D R UG TH ER A PY
Drug Therapy
A L A S T A I R J . J . W O O D , M. D . , Editor
N UTRITIONAL S UPPORT
WILEY W. SOUBA, M.D., SC.D.
T
HE indications for providing nutrients by the
enteral or intravenous route (nutritional sup-
port) are not well defined, and the efficacy of
nutritional support in many circumstances is un-
proved. Nonetheless, nutritional support is widely
used for several reasons: malnutrition is common in
hospitalized patients,1,2 there is an association be-
tween malnutrition and increased morbidity3,4 and
mortality,5 it seems intuitively likely that well-nour-
ished patients will respond most favorably to treat-
ment, nutritional support can be administered safely
to most patients, and clinical trials indicate that it is
beneficial in selected patients.6-10
Virtually all patients can be fed intravenously or
enterally, because of the development of two impor-
tant techniques: the infusion of hypertonic nutrient
solutions by central venous catheterization and the
intraluminal administration of specific enteral diets
through a feeding tube. Both parenteral and enteral
formulations can deliver all essential nutrients, and
many patients who cannot eat normally live pro-
ductive lives while being nourished exclusively by
one or both of these routes. Although the justifica-
tion for providing nutritional support has been to
prevent or reverse the wasting of host tissue, the pri-
mary rationale for its use should be to improve clin-
ical outcome.
IDENTIFICATION OF MALNOURISHED
PATIENTS
Nutritional support is most frequently used as
short-term therapy for patients with protein-calorie
malnutrition, a state of undernutrition or starvation
resulting in a reduction in body cell mass. The con-
dition is common in hospitalized patients,1,2 and al-
though its evolution during illness frequently re-
flects the severity of the underlying disease or the
toxic effects of certain therapies, a cause-and-effect
From the Division of Surgical Oncology and the Nutrition Support
Service, Massachusetts General Hospital and Harvard Medical School, Bos-
ton. Address reprint requests to Dr. Souba at Massachusetts General Hos-
pital, Cox Bldg., Rm. 626, 100 Blossom St., Boston, MA 02114.
©1997, Massachusetts Medical Society.
Downloaded from www.nejm.org on May 6, 2007 . Copyright © 1997 Massachusetts Medical Society. All rights reserved.
relation between protein-calorie malnutrition and a
poorer outcome has not been definitely established.
The identification of protein-calorie malnutrition
has been based on objective measurements, including
weight,4 serum concentrations of proteins produced
by the liver,5 anthropometric measurements,1,2,11 grip
strength,12 anergy,13 immunologic functions,3 the
body-mass index,14 and the nutritional-risk index.7
No single measurement is highly sensitive and speci-
fic in identifying malnutrition. For example, although
serum albumin values are used to predict nutritional
risk,7 and a low serum albumin concentration at the
time of hospital admission can predict death and
length of stay,5 hypoalbuminemia is not specific to
poor nutritional status.3,5
In many patients, weight loss does not increase
the risk of treatment-associated complications.7,15
There is a strong relation between the absence of a
delayed hypersensitivity response and mortality, but
despite mild malnutrition in patients with anergy,
nutritional support has failed to correct the response
and the cellular immune dysfunction.13 Clinical as-
sessment (the history and physical examination) is as
effective as objective measurements in assessing a
patient’s nutritional status.16 The simplest way to
screen patients for malnutrition is to ask them about
unintentional weight loss. If reliable criteria for iden-
tifying malnourished patients at risk were estab-
lished, the value of nutritional intervention could be
studied more scientifically.
The magnitude of the patient’s metabolic stress
also affects the risk of malnutrition.10,17,18 For example,
the increase in basal metabolic rate that occurs during
and soon after major uncomplicated elective surgery
is less than 10 percent,19 so that providing dextrose
solutions (approximately 500 kcal per day) in the
postoperative period is sufficient, and further nutri-
tional support does not improve the outcome.15,20 Se-
verely injured patients, on the other hand, are mark-
edly hypermetabolic, and aggressive early feeding is
beneficial.9,10 Thus, the factors determining the risk of
malnutrition are multiple and interrelated, and in-
clude the patient’s previous nutritional status, the dis-
ease process itself, and the magnitude and anticipated
duration of associated catabolic stresses.
Another reason that it has been difficult to define
the role of nutritional support is the paucity of well-
designed clinical trials. Many studies have had inad-
equate experimental designs, heterogeneous study
groups, small samples, or inappropriate clinical end
points, or have been retrospective. In some studies
the efficacy of nutritional support may have been
masked by the inclusion of well-nourished patients
— those least likely to benefit from nutritional sup-
port. Some authors have inappropriately advocated
the use of nutritional support on the basis of tran-
sient improvements in nutritional measurements de-
spite a lack of effect on the clinical course.
Vol ume 336 Numbe r 1  41
 The New England Journal of Medicine

INDICATIONS FOR NUTRITIONAL
SUPPORT
The provision of nutritional support is based on
two rationales: that it will prevent the effects of star-
vation, such as death or infection, and that it will al-
ter favorably the natural history or treatment of a
specific disease. The first rationale is not disputable,
because patients who cannot eat will die of starva-
tion without nutritional support. The second as-
sumes that correcting nutritional or metabolic defi-
ciencies arising from the disease or its treatment will
improve the outcome. This rationale is controversial,
because improvements in nutritional markers, such
as serum protein concentrations,21 nitrogen bal-
ance,22 and weight gain,23 have not usually been ac-
companied by clinical benefits.
Nutritional support is clearly indicated when ade-
quate food intake is not possible for long periods.
In patients with specific intestinal disorders (such
as short-gut syndrome or chronic intestinal ob-
struction),24,25 permanent neurologic impairment,
or oropharyngeal dysfunction, and in premature in-
fants,26 long-term nutritional support is needed to
prevent death from starvation (Table 1). More often,
however, nutritional support is needed for less than
two weeks, until the disease process or the side ef-
fects of treatment resolve and oral feeding can be re-
sumed. One study of patients who had undergone
major surgery found that the outcome was worse in
the patients who were unable to eat for more than
14 days.15 Thus, nutritional support should probably
be used for nearly all patients who cannot eat for
similar periods of time. Nutritional support improves
the outcome in severely malnourished patients un-
dergoing major elective surgery, patients with major
trauma, and bone marrow–transplant recipients who
undergo intensive anticancer therapy.
