Reviewer: Martin Daniel Rosenthal, MD Assistant Professor
of Trauma, Acute Care Surgery, and Critical Care; Chair of UF Nutrition
Committee, University of Florida, Gainesville, FL
References: Martinez et al. Effect of Preoperative
Administration of Oral Arginine and Glutamine in Patients with Enterocutaneous
Fistula Submitted to Definitive Surgery: a Prospective Randomized Trial.
Journal of Gastrointestinal Surgery. 2020 Feb;24(2):426-434.
doi: 10.1007/s11605-018-04099-4. Epub 2019 Feb 1. PMID: 30710211
What is the study question (in PICO format)? In Patients with enterocutaneous fistulas,
does Intervention with
immunonutrition, as Compared to
standard treatment, improve the clinical Outcomes
of fistula closure, inflammatory biomarkers, and reduce infectious
Why is this study important? Treatment
of enterocutaneous fistulas (ECF) and entero-atmospheric fistulas (EAF) remains
complex as often times a ‘one size fits all’ approach does not apply to
management strategies. Outside of the
acute phase of fistula management where most experts agree on the classic
principles of resuscitation, correction of electrolyte imbalances, source
control of sepsis, skin protection, and metabolic support there is a diverse
approach to ongoing treatment algorithms. Imbedded in the foundation of fistula
management is nutritional support, but not all agree upon the how, what, why,
and when of nutritional support. Countless discussion of parenteral nutrition versus enteral nutrition
support have been had, but there is little to no recent randomized control
trials guiding evidentiary based nutritional support. Since the late Stanely Dudrick gifted us
parenteral nutrition (when we first saw a dramatic improvement in mortality)
the literature has remained stagnant aside from large case series, most of them
single center. This article presented here, published in 2020, is noted
for efforts in pushing ECF management forward, as well as, possibly birthing an
ERAS model for those ECFs undergoing surgery.
Summary: From Jan 2011-2013 the authors performed a randomized single
blinded study using a closed envelop randomization scheme to allocate 40
patients with ECF to 2 equal cohorts 1 week before undergoing surgical reversal. The control cohort continued one with current
nutritional support that they were previously on and the experimental arm
received conventional treatment and additional 4.5g arginine coupled with 10g
glutamine orally for seven days prior to surgery. The researchers determined that the patients
needed at least 1 meter of functional small bowel prior to the fistula for
absorption. Type and timing of the
surgery was determined by the attending surgeon. Primary endpoint was ECF
recurrence and secondary endpoints pertained to inflammatory biomarkers (IL-6,
CRP) or infectious complications (pneumonia, UTI, central line infection,
Of the 40
patients entered, 27 were male, median age was 54, 26 came were referred from
outside hospitals, the origin was postoperative complications in all. Interestingly, in this study colostomy
takedown had the highest risk associated with fistula creation. Fistula was located in the jejunum (n=20),
ileum (n=16), and colon (n=4). 30
patients had enteroatmospheric fistulas, which in 22 was a result of open
abdomens from damage control operations.
25 patient were determined to be malnourished, while all patients could
tolerate enteral nutrition to some varying degree as 29 patients still required
some parenteral support for a median time of 139 days. Surgery consisted of fistula resection and
anastomosis (30 hand sewn and 10 stapled). Complete abdominal closure was
feasible in 14 patients. None of the
demographic characteristics of the cohorts were statistically different, but
trends towards significance was seen as the control group had more patients
with ASA >3 and patients with multiple fistulas. ECF recurrence occurred in 2 patients in the
experimental group and nine patients admits the control (p <0.04). Median time to recurrence was 6 days. IL-6 and CRP had statistically significant
lower serum concentration preoperative and post-operative days 1 (for IL-6),
but not days 3 and 7 post-operative. Infectious morbidity was higher in the control group and not coincidentally
all these patients had fistula recurrence.
