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Perioperative Total Parenteral Nutrition in Malnourished, Gastrointestinal

Cancer Patients: A Randomized, Clinical Trial

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DOI: 10.1177/014860710002400107 · Source: PubMed

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 Journal of Parenteral and Enteral Nutrition
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Perioperative Total Parenteral Nutrition in Malnourished, Gastrointestinal Cancer Patients: A

Randomized, Clinical Trial
Federico Bozzetti, Cecilia Gavazzi, Rosalba Miceli, Nicoletta Rossi, Luigi Mariani, Luca Cozzaglio, Giuliano
Bonfanti and Sabrina Piacenza
JPEN J Parenter Enteral Nutr 2000; 24; 7
DOI: 10.1177/014860710002400107

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 Original Communications
PerioperativeTotal Parenteral Nutrition in Malnourished,
Gastrointestinal Cancer Patients: A Randomized, Clinical Trial

Federico Bozzetti, MD*; Cecilia Gavazzi, MD†; Rosalba Miceli, PhD‡; Nicoletta Rossi, BSc‡;
Luigi Mariani, PhD‡; Luca Cozzaglio, MD*; Giuliano Bonfanti, MD*; and Sabrina Piacenza, MD†
From the *Department of Surgery of the Gastrointestinal Tract, †Nutrition Support Unit, and‡Division of Biometry and Medical Statistics,
Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy

ABSTRACT. Background: Clinical trials investigating the
potential benefits of perioperative total parenteral nutrition
(TPN) for reducing the risk of surgery in malnourished can-
cer patients have yielded controversial results. Methods:
Ninety elective surgical patients with gastric or colorectal
occurred in 37% of the patients receiving TPN us 57% of the
control patients ( p = .03). Noninfectious complications
mainly accounted for this difference, which was 12% us 34%,
respectively (p = .02). Mortality occurred in only 5 of the
control group patients (p .05). The total length of hospital-
=

tumors and weight loss of 10% or more of usual body weight
were randomly assigned to 10 days of preoperative and 9
days of postoperative nutrition us a simple control group. The
daily per kilogram body weight TPN regimen included 34.6 ±
6.3 kcal nonprotein and 0.25 ± 0.04 g nitrogen per kilogram
in a volume of 42.6 ± 7.3 mL of fluid. The glucose-to-fat
calorie ratio was 70:30. Control patients did not receive pre-
operative nutrition but received 940 kcal nonprotein plus
85 g amino acids postoperatively. Results: Complications
ization for TPN patients was longer than for control ( p = .00),
whereas the length of postoperative stay in the two groups
did not differ significantly. Conclusions: This study shows that
10 days of preoperative TPN that is continued postopera-
tively is able to reduce the complication rate by approxi-
mately one third and to prevent mortality in severely mal-
nourished patients with gastrointestinal cancer. (Journal of
Parenteral and Enteral Nutrition 24:
7-14, 2000)

