Nutritional Approach in Malnourished Surgical Patients, A Prospective
Randomized Study
Arch Surg. 2002;137:174-180
Marco Braga, MD; Luca Gianotti, MD, ScD; Luca Nespoli, MD; Giovanni
Radaelli, PhD; Valerio Di Carlo, MD
Hypothesis Perioperative administration of a supplemented enteral formula may
decrease postoperative morbidity.
Design Randomized clinical trial.
Setting Department of surgery at a university hospital.
Patients One hundred ninety-six registered malnourished patients (weight
loss 10%) who were candidates
for major elective surgery for malignancy of the gastrointestinal tract.
Intervention After randomization (n = 150), one group received postoperative
enteral feeding with a standard diet within 12 hours of surgery (control group;
n = 50). Another group orally received 1 L/d for 7 consecutive days of a liquid
diet enriched with arginine, -3 fatty acids,
and RNA (preoperative group; n = 50). After surgery, patients were given the
same standard enteral formula as the control group. A third group orally
received 1 L/d for 7 consecutive days of the enriched liquid diet. After
surgery, patients were given enteral feeding with the same enriched formula
(perioperative group; n = 50).
Main Outcome
Measures Postoperative
complications and length of hospital stay.
Results The 3 groups were comparable for baseline demographics,
biochemical markers, comorbidity factors, and surgical variables. The
intent-to-treat analysis showed that the total number of patients with
complications was 24 in the control group, 14 in the preoperative group, and 9
in the perioperative group (P =
.02, control group vs perioperative group). Postoperative length of stay was
significantly shorter in the preoperative (13.2 days) and perioperative (12.0
days) groups than in the control group (15.3 days) (P = .01 and P
= .001, respectively, vs the control group).
Conclusion Perioperative immunonutrition seems to be the best approach to
support malnourished patients with cancer.
Arch Surg. 2002;137:174-180
PROTEIN ENERGY malnutrition is recognized as an
important risk factor for the occurrence of postoperative complications.1-3 Thus, artificial
nutritional support has been proposed as an essential part of perioperative
care of malnourished surgical patients.4-6 Feeding enterally
rather than parenterally may improve outcome, particularly in malnourished
patients who undergo major surgery for a neoplasm.7-12
Moreover, administration of standard enteral
diets supplemented with arginine, -3 fatty acids, glutamine, and other key nutritional substrates
(immunonutrition) modulates immune and inflammatory responses and gut function.13, 14
Results of 2 randomized, double-blind trials15, 16 consistently
indicated that perioperative (before and after surgery) administration of
immunoenhancing diets could significantly improve several outcome variables,
but none of these studies were designed with separate randomization according
to the nutritional status of the patients. Results of a post-hoc analysis16 suggested that the
positive effects of immunonutrition were more pronounced in a subgroup of
malnourished patients. Another finding was that patients receiving only
preoperative immunonutrition, because of noncompliance with postoperative
immunonutrition, also had a significant reduction in complications (M.B., L.G.,
G.R., et al, unpublished data, 1999). These data suggested that the simple
preoperative approach could be sufficient to improve outcome.
Therefore, this study was designed with the
primary end point of establishing in a prospective fashion whether
administration of perioperative immunonutrition could reduce the rate of
post-operative complications and the length of postoperative hospital stay
compared with administration of standard enteral formulas in a homogeneous group
of patients defined a priori as malnourished. Furthermore, we evaluated, in the
policy of cost minimization, whether the simple preoperative administration of
immunonutrition could be as effective as the perioperative approach.
This was a randomized clinical trial conducted
by a single institution (San Raffaele Hospital, Milan, Italy) between September
1, 1998, and December 31, 2000.
Inclusion and exclusion criteria are summarized
in Table 1.
Patients had to meet all 3 inclusion criteria to be registered. After applying
the exclusion criteria, patients were allocated by computer-generated
individual random numbers into 3 arms. Eligible patients were required to sign
a written informed consent form after the details of the protocol were fully
explained. The protocol was approved by the ethical committee of San Raffaele
Hospital.
