Early nutritional therapy: the role of enteral and parenteral routes

José E. de Aguilar-Nascimentoa and Kenneth A. Kudskb,c

a
Department of Surgery, Federal University of Mato
Grosso, Cuiaba, Brazil, bThe Veterans Administration
Surgical Services, William S. Middleton Memorial
Veterans Hospital and cDepartment of Surgery,
University of Wisconsin-Madison College of Medicine
and Public Health, Madison, Wisconsin, USA
Correspondence to Dr José E. de Aguilar-Nascimento,
MD, PhD, Rua Estevão de Mendonça 81 apto 801,
78043-300 Cuiaba, Brazil
Tel/fax: +55 65 36234020;
e-mail: aguilar@terra.com.br
Current Opinion in Clinical Nutrition and
Metabolic Care 2008, 11:255–260
Purpose of review
Early nutrition is defined as the initiation of nutritional therapy within 48 h of either
hospital admission or surgery. However, optimal timing for initiation of nutritional therapy
through either enteral or parenteral routes remains poorly defined with the existing data.
We reviewed the recent literature investigating the role of early enteral and parenteral
nutrition in critical illness and perioperative care.
Recent findings
Recent studies in both trauma/surgical and nonsurgical patients support the superiority
of early enteral over early parenteral nutrition. However, late commencement of enteral
feeding should be avoided if the gastrointestinal tract is functional. Both prolonged
hypocaloric enteral feeding and hypercaloric parenteral nutrition should be avoided,
although the precise caloric target remains controversial.
Summary
Early enteral nutrition remains the first option for the critically ill patient. However, there
seems to be increased favor for combined enteral–parenteral therapy in cases of
sustained hypocaloric enteral nutrition. The key issue is when the dual regimen should
be initiated. Although more study is required to determine the optimal timing to initiate a
combined enteral–parenteral approach, enteral nutrition should be initiated early and
parenteral nutrition added if caloric–protein targets cannot be achieved after a few
days.

Keywords
critical care, enteral nutrition, parenteral nutrition, perioperative care

Curr Opin Clin Nutr Metab Care 11:255–260

ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
1363-1950

ity, lower costs, and shorter length of hospital stay com-

Introduction
Various consensus statements and guidelines from pro-
fessional societies around the world recommend early and
adequate initiation of specialized nutrition therapy for
critically ill patients admitted for medical and surgical
conditions [1–6]. These clinical conditions are usually
associated with an increased metabolic rate, acute
changes in the immune system, and an amplified inflam-
matory systemic response [5]. This excessive response to
injury produces a significant mobilization and loss of lean
tissue that aggravates any preexisting malnutrition [7].
Malnutrition is most common in ICU setting and is
definitively associated with more complications, a longer
hospitalization, and higher hospital costs [6,8]. Thus,
rationale for early nutritional therapy attempts to mini-
mize the nutritional component of this condition and
improve clinical outcome [2,6].
In the past decade, enteral nutrition has been preferred
over parenteral nutrition to deliver nutrients if the gut
functions [9,10]. Early [11,12] laboratory research, recent
[13
,14
] experimental studies, and various randomized
trials [15,16] and meta-analyses [4,17,18] support this
concept. Enteral nutrition is associated with less morbid-
pared with parenteral nutrition. The main reasons for
these findings are probably the preservation of both the
mucosal barrier and immune competence induced by the
delivery of food into the gut [19].
Early nutrition is defined as the initiation of nutritional
therapy within 48 h of either hospital admission or surgery
[1,2,6]. However, optimal timing for initiation of nutri-
tional therapy through either enteral or parenteral route
remains poorly defined. The Canadian guidelines for
nutrition support in mechanically ventilated, critically
ill adult patients recommend that parenteral nutrition
not be started until all strategies have been attempted to
maximize enteral nutrition delivery [4]. Practice guide-
lines published by The American Society for Parenteral
and Enteral Nutrition (ASPEN) recommend that par-
enteral nutrition be delayed particularly if enteral feeding
can be provided or is expected to be resumed within
7 days [2]. These conclusions follow the examination of
many studies evaluating the use of parenteral nutrition
where the majority of patients resumed consumption of
an oral diet within 6–8 days. These patients are unlikely
to benefit from such a short course of early parenteral