Commentary: The unfortunate
aspect of fistula management is that there is scant contemporary level one
evidence that drives clinical practice. This
is impart secondary to ECFs relative low prevalence in society, but remains
difficult generate high powered studies quickly. A well-executed prospective randomized
control trial would take years at a single center, but perhaps a multicenter
consortium of protocoloized fistula management could answer best practice
questions for ECF management. Several
significant questions that remain are not based on surgical technique but
rather how to manage these patients in the time period between fistula emersion
and operative reversal. Best practice
for nutritional support remains highly debated even among ECF experts.
manuscript Martinez and colleagues attempt to add amino acids as an oral
supplement to enhance outcomes. Though
not powered for specific clinical outcomes this trial has a flavor of Enhanced
Recovery After Surgery (ERAS). Immunonutrition 1 week prior to surgery coupled with a 50g glucose load
the morning of has been demonstrated to improve infectious and non-infectious
complication, length of stay, insulin resistance, and even anastomotic leak
rate.[1-6] Most immune-nutrient formulas include
arginine and omega 3 fatty acids, while some include leucine, glutamine, and
nucleotides.[7-11] The authors should be commended in their
attempt to drive literature forward in determining best practice for ECF
management, but I do have a few critiques.
- No power analysis: it is essential to
demonstrate a power analysis to strengthen clinical outcomes. Though there are little studies to derive
such a power analysis on there exist well designed trials discussing clinical
outcomes such as anastomotic leak in using immunonutrition preoperatively. Which at the end of the day what is a fistula
reversal if not a GI anastomosis once the fistula is excised.
- Cohort mismatch: though none of the demographics
were statistically different (p <0.05) there was a trend to the control
group having multiple fistulas and were sicker based off ASA classification
>3. The lack of statistical
significance is likely related to low number of patients included in the
trial. Increased number of fistulas in
the control group appears to naturally drive an increased number of anastomoses
in the surgical outcomes that was required to reverse the fistulas. Any time there is more anastomoses there is an
inherent greater chance for leak. More
anastomoses coupled with half (n=10) the control group having an ASA >3
could skew primary outcomes of fistula recurrence before any intervention is even
studied such as immunonutrition.
- Amino acid profile: in determining clinical
relevance of an oral supplement I have always wondered if absorption factors
into a potential confounder. The authors
rightfully enrolled only fistula patients with >1meter of bowel prior to the
GI opening. This should be plenty of
length to absorb amino acids, but something as simple as an amino acid profile
(inexpensive, quick test) could demonstrate that arginine and glutamine oral
supplementation actually makes serum concentration improve. Additionally, citrulline levels on the amino
acid profile could serve as a rudimentary surrogate for GI absorption capacity.
Lastly, most immunonutrition supplements for preoperative ERAS protocols also contain
omega 3 fatty acids, which has proven to be beneficial in reducing
inflammation. More as a question I am
curious why fish oil wasn’t added to enhance recovery?
- Criteria for parenteral: the authors make
mention that “all patients were able to tolerate enteral diet while 29 patients
(73%) received parenteral support. For a median of 139 days”. It would be
interesting to see the percentage of support for these patients. Was the patient on total parenteral nutrition
despite being able to tolerate enteral diet? Was parenteral support used as
supplemental parenteral nutrition? Was it added if there were signs of
malabsorption and how did they determine that? To say that all patients
tolerated enteral nutrition to me means they would be eating not ¾ of the study
be on parenteral support. I do recognize
supplemental parenteral support for those who cannot achieve caloric needs
either through GI intolerance or malabsorption, but this was poorly discussed
in the article.
- Infectious morbidity: the authors begin their
discussion with “the results of this study show that the preoperative use of
oral arginine and glutamine in patients with ECF have positive effects in
regard to fistula recurrence, postoperative inflammatory markers, and
infectious complications”. Additionally,
the authors correctly mention that all infectious complications were in
patients that had recurrence of their fistulas.
To make conclusions that the immunonutrients, arginine and glutamine,
decreased post-operative infectious morbidity because all the infections
occurred in the control group would be erroneous. I would submit that the
infectious morbidity, and increased length of stay, in the control group was driven
solely by the fistula recurrence requiring prolonged hospitalization and
interventions. Again this could be in
part reflected for the increased risk of anastomotic leak in the control group
who had more fistulas and were sicker (ASA>3) at baseline.
