodulating diets on mortality. Arg, arginine; A-FO,
depending on the stage at which they are measured. Arginine arginine þ fish oil, FO, fish oil; AFG, arginine þ fish oil þ glutamine; Gl, glutamine.
Used with permission [9].
deficiency is most likely to be present in the earlier stages of
sepsis, although not as severe as seen following major trauma
[26]. In contrast, plasma arginine levels increase progressively as
during severe sepsis and multiple organ dysfunction syndrome
the severity of sepsis worsens, particularly in the setting of
(Fig. 2).
multiple organ dysfunction [26,27]. Thus, the benefit of arginine
during sepsis may depend on the stage at which supplementa-
tion is administered; patients with more severe metabolic Fish oil and gamma-linoleic acid
decompensation would be less likely to benefit and could
potentially be harmed (see below). This hypothesis could Cold-water fish (e.g. sardines, mackerel, tuna) are rich in
account for the findings of a study that observed greater bene- eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA), the
ficial effects of an arginine-supplemented immune formula in active metabolites of alpha-linolenic acid (ALA). The high EPA/
septic ICU patients with less severe disease (Apache II <15) [28]. DHA content of fish results from dietary intake of a food chain
In 2001, Heyland and Novak published a meta-analysis of argi- that includes phytoplankton. Although marine plankton can
nine-supplemented immune-enhancing diets in critically ill efficiently metabolize ALA to EPA and DHA via desaturase
patients, in which they noted evidence for adverse effects on enzymes, humans possess a limited capacity to synthesize EPA
outcome [29]. These ‘‘danger signals’’ were seen mainly in non- and DHA during basal conditions (only 8% of dietary ALA is
trauma patients who were infected at the baseline. Although this converted) [36]. During acute, severe illness, these desaturases
analysis was not designed to uncover a precise mechanism for are markedly downregulated so that EPA and DHA synthesis
these harmful effects, the authors felt that supplementation of from ALA is negligible. Therefore, supplementation of omega-3
arginine in the setting of sepsis could be responsible. This fatty acids in critically ill patients requires administration of fish-
hypothesis was based in large part on data from three studies oil-based lipids. Mechanisms for the anti-inflammatory action of
that showed worsened outcome in septic patients who were EPA and DHA include the following: 1) displacing arachidonic
administered an arginine-supplemented immunonutrient solu- acid (AA) from the phospholipid core of the inflammatory cell
tion (compared to those receiving a standard formula) [30–32]. A (e.g., macrophage, neutrophil) membrane, thereby reducing
subsequent similar meta-analysis concluded that although synthesis of pro-inflammatory eicosanoids; 2) reduction in
beneficial effects of arginine supplementation in surgical synthesis of pro-inflammatory eicosanoids by competing with
patients were consistently seen (e.g., reduction in infectious risk, AA for metabolism by the enzymes cyclooxygenase and lip-
decreased ventilator and ICU days, decreased hospital stay), oxygenase; 3) reducing leukocyte and platelet adhesive
critically ill patients did not benefit and may even have been
harmed [33]. A 2008 meta-analysis of immunonutrition in crit-
ically ill patients 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] (Fig. 1). The mechanism
for potential adverse effects of arginine in severe sepsis is
unknown but could involve a cytokine-mediated induction of
the type 2 isoform of nitric oxide synthase. Once this enzyme is
induced, nitric oxide production is dependent largely on avail-
ability of arginine. Therefore, provision of supplemental arginine
in severe sepsis could promote the generation of large quantities
of nitric oxide that are subsequently metabolized to peroxyni-
trite [34]. This molecule is a potent oxidant and nitrating agent
that damages mitochondria, increases gut barrier permeability,
and promotes organ dysfunction [34–36].
In summary, postoperative and trauma are typically arginine- Fig. 2. Benefit versus harm of arginine-supplemented immune-enhancing diets
deficient states, and these patients consistently benefit from (IED). Patients undergoing elective surgery benefit from the use of IED, exhibiting
a significant decrease in infection rates. Trauma patients may benefit, but only if
arginine supplementation. However, critically ill medical they receive adequate amounts of an IED early after their injury. Medical patients
patients exhibit little if any benefit, and a strong possibility of appear to exhibit little if any benefit. Medical patients with severe sepsis exhibit
increased mortality exists when arginine is supplemented little benefit; potential for increased mortality. Used with permission [16].
704 B. A. Mizock / Nutrition 26 (2010) 701–707