Major Elective Surgery
The results of three randomized clinical trials6,7,27
and a meta-analysis28 indicate that preoperative par-
enteral nutrition in severely malnourished patients
— defined as those with weight losses greater than
10 to 15 percent, serum albumin concentrations less
than 2.8 g per deciliter, or scores of less than 83.5
on the nutrition-risk index7 — reduces the rate of
postoperative complications. The largest of these tri-
als involved 395 patients who underwent elective
laparotomy or thoracotomy.7 They were randomly
assigned to receive either parenteral nutrition for

TABLE 1. ESTABLISHED AND UNPROVED INDICATIONS FOR THE USE OF NUTRITIONAL SUPPORT.

ESTABLISHED INDICATION BENEFIT

Patients unable to eat or absorb nutrients for an indefinite period (permanent neuro- Preserves nutritional status; lifesaving
logic impairment, prematurity in an infant, oropharyngeal dysfunction, short-gut
syndrome)
Well-nourished, minimally stressed patients unable to eat for more than 10–14 days Preserves nutritional status; prevents starvation-induced complica-
tions
Severely malnourished patients who undergo major elective surgical procedures Preoperative nutrition decreases the incidence of major septic com-
plications
Patients with major trauma (major blunt or penetrating trauma, head injury, burn Enteral nutrition is superior to parenteral nutrition in decreasing
injury) the incidence of septic complications; nutritional support im-
proves outcome in patients with head injuries
Bone marrow–transplant recipients undergoing intensive anticancer therapy Improves outcome

UNPROVED INDICATIONS FOR OR EFFECTS

CONDITION OF NUTRITIONAL SUPPORT MATTERS REQUIRING FURTHER STUDY

Cancer Is indicated in patients with severe, treatment-associ- Can specific nutritional formulas improve the efficacy of anticancer
ated gastrointestinal toxic effects in whom oral therapy?
intake is precluded for more than 10 days, and in
patients with a reasonable life expectancy whose
inability to eat is the principal impediment to
normal functioning
Acquired immunodeficiency Preserves nutritional status Effect of nutritional support on treatment tolerance, quality of life,
syndrome number of hospitalizations, and survival
Gastrointestinal tract dysfunc- Preserves nutritional status; can induce disease remis- Effect of nutritional support on flare-ups and long-term outcome
tion sion in patients with Crohn’s disease; can increase in patients with inflammatory bowel disease
the rate of closure of enterocutaneous fistulas
Liver failure Formulas with branched-chain amino acids relieve Effect of nutritional support on survival
encephalopathy
Renal failure Treatment with glucose and essential amino acids may Effect of nutritional support on outcome and dialysis requirements
improve outcome and renal function in patients in patients with chronic renal failure
with acute renal failure
Critically ill (intensive care Nutritional support is indicated to prevent starvation- How long is too long to go without nutrition? Does nutritional
unit) patients (excluding induced complications in patients in whom oral support improve outcome in patients in intensive care units?
patients with trauma) intake is precluded for 7–10 days

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 D R UG TH ER A PY
7 to 15 days before surgery and 3 days afterward, or
a regular diet. Patients with mild malnutrition did
not benefit from parenteral nutrition but had more
infectious complications (such as pneumonia or
wound infections) than patients receiving a regular
diet. Patients with severe malnutrition who received
parenteral nutrition had a lower incidence of com-
plications related to healing (anastomotic disruption
or bronchopleural fistula) than patients receiving a
regular diet. This study has been criticized because
the patients in the control group consumed less than
half the number of calories that were administered
to the parenteral-nutrition group. In a similar study
of 125 patients with gastrointestinal carcinoma, pa-
tients who received preoperative parenteral nutrition
had fewer major postoperative complications (peri-
tonitis or anastomotic leakage), more improvement
in serum protein concentrations and immunologic
function, and a lower mortality rate than the pa-
tients receiving a regular hospital diet.6 This study
has been criticized because information about the
actual nutrient intake in the control group was not
provided and because of unusually high rates of mor-
bidity in that group. In a more recent study of min-
imally malnourished patients with hepatocellular
carcinomas, patients who received perioperative par-
enteral nutrition had significantly less postoperative
pneumonia and less need for diuretics to control as-
cites than patients who ate ad libitum.29
The effect of postoperative parenteral nutrition on
the outcome of major elective surgery has also been
evaluated. In one study of 300 patients treated with
parenteral nutrition or glucose alone,15 60 percent of
the patients in the parenteral-nutrition group were
eating by postoperative day 9, and they did not ben-
efit from parenteral nutrition. Among the patients
who received parenteral nutrition or glucose for 14
days because they could not eat, mortality was high-
er and postoperative complications were more com-
mon in the glucose group. Patients receiving short-
term glucose treatment (nine days or less) also had
significantly lower mortality than patients receiving
glucose for two weeks. The authors concluded that
parenteral nutrition was beneficial in patients who
could not eat within 14 days after surgery, but they
were unable to identify those patients preoperative-
ly. In another study, of 678 patients undergoing ma-
jor elective abdominal surgery, five to seven days of
postoperative parenteral nutrition (compared with a
5 percent glucose infusion) did not alter complica-
tion rates or mortality.30 Thus, some postoperative
weight loss is acceptable, and short-term treatment
with glucose solutions does not complicate recovery
after major surgery.
Collectively, these results suggest that preopera-
tive nutritional support should be reserved for se-
verely malnourished patients undergoing major elec-
tive surgery and should be provided for no more
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than 10 days.6,7,28,30 Whether longer periods are more
beneficial is uncertain. Postoperative nutritional sup-
port is indicated in patients who cannot eat by post-
operative day 10 to 14.15 Earlier intervention may be
indicated in patients with poor nutritional status and
those with postoperative complications. The transi-
tion to oral feeding should begin as soon as the pa-
tient’s gut is functional.