Before surgery, one group drank 1 L of a
supplemented liquid diet (Oral Impact; Novartis Consumer Health, Bern,
Switzerland) per day for 7 consecutive days. After surgery, patients continued
to be fed enterally with the same supplemented formula (perioperative group).
Before surgery, another group drank 1 L of a
supplemented liquid diet (Oral Impact) per day for 7 consecutive days. After
surgery, patients were given a standard enteral formula (preoperative group).
The third group received only postoperative
enteral feeding with a standard diet (control group).
The standard and enriched diets contained the
same amounts of energy and nitrogen (Table 2).
Regardless the type of diet, in all 3 groups, postoperative enteral nutrition
was administered within 12 hours of surgery via a feeding catheter jejunostomy
or a nasojejunal feeding tube. Enteral flow was controlled by using a peristaltic
infusion pump. The initial rate of 10 mL/h was progressively increased 20 mL/h
per day until reaching the full nutritional goal (28 kcal/kg per day). Enteral
infusion was continued until patients resumed adequate oral food intake
(approximately 50% of the basal energy requirement).
All patients were advised to consume regular
food as desired before surgery. In the preoperative and perioperative groups,
presurgical oral supplementation with the enriched formula was given as
outpatient therapy. Patients were also asked to register the daily amount of
the preoperative supplement consumed. Hospital admission was scheduled for all
patients 2 days before surgery.
Eight days before surgery, the following
baseline variables were determined in all patients: body weight, degree of
weight loss (with respect to usual body weight in the previous 6 months),
performance status according to Karnofsky score, hemoglobin level, plasma level
of total protein, albumin level, retinol binding protein level, prealbumin level,
total circulating lymphocyte count, creatinine level, and arginine plasma
level. The arginine level was also determined 1 day before surgery. Comorbidity
factors, as measured by the American Society of Anesthesiologists score, were
also recorded in all patients.
Type of surgery, duration of surgery, operative
blood loss, and rate and amount of homologous blood transfused were registered.
The decision to give homologous blood was based on the perioperative hemoglobin
level (<8 g/dL) or the clinical condition of the patient.
Intestinal washout with an isosmotic solution (3
L) was carried out the day before surgery in patients undergoing colorectal
surgery. The evening before and the morning of surgery, patients were also
treated with enemas. These patients received antibiotic prophylaxis in a single
intravenous dose (2 g of cefotetan disodium) 30 minutes before surgery.
Candidates for gastric, esophageal, or pancreatic surgery were treated with
intestinal washout (1 L) the day before surgery and with antibiotic prophylaxis
in a single intravenous dose (2 g of cefazolin sodium) 30 minutes before
surgery. A second dose of the antibiotic was given if the surgery lasted longer
than 4 hours. Deep-vein thrombosis prophylaxis was carried out daily using
low-molecular-weight heparin (50 IU/kg).
Adverse effects of postoperative enteral
feeding, such as abdominal cramping and distension, diarrhea (defined as >3
liquid stools per day), and vomiting, were evaluated in all patients, as was
the time from canalization to gas and bowel movement.
Patients were defined as nontolerant to
postoperative feeding if they were unable to tolerate a minimum diet infusion
of 800 mL/d by postoperative day 4.
Trained members of the surgical staff who were
not involved in the study registered the postoperative complications
(definitions are given in Table 3).
They also decided independently the day of hospital discharge, the indication,
and the duration of antibiotic therapy in the postoperative course and the
first day of oral food resumption. Total parenteral nutrition was given to
patients who were nontolerant of enteral nutrition.
Death, anastomotic leak, relaparotomy,
complications requiring transfer of the patient to the intensive care unit, and
percutaneous drainage of a deep abscess using interventional radiologic
techniques were defined as major complications. Follow-up for infectious and
noninfectious complications was carried out for 30 days after hospital
discharge via office visits.
STATISTICAL ANALYSIS
It was assumed that postoperative complications would occur in approximately
40% of eligible control patients.7, 16 A reduction in the
incidence to 20% would indicate the efficacy of perioperative immunonutrition
treatment. With a targeted maximum of 50 individuals in each group, we had
approximately 80% power to detect such a reduction at = .05.
