Journal of Parenteral and Enteral

Nutrition http://pen.sagepub.com/

Clinical Evidence for Pharmaconutrition in Major Elective Surgery

Marco Braga, Paul E. Wischmeyer, John Drover and Daren K. Heyland
JPEN J Parenter Enteral Nutr 2013 37: 66S
DOI: 10.1177/0148607113494406

The online version of this article can be found at:

http://pen.sagepub.com/content/37/5_suppl/66S

Published by:

http://www.sagepublications.com

On behalf of:

The American Society for Parenteral & Enteral Nutrition

Additional services and information for Journal of Parenteral and Enteral Nutrition can be found at:

Email Alerts: http://pen.sagepub.com/cgi/alerts

Subscriptions: http://pen.sagepub.com/subscriptions

Reprints: http://www.sagepub.com/journalsReprints.nav

Permissions: http://www.sagepub.com/journalsPermissions.nav

>> Version of Record - Sep 5, 2013

What is This?

Downloaded from pen.sagepub.com at Chang Gung University on May 25, 2014

94406
2013
PENXXX10.1177/0148607113494406<italic>Journal of Parenteral and Enteral Nutrition</italic> / Vol. XX, No. X, Month XXXXBraga et al

Surgical Nutrition Summit Report

Journal of Parenteral and Enteral
Nutrition
Clinical Evidence for Pharmaconutrition in Major Elective Volume 37 Supplement 1
September 2013 66S­–72S
Surgery © 2013 American Society
for Parenteral and Enteral Nutrition
DOI: 10.1177/0148607113494406
jpen.sagepub.com
hosted at
online.sagepub.com
Marco Braga, MD1; Paul E. Wischmeyer, MD2; John Drover, MD3;
and Daren K. Heyland, MD, FRCPC3

Abstract
In recent years, standard nutrition preparations have been modified by adding specific nutrients, such as arginine, ω-3 fatty acids,
glutamine, and others, which have been shown to upregulate host immune response, modulate inflammatory response, and improve
protein synthesis after surgery. Most randomized trials and several meta-analyses have shown that perioperative administration of enteral
arginine, ω-3 fatty acids, and nucleotides (immunonutrition) reduced infection rate and length of hospital stay in patients with upper
and lower gastrointestinal (GI) cancer. The most pronounced benefits of immunonutrition were found in subgroups of high-risk and
malnourished patients. Promising but not conclusive results have been found in non-GI surgery, especially in head and neck surgery and
in cardiac surgery, but larger trials are required before recommending immunonutrition as a routine practice. Conflicting results on the
real benefit of parenteral glutamine supplementation in patients undergoing elective major surgery have been published. In conclusion,
enteral diets supplemented with specific nutrients significantly improved short-term outcome in patients with cancer undergoing elective
GI surgery. Future research should investigate a molecular signaling pathway and identify specific mechanisms of action of immune-
enhancing substrates. (JPEN J Parenter Enteral Nutr. 2013;37:66S-72S)

Keywords
immunonutrition; arginine; ω-3 fatty acids; glutamine; postoperative infections; GI surgery

In the past decade, substantial improvements have been made
in elective surgical care, but postoperative infectious compli-
cations remain common, adding to length of hospital stay,
healthcare costs, and potential excess mortality.1 In addition,
surgeons are increasingly under pressure to reduce healthcare
costs. In many countries, healthcare payers and providers
encourage medical and surgical staff to reduce patients’ hospi-
tal stay, particularly for elective surgery. Therefore, it is imper-
ative to reduce the potential for postoperative infectious
complications.
The pathogenesis of postoperative infectious complications
is multifactorial, depending on the extent of primary disease
and type and magnitude of surgery. Nevertheless, there is
growing evidence that surgical insult is associated with
immune dysregulation, oxidative stress, and immune impair-
ment, which may expose patients to subsequent risk of infec-
tion.2 Surgery, like any injury to the body, elicits a series of
reactions, including release of stress hormones and inflamma-
tory mediators, which cause catabolism of glycogen, fat, and
protein with release of glucose, free fatty acids, and amino
acids into the systemic circulation. These substrates are in part
diverted from the purposes they serve in the nonstressed state
(ie, physical activity) to the task of raising an adequate healing
response. For optimal rehabilitation and wound healing, the
body needs to be well nourished to mobilize adequate sub-
strates, largely derived from muscle and adipose tissue, with
nutrition support to allow synthesis of acute-phase proteins,
white cells, fibroblasts, collagen, and other tissue components
of the wounded area.
Among the proposed strategies to reduce postoperative
infections and its related costs, artificial nutrition is recognized
as an important part of the patient care. Energy substrates can
be given by the enteral or parenteral route. Several studies have
suggested a better outcome when at least part of the patient’s
requirement is met by the enteral route. Improvements in
patient outcome have been obtained with early enteral nutrition
(EN) in both malnourished cancer patients undergoing elective
major surgery and intensive care unit patients.3,4
From 1San Raffaele University, Milan, Italy; 2University of Colorado,
Aurora; and 3Queens University, Kingston General Hospital, Kingston,
ON, Canada.
Financial disclosure: The publication of the supplement in which
this article appears is supported by an educational grant from Nestlé
Healthcare Nutrition. Authors received an honorarium from the Nestlé
Nutrition Institute for their participation in the North American Surgical
Nutrition Summit.
Received for publication April 10, 2013; accepted for publication May
28, 2013.
Corresponding Author:
Marco Braga, MD, Department of Surgery, San Raffaele Hospital, Via
Olgettina 60, 0132 Milan, Italy.
Email: braga.marco@hsr.it.