Major Trauma
In patients with major blunt or penetrating trau-
ma, enteral nutrition has been shown in several stud-
ies to be superior to total parenteral nutrition in
reducing major septic complications such as pneu-
monia and abscess.9,31-33 There were no control
groups (patients who received neither type of nutri-
tional support) in these studies, but in another study
the outcome correlated with enteral protein intake.34
Guidelines for nutritional support have been derived
empirically in patients with burns,35 because there
have been no rigorous clinical trials. In one study,
burned children receiving a high-nitrogen enteral
diet had better hepatic synthetic function, fewer
days of bacteremia, and higher rates of survival than
similar children receiving a normal diet.10 However,
the study was small, and the group on a high-nitro-
gen enteral diet received more nutrients intralumi-
nally and fewer nutrients intravenously than the nor-
mal-diet group.
Aggressive early nutritional support of patients
with severe head injuries is also beneficial.36-40 In two
studies, patients with head injuries who received par-
enteral nutrition had a more favorable outcome than
patients receiving enteral nutrition, but the paren-
teral-nutrition groups received more calories and ni-
trogen.37,38 Additional trials39,40 have shown that en-
teral nutrition is equivalent or superior to parenteral
nutrition when nutrient intake is controlled. Patients
with head injuries are candidates for parenteral nu-
trition if they cannot tolerate enteral feeding be-
cause of ileus or a high risk of aspiration.40
Nutritional support should begin soon after inju-
ry.9,10,31-33 Early enteral feeding in injured patients
(within 24 hours) has established benefits over feed-
ing later in the course of hospitalization.32 Feeding
should be discontinued when adequate oral intake is
achieved.
Bone Marrow Transplantation
Two randomized, prospective clinical trials sub-
stantiate the value of nutritional support in patients
undergoing bone marrow transplantation. In one
study, 137 patients with normal nutritional status
were randomly assigned to receive parenteral nutri-
tion (plus food taken ad libitum orally) for one week
before and four weeks after transplantation, or to re-
ceive hydration with 5 percent glucose (plus food
taken ad libitum orally).41 Patients randomly assigned
Vol ume 336 Numbe r 1  43
 The New England Journal of Medicine
to receive parenteral nutrition exceeded their calcu-
lated basal energy and nitrogen requirements, where-
as those in the glucose group received only about half
of their nutrient requirements. Parenteral nutrition
was associated with weight gain, increased serum
protein concentrations, and longer survival (21 vs.
7 months) and time to relapse as compared with
5 percent glucose. In a similar study, 61 patients re-
ceived parenteral or enteral nutrition for four weeks
after bone marrow transplantation.8 Enteral nutri-
tion was well tolerated, but three quarters of the pa-
tients required supplemental peripheral infusions of
amino acids for an average of one week to meet ni-
trogen needs. Although the enteral-feeding program
was less effective in maintaining body cell mass, the
hematopoietic recovery rate, length of hospitaliza-
tion, and survival did not differ between the groups.
Nutrition-related costs were 2.3 times greater in the
parenteral-nutrition group, suggesting that enteral
nutrition should be used if feasible.
UNPROVED BENEFITS OF NUTRITIONAL
SUPPORT
In some circumstances, the role of nutritional
support is less clear, because its ability to affect the
natural history or treatment of the disease is debat-
able. In these circumstances, nutritional support
may be indicated to prevent morbidity and mortality
from starvation. On the basis of studies demonstrat-
ing that the inability to eat for more than 10 to 14
days influences the outcome negatively,15 providing
nutritional support to patients who cannot eat for
more than 10 days is justifiable.
Chemotherapy and Radiation Therapy for Cancer
The results of the clinical trials of nutritional sup-
port in patients undergoing chemotherapy or radia-
tion therapy are conflicting. However, meta-analyses
reveal no benefit of nutritional support in terms of
survival, treatment tolerance, the side effects of anti-
cancer therapy, or the response of tumors to chemo-
therapy or radiation therapy.42,43 Patients undergoing
chemotherapy who receive total parenteral nutrition
have higher rates of pneumonia and sepsis.42
Selected patients with cancer who have severe
treatment-associated anorexia lasting more than 10
days should receive nutritional support to maintain
their nutritional status during treatment. Nutritional
support is also justified in malnourished patients with
cancer who can be expected to have a reasonable
quality and length of life and whose inability to eat
is the principal impediment to normal functioning.
Acquired Immunodeficiency Syndrome
No rigorous studies have been done to determine
the effects of nutritional support on the tolerance of
therapy, quality of life, number of hospitalizations,
or survival of patients infected with the human im-
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munodeficiency virus or in patients with the acquired
immunodeficiency syndrome (AIDS). In malnour-
ished patients with AIDS, enteral feeding was asso-
ciated with an increase in body potassium and serum
albumin concentrations, but no change in CD4 cell
counts.44 Parenteral nutrition promotes the accrual
of lean body mass in patients with AIDS who have
an inadequate nutrient intake or malabsorption,45
but the effect of nutritional support on more mean-
ingful clinical end points has not been established.
Gastrointestinal Tract Dysfunction
Total parenteral nutrition can induce remission in
60 to 70 percent of patients with active Crohn’s dis-
ease,46 but bowel rest alone, independent of nu-
tritional support, is not a major factor in inducing
remission, and the long-term outcome is unaffect-
ed.46-48 Enteral diets can be as effective as glucocor-
ticoid therapy in inducing remission, but the effects
of treatment on flare-ups or outcome were not eval-
uated in such patients.49-51 There are no trials com-
paring enteral with parenteral nutrition in patients
with active inflammatory bowel disease.
Total parenteral nutrition increases the rate of
spontaneous closure of enterocutaneous fistulas, but
reductions in mortality rates are due to the im-
proved care of fistulas rather than nutritional inter-
vention.52,53 Fistulas close within five weeks in 40 to
60 percent of patients treated with total parenteral
nutrition, and during this period the patients’ nutri-
tional status will be maintained should surgical in-
tervention be required. Although elemental diets
have been used in patients with distal intestinal fis-
tulas and jejunal-tube feedings have been adminis-
tered to patients with proximal fistulas to provide lu-
minal nutrition, there are no randomized studies
comparing parenteral with enteral nutrition.