All patients were analyzed on an intent-to-treat
basis. Descriptive results are given as mean (SD) or number (percentage) of
observations. One-way analysis of variance and the Kruskal-Wallis test (for
nonnormally distributed data, ie, operative time, operative blood loss, length
of stay, resumption of oral food intake, duration of antibiotic therapy) were
used to compare continuous variables among groups. Post-hoc multiple
comparisons were performed using the Bonferroni correction. The 2 test (with Yates correction if there were
cells with <10 observations) and the Fisher exact test were used to compare
discrete variables. All P values
are 2-sided, and significance was set at P<.05.
A statistical software program (SPSS version 8.0 for Windows; SPSS Inc,
Chicago, Ill) was used for statistical analysis.
During the study, 196 patients were observed: 46
were excluded and 150 were eligible and entered by randomization into the
control group (n = 50), the preoperative group (n = 50), or the perioperative
group (n = 50). All eligible patients were analyzed on an intent-to-treat basis
(Figure 1).
The mean preoperative intake of the oral
supplementation was 910 mL/d, with no difference between the preoperative and
perioperative groups. Table 4
lists the preoperative (day -8) characteristics and the comorbidity factors of
the eligible participants. The 3 study arms were well-balanced for all variables.
Mean weight loss was 13%. Mean serum levels of total protein, albumin,
prealbumin, and retinol binding protein were below the reference range in all
groups. The arginine plasma level was similar 8 days before surgery in all
groups, whereas 1 day before surgery the level was 1.15 mg/dL in the control
group, 1.64 mg/dL in the preoperative group, and 1.69 mg/dL in the
perioperative group (P = .03).
The 3 groups were comparable for surgical variables (Table 5).
Most patients underwent upper gastrointestinal tract operations.
Outcome variables are given in Table 6.
The total number of patients who developed postoperative complications was
significantly lower in the perioperative group than in the control group (P = .02). Moreover, the number of patients
with complications was 9 (18%) of 50 in the perioperative group vs 14 (28%) of
50 in the preoperative group (50% relative reduction), but this difference did
not reach statistical significance (P
= .34). Also, comparing the preoperative and control groups, a substantial
reduction in complications was observed (28% vs 42%; P = .21). Mean length of postoperative hospital stay was
significantly shorter in the preoperative (P
= .01) and perioperative (P =
.001) groups than in the control group.
Table 7
gives the complications in each group. Considering infectious morbidity,
respiratory tract and wound infections were the most frequent, with a lower
incidence in the groups receiving immunonutrition than in controls. Among major
complications, anastomotic leak seemed to be the most frequent, with a similar
trend toward reduction in both groups receiving the enriched diet.
The duration of antibiotic therapy needed to
treat postoperative infections was 6.1 (1.7) days in the perioperative group vs
5.8 (3.5) days in the preoperative group and 10.2 (6.3) days in the control
group.
One hundred four patients (69%) did not
experience any adverse effects related to postoperative enteral nutrition.
Abdominal cramps or distension were observed in 29 patients (19%), diarrhea in
13 (9%), and vomiting in 4 (3%). The rate of gastrointestinal tract adverse
effects was similar in the 3 groups. Because most adverse effects were
controlled by the temporary interruption or reduction of the jejunal infusion,
overall the nutritional goal was achieved in 138 patients (92%). Twelve
patients (8%) had to be switched to total parenteral nutrition for intolerance
(5 patients in the control group, 3 in the preoperative group, and 4 in the
perioperative group).
Recovery of bowel function as measured by
canalization to gas and feces occurred after 3.5 (1.7) and 5.2 (2.1) days,
respectively, without any substantial difference among groups. Patients
recovered adequate oral food intake 9.8 (5.4) days after surgery in the control
group, 8.2 (2.3) days in the perioperative group, and 8.4 (3.6) days in the
preoperative group.
Between surgery and hospital discharge, patients
lost an additional 3.1% of their body weight. The value was similar among
groups.
Malnutrition in patients who are candidates for
major surgery is a considerable problem for the surgeon because it represents a
risk factor for postoperative morbidity and mortality.1-3 Cancer-bearing
patients may have additional protein energy depletion due to the occurrence of
cachexia.17 Despite
extensive research in the field of clinical nutrition,18 indisputable results
on which to base rational nutritional support in malnourished surgical patients
are sparse.