Downloaded from pen.sagepub.com at Chang Gung University on May 25, 2014

Braga et al 67S
Table 1.  Systematic Reviews and Meta-Analyses Examining the Effectiveness of Immunonutrition in Surgery.
Author RCTs Control Group
13
Waitzberg et al, 2006 17 Standard EN/parenteral
Marik and Zaloga, 201015 21 Standard EN
Cerantola et al, 201114 21 Standard EN
Drover et al, 201118 35 Standard EN
Marimuthu et al, 201221 26 Standard EN
EN, enteral nutrition; GI, gastrointestinal; LOS, length of stay; RCT, randomized clinical trial.
a
Nestlé HealthCare Nutrition (Florham Park, NJ).
Pharmaconutrition
Recently, the main focus of clinical nutrition has moved from
simply covering energy and nitrogen requirements (nutrition
support) to the new concept of supplementing selected nutri-
tion substrates, mainly arginine, glutamine, and ω-3 fatty acids,
because of their specific pharmacological effects (nutrition
therapy). The main target of these new diets is not solely to
provide energy and nitrogen but to modulate inflammatory
postinjury response and to counteract postoperative immune
impairment, which may per se increase patient susceptibility to
infectious complications.
In the past years, most randomized clinical trials (RCTs)
have focused on the effect of the combination of arginine, ω-3
fatty acids, and nucleotides, whereas glutamine mainly has
been used alone.
Arginine is involved in multiple metabolic pathways. It is a
precursor of both nitric oxide and hydroxyproline, which has a
key role for connective tissue repair. In addition, arginine is an
essential substrate for immune cells, particularly for lympho-
cyte function.5
Glutamine has a key role to improve immune response,
increase protein synthesis, preserve gut barrier structure and
function, reduce oxidative stress, and enhance glucose metabo-
lism.6,7 In stress conditions, there is a flux of endogenous glu-
tamine from muscles to other tissues/organs with rapid cell
turnover and metabolism, such as gut, bone marrow, brain,
immune cells, and fibroblasts, which use glutamine as their
principal metabolic fuel.
ω-3 Fatty acids have potent anti-inflammatory properties
mediated through incorporation in membrane structure and
function, suppression of proinflammatory transcription factors,
and modulation of eicosanoid production. These effects may
play important roles in suppressing the generalized inflamma-
tory response and subsequent immunosuppression and capillary
leakage after major surgery. Resolvins and protectins are novel
ω-3 fatty acid products derived from eicosapentaenoic acid and
Downloaded from pen.sagepub.com at Chang Gung University on May 25, 2014
Patients Short-Term Outcome Patients Who Benefit
2305 Lower infections GI cancer
Shorter LOS
1908 Lower morbidity Malnourished and well nourished
Shorter LOS
2730 Lower morbidity Upper GI
Shorter LOS Lower GI
3445 Lower morbidity GI and non-GI
Shorter LOS Upper/lower GI
Receiving Impacta
2496 Lower morbidity GI cancer
Shorter LOS
docosahexaenoic acid following neutrophil-endothelial interac-
tions. These lipid mediators play a key role in the resolution of
inflammation and promotion of wound healing.8
Immunonutrition
Most RCTs performed so far in gastrointestinal (GI) cancer
elective surgical patients have tested a combination of argi-
nine, ω-3 fatty acids, and nucleotides (Impact; Nestlé
HealthCare Nutrition, Florham Park, NJ), commonly defined
as immunonutrition.
Prospective, randomized, double-blind clinical trials have
demonstrated that patients fed before and after elective major
GI surgery with immunonutrition had a significant reduction of
both postoperative infections and length of hospital stay when
compared with patients fed a standard enteral formula.9,10
Interestingly, preoperative administration of immunoenhanc-
ing diets has reduced the postoperative infection rate also in a
series of well-nourished patients with GI cancer.11 According
to several studies, European guidelines have reported that peri-
operative immunonutrition is effective regardless of the base-
line nutrition status of the patients.12
Nevertheless, several trials have differed in patient groups,
nutrition formulas, and protocols for immunonutrition admin-
istration, and control groups have received various treatments
such as standard enteral formula, parenteral nutrition (PN), or
no nutrition support. Therefore, systematic reviews and meta-
analyses have been carried out to further clarify the clinical
relevance of perioperative immunonutrition (Table 1).
Waitzberg et al13 found that perioperative immunonutrition
was associated with no change in postoperative mortality, but a
significant decrease in both infection rate and length of hospi-
tal stay has been reported. However, selection of trials included
in the analysis was suboptimal, resulting in data heterogeneity
and nonhomogeneous control groups. In fact, some of the
included studies compared enteral immunonutrition with PN,