Although it is widely accepted that malnutrition participate in the trial if they had newly detected,
adversely affects the postoperative outcome of pa- histologically proven gastric or colorectal carcinoma
tients, there is little evidence that perioperative nutri- requiring surgical treatment in addition to weight loss
tion support can reduce surgical risk in malnourished of 10% or more in the previous 6 months. Patients older
cancer patients. than 80 years of age were excluded, as were those
A review of the literature shows that 20 clinical inves- requiring urgent surgery because of severe bleeding or
tigations have been carried out on the role of perio- obstruction or those with severe organ failure (jaun-
perative total parenteral nutrition (TPN) in patients dice, cardiac or respiratory failure, etc) contraindicat-
with cancer of the gastrointestinal tract who require
ing the preoperative TPN as planned by the protocol.
surgery. 1-20 However, only 15 of these were randomized The Institute’s Ethical Committee approved the study
clinical trials 2,6-14,16-20 and only four 12,16,18,19 required
that patients be malnourished in order to be eligible for from
protocol and informed consent was always obtained
randomization.
patients.
After being stratified for age (S 65, > 65 years) and
The varying results obtained by these studies tumor localization
(gastric, colorectal), patients were
prompted us to investigate prospectively the potential randomly assigned to receive either TPN for 10 days
of perioperative TPN to reduce morbidity and mortal-
perioperatively and 9 days postoperatively, or to
ity in patients with cancer of the stomach or the colon- undergo surgery without preoperative nutrition sup-
rectum and weight loss of at least 10% of the usual
port and subsequently have IV fluids administered
body weight, operated on in a single surgical oncology according to our standard prescription (control group,
unit at the Istituto Nazionale Tumori, Milan.
CTR) until recovering the ability to be nourished
MATERIALS AND METHODS
orally. No blinding procedure was adopted. After
checking that the patient fulfilled the eligibility crite-
Patients consecutively admitted to the Division of ria, randomization was carried out by the principal
Surgical Oncology A of the Istituto Nazionale per lo investigator (F.B.) in accordance with computer-gener-
Studio e la Cura dei Tumori of Milan were eligible to ated randomization lists (one for each stratum). The
latter was informed of the type of assignment by a
nurse from the nutrition support team who held the
lists.
Correspondence and reprint requests: Federico Bozzetti, MD, Isti- Overall, 107 patients were randomized from 1987 to
tuto Nazionale Tumori, Via G. Venezian, 1, 20133 Milano, Italy. 1996. However, 8 of these patients (5 TPN and 3 CTR)

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8
were not operated on because surgery was deemed
unsuitable at a more detailed staging; 1 patient was
unable to receive TPN because of the appearance of an
important vasovagal syndrome while the central
venous catheter was being positioned; 6 patients (2
TPN and 4 CTR) did not fulfill all of the admission
criteria (including minimum weight loss of 10%) at the
subsequent careful evaluation; and in 2 CTR patients,
no malignancy was found on examination of the spec-
imen. Consequently, this case series comprised only 90
patients, 43 of whom were randomly assigned to the
TPN group and 47 to the CTR group.
In the patients randomly assigned to perioperative
TPN, the artificial nutritional regimen was planned at
1.5-fold the resting energy expenditure, as estimated
by the Harris-Benedict equation. The nonprotein cal-
orie source included glucose and fat (Intralipid 20%;
Kabi Pharmacia AB, Stockholm, Sweden), which
accounted for 70% and 30% of the energy intake,
respectively. The calorie/nitrogen ratio was 143.0 ( ~-
26.9) :1. The protein source was supplied by a free
amino acid solution (Freamine III; Baxter, Kendall
McGaw Laboratories Inc, Irvine, CA). Electrolytes,
vitamins, and trace elements (zinc, copper, manganese,
chromium) were administered according to current rec-
ommendations. Consequently, in this study the daily
nutritional regimen included an average of 34.6 -!- 6.3
kcal nonprotein per kilogram body weight, and 0.25 ±
0.04 g of nitrogen per kilogram body weight.
The TPN mixture was delivered through a central
venous catheter in a subclavian vein, using an ethyl
vinyl acetate &dquo;all-in-one&dquo; bag, while vitamins only were
infused through a separate line. During preoperative
TPN, patients consumed very few calories by the oral
route. TPN was administered postoperatively in addi-
tion to the oral feeding that was provided gradually as
bowel function normalized. Patients in the CTR group
were given a standard hospital oral diet before surgery
and a hypocaloric (but adequate in terms of nitrogen
content) parenteral solution (940 kcal nonprotein and
85 g amino acid) in the postoperative period, until
gastrointestinal function had recovered completely.
The majority of the patients in the control group
received the IV feeding through a central venous cath-
eter placed by the anesthesiologist during the opera-
tion, and the nutritive solution was compounded in a
single bag.
*Presence of dyspnea or respiratory rate > 35/min or
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During the preoperative period accurate staging of
the tumor was performed using the appropriate tech-
niques, irrespective of the previous examination
results provided by the patient.
After surgery, patients were monitored daily for
postoperative complications in accordance with the def-
initions given in Table I. In general, complications
were scored as minor when only medical treatment was
required and as major when necessitating surgical or
radiologic intervention or treatment in an intensive
care unit. Different criteria were adopted for liver fail-
ure and clotting abnormalities, as defined in Table I.
Complications related to the presence of a central
venous catheter were monitored according to the prac-
tice of this unit and included chest x-ray after cathe-
terization, peripheral and central blood culture if there
was an unexplained pyrexia (2:: 38°C), notation in the
clinical chart if an accidental removal or any malfunc-
tion of the line occurred. Blood chemistry was checked
every other day in absence of complications.
The occurrence of a complication and the subsequent
diagnostic and therapeutic workup were noted in the
charts by the surgical staff. Excluding the principal
investigator, the members of the staff and the person-
nel of the Radiologic Department and the Clinical
Analysis Department were unaware whether the
patients were enrolled in the prospective study or not.
The occurrence and causes of death during hospital-
ization and the length of hospitalization (presurgery
and postsurgery) were recorded. In the TPN group,
nutritional status was monitored by measuring body
weight, serum albumin and prealbumin levels, total
lymphocyte count, retinol-binding protein (RBP), and
total iron-binding capacity (TIBC). These indices were
assessed just before initiating TPN and before surgery,
after 10 days of TPN.
Statistical Methods
The primary study outcome was the occurrence of
postoperative complications. Secondary end points
were postoperative mortality and length of hospitaliza-
tion. The frequency of postoperative complications in
the two trial arms was compared by means of the
stratified Mann-Whitney test. Patients were catego-
rized as having had no complications, at least one
minor complication (and no major complications), or at
TABLE I
Definition of complications
Pao2 < 70 mm Hg.

