Inmunonutrition in High-Risk Surgery PDF

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Journal of Parenteral and Enteral Nutrition
DOI: 10.1177/0148607110362692
2010; 34; 378 JPEN J Parenter Enteral Nutr
Paul E. Marik and Gary P. Zaloga
Immunonutrition in High-Risk Surgical Patients: A Systematic Review and Analysis of the Literature
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378
Journal of Parenteral and
Enteral Nutrition
Volume 34 Number 4
July 2010 378-386
2010 American Society for
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M
alnutrition is an important risk factor for the
occurrence of postoperative complications,
most notably infections and poor wound heal-
ing.
1-3
Malnutrition decreases both cell-mediated and
humoral immune responses, which are restored with
refeeding. The early initiation of enteral nutrition has
been demonstrated to decrease infectious complications
and hospital length of stay (LOS) in patients undergoing
abdominal surgery.
4
Consequently, enteral nutrition is con-
sidered an essential part of the perioperative management of
malnourished and high-risk surgical patients. An increased
understanding of the effects of different nutrients on disease
processes has led to the development of specialized enteral
From the
1
Division of Pulmonary and Critical Care Medicine,
Thomas Jefferson University, Philadelphia, Pennsylvania;
2
Baxter Healthcare, Deerfield, Illinois.
Received for publication March 24, 2009; accepted for publica-
tion July 28, 2009.
Address correspondence to: Paul Marik, MD, Eastern Virginia
Medical School, EVMS Internal Medicine, Suite 410, 825
Fairfax Ave, Norfolk, VA 23507; e-mail: marikpe@evms.edu.
nutrition formulas. Immunomodulating diets (IMDs) are
characterized by increased quantities of nutrients that
improve immune cell function and modulate inflamma-
tion.
5-7
Immune-modulating nutrients that have been added
to IMDs include arginine, -3 polyunsaturated long-chain
fatty acids (PUFAs), RNA, and antioxidants (such as ascor-
bic acid and selenium).
Although the biological properties of immunonutri-
ents have been well studied in experimental models, the
role of IMDs during routine clinical care is controver-
sial.
8-10
The Canadian Clinical Practice Guidelines for
Nutrition Support in Critically Ill Patients recommend
that diets supplemented with arginine and other select
nutrients not be used for critically ill patients.
11
In con-
trast, the European Society for Parenteral and Enteral
Nutrition guidelines for intensive care state, Immune
modulating formulae (formulae enriched with arginine,
nucleotides, and omega-3 fatty acids) are superior to
standard enteral formula.
12
Although IMDs represent a class of specialized nutri-
tional formulas, the formulas differ substantially from each
other in both composition and physiologic actions. In addi-
tion, it is likely that the clinical response varies according
to the patients disease state. Arginine has been shown to
Background: Immunomodulating diets (IMDs) have been demon-
strated to improve immune function and modulate inflammation.
However, the clinical benefit of these diets in patients undergoing
elective surgery is controversial. The goal of this meta-analysis
was to determine the impact of IMDs on the clinical outcomes of
high-risk patients undergoing elective surgery. Methods: The
review included prospective, controlled, clinical trials that com-
pared the clinical outcome of elective surgical patients who were
randomized to receive an IMD or a control enteral diet. Studies
were stratified according to the type of IMD and the timing of the
initiation of the IMD. Data were abstracted on study design,
study size, patient population, and IMD used. The outcomes of
interest were the acquisition of new infections, wound complica-
tions, length of hospital stay (LOS), and mortality. Meta-analytic
techniques were used to analyze the data. Results: Twenty-one
relevant studies were identified, which included a total of 1918
patients. Immunonutrition significantly reduced the risk of
acquired infections, wound complications, and LOS. The mortal-
ity rate was 1% in both groups. The treatment effect was similar
regardless of the timing of the commencement of the IMD. The
benefits of immunonutrition required both arginine and fish oil.
Conclusions: An immunomodulating enteral diet containing
increased amounts of both arginine and fish oil should be consid-
ered in all high-risk patients undergoing major surgery. Although
the optimal timing cannot be determined from this study, it is
suggested that immunonutrition be initiated preoperatively when
feasible. (JPEN J Parenter Enteral Nutr. 2010;34:378-386)
Keywords: immunonutrition; surgery; arginine; omega 3 fatty
acids; enteral nutrition; wound complications; infections
Immunonutrition in High-Risk
Surgical Patients: A Systematic Review
and Analysis of the Literature
Paul E. Marik, MD, FCCM
1
; and Gary P. Zaloga, MD, FCCM, FACN
2
Financial disclosure: Dr Zaloga declares that he is a paid employee of Baxter Healthcare, Inc. Baxter Healthcare does not
manufacture any of the enteral immune-modulating diets that are mentioned in the article.