Short-term total parenteral nutrition does not al-
ter the clinical course of severe acute pancreatitis,
and it results in a higher rate of catheter-related
sepsis54,55 and higher total hospital costs.22 However,
it is unclear how long nutritional support can be
withheld from patients with this condition. If it is
anticipated that the patient will not be able to eat
for 10 days, nutritional support should be initiated.
Earlier intervention may be indicated in patients
with preexisting weight loss or sepsis.
Liver Failure
The effectiveness of nutritional intervention in pa-
tients with liver failure is uncertain. Nutritional sup-
port may have beneficial effects on liver tissue and
on the biochemical abnormalities that develop in pa-
tients with hepatic insufficiency, and it may improve
survival. The principal data supporting this conten-
tion are from a multicenter study56 that found a 50
percent reduction in mortality among patients re-
ceiving parenteral nutrition enriched with branched-
 D R UG TH ER A PY
chain amino acids as compared with patients receiv-
ing 25 percent glucose and enteral neomycin. The
results of other studies57,58 and a meta-analysis59 did
not provide evidence of improved survival in patients
receiving nutritional support. Collectively, the stud-
ies indicate that formulas enriched with branched-
chain amino acids improved mental status in patients
with hepatic encephalopathy,59 but follow-up was
short. The enteral route of administration should be
used when the gut is functional.60 Enteral nutrition
is well tolerated after liver transplantation and is as
effective as parenteral nutrition in terms of out-
come.61
Renal Failure
In a well-designed clinical trial in 53 patients with
acute renal failure,62 survival was increased in the pa-
tients treated with parenteral glucose and essential
amino acids as compared with those treated with
glucose alone. In two similar but smaller studies,63,64
similar treatment did not accelerate the recovery of
renal function. In one of these studies,64 there was a
statistically insignificant improvement in survival in
patients receiving essential amino acids. Diets con-
taining amino acids of high biologic value may de-
crease the frequency of dialysis and improve the
nutritional status of patients with chronic renal fail-
ure,65 but this remains to be proved.
OPTIMAL ROUTE OF DELIVERY AND
COMPOSITION OF NUTRITIONAL
FORMULAS
The recommendation that the enteral route be
used preferentially for nutritional support is based
on cost information66 and on studies in injured
patients9,31-33 that demonstrate the superiority of en-
teral over parenteral nutrition. In one study of 98
patients with severe blunt or penetrating abdominal
trauma, enteral nutrition initiated within 24 hours
after injury was well tolerated and resulted in a lower
incidence of postoperative pneumonia, intraabdom-
inal abscess, and catheter-related sepsis than in pa-
tients with trauma who received parenteral nutri-
tion.31 Studies in patients with burns10 and head
injuries39 also indicate that early enteral nutrition is
beneficial. Recent studies in animals demonstrating
the importance of luminal feedings in supporting
the body’s mucosal immune system provide further
justification for enteral nutrition.67,68
The effects of total parenteral nutrition on the
gastrointestinal tract include decreases in brush-bor-
der hydrolase69 and nutrient-transporter activity,70
an increase in mucosal permeability,71 and a slight
decrease in microvillus height.71 With the resump-
tion of oral alimentation, brush-border enzyme ac-
tivities and microvillus height return to near-normal
values within one week.69 The splanchnic response
to endotoxin appears to be exaggerated in normal
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subjects fed parenterally as compared with subjects
fed enterally, suggesting that total parenteral nutri-
tion may amplify the metabolic derangements that
develop during sepsis.72 The incidence of pneumo-
nia and sepsis is increased in patients receiving par-
enteral nutrition.20,28,42
Despite its benefits, enteral nutrition is not used
in all eligible patients — that is, those with function-
al guts.73 Gastric retention, diarrhea, and abdominal
distention can limit the physician’s willingness to use
enteral feeding. The route of feeding is more im-
portant than the amount of nutrition provided,31
and the outcome correlates with the enteral protein
intake in injured patients.34 Thus, even if the pa-
tient’s calorie and nitrogen requirements cannot be
met with luminal nutrition, the enteral route of
feeding should be used unless it is contraindicated
(for example, by bowel obstruction, intractable diar-
rhea, an inadequate bowel-surface area, or feeding
intolerance). The enteral and parenteral routes may
be used simultaneously to meet nutritional require-
ments.
A variety of parenteral and enteral solutions con-
taining various amounts of protein (amino acids),
carbohydrate (glucose), fat, micronutrients, and elec-
trolytes have been used. No single formulation has
been found to be ideal for all patients. Energy and
nitrogen requirements can be estimated from nomo-
grams19 and will vary depending on the patient’s
body-surface area, nutritional status, and degree of
hypermetabolism. Minimally stressed patients re-
quire about 25 to 30 kcal per kilogram of body
weight per day and 1 g of protein per kilogram per
day to remain in nitrogen and energy equilibrium.
Energy requirements may double and protein re-
quirements may triple in severely burned patients.35
Critically ill patients metabolize glucose at reduced
rates, so that the exogenous glucose load should not
exceed approximately 500 g per day.74 Although fat
is an efficient source of energy, the amount that
should be provided to patients is controversial.
Monitoring of patients receiving nutritional sup-
port, particularly parenteral nutrition, should in-
clude periodic evaluation of serum electrolyte and
glucose concentrations, liver function, and nitrogen
balance. Weight gain of more than 1 kg per week
generally indicates a positive fluid balance rather
than the accrual of lean body mass. Complications
of the use of nutritional support range from mild
electrolyte disorders to life-threatening sepsis.
BENEFITS AND COSTS OF NUTRITIONAL
SUPPORT
Nutritional support is an expensive technological
innovation. Data from published clinical trials indi-
cate that nutritional support is currently overused
and improperly used. Although many studies have
shown that nutritional intervention can alter bio-
Vol ume 336 Numbe r 1  45
 The New England Journal of Medicine

chemical and metabolic indexes, few have docu-
mented an improvement in clinical outcome.