A recent consensus statement18 concluded that
malnourished patients are candidates for preoperative artificial nutritional
support. This support could reduce the rate of postoperative complications by
approximately 10%. These general conclusions have several potential flaws: (1)
in the trials analyzed, malnutrition was defined by a multitude of different
scores and threshold values for weight loss and serum protein; (2) the study
design was rarely a priori dedicated to malnourished patients; (3) enrolled
patients were often heterogeneous for the primary diagnosis; (4) the quantity
of calories was, in most cases, excessive compared with current standards; and
(5) the type of nutrients and the presence of lipids were frequently
uncontrolled. These considerations made the comparison among trial results
puzzling and the conclusions difficult to be applied in clinical practice.
Moreover, nutritional support, with the suggested modalities, requires
preoperative hospitalization for at least 7 to 10 days, with an obvious
increase in sanitary costs. Another reason for skepticism is that severe
malnutrition (the only condition that benefits from preoperative parenteral
feeding)19 is often an
indirect sign of advanced neoplastic disease (unresectable tumor, metastatic
spread, peritoneal carcinosis, etc), which usually makes patients unsuitable
for a surgical approach. Therefore, the cost-effectiveness of this nutritional
treatment may be limited.20
Results of recent studies strongly suggest that
in malnourished patients, postoperative enteral feeding with standard feeds
should be preferred to parenteral nutrition. In fact, surgical patients fed
enterally had an improved outcome compared with patients treated parenterally,7-12 and the
nutrition-related sanitary costs are substantially reduced when using the
enteral route.7, 21-23 Thus, we believe
that postoperative enteral nutrition with a standard diet could be considered
the reference treatment. In the present study, we did not include an unfed
group because it was considered unethical to restrain such patients from any
support.
In the past decade, research in clinical
nutrition focused on the addition of key substrates (arginine, -3 fatty acids, glutamine, RNA, etc) to standard
formulas. Two meta-analyses24, 25 showed that in
surgical patients, postoperative use of enteral immunonutrition seems to
improve outcome compared with standard formulas. Nevertheless, by analyzing
singularly the major studies,26-30 the results were
conflicting. In fact, the positive findings reported by Daly et al26, 27 were partially
confirmed by others.28-30 Postoperative
treatment is conceptually limited because the amount of key substrates given in
the first days after surgery is little and therefore may be insufficient for an
efficacious modulation of the immune and inflammatory responses after surgery.31-34 As any other
substance with supposed pharmacological action, immunonutrients should reach
suitable tissue and plasma concentrations to be active. Thus, a different
approach was tested to anticipate the provision of immunonutrients before
surgery to obtain high levels at the time of surgical stress, when the depression
of the host response is maximal.
Phase 2 clinical trials35-37 showed that
perioperative treatment (before and after surgery) with an enteral diet
enriched with arginine, -3 fatty acids,
and RNA significantly prevented early postoperative impairment of the host
defense mechanisms, controlled the overwhelming inflammatory reaction, improved
intestinal microperfusion and postoperative gut mucosal oxygen metabolism, and
modulated the metabolic response favoring the synthesis of constitutive
proteins instead of acute-phase proteins.
The impact of perioperative administration of
immunoenhancing diets was tested subsequently in phase 3 double-blind trials to
address whether the advantages listed in the previous paragraph on surrogate
end points could translate into true outcome benefits. Senkal and colleagues15 showed that patients
receiving enteral immunonutrition had significantly fewer infections than the
control group (14 vs 27). We16 reported that in the
intent-to-treat analysis, the overall rate of postoperative infectious
complications was 14% in the supplemented group and 30% in the control group (P = .009), and length of hospital stay was
also shorter in the supplemented group (P
= .01). Furthermore, our data suggested that perioperative immunonutrition is
efficacious regardless of the baseline nutritional status of the patients. In
fact, the rate of complication in well-nourished patients was 10% (6/63) in the
supplemented group vs 27% (14/68) in the control group (P = .05). In a subgroup of malnourished
patients, the rate of complication was 14% (3/22) in the supplemented group vs
39% (7/18) in the control group (P
= .05).