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 256 Pharmaceutical issues and technical problems
nutrition (EPN) administration. Even with significant
malnutrition, a few days of parenteral nutrition is unlikely
to yield substantial benefit [20].
The clinical status of the patient influences the timing,
optimal caloric load/composition, and route for nutritional
support (enteral nutrition vs. parenteral nutrition).
Although preoperative parenteral nutrition administered
to severely malnourished patients reduces postoperative
complications, initiation of parenteral nutrition in well
nourished patients after major operations appears to
increase the chance of infection [3]. Parenteral nutrition
allows a more rapid advancement of nutrients to goal rate
than enteral nutrition so that the total caloric intake is
generally faster with parenteral nutrition. This may result
in more hyperglycemia with parenteral nutrition than
with enteral nutrition [21]. Without preexisting severe
malnutrition, early aggressive administration of paren-
teral nutrition to a hypermetabolic patient may not pro-
vide any benefit. A meta-analysis focusing on parenteral
nutrition vs. standard care showed that parenteral nutri-
tion may increase risks for the critically ill patients [21]
such that the benefits associated with early enteral nutri-
tion (EEN) may not occur with EPN. Therefore, we
reviewed the recent literature investigating the role of
early enteral and parenteral nutrition in critical illness and
perioperative care.
Is early enteral nutrition always possible? The
role for combined enteral–parenteral
nutrition
A recent multicentered German study documented that
enteral nutrition provided the sole source of nutrition
support in only 16.8% of critically ill patients in most of
the ICUs with a combined enteral–parenteral regimen
used in most patients (69.8%) [22]. Less than 14% of
patients used parenteral nutrition alone. This study
showed both an increased use of combined enteral–
parenteral regimen and a decreased use of parenteral
nutrition alone in critically ill patients compared with
an earlier European study [23].
The guts of many postoperative/trauma patients and
nonsurgical critically ill patients remain functional
enough so that the patients can be fed enterally, although
not necessarily at goal rate. Therefore, the calculated
energy requirements may be more difficult to attain with
enteral nutrition than with parenteral nutrition in criti-
cally ill patients [24]. In addition, even when enteral
nutrition is tolerated, the nutritional target with enteral
nutrition may require 5–7 days to achieve goal rate for
many reasons. Delay may be due to gastrointestinal
intolerance from gastroparesis, adynamic ileus, and diar-
rhea. Other factors such as mechanical ventilation,
opiates, sedatives, and catecholamines [25,26] may also
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
delay advancement of enteral nutrition. In addition,
advancement of a nasoenteral tube to a suitable location
for enteral nutrition administration may be challenging
and require transport of the patient to the radiological or
endoscopic suite. Blind advancement of a styleted tube
may injure the patient because of inadvertent airway
displacement [27
,28]. Therefore, prolonged hypocaloric
feeding from these factors explains the rationale for com-
bined enteral–parenteral nutrition regimen [22,24–26].
Implementing combined enteral–parenteral
feeding
Although the precise caloric target remains controversial,
the general consensus advocates avoidance of prolonged
hypocaloric or hypercaloric feeding [29
]. Insisting on
enteral nutrition as the sole route for nutrition support
may result in prolonged under-feeding; hence, a combined
regimen of EEN and parenteral nutrition seems reason-
able [9,30], as the prolonged under-feeding may increase
infectious complications [31]. However, hypercaloric par-
enteral nutrition may overfeed patients and increase the
risk of hyperglycemia, hyperlipidemia, hepatic steatosis,
and ventilator dependency [24,30]. Providing 25–66% of
calculated energy requirements seems to be advantageous
for both obese [32] and nonobese [30,33] hypermetabolic,
critically ill patients. This hypocaloric regimen should be
used short-term during critical illness with advancement to
full caloric rate as the patient stabilizes clinically [6]. Under
these conditions, the use of EEN to maintain intestinal
function with parenteral nutrition supplementation
appears well tolerated and effective in achieving early
adequate caloric support compared with either parenteral
nutrition or enteral nutrition alone [24].
The key issue is how early should the dual routes be
initiated? Should parenteral nutrition be initiated simul-
taneously with EEN or only after a few days of hypocaloric
EEN? A meta-analysis focusing on this issue suggested
that an early combination of the two therapies promotes
more harm than benefit [34]. Conversely, ESPEN guide-
lines for critically ill patients advocate that parenteral
nutrition be initiated whenever enteral nutrition is insuffi-
cient to meet caloric needs (but does not propose a precise
time for the dual prescription) [6]. The potential detri-
mental effect of early combination therapy should be
interpreted in light of the somewhat controversial concept
of extremely tight glycemic control [35]. A new study
recommends that parenteral nutrition supplementation
be started only when enteral nutrition delivery remains
inadequate after 3 days of feeding [36
]. However, defining
‘inadequate’ is difficult, as the optimal protein and caloric
load necessary to support critically ill patients and
improve outcome remains unknown [30]. Therefore, a
combined enteral–parenteral approach seems logical in
the following steps:

(1) EEN should be the first option.
(2) Parenteral nutrition should be instituted if enteral
nutrition alone fails to achieve or approach nutritional
goals after a few days (no longer than a week).
Early nutritional therapy in elective surgery,
trauma, and burn injury
Many studies show that EEN improves recovery after
major operations and several guidelines recommend early
initiation of enteral feeding to lower postoperative infec-
tions and shorten hospital stay [1–4]. A recent Chinese
randomized study compared early postoperative enteral
nutrition and parenteral nutrition in 106 patients under-
going esophageal resection due to cancer. Patients receiv-
ing EPN developed significantly more fistulas, pneumonia,
and delayed incision healing [37]. A recent systematic
review including 29 trials and 2552 patients demonstrated
the superiority of postoperative EEN over EPN after
elective gastrointestinal surgery. EEN reduced postopera-
tive complications [relative risk (RR): 0.85; 95% confidence
interval (CI): 0.74–0.99; P ¼ 0.04], infectious compli-
cations (RR: 0.69; 95% CI: 0.56–0.86; P ¼ 0.001), anasto-
motic leaks (RR: 0.67; 95% CI: 0.47–0.95; P ¼ 0.03),
intraabdominal abscesses (RR: 0.63; 95% CI: 0.41–0.95;
P ¼ 0.03), and duration of hospital stay (weighted mean
difference: 0.81; 95% CI: 1.25 to 0.38; P ¼ 0.02) [38