In patients who cannot eat for more than 10 to
14 days, nutritional support is indicated to prevent
morbidity and mortality from starvation. In patients
with major trauma9,31 and in severely malnourished
patients undergoing major elective surgery,6,7 the re-
duction in major complications associated with the
use of nutritional support is not associated with a re-
duction in the length of the hospital stay. Enteral
nutrition is less expensive than parenteral nutrition,
but studies in patients with trauma demonstrating
the benefits of immediate postoperative enteral nu-
trition have not compared total patient costs or care-
fully evaluated survival. Nutritional support can
improve the outcome in bone marrow–transplant re-
cipients.8,41
FUTURE DIRECTIONS AND CONCLUSIONS
Despite aggressive nutritional support, it is often
difficult to attenuate the catabolic response to illness
or injury.18 Several new strategies to accomplish this
are under investigation. These include the adminis-
tration of growth hormone to promote anabolism,
the provision of conditionally essential amino acids
(glutamine), and the use of diets enriched with ar-
ginine, nucleotides, and n3 fatty acids75,76 — nutri-
ents that can modulate immune function. Although
use of these “immune-enhancing” diets has been ad-
vocated, their benefits remain controversial.77
Glutamine is not routinely added to parenteral-
nutrition solutions and is present in low concentra-
tions in most enteral formulations. The results of
clinical trials suggest that glutamine supplementa-
tion may be beneficial in selected groups of patients
(Table 2). These studies have shown that glutamine
(0.2 to 0.5 g per kilogram per day) is safe and inex-
pensive and results in an improvement in nitrogen
balance78,79,81 and gut barrier function,71 a decrease
in infections79 and in the number of days of ventila-
tory support,82 and a reduction in the length of the
hospital stay79,80 and in expenses.79,81 These studies
have focused on the use of parenteral glutamine, and
there is a need for studies to evaluate the efficacy of
glutamine-enriched enteral feedings.
The administration of recombinant human growth
hormone as an adjunct to nutritional support im-
proves the intestinal uptake of amino acids83 and the
retention of nitrogen,84-88 but whether these bio-
chemical changes are associated with an improvement
in outcome is not known.
Several conclusions can be drawn from the studies
that have been done. Most patients do not require
formal nutritional support; clear-cut benefits have
been established only in select groups of patients
(Table 1). In most patients, short-term treatment (10
to 14 days) with isotonic glucose solutions does not
affect the outcome negatively after major elective
operations or other therapy. To prevent starvation-
induced complications, nutritional support should
be initiated in most patients who are unable to eat
for more than 10 to 14 days. Stressed patients tol-

TABLE 2. CLINICAL STUDIES EVALUATING THE USE OF GLUTAMINE-ENRICHED PARENTERAL NUTRITION.

PROCEDURE OR CONDITION TYPE OF RESULTS OF GLUTAMINE

STUDIED STUDY END POINTS MEASURED SUPPLEMENTATION COMMENTS

Postoperative resection Clinical trial Nitrogen balance; muscle Improved cumulative nitrogen bal- These patients would not ordinarily re-
for colorectal cancer78 glutamine concentration ance; preserved muscle glutamine ceive nutritional support; effect on
concentrations outcome was not evaluated
Bone marrow transplanta- Clinical trial Nitrogen balance; incidence Improved nitrogen balance; dimin- Improvements observed despite the
tion for hematologic of infection; length of hos- ished incidence of infection; short- absence of differences between
cancers79 pital stay ened hospital stay by 7 days groups in the incidence of fever,
need for antibiotics, or time to
neutrophil engraftment
Bone marrow transplanta- Clinical trial Total body water; clinical in- Reduction in total body water; A 6-day reduction in hospital stay was
tion (liquid or solid fections; length of hospital reduced length of hospital stay associated with considerable cost
tumors)80 stay savings
Gastrointestinal diseases71 Clinical trial Intestinal permeability; mu- Improved defect in gut permeability; Glutamine is a principal gut mucosal
cosal morphometrics preserved mucosal structure fuel; it is unclear whether the chang-
es in permeability or morphology
accurately reflect gut barrier
function
Short-gut syndrome 81 Each patient Nutrient absorption; stool 39% improvement in protein absorp- Growth hormone was administered in
served as output; need for parenteral tion; 33% decrease in stool volume; conjunction with glutamine
own control nutrition; cost reduction in need for total paren-
teral nutrition; cost savings
Prematurity in infants 82 Clinical trial Number of days of parenteral Reduction in days of parenteral nutri- A larger study with longer follow-up is
nutrition; time to full feed- tion, days of ventilator use, and necessary to evaluate fully the safety
ing; days of ventilator use; time to full feeding; a trend toward of this treatment
length of hospital stay a shortened hospital stay in babies
weighing 800 g who received
glutamine

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 D R UG TH ER A PY
erate starvation for shorter periods, but it is de-
batable how long nutritional support can be with-
held from critically ill patients.89 The limited data
preclude drawing conclusions, except in severely in-
jured patients and in bone marrow–transplant re-
cipients, in whom early enteral nutrition is bene-
ficial.9,31,41
The lack of evidence that nutritional support af-
fects the outcome favorably in a particular circum-
stance does not necessarily condemn its use. In se-
lected patients, such as those with cancer who have
very short life expectancies or those in intensive care
units whose families have chosen to withhold care
other than comfort measures, nutritional support
should not be initiated. When nutritional support is
used, the enteral route is always preferred.
Finally, the hospital nutritional-support team must
justify its role by demonstrating that it provides
quality control and polices the administration of
nutritional support to avoid its inappropriate use.
Simultaneously, patients who need nutritional sup-
port should be identified and nourished. The nutri-
tional-support team should participate in developing
clinical pathways and implementing measurements
of outcomes.90
Although the dividends from nutritional support
have been modest, this should not dampen our en-
thusiasm, because there are investigational areas that
should be actively pursued (Table 1). Carefully con-
ducted clinical trials may identify additional groups
of patients who will benefit from nutritional inter-
vention.
REFERENCES
1. Bistrian BR, Blackburn GL, Vitale J, Cochran D, Naylor J. Prevalence
of malnutrition in general medical patients. JAMA 1976;235:1567-70.
2. Bistrian BR, Blackburn GL, Hallowell E, Heddle R. Protein status of
general surgical patients. JAMA 1974;230:858-60.