which is known to be less effective in elective surgical patients
68S Journal of Parenteral and Enteral Nutrition 37(Suppl 1)
with a working gut. In these cases, the better outcome found in
the immunonutrition group could be explained not only by the
properties of specific substrates given but also by the different
route of nutrient administration.
Cerantola et al14 included 21 RCTs with 2730 patients
(>70% were well nourished), showing that perioperative
immunonutrition significantly reduced overall morbidity rate,
particularly postoperative infectious complications, and length
of stay in both upper and lower GI surgery. In all the included
RCTs, control groups received an isoenergetic, isonitrogenous
standard enteral formula.
Marik and Zaloga15 included 21 RCTs that partially over-
lapped with the meta-analysis by Cerantola et al.14
Immunonutrition improved outcome in both malnourished and
well-nourished patients with GI cancer. Moreover, the best
clinical results were obtained when arginine and ω-3 fatty
acids were given together. It could be speculated that they may
act synergistically to modulate both immune and inflammatory
postoperative response and consequently improve short-term
postoperative outcome. Single ω-3 fatty acid supplementation
did not affect clinical outcome in patients who underwent
esophagogastric cancer surgery.16 Similarly, arginine supple-
mentation alone did not improve outcome in patients with head
and neck cancer.17
Drover et al18 performed the largest systematic review on
the perioperative administration of arginine-supplemented
diets in either GI or non-GI surgery. Four subgroup analyses
showed significant outcome benefits in the following condi-
tions: (1) both GI and non-GI surgery (7 head and neck sur-
gery, 2 cardiac surgery, and 1 gynecology surgery), (2) both
upper GI and lower GI surgery, (3) only when immunonutri-
tion (Impact; Nestlé HealthCare Nutrition) was used (no effect
for diets supplemented with arginine alone), and (4) when
immunonutrition treatment was started before surgery. A pos-
sible explanation for the better effect of immunonutrition vs
other formulas is the higher arginine concentration and the spe-
cific combination of nutrients that can interact to produce a
benefit. An early postoperative increase of myeloid-derived
cells expressing arginase 1, which deplete arginine, has been
reported.19 Arginine supplementation can overcome this defi-
ciency, while ω-3 fatty acid supplementation can blunt upregu-
lation of myeloid-derived cells.20
The last published meta-analysis21 included 26 RCTs with
2496 patients who underwent major open GI surgery. Control
groups received a standard enteral diet with the same dose and
timing as treated groups. Perioperative immunonutrition sig-
nificantly reduced both postoperative complications and length
of hospital stay.
Starting immunonutrition before surgery is a key point for
improving clinical outcome. In fact, when immunonutrition
was started after surgery, improvement in phagocytosis ability,
lymphocyte mitogenesis, and cytokine profiles occurred days
after the operation.22
This supports the hypothesis that the amount of substrates
given in the first days after surgery is not sufficient to reach an
Downloaded from pen.sagepub.com at Chang Gung University on May 25, 2014
adequate tissue and plasma concentration. In fact, it takes some
days for immune-enhancing nutrients to become incorporated
into the host tissues and alter inflammatory mediators and fatty
acid profiles. Since the impairment of the host defense mecha-
nisms occurs immediately after surgery, immunonutrients
should be given prior to surgery to obtain adequate levels at the
time of surgical stress. When immunonutrition was given
orally for 7 days before surgery, better metabolic effects were
obtained in comparison with standard diets. In particular, mod-
ulation of inflammatory response, enhancement of cell-mediated
immune response, and upregulation of gut microperfusion and
oxygenation have been found early after surgery.23,24
The high cost of these new nutrition products could be con-
sidered a major drawback for their routine use, but economic
analyses carried out by blinded economists on data gathered
from RCTs showed that perioperative immunonutrition led to a
substantial saving in healthcare resources consumed.10,25 In
fact, the saving due to significant reduction in postoperative
infectious complications by perioperative immunonutrition
more than offsets the higher cost of the supplemented diet.
Glutamine
There are several reasons to assume a clinical efficacy of glu-
tamine supplementation in surgical patients, mainly its proven
metabolic, immunologic, and pharmacologic effects,6,7 as well
as the increased demand and tissue consumption of glutamine
following surgery.26
Previous meta-analyses suggested a positive effect of intra-
venous (IV) glutamine dipeptide on both postoperative mor-
bidity and length of hospital stay in patients undergoing major