].
Several randomized trials and meta-analyses show that
EEN after trauma reduces infectious complications and
hospital stay compared with EPN [4,15–17,39]. However,
late initiation of enteral nutrition may be detrimental. A
recent meta-analysis by Simpson and Doig [40] included a
mixed population of ICU (most of them trauma) patients
and showed significantly more infectious complications
with EPN compared with EEN [odds ratio (OR): 1.66; 95%
CI: 1.09–2.51; P ¼ 0.02]. However, survival of critically ill
patients with parenteral nutrition was improved compared
with that of patients given enteral nutrition late (OR: 0.29;
95% CI: 0.12–0.70; P ¼ 0.006). This effect was not seen
when comparing EEN with EPN (OR: 1.07; 95% CI: 0.39–
2.95; P ¼ 0.89). From the data provided, it is unclear
whether late enteral nutrition played any role in the late
mortality and what the causes of deaths were.
Recently, Collier et al. [41] reported the results of EEN in a
retrospective study of 78 patients with open abdomen after
damage-control celiotomy for trauma. Forty-three patients
received EEN (defined as initiation of therapy within
4 days after celiotomy), whereas 35 received late enteral
nutrition (>4 days after celiotomy). Patients receiving
EEN had earlier closure of the abdominal cavity (78 vs.
43%; P ¼ 0.02), fewer fistulas (9 vs. 26%; P ¼ 0.05), and
lower hospital costs. Although retrospective and with EEN
initiated at least 4 days after operation, the study confirms
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Early nutritional therapy de Aguilar-Nascimento and Kudsk 257
improved outcome with enteral nutrition started as soon
as feasible.
Early nutritional support is also recommended in the
treatment of burn patients [1,2]. These patients experi-
ence the rapid onset of accelerated catabolism leading to a
negative nitrogen balance and loss of lean body tissue.
EEN by intragastric route should be started promptly, as
EEN reduces the development of gastroparesis compared
with enteral nutrition initiated at 18 h [42]. However, a
recent systematic review comprising five studies and a total
of 90 patients showed no effect of early vs. late enteral
nutrition on the length of hospital stay, infections, days of
ventilator support, or mortality [43].
However, there are other documented advantages of EEN
over EPN following burn injury. Lam et al. [44
] random-
ized 82 patients with a burn surface area of 40–70% to
receive either EEN or EPN. The EPN group received
more total calories, protein, and carbohydrate compared
with EEN group. The absolute counts of CD4 and CD8
positive cells significantly increased between admission
and day 7 in both groups, but the CD4 count increased
more significantly with EEN than with EPN (555 vs.
327 cells/ml; P < 0.01) as did the CD4/CD8 ratio. IgG
and IgM levels reached statistical significance only in
the EEN patients compared with that in the EPN-treated
patients. Pneumonia, septic shock, overall complications,
and death were also greater in the EPN group. In a small
study of 19 patients, Chen et al. [45
] randomized patients
with a burned surface area of 30–60% to receive EEN
(n ¼ 10) or EPN (n ¼ 9). Fours days of EEN increased
serum gastrin and motilin and decreased intestinal per-
meability compared with EPN. Plasma malondialdehyde,
tumor necrosis factor, and endotoxins were lower and
superoxide dismutase higher in EEN group when com-
pared with that in the EPN group. The authors concluded
that EEN was superior to EPN after burn injury and
suggested that EEN more effectively preserves gastroin-
testinal secretion and motility, lowers intestinal ischemia/
reperfusion injury, reduces intestinal permeability altera-
tions, decreases plasma endotoxin and inflammatory
mediator levels, and maintains mucosa barrier function.
Early nutritional therapy in nonsurgical
conditions
Establishing the exact onset of illness and the immune-
inflammatory response in nonsurgical critical care patient
is often difficult. The process is often well established at
the time of admission, which differentiates it from elective
surgical or trauma in which the onset of the initiating injury
or inflammation is well known. Under the latter conditions,
‘timing’ of nutritional therapy is better defined. In
addition, the use of EEN for either surgical or nonsurgical
patients has frequently served different purposes in the
 258 Pharmaceutical issues and technical problems
literature: EEN is prescribed aiming at reducing the
incidence of sepsis in studies of general surgical and
trauma patients [16,17,37], whereas EEN is used as an
adjunctive treatment for sepsis in the medical ICU patient
[46,47]. As a possible result of these issues, evidence
