*

1. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
CURRENT
OPINION Enteral vs. parenteral nutrition in septic shock: are
they equivalent?
Matthias Kotta
, Wolfgang H. Hartlb
, and Gunnar Elkea
Purpose of review
The current review focuses on recent clinical evidence and updated guideline recommendations on the
effects of enteral vs. parenteral nutrition in adult critically ill patients with (septic) shock.
Recent findigs
The largest multicenter randomized-controlled trial showed that the route of nutrient supply was unimportant
for 28-day and 90-day mortality, infectious morbidity and length of stay in mechanically ventilated patients
with shock. The enteral route, however, was associated with lower macronutrient intake and significantly
higher frequency of hypoglycemia and moderate-to-severe gastrointestinal complications. Integrating these
findings into recent meta-analyses confirmed that the route per se has no effect on mortality and that
interactions with (infectious) morbidity are inconsistent or questionable.
Summary
The strong paradigm of favoring the enteral over the parenteral route in critically ill patients has been
challenged. As a consequence, updated guidelines recommend withholding enteral nutrition in patients
with uncontrolled shock. It is still unclear, however, whether parenteral nutrition is advantageous in patients
with shock although benefits are conceivable in light of less gastrointestinal complications. Thus far, no
guideline has addressed indications for parenteral nutrition in these patients. By considering recent
scientific evidence, specific guideline recommendations, and expert opinions, we present a clinical
algorithm that may facilitate decision-making when feeding critically ill patients with shock.
Keywords
critical illness, enteral nutrition, medical nutrition therapy, organ dysfunction, parenteral nutrition, sepsis, shock
INTRODUCTION
According to the SEPSIS-3 criteria, septic shock is
defined as ‘a subset of sepsis in which particularly
profound circulatory, cellular, and metabolic abnor-
malities are associated with increased mortality’ [1].
This updated definition highlights the widely
recognized pathophysiological importance of sep-
sis-induced metabolic dysregulation. Classically,
metabolic derangements involve changes in energy
expenditure, stress hyperglycemia, and acute mus-
cle protein breakdown, and an increased recycling
of endogenous amino acids accelerating hepatic
glucose production accompanied by insulin resis-
tance [2,3]. Dysregulation of glucose metabolism
and development of insulin resistance are centrally
involved in the process of sepsis-induced hypergly-
cemia representing an adaptive host response to
acute systemic infections [4,5]. Recent evidence
suggests that maintenance of a sufficient hepatic
glucose production not only depends on the supply
of gluconeogenic substrates but also involves
mechanisms far more subtle such as the induction
of the iron-sequestering ferritin H chain [6
&&
]. Medi-
cal nutrition therapy (MNT) includes various com-
ponents such as timing, route of substrate delivery
(enteral and parenteral), and amount and composi-
tion of macronutrients and micronutrients. MNT is
thought to distinctly interfere with this endogenous
metabolic response depending on the disease phase
and nature of the triggering disturbance of homeo-
stasis and thereby likely affects clinical outcome. For
a
Department of Anaesthesiology and Intensive Care Medicine, University
Medical Center Schleswig-Holstein, Campus Kiel, Kiel and b
Department
of Surgery, University School of Medicine, Grosshadern Campus, Lud-
wig-Maximilian University, Munich, Germany
Correspondence to Gunnar Elke, Department of Anaesthesiology and
Intensive Care Medicine, University Medical Center Schleswig-Holstein,
Campus Kiel, Arnold-Heller-Str. 3, 24105 Kiel, Germany.
Tel: +49 431 500 20705; fax: +49 431 500 20804;
e-mail: gunnar.elke@uksh.de
Curr Opin Crit Care 2019, 25:340–348
DOI:10.1097/MCC.0000000000000618
www.co-criticalcare.com Volume 25 Number 4 August 2019
REVIEW

2. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
more than a decade, it has been one of the mainstays
of various expert opinions and guideline recom-
mendations that the enteral route is clearly superior
to the parenteral route. However, this paradigm has
recently been challenged. Purpose of this review is to
provide an up-to-date overview on trials and recom-
mendations of the last 18 months addressing risks
and benefits of the enteral vs. the parenteral route of
nutrient delivery in critically ill patients with
(septic) shock.