Again the authors should be
commended for studying a very difficult patient population, as the authors
point out to us in their conclusions the tenets of fistula management remains
the same for decades: “source control, appropriate management of sepsis, and
nutritional support are key steps in the preoperative phase, and they need to
be fulfilled before planning the operation itself”. I would add to their statement that
correcting electrolyte imbalances and skin care are the complete foundation of
fistula management, but there remains a nebulous middle ground that needs to be
further explored. After the acute phase
(>2months) when the fistula is likely not going to spontaneously close there
is a vast black hole of literature providing guidance for nutritional
support. Most experts would agree that
the non-caloric benefits of oral/enteral nutrition (even if it is oral food for
comfort or trophic feeds) far outweigh parenteral nutrition[12, 13],
but still fistula patients remain on parenteral support throughout their course
awaiting surgical intervention without transitioning to or challenging the GI
tract. The authors mentioned that all
patients could tolerate diets and had bowel length >1m prior to the fistula,
but the rationale for parenteral support was lacking (perhaps the patients
couldn’t tolerate >60% of their goal calories). Nevertheless, at every turn in managing ECF
we ought to be trying to get more and more enteral stimulation all the while
checking for GI intolerance, malabsorption, dehydration, and other potential
complications of intra-luminal nutrition. Nutritional support for fistulas should be dynamic and every attempt to
de-escalate parenteral support should be made throughout the ‘middle ground’
management between fistula appearance and reversal. Prior to reversal using studies like Martinez
et al and Wang et al, there is no reason ECF surgical intervention shouldn’t
follow most ERAS protocols using a week of immunonutrition to improve outcomes
and shorten lengths of stay.
- Marimuthu, K., et al., 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(6): p. 1060-8.
- Osland, E., et al., Effect of timing of pharmaconutrition (immunonutrition)
administration on outcomes of elective surgery for gastrointestinal
malignancies: a systematic review and meta-analysis. JPEN J Parenter
Enteral Nutr, 2014. 38(1): p. 53-69.
- Mazaki, T., Y. Ishii, and I. Murai, Immunoenhancing enteral and parenteral
nutrition for gastrointestinal surgery: a multiple-treatments meta-analysis.
Ann Surg, 2015. 261(4): p. 662-9.
- Amer, M.A., et al., Network meta-analysis of the effect of
preoperative carbohydrate loading on recovery after elective surgery. Br J
Surg, 2017. 104(3): p. 187-197.
- Bilku, D.K., et al., Role of preoperative carbohydrate loading: a
systematic review. Ann R Coll Surg Engl, 2014. 96(1): p. 15-22.
- Smith, M.D., et al., Preoperative carbohydrate treatment for
enhancing recovery after elective surgery. Cochrane Database Syst Rev,
2014(8): p. CD009161.
- Braga, M. and L. Gianotti, Preoperative immunonutrition: cost-benefit
analysis. JPEN J Parenter Enteral Nutr, 2005. 29(1 Suppl): p. S57-61.
- Braga, M., et al., Preoperative oral arginine and n-3 fatty
acid supplementation improves the immunometabolic host response and outcome
after colorectal resection for cancer. Surgery, 2002. 132(5): p. 805-14.
- Buzquurz, F., et al., Impact of oral preoperative and
perioperative immunonutrition on postoperative infection and mortality in
patients undergoing cancer surgery: systematic review and meta-analysis with
trial sequential analysis. BJS Open, 2020.
- Cerantola, Y., et al., Immunonutrition in gastrointestinal surgery.
Br J Surg, 2011. 98(1): p. 37-48.
- Gade, J., et al., The Effect of Preoperative Oral Immunonutrition on Complications and
Length of Hospital Stay After Elective Surgery for Pancreatic Cancer--A
Randomized Controlled Trial. Nutr Cancer, 2016. 68(2): p. 225-33.
- Kudsk, K.A., Effect of route and type of nutrition on intestine-derived inflammatory
responses. Am J Surg, 2003. 185(1):
- Kudsk, K.A., et al., Enteral feeding of a chemically defined diet
preserves pulmonary immunity but not intestinal immunity: the role of
lymphotoxin beta receptor. JPEN J Parenter Enteral Nutr, 2007. 31(6): p. 477-81.
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