supporting EEN are better defined in elective surgical
and trauma patients [46], many of whom receive nutrition
outside an ICU setting, unlike the nonsurgical ICU popu-
lation [47].
In this regard, controversy surrounds the use of immune-
enhancing formula containing arginine in septic patients
and The Canadian guidelines do not advise its use in
septic patients [4]. The ESPEN guidelines, however,
recommend their use provided the patient is not in
poor condition, with an APACHE score below 15 [6,48].
Radrizzani et al. [49] analyzed critically ill (about 75%
were nonsurgical patients), nonseptic patients with a
median SOFA score of 6 in an unblinded, randomized
multicenter (33 ICUs) trial. This study compared EEN
supplemented with immunonutrients with EPN. The
investigators limited caloric goal to 25–28 kcal/kg in the
two groups and kept glucose levels below 180 mg/dl.
Parenteral nutrition provided a greater daily caloric
intake, especially during the first 3 days. Mortality at
28 days was similar but ICU stay (21.6 vs. 17.6 days;
P ¼ 0.04) and number of patients developing severe
sepsis, primarily related to pneumonia, were greater with
EPN than with EEN (13.1 vs. 4.9; P ¼ 0.02). The authors
conclude that EPN should be avoided in these patients
whenever EEN is possible, even with an initial low
caloric intake. The same group compared EEN supple-
mented with immunonutrients with EPN in severely
septic patients in a second trial. In an interim analysis
of that trial, the group receiving the EEN formula sus-
tained a higher mortality rate than those receiving par-
enteral nutrition (44.4 vs. 14.3%; P ¼ 0.039) [50]. The
reason for this result may lie in the complex interaction
between arginine in the formula and the role of arginase
and iNOS in the metabolism of arginine in severe sepsis.
In trauma and surgical patients, arginase levels increase
and the arginase pathway dominates, resulting in the
formation of proline and polyamines. Conversely, in sepsis,
arginase levels drop and an increased formation of nitric
oxide through the iNOS predominates in arginine metab-
olism. This excessive generation of nitric oxide may
decrease vascular resistance and increase shock and poor
tissue perfusion [51]. Therefore, the critical issue in
‘timing’ becomes one of whether the specialty supple-
mented formulas are administered to prevent or treat
sepsis.
Recently, randomized trials have compared EEN and
EPN in the treatment of severe acute pancreatitis. In a
systematic review by McClave et al. [52], the meta-analysis
of seven randomized trials showed that EEN reduced
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
infectious morbidity (RR: 0.46; 95% CI: 0.29–0.74;
P < 0.001) in pancreatitis and shortened hospital stay by
3.9 days with no effect on mortality. The authors also
compared early and late parenteral nutrition strategies
from two studies that compared parenteral nutrition with
no nutrition. In one trial, EPN prolonged hospital stay by a
median of 6 days with no other benefit [53]. In the second
trial, Xian-Li et al. [54] initiated parenteral nutrition later in
the hospital course when patients had been stable for 24–
48 h. This ‘later’ use of parenteral nutrition resulted in
significantly fewer complications, a shorter length of hos-
pital stay, and a mortality comparable to ‘standard care’
with no nutrition support. The benefits of EEN in acute
pancreatitis are often attributed to the maintenance of
the gut barrier and decreases in bacterial translocation
(although translocation has never been shown to be clini-
cally relevant to clinical outcome). In addition, better
glucose control may be a factor. Insulin requirements
are usually higher for parenteral nutrition fed patients than
for those enterally fed ones [55]. McClave et al. showed
better glucose control with EEN than with EPN. In a
recent systematic review [56
], EEN reduced the risk of
hyperglycemia (RR: 0.53; 95% CI: 0.29–0.98; P ¼ 0.04)
and insulin requirement (RR: 0.41; 95% CI: 0.24–0.70;
P ¼ 0.001) in a subset of critically ill patients.
Conclusion
EEN is usually possible after elective surgery and
trauma, as the gut is often functional in such patients.
Although critically ill medical patients may not tolerate
enteral feeding as readily, EEN should be attempted and
parenteral nutrition instituted either alone or in combi-
nation with hypocaloric enteral nutrition after a few days
only if enteral feeding is impossible or inadequate. Both
prolonged hypocaloric feeding and hypercaloric feeding
may be detrimental in ICU patients.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as

of special interest


of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 343–344).
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