elective operations.27-29 However, trials included in the meta-
analyses had drawbacks: (1) none had a calculated sample size,
and the number of randomized patients per group was low,
with potential statistical underpower; (2) parenteral glutamine
dipeptide was always associated with PN, even if most patients
had normal nutrition status; (3) patients included were often
nonhomogeneous for primary disease (cancer and benign dis-
ease together), types of surgery (vascular, abdominal, urogeni-
tal), and baseline nutrition status; and (4) the dose of glutamine
dipeptide ranged widely. For these reasons, firm conclusions
based on the above meta-analyses are difficult to draw, and the
results should be considered more as hypothesis generating
rather than as strong clinical evidence.
Conflicting results on the real benefit of glutamine supple-
mentation in cancer surgical patients came from 2 trials not
included in the above-mentioned meta-analyses.30,31
Postoperative glutamine supplementation did not affect mor-
bidity following pancreatoduodenectomy,30 whereas high
doses of perioperative glutamine dipeptide reduced surgical
site infections in well-nourished patients who underwent
colorectal surgery.31
A recent multicenter RCT carried out in 428 well-nourished
patients with GI cancer showed that parenteral glutamine sup-
plementation did not significantly affect relevant outcome
Braga et al 69S
measures.32 Glutamine supplementation significantly increased
the plasma pool, suggesting that postoperative use and con-
sumption of glutamine did not increase differently from critical
conditions.33 Interestingly, plasma glutamine remained stable
after surgery in control patients not receiving glutamine sup-
plementation. This could be due to the constant flux of gluta-
mine from muscle or reflect that glutamine consumption did
not increase in other tissues.
Candidates for Pharmaconutrition
Perioperative immunonutrition significantly reduced both the
postoperative infection rate and the length of hospital stay in
patients undergoing elective major GI surgery. Promising
results have been obtained also in non-GI surgery, especially in
head and neck surgery and in cardiac surgery,18 but larger trials
are required before recommending immunonutrition as a rou-
tine practice.
According to literature data, the appropriate candidates for
immunonutrition are all patients undergoing elective major
surgery with a high risk of postoperative infectious complica-
tions, regardless of their baseline nutrition status.12,15 The most
pronounced benefits of immunonutrition were found in sub-
groups of high-risk and malnourished patients.34,35 Malnutrition
and its metabolic consequences are recognized as important
risk factors for the development of postoperative infections.
Yet, well-nourished patients may also experience severe post-
operative infections,34 possibly because their pathophysiology
is multifactorial.
Postoperative infection risk is continuously changing
according to new advances in perioperative care and surgery
techniques. In the past years, mini-invasive surgery and
enhanced recovery after surgery (ERAS) multimodal protocols
(no postoperative fasting, early mobilization after surgery, and
restrictive IV infusion policy) are gaining popularity among
surgeons, and both have been associated with a lower postop-
erative infection rate and shorter hospital stay after colorectal
surgery.36,37 Since the vast majority of trials showing the effec-
tiveness of immunonutrition have been carried out in patients
who underwent open surgery with traditional perioperative
care, it could be interesting to investigate if mini-invasive sur-
gery and the ERAS pathway could change nutrition and phar-
maconutrition policies.
Future Trends
Future research should investigate the molecular signaling
pathway and identify specific mechanisms of action of
immune-enhancing substrates. Moreover, dose-response stud-
ies should better clarify which is the optimal dose of substrates
to maximize benefits in surgical patients.
New trials should be performed to confirm the effectiveness
of immunonutrition in patients undergoing major mini-
invasive surgery with the application of ERAS protocols.
Downloaded from pen.sagepub.com at Chang Gung University on May 25, 2014
Another interesting field of research could be testing the effi-
cacy of immune-enhancing diets in cancer patients receiving
neoadjuvant therapy.
Glutamine supplementation should be tested in malnour-
ished patients who represent cohorts with high glutamine
demand and/or potential baseline deficits. Moreover, both the
length of preoperative treatment and the amount of glutamine
should be increased to obtain adequate tissue and plasma levels
at the time of surgery.
Discussion
John Drover: Thanks, Marco. That was great. Just one cau-
tionary note about the subgroup analysis; it is a hypothesis-
generating exercise. The overall meta-analysis is meant to