3. Chandra RK. Nutrition, immunity, and infection: present knowledge
and future directions. Lancet 1983;1:688-91.
4. Windsor JA, Hill GL. Risk factors of postoperative pneumonia: the im-
portance of protein depletion. Ann Surg 1988;208:209-14.
5. Herrmann FR, Safran C, Levkoff SE, Minaker KL. Serum albumin level
on admission as a predictor of death, length of stay, and readmission. Arch
Intern Med 1992;152:125-30.
6. Muller JM, Brenner U, Dienst C, Pichlmaier H. Preoperative parenteral
feeding in patients with gastrointestinal cancer. Lancet 1982;1:68-71.
7. The Veterans Affairs Total Parenteral Nutrition Cooperative Study
Group. Perioperative total parenteral nutrition in surgical patients. N Engl
J Med 1991;325:525-32.
8. Szeluga DJ, Stuart RK, Brookmeyer R, Utermohlen V, Santos G. Nu-
tritional support of bone marrow transplant recipients: a prospective, ran-
domized clinical trial comparing total parenteral nutrition to an enteral
feeding program. Cancer Res 1987;47:3309-16.
9. Moore FA, Feliciano DV, Andrassy RJ, et al. Early enteral feeding, com-
pared with parenteral, reduces postoperative septic complications: the re-
sults of a meta-analysis. Ann Surg 1992;216:172-83.
10. Alexander JW, MacMillan BG, Stinnett JD, et al. Beneficial effects of
aggressive protein feeding in severely burned children. Ann Surg 1980;192:
505-17.
11. Weinsier RL, Hunker EM, Krumdieck CL, Butterworth CE Jr. Hos-
pital malnutrition: a prospective evaluation of general medical patients dur-
ing the course of hospitalization. Am J Clin Nutr 1979;32:418-26.
12. Klidjian AM, Foster KJ, Kammerling RM, Cooper A, Karran SJ. Rela-
tion of anthropometric and dynamometric variables to serious postopera-
tive complications. BMJ 1980;281:899-901.
13. Christou NV, Meakins JL, Gordon J, et al. The delayed hypersensitiv-
Downloaded from www.nejm.org on May 6, 2007 . Copyright © 1997 Massachusetts Medical Society. All rights reserved.
ity response and host resistance in surgical patients: 20 years later. Ann
Surg 1995;222:534-48.
14. Heymsfield SB, Tighe A, Wang ZM. Nutritional assessment by anthro-
pometric and biochemical methods. In: Shils ME, Olson JA, Shike M, eds.
Modern nutrition in health and disease. 8th ed. Philadelphia: Lea & Feb-
iger, 1994:812-41.
15. Sandstrom R, Drott C, Hyltander A, et al. The effect of postoperative
intravenous feeding (TPN) on outcome following major surgery evaluated
in a randomized study. Ann Surg 1993;217:185-95.
16. Baker JP, Detsky AS, Wesson DE, et al. Nutritional assessment: a com-
parison of clinical judgment and objective measurements. N Engl J Med
1982;306:969-72.
17. Clifton GL, Robertson CS, Choi SC. Assessment of nutritional re-
quirements of head-injured patients. J Neurosurg 1986;64:895-901.
18. Monk DN, Plank LD, Franch-Arcas G, Finn PJ, Streat SJ, Hill GL.
Sequential changes in the metabolic response in critically injured patients
during the first 25 days after blunt trauma. Ann Surg 1996;223:395-405.
19. Wilmore DW. The metabolic management of the critically ill. New
York: Plenum Medical, 1977:36.
20. Brennan MF, Pisters PWT, Posner M, Quesada O, Shike M. A pro-
spective randomized trial of total parenteral nutrition after major pancre-
atic resection for malignancy. Ann Surg 1994;220:436-44.
21. De Cicco M, Panarello G, Fantin D, et al. Parenteral nutrition in can-
cer patients receiving chemotherapy: effects on toxicity and nutritional sta-
tus. JPEN J Parenter Enteral Nutr 1993;17:513-8.
22. Sax HC, Warner BW, Talamini MA, et al. Early total parenteral nutri-
tion in acute pancreatitis: lack of beneficial effects. Am J Surg 1987;153:
117-24.
23. Valdivieso M, Frankmann C, Murphy WK, et al. Long-term effects of
intravenous hyperalimentation administered during intensive chemothera-
py for small cell bronchogenic carcinoma. Cancer 1987;59:362-9.
24. Gouttebel MC, Saint-Aubert B, Astre C, Joyeux H. Total parenteral
nutrition needs in different types of short bowel syndrome. Dig Dis Sci
1986;31:718-23.
25. Messing B, Lemann M, Landais P, et al. Prognosis of patients with
nonmalignant chronic intestinal failure receiving long-term home parenter-
al nutrition. Gastroenterology 1995;108:1005-10.
26. Driscoll JM Jr, Heird WC, Schullinger JN, Gongaware RD, Winters
RW. Total intravenous alimentation in low-birth-weight infants: a prelimi-
nary report. J Pediatr 1972;81:145-53.
27. Bellantone R, Doglietto GB, Bossola M, et al. Preoperative parenteral
nutrition in the high risk surgical patient. JPEN J Parenter Enteral Nutr
1988;12:195-7.
28. Detsky AS, Baker JP, O’Rourke K, Goel V. Perioperative parenteral nu-
trition: a meta-analysis. Ann Intern Med 1987;107:195-203.
29. Fan S-T, Lo C-M, Lai ECS, Chu K-M, Liu C-L, Wong J. Perioperative
nutritional support in patients undergoing hepatectomy for hepatocellular
carcinoma. N Engl J Med 1994;331:1547-52.
30. Doglietto GB, Gallitelli L, Pacelli F, et al. Protein-sparing therapy after
major abdominal surgery: lack of clinical effects. Ann Surg 1996;223:357-
62.
31. Kudsk KA, Croce MA, Fabian TC, et al. Enteral versus parenteral feed-
ing: effects on septic morbidity following blunt and penetrating abdominal
trauma. Ann Surg 1992;215:503-13.