least one major complication. The same type of analy-
sis was performed for both infectious and noninfectious
complications. When planning the study, we had esti-
mated that 64 patients in each of the treatment groups
(a total of 128) would yield a power of 90% to detect a
decrease in the frequency of major complications from
30% (in the CTR group) to 10% (in the TPN group),
with a one-tailed test at the 5% significance level.
Because patient accrual lagged, we decided to stop the
trial before reaching the target sample size based on
the fact that with the sample of 90 patients and given
the above assumptions, the estimated power was
instead approximately 80%. An even greater power
could be expected by taking into account both minor
and major complications with the Mann-Whitney test.
The interaction test described by Zelen 21 was used to
verify whether the treatment effect on the occurrence
of postoperative complications was modified by other
factors, such as patient age ( ~ 65, > 65 years), tumor
site (gastric, colorectal), weight loss (grade I: ~ 10
and < 15%; grade II: 2:: 15 and < 25%; grade III: 2:: 25%
of the usual body weight), or blood transfusions (none
or autologous, homologous). The presence of an inter-
action would imply a significant differential treatment
effect according to the categories of each factor. There-
fore, patients were simply categorized as having had
either no complications or at least one complication,
regardless of severity. In this analysis, weight loss was
regarded as an indicator of nutritional status.
Mortality was compared in the two trial arms by
means of the Fisher exact test. The Kolmogorov-Smir-
nov test was used for comparing length of hospitaliza-
tion (patients who died after surgery were excluded
when calculating postoperative stay).
Post-TPN mean levels of nutritional variables (body
weight, serum albumin and prealbumin levels, total
lymphocyte count, RBP and TIBC) in patients with
postoperative complications were compared with those
of patients without complications by means of linear
regression models in which baseline measurements of
nutritional variables were included as a covariate. The
assumption of parallelism between the regression lines
of post-TPN us baseline measurements in the groups of
patients with and without complications had previ-
ously been verified.
The analyses of categorical data (complications and
mortality) were performed using StatXact;22 p values
reported are those obtained from exact tests. The other
analyses were performed using SAS software.23 The
conventional, two-sided, 5% significance level was
adopted in all of the analyses.
RESULTS
Main patient characteristics in the two trial arms
are reported in Table II. The two arms were well
matched in all the baseline characteristics considered.
Surgical interventions included simple exploration,
bypass, and resection. Radicality was obtained in
46.5% and 40.4% in the TPN group and CTR group,
respectively. No TPN- or catheter-related complica-
tions occurred in patients who received perioperative
nutrition support.
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9
The number of postoperative complications per study
group is shown in Table III. In both groups, the most
frequent complication was pulmonary tract infection.
The same data are reported in compact form in Table
IV, after classifying each patient as having had no
complications, minor complications, or major complica-
tions, as described in the Materials and Methods sec-
tion. Both minor and major complications, either infec-
tious or noninfectious, were less frequent in the TPN
group. More specifically, the overall complication rate
was 16 of 43 in the TPN group and 27 of 47 in the CTR
arm (percentage difference: 57-37 20%; 95% asymp- =
totic confidence interval: 0% to 40%). Statistical testing
yielded significant results when considering complica-
tions of any type (p .03) or noninfectious complica-
=
tions (p .01) but not in the case of infectious ones (p
= =
.22) or major ones only (p =
.11).
Table V reports the number of patients with minor or
major complications in the various strata defined by
age, tumor localization, weight loss, and transfusion.
The frequency of noninfectious complications was
clearly lower for TPN patients in all of the strata. In
line with these results, the interaction test between
treatment and age, location, weight loss, and blood
transfusions, respectively, never achieved statistical
significance. With regard to infectious complications,
TPN had an advantage for patients aged 65 or younger,