be a hypothesis-confirming exercise, but once we do the
subgroup analysis, we are then starting to tease the data
apart and ask questions. It doesn’t necessarily give us firm
answers but firm questions. You raise some good questions
about whether we have enough information to say that the
non-gastrointestinal (GI) cancer patients benefit or benefit
as much. The other aspect of the issue is mechanisms. Juan
talks much more eloquently than I about how the effect of
surgical stress impacts the patient, particularly as it relates
to arginase activity. One mechanism that may translate over
into the head and neck cancer patients is that additional
arginine in the context of increased arginase activity gives
you the ability to increase nitrous oxide production. It is one
of those phenomena where the evidence around efficacy
comes forward and then that leads to further investigation
as to why it might be the case. Now we have developed
biologic plausibility, but clinical trials aren’t really designed
to answer those questions but need to be answered in the
lab. The other issue is that of the combined arginine and ω-3
effect. We tried in the meta-analysis to look at other formu-
las to combine the results with Impact. The alternative
products were mostly not commercial products and con-
tained a variety of nutrients such as arginine alone, arginine
with some ω-3 fatty acids, arginine with a bit of glutamine,
and so forth.
Marco Braga: In GI cancer patients receiving perioperative
immunonutrition, we found a significant increase in nitric
oxide production. It is one of the most important determi-
nants of the enhancement of both immune activity and gut
microperfusion. I totally agree that the combination of argi-
nine and ω-3 fatty acids is the key point for explaining the
clinical benefits reported in patients receiving immunonu-
trition. The other main difference from other formulas is the
higher amount of arginine.
John Drover: The other issue raised was, as changes in our
practice are introduced, such as minimally invasive surgery,
ERAS, and other therapy protocols, it changes the baseline.
As Dave pointed out, though, is it changing just the baseline
70S Journal of Parenteral and Enteral Nutrition 37(Suppl 1)
risk or is there something else that is changing as well? Is
the relative risk the same, even though the absolute risk is
changing? Some of that may have to do with the degree of
intervention. Minimally invasive surgery may make a dif-
ference because if the surgical stress is less, then the activa-
tion of arginase activity is less as well. The other aspect
goes back to some of the genomic data that we heard earlier
today. Certain individuals may react to surgical stress with
different amounts arginase. With “personalized medicine,”
your genetic profile can predict your risk.
Marco Braga: ERAS is a multimodal pathway which impacts
on about 20 different items of the perioperative care pro-
cess. We just carried out a meta-analysis of 16 RCTs in
colorectal surgery. The benefit of ERAS was more pro-
nounced in reducing respiratory and cardiovascular postop-
erative complications than surgical site infections.
Considering that perioperative immunonutrition reduced
more infections complications than noninfectious ones,
ERAS pathway and immunonutrition should be associated
to further improve postoperative short-term outcome.
Paul Wischmeyer: Juan has shown in the lab that the more he
manipulates the bowel, the more profound the effect on
immunosuppression. Having a smaller surgery appears to
lead to less arginase induction and so perhaps less of a need
for the interventional formulas. The second thing I would
say is we do have glutamine trials in the postoperative set-
ting where glutamine has been given as a supplement to
parenteral nutrition. That was part of the meta-analysis that
Daren published in 2003. There were 6 trials and they did
show significant improvements in length of stay and infec-
tious risk in those patients receiving glutamine. And like
you said, the only qualm I ever had with your trial was the
dose was small for those patients. The other question I
would have for you is, you are seeing glutamine levels in
your preoperative patients that are far lower than what we
are seeing in the critical care setting? I’m referring to
patients with multiple organ failure and high APACHE
scores. We found that those patients had much higher gluta-
mine levels than your presurgical patients. It might be a
methodologic difference in the way Juan runs his amino
acids versus the way you run them. But your levels of 200–
400 micromoles are barely normal. Those levels aren’t
nearly what we saw in REDOX and what the Scandinavians
saw in their trials. It is very interesting to me as we think
about glutamine in the future that patients may have very
different glutamine levels based on if they have cancer or if
they have critical illness.
Marco Braga: I agree that glutamine dose was quite low;