Original Communication
Immunonutrition in High-Risk Surgical Patients / Marik and Zaloga 379
improve wound healing and enhance immune responses in
experimental models. Some investigators have suggested
that arginine-supplemented enteral formulations may
increase the inflammatory response and mortality in
patients with sepsis and/or the systemic inflammatory
response syndrome (SIRS),
9,13
whereas others disagree
with this conclusion.
14
We have previously reported that
fish oil (FO) supplementation decreases mortality, acquisi-
tion of infections, and LOS in intensive care unit (ICU)
patients with nonsurgical causes of sepsis and acute respi-
ratory distress syndrome (ARDS) and that this benefit was
abrogated with the addition of arginine.
15
Patients with
sepsis and surgical trauma regulate arginine metabolism
differently. Arginine levels are lower and arginase activity is
higher in patients following surgical trauma compared with
sepsis.
16-18
Nitric oxide, a major metabolite of arginine, is
elevated in sepsis and decreased following surgical
trauma.
16-18
Because metabolism of arginine differs in sur-
gical vs nonsurgical patients, the effects of arginine sup-
plementation in these patients is also likely to differ. Thus,
both arginine and FO may have important immunomodu-
lating properties that affect clinical outcomes in nonin-
fected patients undergoing elective surgery. To test this
hypothesis, we performed a systematic review and meta-
analysis of studies that investigated the benefit of an IMD
supplemented with arginine and FO either alone or in
combination in patients undergoing major surgery. A priori
we stratified patients according to the type of IMD and the
timing of the initiation of the IMD.
Methods
Identification of Trials
Our aim was to identify all relevant randomized con-
trolled clinical trials that investigated the clinical out-
comes of IMDs containing arginine and FO either alone
or in combination in patients undergoing major elective
surgery. We included only studies that randomized
patients to an IMD or a control enteral formula that was
similar in composition to the IMD except for the specific
immunonutrients that were being tested. There was no
restriction as to the type of patient or the clinical setting
where the study was performed. We used a multimethod
approach to identify relevant studies for this review. Both
authors independently searched the National Library of
Medicines MEDLINE database for relevant studies in
any language published from 1966 to December 2008
using the following Medical Subject Headings (MeSH)
and keywords: immunonutrition, arginine, -3 fatty acid,
and fish oil. The search was limited by the following
terms: randomized clinical trial or controlled clinical trial
and surgery or perioperative complications/care. In addi-
tion we searched Embase and the Cochrane Database of
Systematic Reviews. Bibliographies of all selected articles
and review articles that included information on IMDs
were reviewed, and experts in the field were contacted to
identify additional relevant studies. This search strategy
was done iteratively, until no new potential citations were
found. We performed this meta-analysis according to the
guidelines proposed by the QUOROM group.
19
Study Selection and Data Extraction
In keeping with previous meta-analyses on immunonutri-
tion, we included studies that reported 1 or more of the
following clinical outcomes: (1) number of patients with
new infections, (2) wound complications (fistula, anasto-
mosis, or incision dehiscence), (3) hospital LOS, and (4)
mortality.
20-22
Outcomes were recorded according to
intention-to-treat analysis. Both authors independently
abstracted data from all eligible studies using a standard-
ized form. Data were abstracted on study design, study
size, study setting, patient population, timing of initiation
of immunonutrition, and enteral formulation used. We
recorded the method of randomization, blinding, and
concealment. A priori the studies were grouped according
to the timing of initiation of the IMD as follows: (a) pre-
operatively only, (b) postoperatively only, and (c) periop-
eratively. Studies were also grouped according to the type
of IMD as follows: (a) arginine supplementation alone,
(b) FO supplementation alone, or (c) both.
We used the fixed effects models using Comprehensive
Meta-analysis 2.0 (Biostat, Englewood, NJ) and Review
Manager 5.016 (Cochrane Collaboration, Oxford, UK) for
all analyses and considered P .05 (2 sided) as significant.
We report binary outcomes as odds ratios (ORs) and con-
tinuous outcomes as weighted mean differences (measure of
absolute change). Summary effects estimates are presented
with 95% confidence intervals (CIs). We assessed heteroge-
neity between studies for each outcome using the Cochran
Q statistic,
23
with P .10 indicating significant heterogene-
ity,
24
and I
2
with suggested thresholds for low (25%49%)
moderate (50%74%), and high (>75%) values.