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 [37–39].
Gamma linolenic 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 [37,40]. In
addition, GLA is ultimately metabolized to one-series prosta-
glandins (e.g., PGE1) that promote pulmonary vasodilation; this
in turn helps to counteract the excessive pulmonary vasocon-
striction that occurs in patients with acute lung injury (ALI) and
ARDS [41].
Positive effects of an immunonutrient formula containing fish
oil, borage oil, and antioxidants on mechanically ventilated
patients with ALI or ARDS were documented in three major
randomized clinical trials [42–44]. 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-d mortality in the treatment group [43,44]. A
meta-analysis combined the results of the three 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 [45].
Two additional trials investigating nutritional supplementa-
tion 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 g/d divided every 6 h) 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 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. The relevance of
this data to clinical practice is unclear since the immune
response to modular administration of pharmaconutrients may
be dissimilar to that of the immunonutrient formula containing
fish oil, GLA, and antioxidants.
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) [46–48]. These guidelines are organized based on indica-
tions for micro- and macronutrient supplementation in various
populations of critically ill patients (e.g., sepsis, burn, trauma,
postoperative). The CCPG recommendations are categorized as
follows: recommended, should be considered, should not be
used, and 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 [48].
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 summa-
rized 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

Table 1
Immune nutrients for specific patient populations: summary of clinical practice recommendations

Nutrients Elective surgery General Septic Trauma Burns ALI/ARDS

Arginine*
CCPG No rec No benefit Harm No benefit No benefit No benefit
ESPEN Benefit (B) No rec Benefit (mild) (B) Benefit (B) No rec No rec
Harm (severe) (B)
SCCM/ASPEN Benefit (A) Poss benefit (A) Poss benefit (mild/mod) (B) Benefit (A) Benefit (A) No rec
Poss harm (severe) (B)
y
Glutamine
CCPG No rec No rec No rec Poss benefit Poss benefit No rec
ESPEN No rec No rec No rec Benefit (A) Benefit (A) No rec
SCCM/ASPEN No rec Poss benefit (B) No rec Poss benefit (B) Poss benefit (B) No rec
U-3 fatty acidsz
CCPG No rec No rec No rec No rec No rec Benefit
ESPEN No rec No rec No rec No rec No rec Benefit (B)
SCCM/ASPEN No rec No rec No rec No rec No rec Benefit (A)
Antioxidantsx
CCPG No rec Poss benefit No rec No rec No rec No rec
ESPEN No rec No rec No rec No rec Benefit (A) No rec
SCCM/ASPEN No rec Benefit (B) Benefit (B) Benefit (B) Benefit (B) Benefit (B)

* Arginine administered in context of immune-enhancing diet that also contains fish oil, antioxidants,  nucleotides.
y
Enteral glutamine added to enteral nutrition regimen.
z
Fish-oil-derived U-3 fatty acids (EPA and DHA) administered in context of immune-enhancing diet that also contains borage oil and antioxidants.
x
Antioxidant vitamins (including selenium) and trace elements.
 B. A. Mizock / Nutrition 26 (2010) 701–707 705