however, it was enough to significantly increase plasma
levels.
Leah Gramlich: In your meta-analysis, you divided GI versus
non-GI surgical patients. As we think about what our
Downloaded from pen.sagepub.com at Chang Gung University on May 25, 2014
recommendation should look like, how do we think about
other types of surgeries that are less well defined with the
respect to immunonutrition?
Paul Wischmeyer: To take your question further. What about
major thoracic or spine surgeries?
Marco Braga: My personal view is that theoretically we have
a strong rationale to include these types of patients in an
immunonutrition program, as any surgical patient with a
substantial postoperative infection risk. However, there is
no randomized trial dealing with these patients so far, so we
cannot give a strong recommendation to use immunonutri-
tion. Data are very clear in GI cancer patients and also in
head and neck cancer patients the benefits of immunonutri-
tion have been reported.
Juan Ochoa: A very quick comment on arginine deficiency.
The message is very simple. When a stimulus occurs that
preferentially induces an alternative response, an arginine
deficiency state occurs. That stimulus, in the case of physi-
cal injury, is independent of the site. It is highly propor-
tional, and in fact our correlation with lactic acid levels was
0.9 in humans on the first day. It is also highly linear to the
severity of injury. Arginine deficiency states have been
described in a growing number of diseases. The one that is
best characterized is in certain cancers. The tumor manipu-
lates the body’s immune system to create an arginine defi-
ciency state. This allows tumor invasion by downregulating
the lymphocyte response. That seems to happen in pancre-
atic cancer and colon cancer as well as squamous cell carci-
nomas. So there are a number of arginine deficiency states
that we can target.
David Flum: The idea of evaluating a nutritional intervention
across a whole spectrum of operations is appealing for a lot
of reasons. You will know whether there is a unique effect
in a certain surgery. I think it is the same problem that we
might see with laparoscopy and ERAS, which is that the
rates are so low that you are really susceptible to type II
errors. When you have event rates that are 2% and 3% and
you are trying to drop them to 1.5%, you need 1000 people
on each arm, which is not a manageable feat. The question
I have is about safety. Is there any patient population that
you think giving this kind of immunonutrition to is going to
be a problem? Why might that be the case? Why for one
cancer and but not for another?
Juan Ochoa: We have long-term data in head and neck cancer
with a small study done by Paul VanLeland and his group.
There was a very dramatic benefit over 10 years with both
improvement in tumor-free survival and overall survival in
patients receiving perioperative arginine. There is some
concerning biological data in breast cancer, so I would be
very cautious particularly because the morbidity of breast
cancer is so low. In animal models, we have shown that
either arginine alone or arginine plus arginase blockade
Braga et al 71S
drops tumor growth by about 50%. In other models, partic-
ularly in leukemia, where cells are arginine dependent, argi-
nine increased tumor growth. So, we have to be very careful,
particularly in lower morbidity states. The types of cancers
that I would use perioperative immunonutrition is GI can-
cers, head and neck and squamous cell carcinomas, which
also includes lung, renal cell carcinoma, and possibly
prostate.
Robert Martindale: So all of the adenocarcinoma and all of
the squamous cell carcinomas and solid tumor malignancies
are fine? But the bone marrow origin tumors we have to be
very careful?
Juan Ochoa: Agreed.
Daren Heyland: If I understand correctly, we have a type of
surgery that induces the stress and there are mechanisms
that can explain reduced immunity and increased infectious
complications. But we are in a new world here where we
have ERAS and other changes in surgical procedures. We
are reducing the physiological stress and wondering if it
still applies. Why aren’t we looking from the other end and
saying, if there is a risk of infectious complication, regard-
less of the specific type of surgery, why not build a recom-
mendation based on the risk regardless of whether it is an
orthopedic or gynecologic surgery, for example? Stress
leads to impaired immunity, and you know that because you
are monitoring your infectious complication rates. Is there a
problem with that line of thinking?
Marco Braga: In the current practice, patients with expected
high postoperative infection risk should receive periopera-
tive immunonutrition. However, a general recommendation
should be supported by evidences from properly designed
clinical trials.
Paul Wischmeyer: We don’t need large-scale randomized tri-
als for every small subset of patients to be able to apply
certain principles to them. I would flip the argument around