32. Moore EE, Jones TN. Benefits of immediate jejunostomy feeding after
major abdominal trauma — a prospective, randomized study. J Trauma
1986;26:874-81.
33. Moore FA, Moore EE, Jones TN, McCroskey BL, Peterson VM. TEN
versus TPN following major abdominal trauma — reduced septic morbid-
ity. J Trauma 1989;29:916-23.
34. Border JR, Hassett J, LaDuca J, et al. The gut origin septic states in
blunt multiple trauma (ISS40) in the ICU. Ann Surg 1987;206:427-48.
35. Cunningham JJ, Lydon MK, Russell WE. Calorie and protein provi-
sion for recovery from severe burns in infants and young children. Am J
Clin Nutr 1990;51:553-7.
36. Young B, Ott L, Twyman D, et al. The effect of nutritional support
on outcome from severe head injury. J Neurosurg 1987;67:668-76.
37. Rapp RP, Young B, Twyman D, et al. The favorable effect of early par-
enteral feeding on survival in head-injured patients. J Neurosurg 1983;58:
906-12.
38. Hadley MN, Grahm TW, Harrington T, Schiller WR, McDermott
MK, Posillico DB. Nutrition support and neurotrauma: a critical review of
early nutrition in forty-five acute head injury patients. Neurosurgery 1986;
19:367-73.
39. Grahm TW, Zadrozny DB, Harrington T. The benefits of early jejunal
hyperalimentation in the head-injured patient. Neurosurgery 1989;25:
729-35.
40. Norton JA, Ott LG, McClain C, et al. Intolerance to enteral feeding
in the brain-injured patient. J Neurosurg 1988;68:62-6.
41. Weisdorf SA, Lysne J, Wind D, et al. Positive effect of prophylactic to-
Vol ume 336 Numbe r 1  47
 The New England Journal of Medicine
tal parenteral nutrition on long-term outcome of bone marrow transplan-
tation. Transplantation 1987;43:833-8.
42. Klein S, Simes J, Blackburn GL. Total parenteral nutrition and cancer
clinical trials. Cancer 1986;58:1378-86.
43. American College of Physicians. Parenteral nutrition in patients receiv-
ing cancer chemotherapy. Ann Intern Med 1989;110:734-6.
44. Kotler DP, Tierney AR, Ferraro R, et al. Enteral alimentation and re-
pletion of body cell mass in malnourished patients with acquired immuno-
deficiency syndrome. Am J Clin Nutr 1991;53:149-54.
45. Kotler DP, Tierney AR, Culpepper-Morgan JA, Wang J, Pierson RN
Jr. Effect of home total parenteral nutrition on body composition in pa-
tients with acquired immunodeficiency syndrome. JPEN J Parenter Enteral
Nutr 1990;14:454-8.
46. Greenberg GR, Fleming CR, Jeejeebhoy KN, Rosenberg IH, Sales D,
Tremaine WJ. Controlled trial of bowel rest and nutritional support in the
management of Crohn’s disease. Gut 1988;29:1309-15.
47. Dickinson RJ, Ashton MG, Axon AT, Smith RC, Yeung CK, Hill GL.
Controlled trial of intravenous hyperalimentation and total bowel rest as
an adjunct to the routine therapy of acute colitis. Gastroenterology 1980;
79:1199-204.
48. McIntyre PB, Powell-Tuck J, Wood SR, et al. Controlled trial of bowel
rest in the treatment of severe acute colitis. Gut 1986;27:481-5.
49. O’Morain C, Segal AW, Levi AJ. Elemental diet as a primary treatment
of acute Crohn’s disease: a controlled trial. BMJ 1984;288:1859-62.
50. Saverymuttu S, Hodgson HJ, Chadwick VS. Controlled trial compar-
ing prednisolone with an elemental diet plus non-absorbable antibiotics in
active Crohn’s disease. Gut 1985;26:994-8.
51. Gonzalez-Huix F, de Leon R, Fernandez-Banares F, et al. Polymeric
enteral diets as primary treatment of active Crohn’s disease: a prospective
steroid controlled trial. Gut 1993;34:778-82.
52. Rose D, Yarborough MF, Canizaro PC, Lowry SF. One hundred and
fourteen fistulas of the gastrointestinal tract treated with total parenteral
nutrition. Surg Gynecol Obstet 1986;163:345-50.
53. Soeters PB, Ebeid AM, Fischer JE. Review of 404 patients with gas-
trointestinal fistulas: impact of parenteral nutrition. Ann Surg 1979;190:
189-202.
54. Grant JP, James S, Grabowski V, Trexler KM. Total parenteral nutrition
in pancreatic disease. Ann Surg 1984;200:627-31.
55. Goodgame JT, Fischer JE. Parenteral nutrition in the treatment of
acute pancreatitis: effect on complications and mortality. Ann Surg 1977;
186:651-8.
56. Cerra FB, Cheung NK, Fischer JE, et al. Disease-specific amino acid
infusion (F080) in hepatic encephalopathy: a prospective, randomized,
double-blind, controlled trial. JPEN J Parenter Enteral Nutr 1985;9:288-
95.
57. Naveau S, Pelletier G, Poynard T, et al. A randomized clinical trial of
supplementary parenteral nutrition in jaundiced alcoholic cirrhotic pa-
tients. Hepatology 1986;6:270-4.
58. Nasrallah SM, Galambos JT. Aminoacid therapy of alcoholic hepatitis.
Lancet 1980;2:1276-7.
59. Naylor CD, O’Rourke K, Detsky AS, Baker JP. Parenteral nutrition
with branched-chain amino acids in hepatic encephalopathy: a meta-anal-
ysis. Gastroenterology 1989;97:1033-42.
60. Cabre E, Gonzalez-Huix F, Abad-Lacruz A, et al. Effect of total en-
teral nutrition on the short-term outcome of severely malnourished cir-
rhotics: a randomized controlled trial. Gastroenterology 1990;98:715-20.
61. Wicks C, Somasundaram S, Bjarnason I, et al. Comparison of enteral
feeding and total parenteral nutrition after liver transplantation. Lancet
1994;344:837-40.