those with colorectal tumors, and those with moderate
(grade II) or severe (grade III) weight loss. However, no
significant results were obtained with the interaction
tests.
Five patients (all in the CTR group) died after devel-
oping the
following major complications: respiratory
failure (1 patient); cardiocirculatory failure (1 patient);
pulmonary tract infection (2 patients); and anasto-
motic leakage and abdominal sepsis (1 patient). A bor-
derline p value was obtained for the difference between
the two groups in terms of mortality (p .05). =
The total perioperative and postoperative median
(minimum-maximum) length of hospitalization were
33 (18-161) us 27 (15-103) days and 14 (7-143) vs 14
(6-59) days in the TPN us CTR patients, respectively.
The total length of hospitalization for TPN patients
was significantly longer than that for CTR (p .00), =
while the length of postoperative stay in the two groups
did not differ significantly (p .98). =
As reported in the Statistical Methods section,
patients who died after the operation were excluded
from the above computations. Assuming that the
length of hospitalization for these subjects, had they
survived, would have been longer than average, it fol-
lows that their exclusion tends to reduce the length of
stay data for the control group (this downward bias
would be even stronger by not excluding these sub-
jects). Surprisingly, there was no significant difference
in postoperative stay between patients with complica-
tions and those without (p .08). However, the fre-
=
quency of patients with an anomalous length of post-
operative hospitalization (eg, < 30 days) was 12% in
patients with complications and 2% in those without.
Table VI shows mean levels (and corresponding 95%
confidence intervals) of nutritional variables at base-
line and after perioperative TPN; mean levels were
10
Distribution of cli>iical/patfiologic
TPN, total parenteral nutrition; CTR, control group.
also calculated separately for patients with (16 cases)
and without (27 cases) complications of any type and
grade. Post-TPN mean levels, adjusted for baseline
measurements, did not differ significantly in either of
the two patient subgroups for any of the nutritional
variables (p values from .16 to .81).
DISCUSSION
Investigations of the potential role of TPN in restor-
ing the nutritional status of malnourished patients
should distinguish between cancer and noncancer
patients, because it is well known that nutritional
repletion in patients with cancer is much more limited
than in those with benign disease.24
This study represents the largest randomized clini-
cal trial to explore the role of perioperative TPN in
patients with gastrointestinal cancer and severe mal-
nutrition (weight loss ~:10% of usual body weight).
Moreover, it differs from three similar trials, which
involved the administration of TPN only in the preop-
erative period,l9 preoperative administration lasting
for only 3 to 5 days, 12 or weight loss in randomly
assigned patients of only 5 kg or less.16 Therefore, the
failure of these trials to demonstrate a benefit with
perioperative TPN cannot be taken as an absolute
Downloaded from http://pen.sagepub.com at UMDNJ on March 5, 2010
TABLE II
and nzstritional clzaracteristics of the series
argument against the efficacy of TPN and may simply
be explained on the basis of different investigative
conditions.
We reported a statistically significant reduction in
the overall complication rate from 57% to 37%, and
from 34% to 12% for noninfectious complications in the
control group and TPN group, respectively. In addition,
we had no mortality in the TPN patient group. The two
treatment arms were well balanced for prognostic
characteristics. However, the reasons for patient drop-
out were slightly different in the two arms, in a way
that might somewhat favor the TPN group. For exam-
ple, six of the eight TPN patients who were excluded
had a worse prognosis (unsuitable for surgery, unsta-
ble cardiovascular status as reflected by venous cath-
eter complications), whereas six of the nine controls
who were excluded had better prognosis (did not have
cancer, <10% weight loss). Nonetheless, we believe
that the observed differences reflect the effectiveness of
TPN in the investigated sample.
Our data are substantially in keeping with the
results of the randomized clinical trial of von Meyen-
feldt et all8 and of the Veterans Affairs TPN Coopera-
tive Study Group, 25 which showed a clinical benefit in
a limited number of patients with a degree of malnu-