25,26
Results
Trail Flow
The initial search strategy generated 42 citations; of these
22 studies were excluded because the intervention/control
group received parenteral nutrition, the study did not
include a group that received a control diet,
27-30
the study
did not report a prespecified clinical outcome,
31
or the
study was not relevant to our review. A review of the bib-
liographies of the selected articles, meta-analyses, and
review articles failed to identify additional studies. An
additional study was identified by an expert reviewer.
32
380 Journal of Parenteral and Enteral Nutrition / Vol. 34, No. 4, July 2010
Study Characteristics and Outcomes
Twenty-one studies met the inclusion criteria and were
included in the meta-analysis.
32-52
In all, 1918 patients
were randomized to an immunomodulating or standard
diet and their clinical outcomes were reported. These
studies are summarized in Table 1. Of the 21 studies, 18
used an IMD with added arginine and FO, 2 studies used
added arginine alone, and 1 study used FO alone. Impact
(Novartis Nutrition, Bern Switzerland), which contains
added arginine, FO, RNA, and selenium, was used in 16
studies, whereas Stresson (Nutricia, The Netherlands),
which contains added arginine, FO, and selenium, was
used in 2 studies. In 15 studies, the IMD was given
postoperatively, whereas 5 studies used the IMD during
the perioperative (both preoperative and postoperative)
period, and 1 study used preoperative immunonutrition
alone. Fifteen studies enrolled patients undergoing
abdominal surgery for a gastrointestinal (GI) malignancy,
2 studies evaluated patients undergoing general abdominal
surgery, 3 studies evaluated head/neck surgery patients
undergoing resection for malignancy, and 1 study enrolled
high-risk cardiac surgery patients.
Infectious complications were reported in all studies,
LOS in 17 studies, and wound complications in 11 stud-
ies. Immunonutrition significantly reduced the risk of
acquired infections (OR 0.49; 95% CI, 0.390.62, P <
.0001). This benefit was noted in the postoperative and
perioperative subgroups that received an IMD with both
arginine and FO (Figure 1). Similarly, the risk of infection
was lower in those studies that enrolled patients with GI
malignancy (OR 0.44; 95% CI 0.340.59) as well as those
without GI malignancy (OR 0.50; 95% CI 0.320.77).
There was a trend toward a lower infection rate in the
arginine-only group (n = 2) as well as the preoperative
group that received arginine and FO (n = 1); however,
given the small number of patients (and studies), this did
not reach statistical significance. In terms of infectious
complications, the data suggest that the benefit of immu-
nonutrition required both arginine and FO. Furthermore,
Table 1. Summary of Studies Included in Meta-Analysis
Author Year Setting Type Blind
No. of
Patients
Preoperative immunonutrition (n = 1)
Xu
33
2006 GI malignancy Impact
a
N 60
Postoperative immunonutrition (n = 15)
Daly
34
1992 GI malignancy Impact N 85
Daly
35
1995 GI malignancy Impact Y 60
Kenler
36
1996 GI malignancy Fish oil Y 35
Braga
37
Schilling
38
Gianotti
39
Senkal
40
Braga
41
Snyderman
42
1999 H&N malignancy Impact Y 129
Di Carlo
43
De Luis
44
2002 H&N malignancy Arginine Y 47
Jiang
45
2004 GI surgery Stresson
b
Y 120
Farreras
46
Lobo
32
2006 GI malignancy Stresson Y 108
Casas-Rodera
47
2008 H&N malignancy Arginine Y 30
Perioperative immunonutrition (n = 5)
Braga
48c
Senkal
49
Tepaske
50d
2001 Cardiac surgery Impact Y 50
Braga
51
Helminen
52
2007 GI surgery Impact Y 100
GI, gastrointestinal; H&N, head and neck.
a
Novartis Nutrition, Bern Switzerland.
b
Stresson, Nutricia, The Netherlands.
c
Control group received a standard formula postoperatively, whereas the treatment group received Impact both preoperatively and
postoperatively.
d
Postoperative patients who required mechanical ventilation and tube feedings received the same preoperative formula.
Figure 1. Effect of immunomodulating diets (IMDs) on acquisition of new infections, stratified by both the type of IMD and the
time of initiation of the experimental diet. Weight is the relative contribution of each study to the overall treatment effect (odds ratio
and 95% confidnce interval [CI]) on a log scale assuming a fixed effects model. FO, fish oil; A-F, arginine and fish oil; M-H, Mueller-
Hinton.
the treatment effect did not appear to depend on the tim-
ing of the initiation of the IMD. In most studies, wound
infections, pneumonia, and other postoperative infections
were grouped together as infectious complications, and
we were unable to break down the infections complica-
tions by site. Wound complications (OR 0.60; 95% CI
0.400.91, P = .02) and LOS (3.03 days; 95% CI 3.43
to 2.64 days, P < .0001) were significantly reduced in
the patients who received an IMD (Figures 2 and 3). The
mortality rate was 1% in both groups. There was signifi-
cant heterogeneity between studies for the LOS analysis;
however, the Q statistic was insignificant for the analysis
of infectious and wound complications.