to you, Marco, and say help me understand how a malnour-
ished frail, urgent hip fracture patient that we know from
the last 100 patients that we operated on will have a 25%
infectious complication rate. Why would you exclude that
patient from getting any benefit from immunonutrition
given our understanding of mechanisms of action and com-
plication risk? We do this all of the time, where we have one
study in one population and we apply it broadly.
Marco Braga: I totally agree. There is a strong rationale to
treat with immunonutrition patients with high postoperative
infection risk.
Paul Wischmeyer: I think that Leah brought up a good point.
The patient with a high risk of infection and the surgical or
traumatic stress is the patient we should be recommending
immunonutrition.
Downloaded from pen.sagepub.com at Chang Gung University on May 25, 2014
Robert Martindale: I think we can make a recommendation,
as Marco says, from the data we have. We can say that there
is good evidence in GI cancer and head and neck cancer,
and multiple randomized trials in major hip surgery and
major spine surgery.
Daren Heyland: I think that language is important. High risk
for infection.
John Drover: Is it in those patient groups that have a high risk
of infection with a significant surgical insult that are most
likely to benefit? I don’t think you need to define it as the
abdominal wall reconstruction or the hip fracture patient
but rather in the context of risk of infection. The subsequent
study that needs to be done, then, is in people with a lower
baseline risk to see if they benefit.
David Flum: If the relative risk is the same, then the absolute
risk of infection in the population is maybe a meaningful
discriminator, but this is really a number needed to treat
issue, right? It just may be that you need to treat, for exam-
ple, 10 patients with gastric cancer and you see enough of
an effect and you save money but you may need to treat
175,000 people for a skin biopsy at the other extreme. I
think it only becomes a matter of what is the number needed
to treat and what is too big before it starts not being worth
it. So I think that I disagree that you need to pick people
with an absolute risk of infection before you say that we
should think about this as an indication.
John Drover: But the value of diminishing return eventually
becomes zero. The absolute risk can’t stay the same without
eventually reaching infinity, and so where is the line?
Robert Martindale: Nestlé actually has a calculator that does
this. You plug in the infection risk at your hospital and it
will tell you how many patients or what your percentage
you need to make a difference. The number needed to treat
is the key. If you have to treat 1000 patients to get 1 decrease
in the variant, it is not worth your money. If you have to
only treat 10, you have made a difference.
David Flum: But that is a money aspect and not a patient. If I
was the 1 patient, I would probably take it.
References
1. De Lissovoy G, Fraeman K, Hutchins V, et al. Surgical site infection: inci-
dence and impact on hospital utilization and treatment costs. Am J Infect
Control. 2009;37:387-397.
2. Braga M. Perioperative immunonutrition and gut function. Curr Opin
Nutr Metab Care. 2012;15:485-488.
3. Bozzetti F, Braga M, Gianotti L, et al. Postoperative enteral vs. paren-
teral nutrition in malnourished patients with gastrointestinal cancer: a ran-
domised multicentre trial. Lancet. 2001;358:1487-1492.
4. Kudsk KA, Croce MA, Fabian TC, et al. Enteral versus parenteral feeding:
effect on septic morbidity after blunt and penetrating trauma. Ann Surg.
1992;215:503-513.
5. Morris SM Jr. Recent advances in arginine metabolism. Curr Opin Nutr
Metab Care. 2004;7:45-51.
72S Journal of Parenteral and Enteral Nutrition 37(Suppl 1)
6. Melis GC, ter Wengel N, Boelens PG, et al. Glutamine: recent develop-
ments in research on the clinical significance of glutamine. Curr Opin Clin
Nutr Metab Care. 2004;7:59-70.
7. Labow BI, Souba WW. Glutamine. World J Surg. 2000;24:1503-1513.
8. Yacoob P. Mechanisms underlying the immunomodulatory effects of n-3
PUFA. Proc Nutr Soc. 2010;69:311-315.
9. Braga M, Gianotti L, Radaelli G, et al. Perioperative immunonutrition in
patients undergoing cancer surgery: results of a randomized double-blind
phase 3 trial. Arch Surg. 1999;134:428-433.
10. Senkal M, Zumtobel V, Bauer KH, et al. Outcome and cost effectiveness
of perioperative enteral immunonutrition in patients with elective upper
gastrointestinal surgery: a prospective randomised study. Arch Surg.
1999;134:1309-1316.
11. Gianotti L, Braga M, Nespoli L, et al. A randomized controlled trial
on pre-operative oral supplementation with a specialized diet in
patients with gastrointestinal cancer. Gastroenterology. 2002;122:
1763-1770.
12. Weimann A, Braga M, Harsanyi L, et al. ESPEN guidelines on enteral
nutrition: surgery including organ transplantation. Clin Nutr. 2006;25:
224-244.
13. Waitzberg DL, Saito H, Plank LD, et al. Postsurgical infections are
reduced with specialized nutrition support. World J Surg. 2006;30:
1592-1604.
14. Cerantola Y, Hubner M, Grass F, et al. Immunonutrition in gastrointesti-
nal surgery. Br J Surg. 2011;98:37-48.
15. Marik PE, Zaloga GP. Immunonutrition in high-risk surgical patients: a
systematic review and analysis of the literature. JPEN J Parenter Enteral
Nutr. 2010;34:378-386.
16. Sultan J, Griffin SM, Di Franco F, et al. Randomized clinical trial of
omega-3 fatty acid–supplemented enteral nutrition vs. standard enteral
nutrition in patients undergoing oesophagogastric cancer surgery. Br J
Surg. 2012;99:346-355.
17. Van Bokhorst-de van der Schueren MA, Quak JJ, van Blomberg-Van der
Flier BM, et al. Effect of perioperative nutrition with and without arginine
supplementation, on nutritional status, immune function, postoperative
morbidity, and survival in severely malnourished head and neck cancer
patients. Am J Clin Nutr. 2001;73:323-332.
18. Drover JW, Dhaliwal R, Weitzel L, et al. Perioperative use of arginine-
supplemented diets: a systematic review of the evidence. J Am Coll Surg.
2011;212:385-399.
19. Popovic PJ, Zeh HJ, Ochoa JB. Arginine and immunity. J Nutr.
2007;137(suppl):1681S-1685S.
20. Bansal V, Syres KM, Makarenkova V, et al. Interaction between fatty
acids and arginine metabolism: implications for the design of immune-
enhancing diets. JPEN J Parenter Enteral Nutr. 2005;29(suppl):
S75-S80.
21. Marimuthu K, Varadhan KK, Ljungqvist O, Lobo DN. A meta-analysis
of the effect of combinations of immune modulating nutrients on outcome
in patients undergoing major open gastrointestinal surgery. Ann Surg.
2012;255:1060-1068.
Downloaded from pen.sagepub.com at Chang Gung University on May 25, 2014
22. Senkal M, Kemen M, Homann HH, et al. Modulation of postoperative
immune response by enteral nutrition with a diet enriched with arginine,
RNA, and omega-3 fatty acids in patients with upper gastrointestinal can-
cer. Eur J Surg. 1995;161:115-122.
23. Braga M, Gianotti L, Cestari A, et al. Gut function and immune and
inflammatory responses in patients perioperatively fed with supplemented
enteral formulas. Arch Surg. 1996;131:1257-1265.
24. Gianotti L, Braga M, Fortis C, et al. A prospective randomized clinical
trial on perioperative feeding with arginine, omega 3 fatty acids, and RNA
enriched enteral diets: effect on host response and nutritional status. JPEN
J Parenter Enteral Nutr. 1999;23:314-320.
25. Braga M, Gianotti L, Vignali A, et al. Hospital resources consumed for
surgical morbidity: effects of preoperative arginine and omega-3 fatty acid
supplementation on costs. Nutrition. 2005;21:1078-1086.
26. van Acker BAC, Hulsewè KWE, Wagenmakers AJM, et al. Response of
glutamine metabolism to glutamine-supplemented parenteral nutrition.
Am J Clin Nutr. 2000;72:790-795.
27. Novak F, Heyland DK, Avenell A, et al. Glutamine supplementation
in serious illness: a systematic review of the evidence. Crit Care Med.
2002;30:2022-2029.
28. Zheng YM, Li F, Zhang MM, et al. Glutamine dipeptide for parenteral
nutrition in abdominal surgery: a meta-analysis of randomized controlled
trials. World J Gastroenterol. 2006;12:7537-7341.
29. Jiang Z-M, Jiang H, Furst P. The impact of glutamine dipeptides on out-
come of surgical patients: systematic review of randomized controlled tri-
als for Europe and Asia. Clin Nutr. 2004;1(suppl 1):17-23.
30. Jo S, Choi SH, Heo JS, et al. Missing effect of glutamine supplementation
on the surgical outcome after pancreaticoduodenectomy for periampullary
tumors: a prospective, randomized, double-blind, controlled clinical trial.
World J Surg. 2006;30:1974-1982.
31. Oguz M, Kerem M, Bedirli A, et al. L-alanine–L-glutamine supplementa-
tion improves the outcome after colorectal surgery for cancer. Colorectal
Dis. 2007;9:515-520.
32. Gianotti L, Braga M, Biffi R, et al. Perioperative intravenous glutamine
supplementation in major abdominal surgery for cancer: a randomized
multicentre study. Ann Surg. 2009;250:684-690.
33. Kelly D, Wischmeyer PE. Role of L-glutamine in critical illness: new
insights. Curr Opin Clin Nutr Metab Care. 2003;6:217-222.
34. Bozzetti F, Gianotti L, Braga M, et al. Postoperative complications in gas-
trointestinal cancer patients: the joint role of the nutritional status and the
nutritional support. Clin Nutr. 2007;26:698-709.
35. Fujitani K, Tsujinaka T, Fujita J, et al. Prospective randomized trial on
preoperative enteral immunonutrition followed by elective total gastrec-
tomy for gastric cancer. Br J Surg. 2012;99:621-629.
36. Braga M, Vignali A, Gianotti L, et al. Laparoscopic versus open
colorectal surgery: a randomized trial on short-term outcome. Ann Surg.
2002;236:759-766.
37. Varadhan KK, Neal KR, Dejong CHC, et al. The ERAS pathway for
patients undergoing major elective open colorectal surgery: a meta-analysis
of randomized controlled trials. Clin Nutr. 2010;29:434-440.