62. Abel RM, Beck CH Jr, Abbott WM, Ryan JA Jr, Barnett GO, Fischer
JE. Improved survival from acute renal failure after treatment with intrave-
nous essential L-amino acids and glucose: results of a prospective, double-
blind study. N Engl J Med 1973;288:695-9.
63. Leonard CD, Luke RG, Siegel RR. Parenteral essential amino acids in
acute renal failure. Urology 1975;6:154-7.
64. Feinstein EI, Blumenkrantz MJ, Healy M, et al. Clinical and metabolic
responses to parenteral nutrition in acute renal failure. Medicine (Balti-
more) 1981;60:124-37.
65. Kopple JD. Effect of nutrition on morbidity and mortality in mainte-
nance dialysis patients. Am J Kidney Dis 1994;24:1002-9.
66. Bower RH, Talamini MA, Sax HC, Hamilton F, Fischer JE. Postoper-
ative enteral vs parenteral nutrition: a randomized controlled trial. Arch
Surg 1986;121:1040-5.
48  Januar y 2 , 1 9 9 7
Downloaded from www.nejm.org on May 6, 2007 . Copyright © 1997 Massachusetts Medical Society. All rights reserved.
67. Kudsk KA, Li J, Renegar KB. Loss of upper respiratory tract immunity
with parenteral feeding. Ann Surg 1996;223:629-38.
68. Li J, Kudsk KA, Gocinski B, Dent D, Glezer J, Langkamp-Henken B.
Effects of parenteral and enteral nutrition on gut-associated lymphoid tis-
sue. J Trauma 1995;39:44-52.
69. Guedon C, Schmitz J, Lerebours E, et al. Decreased brush border hy-
drolase activities without gross morphologic changes in human intestinal
mucosa after prolonged total parenteral nutrition of adults. Gastroenterol-
ogy 1986;90:373-8.
70. Inoue Y, Espat NJ, Frohnapple DJ, Epstein H, Copeland EM, Souba
WW. Effect of total parenteral nutrition on amino acid and glucose trans-
port by the human small intestine. Ann Surg 1993;217:604-14.
71. van der Hulst RR, van Kreel BK, von Meyenfeldt MF, et al. Glutamine
and the preservation of gut integrity. Lancet 1993;341:1363-5.
72. Fong YM, Marano MA, Barber A, et al. Total parenteral nutrition and
bowel rest modify the metabolic response to endotoxin in humans. Ann
Surg 1989;210:449-57.
73. Heyland D, Cook DJ, Winder B, Brylowski L, Van deMark H, Guyatt
G. Enteral nutrition in the critically ill patient: a prospective survey. Crit
Care Med 1995;23:1055-60.
74. Wolfe RR, Durkot MJ, Allsop JR, Burke JF. Glucose metabolism in
severely burned patients. Metabolism 1979;28:1031-9.
75. Daly JM, Lieberman MD, Goldfine J, et al. Enteral nutrition with sup-
plemental arginine, RNA, and omega-3 fatty acids in patients after opera-
tion: immunologic, metabolic, and clinical outcome. Surgery 1992;112:
56-67.
76. Bower RH, Cerra FB, Bershadsky B, et al. Early enteral administration
of a formula (Impact) supplemented with arginine, nucleotides, and fish oil
in intensive care unit patients: results of a multicenter, prospective, random-
ized, clinical trial. Crit Care Med 1995;23:436-49.
77. Koretz RL. The impact of immunonutrition. Gastroenterology 1995;
109:1713-4.
78. Stehle P, Zander J, Mertes N, et al. Effect of parenteral glutamine pep-
tide supplements on muscle glutamine loss and nitrogen balance after ma-
jor surgery. Lancet 1989;1:231-3.
79. Ziegler TR, Young LS, Benfell K, et al. Clinical and metabolic efficacy
of glutamine-supplemented parenteral nutrition after bone marrow trans-
plantation: a randomized, double-blind, controlled study. Ann Intern Med
1992;116:821-8.
80. Schloerb PR, Amare M. Total parenteral nutrition with glutamine in
bone marrow transplantation and other clinical applications (a random-
ized, double-blind study). JPEN J Parenter Enteral Nutr 1993;17:407-
13.
81. Byrne TA, Persinger RL, Young LS, Ziegler TR, Wilmore DW. A new
treatment for patients with short-bowel syndrome: growth hormone,
glutamine, and a modified diet. Ann Surg 1995;222:243-55.
82. Lacey JM, Crouch JB, Benfell K, et al. The effects of glutamine-sup-
plemented parenteral nutrition in premature infants. JPEN J Parenter En-
teral Nutr 1996;20:74-80.
83. Inoue Y, Copeland EM, Souba WW. Growth hormone enhances
amino acid uptake by the human small intestine. Ann Surg 1994;219:715-
24.
84. Ziegler TR, Lazarus JM, Young LS, Hakim R, Wilmore DW. Effects
of recombinant human growth hormone in adults receiving maintenance
hemodialysis. J Am Soc Nephrol 1991;2:1130-5.
85. Suchner U, Rothkopf MM, Stanislaus G, Elwyn DH, Kvetan V,
Askanazi J. Growth hormone and pulmonary disease: metabolic effects in
patients receiving parenteral nutrition. Arch Intern Med 1990;150:1225-
30.
86. Ziegler TR, Rombeau JL, Young LS, et al. Recombinant human
growth hormone enhances the metabolic efficacy of parenteral nutrition:
a double-blind, randomized controlled study. J Clin Endocrinol Metab
1992;74:865-73.
87. Voerman HJ, van Schijndel RJ, Groeneveld AB, et al. Effects of recom-
binant human growth hormone in patients with severe sepsis. Ann Surg
1992;216:648-55.
88. Mulligan K, Grunfeld C, Hellerstein M, Schambelan M. Growth hor-
mone treatment of HIV-associated catabolism. FASEB J 1992;6:A1942.
abstract.
89. Koretz RL. Nutritional supplementation in the ICU: how critical is
nutrition for the critically ill? Am J Respir Crit Care Med 1995;151:570-3.
90. Nelson J. The impact of health care reform on nutrition support —
the practitioner’s perspective. Nutr Clin Pract 1995;4:1-7.