TABLE III
Number in each trial
of comPlications arm
TPN, total parenteral nutrition; CTR, control group.
trition similar to that of our patients. In fact, von
Meyenfeldt et al 18 demonstrated a statistically signif-
icant decrease in the rate of septic complications (from
81.8% to 5.5%) in a subgroup of 29 patients (18 receiv-
ing preoperative and postoperative TPN and 11 con-
trols) with weight loss of more than 10% of the usual
body weight.
The Veterans Affairs TPN Cooperative Study,25
although not specifically involving cancer patients
(who accounted for only two thirds of the entire ran-
domized population), showed that preoperative TPN
reduced postoperative noninfectious complications
from 42.9% to 5.3% (p .03) in a small subgroup of 33
=
patients defined as severely undernourished in accor-
dance with the Nutrition Risk Index.26
It is noteworthy that the benefit with perioperative
TPN was achieved in our trial in comparison with a
control group of patients who did not simply receive
TABLE IV
Number of patients with no complications, minor complications,
major complications in the two trial arms
’1’Y1~. total parenteral nutrition; CTH,, control group.
TPN us control: all complications p .01; TPN us control: infectious
=
complications p = .11; TPN us control: noninfectious complications
p =
.01; TPN us control: major complications p .07.
=
Downloaded from http://pen.sagepub.com at UMDNJ on March 5, 2010
11
postoperative saline solutions but were also adminis-
tered a nutrition support that was adequate in nitro-
gen, although hypocaloric.
The success of this study in demonstrating a benefit
of TPN is most likely due to the safety of the nutri-
tional regimen and some specific characteristics of this
trial, namely the eligibility criteria for the patients and
the limited number of surgeons involved in the surgical
procedures, because 75% of the patients were operated
on by the same three senior surgeons and all the
patients were treated in a single surgical oncology unit.
In fact, for weight loss alone to influence postsurgery
prognosis, a high percentage is required, probably in
the range of 15% to 20% .27-29 A median weight loss of
15% to 16% in our patients identified them as being at
a clear nutritional risk. Furthermore, hypoalbumine-
mia is also considered a major risk factor for postoper-
ative complications, even if the cutoff point for severe
hypoalbuminemia varies from study to study. There is,
however, a certain consensus 21-11 that values below
3.6 g/dL (as occurred in many of our patients) indicate
a consistent risk. Finally, lymphocytopenia, a well-
known indication of susceptibility to postoperative
infections,32-35 was also present in most of these
patients. Therefore, it would appear that the nutri-
TABLE V
Number of patients with complications (minor or major) in the two trial
arms, in different strata defined by age, tumor localization,
weight loss, and transfusion
or
TPN, total parenteral nutrition; CTR. control group.
*Percentage calculated with respect to overall number of patients
within each strata and treatment group.
&dquo;Weight loss: Grade I (= 10c,., < 15% Grade II < =15%= < 25% !;
Grade III ’=25~).1,
12
TABLE VI
Nutritional variables in preoperative TPN
TPN, total parenteral nutrition; RBP, retinol-binding protein; TIBC, total iron-binding capacity.
tional risk of our patient population was well defined
and discrepancies in surgical technique minimized.
Some authors have claimed that certain side
effects of TPN, namely expansion of the extracellu-
lar fluid and increase in blood glucose level with the
accompanying risks, might outweigh the potential
benefits of TPN. This could at least partially
explain the negative results of similar trials. In
fact, in 1947, Gamble36 reported that glucose
induces sodium and water retention, and in 1975,
Rudman et a137 showed that this effect is potenti-
ated by the addition of sodium to the TPN. This