Table 2
Enteral products containing immunonutrients

Crucial Peptamen AF Impact Optimental Oxepa Peritive Pivot 1.5

Manuf Nestle Nestle Nestle Abbott Abbott Abbott Abbott
Fat MCT MCT MCT Struct lipid MCT MCT Struct lipid
Fish Fish Fish (Fish, MCT) Canola Canola (Fish, MCT)
Soy Soy Sunf Canola Soy Fish Borage Corn Canola Soy
Pro (g/L) 94 peptide 75.6 peptide 56 51.3 peptide 62.5 66.7 peptide 94 peptide
CHO (g/L) 94 107 130 138.5 105.5 180.3 172
Fat (g/L) 68 54.8 28 28.4 93.7 37.3 50.8
Cat/mL 1.5 1.2 1.0 1.0 1.5 1.3 1.5
Arg (g/L) 15 IPS 12.5 3.6 IPS 8.0 13
(% cal) 4% 5% 1.4% 2.5% 3.5%
EPA/DHA (g/L) 2.8 2.4 1.7 3.3 6.6 0 3.9
U-6 FA (g/L) 7.7 16.7 2.5 6.4 18.8 6.0 5.8
U-6/U-3 2:1 1.8:1 1.4:1 0.9:1 1.75:1 4.8:1 1.5:1
Osm (mOsm/kg) 490 390 375 586 493 304 595
Vit A (IU/L) 15,000 8000 6700 8223 11910 8675 10,000
Vit C (mg/L) 1000 384 80 210 850 260 300
Vit E (IU/L) 100 120 60 210 120 39 250
Selenium (mcg/L) 100 160 100 50 76 63 70
Note High ARG Cal dense prebiotic High ARG ARG Cal dense High ARG High ARG
Cal dense Nucleotides Prebiotic GLA Cal dense Cal dense
prebiotic

No rec, no recommendation; IPS, inherent in protein source; ARG, arginine; GLA, gamma-linolenic acid; MCT, medium-chain triglycerides

be arginine-deficient (e.g., elective surgery, trauma). Bistrian
and McCowen recommend that immune-enhancing formulas
should ideally contain greater than 12 g arginine/L (>4% of
resting energy expenditure) [36]. The optimal duration of
administration is at least 3 d, preferably 5–10 d [36]. 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 (especially
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 [44]. A Brazilian trial
is 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. The optimal dose of EPA/DHA in patients with ALI
and ARDS has not been determined. A reasonable goal would
be to provide the mean daily dose administered in the clinical
trials mentioned above (e.g., 7–10 g EPA/DHA/d).
Enteral immune products contain varying amounts of anti-
oxidant vitamins and trace elements. Supplementation with
additional pharmaconutrients (e.g., selenium) may be desirable
in certain patients. Positive effects of high-dose parenteral sele-
nium supplementation were recently documented in patients
with SIRS, sepsis, and septic shock [49]. In contrast, another trial
of selenium supplementation in septic shock failed to demon-
strate beneficial effects [50]. It was suggested that lack of efficacy
in this study may have been due to an excessive dose of selenium
[51]. Concerns regarding the safety of high doses of antioxidants
(e.g., potential pro-oxidant effects) were addressed in a dose-
optimizing study [52]. This trial found that supplementation
with 800 mg 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 and 800–1000 mg/d for 1–3 weeks
have been suggested [19,51]. Somewhat lower doses (e.g., 300–
500 mg/d) were recommended for major trauma and burns [53].
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.
The importance of early initiation of enteral feeding (e.g.,
within the first 24–48 h 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
[46–48]. 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 h before significant
effects of EPA and GLA on the polyunsaturated fatty acid profile
of inflammatory cell membranes becomes apparent (e.g.,
reducing AA content) [54]. In elective surgery patients, the
beneficial effects of immunonutrition are most apparent when
the formula is given in the preoperative period [6,48]. 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
[48]. Dysfunction of the gastrointestinal tract is common in
acutely ill patients and can limit the amount of immunonu-
trition delivered enterally [55]. ESPEN guidelines maintain that
critically ill ICU patients who do not tolerate more than 700 mL
of enteral nutrition/d should not receive immune-enhancing
diets [47].
In mechanically ventilated patients receiving continuous
infusion of propofol for sedation (especially at higher doses), the
associated caloric load can be substantial (each milliliter
provides 1.1 kcal) [56]. For example, an 80 kg patient infused at
a rate of 60 mg/kg/min receives approximately 760 kcal per day.
This in turn could be counterproductive by promoting over-
feeding, as well as by limiting the amount of fish-oil-based lipids
that can be administered. Other associated risks of high-dose
propofol infusion include the following: increased potential
for developing hyperlipidemia, adverse effects of parenteral
soy-based lipids in ICU patients, and the propofol-infusion
syndrome [46,48,57].
706 B. A. Mizock / Nutrition 26 (2010) 701–707
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.
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