Discussion
This meta-analysis demonstrates that immunonutrition
formulas with added arginine and FO reduce the risk of
acquired infections, reduce wound complications, and
shorten hospital LOS in high-risk patients undergoing
elective surgery. Although the majority of studies included in
this review enrolled patients with GI malignancies, 2 studies
enrolled patients undergoing general abdominal surgery, 3
studies enrolled patients with head/neck malignancy, and
1 study enrolled high-risk patients undergoing cardiac
surgery (age >70 years, ejection fraction <40% or mitral
valve replacement). The treatment benefit was noted
among all patient groups. The data suggest that patients
at high risk of postoperative complications (malnourished
and high-risk patients) may benefit from an immunonu-
trition enteral diet.
Although an IMD with added arginine failed to
improve outcomes in trauma patients and patients with
sepsis,
15
this analysis reports that these IMDs are benefi-
cial in high-risk elective surgery patients. The biological
explanation for these differences in clinical outcomes is
unclear. It is likely that in patients with trauma and sep-
sis, arginine supply and metabolism are adequate for
arginine action and that additional arginine has no effect.
It has also been postulated that arginine may augment
inflammatory responses in these patients. For example,
conversion of arginine to nitric oxide is increased in
patients with sepsis. In contrast, arginine levels are
decreased and arginine degradation (via arginase) is
increased in patients with surgical trauma. In high-risk
surgical patients, arginine may restore depressed humoral
and cell-mediated immunity and promote wound healing.
In experimental studies, L-arginine improved wound
healing, restored postoperative depressed macrophage
function and lymphocyte responsiveness, and augmented
resistance to infection.
14,16,53
Improved indices of cell-
mediated immunity have been demonstrated in postop-
erative patients who received an arginine-containing
IMD.
31,34,50, 4-56
Tepaske et al
50
demonstrated that patients
treated preoperatively with an arginine-containing IMD
had increased expression of human leukocyte antigen
DR epitopes on monocytes and significantly lower levels
of serum interleukin-6.
50
These patients had an improved
delayed hypersensitivity response to recall antigens, which

Figure 2. Effect of immunomodulating diets (IMDs) on wound complications. Weight is the relative contribution of each study to
the overall treatment effect (odds ratio and 95% confidence interval [CI]) on a log scale assuming a fixed effects model.
Figure 3. Effect of immunomodulating diets (IMDs) on length of hospital stay (LOS). Weight is the relative contribution of each
study to the overall treatment effect (fixed effects model of weighted mean difference with 95% confidence interval [CI]). AF,
arginine + fishoil; IV.
persisted until hospital discharge. Arginine is metabo-
lized by arginase into urea and ornithine.
57
Ornithine is
subsequently converted to proline, the backbone of collagen,
and polyamines, essential regulators of cell proliferation.
Farreras and coauthors
46
randomized patients undergo-
ing abdominal surgery to receive an IMD supplemented
with arginine and -3 PUFA or a control diet.
46
In this
study, patients fed with the arginine/-3supplemented
formula had higher local hydroxyproline levels in their
surgical wounds and developed fewer surgical wound
complications.
Surgery induces a potent local and systemic inflamma-
tory response manifest by changes in plasma concentrations
of various acute-phase proteins and proinflammatory
cytokines.
58,59
Elevation of these substances is associated
with an increased risk of infectious complications and over-
all morbidity.
60
-3 PUFAs found in FO have potent anti-
inflammatory properties.
5,6
These anti-inflammatory effects
are mediated through a variety of mechanisms that include
alterations in membrane structure and function, modulation
of signaling pathways, suppression of proinflammatory tran-
scription factors such as nuclear factor-B, alterations in
gene expression, and modulation of eicosanoid production.
FO has been shown to reduce arachidonic acid and increase
eicosapentaenoic acid (EPA) and docosahexaenoic acid
(DHA) levels in membrane phospholipids.
61
The increased
concentrations of EPA in phospholipids compete with
arachidonic acid for cyclooxygenase and 5-lipoxygenase
binding sites, reduce eicosanoid formation from arachidonic
acid, and thereby reduce tissue inflammation without com-
promising mononuclear cell function.