observation has subsequently been in the
replicated
clinical setting by other authors,3 ’39 who have
shown that glucose-rich TPN may cause excessive
water/weight gain. The clinical relevance of this
finding was made clear by the retrospective study of
Starker et a1,4° and more recently by the prospec-
tive study of Gil et al, 41 which demonstrated that
extracellular fluid retention may occur during pre-
operative TPN and have deleterious consequences
in the postoperative period. In fact, it is interesting
to note that in three different trials, 18,19,25 pulmo-
nary tract complications were more common in
patients who had received preoperative TPN than
in the control group. It has also been shown42 that
the distribution volume of antibiotics increases
with a glucose-rich TPN regimen.
A further risk posed by a glucose-based TPN reg-
imen that has recently been reported by Kwoun43 is
that TPN-related hyperglycemia is associated with
abnormalities in granulocyte adhesion, chemotaxis,
phagocytosis, respiratory burst function, and intra-
cellular killing44-4s; impairment of the complement
function 17 ; depressed immunity through nonenzy-
matic glycosylation of circulating immunoglobu-
lin 48 ; and finally, with increased susceptibility to
Candida infection. 47,19 Consequently, we were care-
ful to avoid excessive hydration; total fluid and
sodium intake administered with TPN was only
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2100 -~- 300 mL (approximately 42.6 ~- 7.3 mL/kg
body weight) and 1.6 ± 0.5 mEq/kg body weight,
respectively. The glucose load was 5.9 ± 1.3 g/kg/d,
which is well within the range of the oxidative
capacity of the body, and hyperglycemia was found
only sporadically. We were unable to find any relation-
ship between weight gain or dilutional hypoalbumine-
mia and occurrence of complications in the TPN group.
Furthermore, the amount of lipid emulsion we
administered was less than 0.12 g/kg/h (ie, the rate
above which emulsion triglyceride particles begin
to accumulate 50 with potentially adverse effects on
immunologic functions51,52 and pulmonary hemo-
dynamics53-55).
We were unable to pinpoint in the post-TPN period
and before surgery those patients at risk for complica-
tions who would have warranted special clinical sur-
veillance during the postoperative period. This means
that the indices monitored (body weight, serum albu-
min, peripheral lymphocytes) were poor indicators of
the potential clinical benefits of TPN and should be
used more as markers of nutritional risk than to mon-
itor the effects of TPN.
It is possible that financial constraints and payment
systems based on diagnosis-related groups will make a
10-day hospitalization for preoperative nutrition a
thing of the past. However, the cost of preoperative
TPN was not excessive in our study. Although we did
not specifically address the economic issues involved,
we can extrapolate from this trial that 10 patients
would need to be treated with TPN in order to avoid 1
death, with a net cost of about $5000 (U.S.).
This preoperative approach to malnourished pa-
tients could be reserved for those who must undergo an
extensive preoperative staging. Alternatively, IV feed-
ing could be administered at home before admittance
to the hospital, or other kind of perioperative nutrition
support should be explored.
It is worthy to note, however, that we were not able
to find any nutritional indicator of potential benefit of

TPN and the literature is poor for suggestions about
this. It could be possible that even a shorter period of
preoperative TPN that continues postoperatively
might be useful in these patients.
In conclusion, we believe that this study shows
that perioperative TPN has clinical benefits in can-
cer patients, provided that the patient’s weight loss
is at least 10%, that urgent surgery is not required,
and that the total fluids and calories administered
are adequate.
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