Yet, these studies were not originally designed
to randomize patients by their nutritional status. To overcome this bias, we
designed a prospective study to investigate the effect of perioperative
immunonutrition on outcome in patients a priori homogeneous for nutritional
status. In the present trial, we also included a group receiving only
preoperative immunonutrition because previous results (M.B., L.G., G.R., et al,
unpublished data, 1999) suggested that patients receiving only preoperative
immunonutrition because noncompliant with postoperative immunonutrition had a
significant reduction in complications. This suggested that the simple
preoperative approach could be sufficient to improve outcome. Moreover, in the
light of cost-minimization policy, the restriction to preoperative treatment
only may save approximately $90 to $180 per treated patient.15, 38
The results of the present trial are consistent
with those of the previous subset analysis and confirm that perioperative
treatment with immunonutrition may significantly decrease the postoperative
morbidity rate in malnourished patients. In contrast, the expected equivalence
between perioperative and preoperative immunonutrition was not achieved. This
may be explained by the fact that malnourished patients, beside having energy
and nitrogen needs, have marked impairment of the immune response, and, thus,
prolonged and increased administration of key nutrients is required. This
speculation is consistent with recent data39 suggesting instead
that in well-nourished patients, the simple provision of immunonutrients before
surgery was sufficient to improve outcome.
The present data showed a clear trend on the
incidence of postoperative complications according to the type of nutrition
strategy. In particular, a progressive effect was noted, with perioperative
immunonutrition giving the best outcome, postoperative standard formula the
worst results, and preoperative immunonutrition intermediate results. Thus, a
dose-response effect of key nutrients on the occurrence of complications may be
hypothesized.
The 2 groups supplemented with the enriched
formula received more energy and proteins than the control group before
surgery. However, the better outcome in the groups receiving immunonutrition
should not be attributed to the differences in preoperative energy and nitrogen
intake compared with the control group because it has been shown previously
that when isoenergetic and isonitrogenous preoperative load was used, the
results were still in favor of immunonutrition.15, 16 This allows us to
speculate that the key factor for improved outcome was the provision of
immune-enhancing substrates rather than the simple provision of energy and
proteins.
In the present study, the incidence of infection
was not significantly different among groups. Yet, patients receiving the
supplemented diet required a shorter duration of antibiotic therapy to treat
infectious complications. These data may be interpreted as the result of the
therapeutic combination of drugs and a more efficient host response on the
process of bacterial clearance. Also, it may be hypothesized that the reduction
in the postoperative infectious morbidity rate in the supplemented groups is
related to improved gut oxygen metabolism and tension already reported in
patients perioperatively supplemented with immunonutrition.35 This may result in
advantages on intestinal barrier function and subsequent decreased bacterial
translocation that, coupled with malnutrition, may become clinically relevant.40
This study was not designed to address treatment
and complication costs. Nevertheless, the health care resources saved by the
marked reduction in the morbidity rate by using perioperative immunonutrition
may largely outnumber the additional costs of the supplemented diet.15, 38
In conclusion, the present trial is the first,
to our knowledge, to report that in a selected population of malnourished
patients with cancer undergoing major elective surgery, the administration of
key substrates was beneficial to outcome. Administration of the supplemented
diet before and after surgery seemed to be the best strategy to reduce
complications and length of hospital stay.
Author/Article Information
From the Department of Surgery, San Raffaele University (Drs Braga, Gianotti,
Nespoli, and Di Carlo), and the Department of Informative Systems and
Statistics, University of Milan (Dr Radaelli), Milan, Italy.
Corresponding author and reprints: Luca Gianotti, MD, ScD, Department of
Surgery (Chirurgia 3) San Gerardo Hospital, Via Donizetti 106, 20052 Monza
(MI), Italy (e-mail: [log in to unmask]).
The diets were provided by Novartis Consumer
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MEDLINE
Edward E.
Rylander, M.D.
Diplomat American
Board of Family Practice.
Diplomat American
Board of Palliative Medicine.