61-63
These effects may
play important roles in suppressing the generalized inflam-
matory response and subsequent immunosuppression and
capillary leakage after major surgery. In addition, resolvins
and protectins are novel -3 fatty acid products derived from
EPA and DHA following neutrophilendothelial interac-
tions.
64,65
These lipid mediators are reported to play an
important role in the resolution of inflammation and promo-
tion of wound healing.
64,65
In this meta-analysis, we report improved clinical out-
comes (infection rates, wound complications, LOS) in elec-
tive surgery patients receiving an enteral diet supplemented
with arginine and -3 polyunsaturated fatty acids. In con-
trast, in our previous meta-analysis of 8 studies of trauma
patients admitted to the ICU,
15
we reported no improvement
in mortality, infections, or length of hospital stay using simi-
lar formulations. It is unclear why trauma patients do not
respond to these diets in the same manner as elective sur-
gery patients. However, the metabolic response to traumatic
tissue injury may be different than surgical tissue injury. In
addition, the trauma patients had multiple organ injuries
that differ from the isolated tissue effects of elective surgery
(ie, removal of malignant tissue). Further studies are required
to delineate the different metabolic responses of these 2
patient populations.
The results of our meta-analysis suggest that both
perioperative and postoperative immunonutrition reduces
secondary infections, wound complications, and hospital
LOS. The treatment effect did not depend on the timing
of the initiation (ie, preoperatively, postoperatively) of the
enteral formula. However, it is probable that the benefit
of an IMD takes a number of days to manifest. Indeed,
experimental and clinical data suggest that the benefits of
immune-enhancing nutrition may take 37 days to mani-
fest.
34,66-68
In addition, given postoperative nausea and
ileus, the intake of enteral nutrition may be limited in the
first few days after surgery. Thus, it is reasonable to initi-
ate these formulations preoperatively, if feasible. The
postulate of starting IMDs preoperatively is supported by
the study of Braga et al,
51
who demonstrated fewer infec-
tious and noninfectious complications when an IMD was
used perioperatively compared with use during the post-
operative period alone.
51
Giger and colleagues
29
rand-
omized patients undergoing major abdominal surgery to
an IMD started either 5 days (5-day group) or 2 days
(2-day group) before surgery and continued for 7 days
postoperatively.
29
The control group (postoperative
group) received the IMD in the postoperative period
only. In this study, the C-reactive protein and inter-
leukin-6 levels on postoperative day 3 were significantly
lower in the 5-day group compared with the 2-day and
postoperative groups, with significantly fewer infectious
and noninfectious complications in the 5-day group.
These data suggest that an IMD should be started at
least 3 days (but preferably 57 days) prior to surgery and
continued postoperatively.
It is unclear what type of immune formulations should
be used in elective surgery patients who develop systemic
infections. In the studies cited in this meta-analysis, infected
patients remained in their study group for the duration of
the study. In our previous meta-analysis of septic patients,
15

the arginine plus -3 fatty acidsupplemented formulations
failed to demonstrate improved outcomes. However, it is
unclear which formulations are optimal for the surgical
patient with an infection. We postulate that these patients
are similar to elective surgery patients in terms of low
arginine and high arginase activity. However, a randomized
clinical trial will be required to define the optimal nutrition
formulations for such patients.
The majority of studies in this meta-analysis were
performed with the product Impact (Novartis Nutrition,
Bern, Switzerland). This enteral formulation contains
added antioxidants and nucleotides. It is unclear whether
the clinical benefits of the formulation result from 1 or
more of the supplemented nutrients. It is also unclear
whether the effects from this formulation can be extrapo-
lated to other immune formulations that differ in compo-
sition. Further study is required to address these issues.
The strength of our meta-analysis includes the fact
that we used several methods to reduce bias (comprehen-
sive literature search, duplicate data abstraction, pre-
specified criteria for analysis) and analyzed standardized
and clinically important clinical outcomes (by intention-
to-treat analysis). The major limitation of our study was
the small number of studies in certain subgroups accord-
ing to type of IMD used.
We have demonstrated that IMDs have important
beneficial effects on clinical outcomes in both mal-
nourished and nonmalnourished high-risk surgical
patients. Furthermore, our study suggests that arginine
and -3 PUFAs may act synergistically to improve out-
comes in noninfected surgical patients. Although the
optimal time to initiate immunonutrition (ie, preopera-
tively vs postoperatively) could not be determined from
this meta-analysis, both experimental and clinical data
support the concept that immunonutrition may be
more effective when initiated prior to the surgical
insult. We recommend starting at least 5 days prior to
surgery and continuing into the postoperative period,
when such initiation is feasible.
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