(PATHO-)PHYSIOLOGICAL CHANGES IN
SHOCK: RELEVANCE FOR MEDICAL
NUTRITION THERAPY
Critical illness disrupts the mutual beneficial bal-
ance between the gut epithelium and microbiome
with subsequent induction and perpetuation of
multiple organ dysfunction [7
,8
,9]. Cytokine
release during sepsis directly impedes intestinal
myocyte function, inhibits enteric neuromuscular
transmission, leads to a dysregulation of gastroin-
testinal hormones and provokes formation of intes-
tinal edema [10]. In addition to these ‘intrinsic’
mechanisms, a major ‘extrinsic’ risk factor for gas-
trointestinal dysfunction in shock is the use of
agents with vasoconstricting properties, such as cat-
echolamines or vasopressin. Although shock per se
leads to a redistribution of blood away from the gut,
the frequent use of vasopressors particularly with
a1-activity or V1a-activity amplifies splanchnic
vasoconstriction, which may vary by the type of
shock or vasoactive agent used [11,12]. Further-
more, effects of vasoactive agents on total splanch-
nic blood flow may not be representative for
changes in individual splanchnic organs.
The decision on whether to choose the enteral
or the parenteral route in the acute phase of critical
illness primarily depends on the function of the
gastrointestinal tract, but individual metabolic tol-
erance, however, should determine macronutrient
intake. Largely based on experiments in rodents,
benefits of enteral nutrition had been linked to
various positive physiological (nonnutritional)
effects on gastrointestinal function including mech-
anisms that maintain structural, functional, and
hormonal gut integrity and attenuate luminal oxi-
dative stress [13]. Thus, early enteral nutrition after
hemodynamic stabilization was believed to improve
outcome via a ‘stabilization’ of the gut as the motor
of sepsis-induced organ dysfunction. The enthusi-
asm for the enteral route, however, largely ignored
the fact that there are major differences between the
gastrointestinal tract of rodents and man. Further-
more, also the parenteral route of exogenous sub-
strate supply can be beneficial to intestinal health
[14]: parenteral nutrition supports the renewal rate
of intestinal cells and increases the rate of intestinal
protein synthesis, and reduces the apoptosis rate by
providing substrates directly to the basis of the
crypts. Furthermore, even after several weeks of
exclusively parenteral nutrition, no significant
changes in intestinal protein content, enterocyte
proliferation or microvillus morphology are
observed in humans. Conversely, aggressive enteral
nutrition neither prevents a significant increase in
liver fat content nor persistent protein catabolism
[2,15]. Independent from the route of nutrient sup-
ply, however, the amount and type of macronu-
trients provided may be important for autophagy
and activity of inflammatory reactions [16
]. Table 1
summarizes the pros and cons of enteral nutrition
and parenteral nutrition in critically ill patients with
(septic) shock modified according to [17].
OBSERVATIONAL STUDIES
During the last 12–18 months, three observational
studies were published addressing the importance of
enteral nutrition in ‘hemodynamically compro-
mised’ patients. Merchan et al. [18] evaluated
variables possibly important for the tolerance to
enteral nutrition in a single-center retrospective
study including 120 medical ICU patients with
septic shock and vasopressor support, whose
hemodynamics were stable after initial fluid
KEY POINTS
Metabolic (mal-)adaption plays a central role in sepsis-
induced host response and resistance to acute
systemic infections.
The route of nutrient supply has no impact on mortality
in critically ill adults with (septic) shock.
The physiological rationale of a gut-protecting effect by
early enteral nutrition has not been confirmed by
randomized-controlled trials while a contentious meta-
analysis shows a questionable benefit with respect to
infectious complications.
Exclusive parenteral nutrition reduces the frequency of
moderate-to-severe gastrointestinal complications and
risk of hypoglycemia.
Up-to-date guidelines uniformly suggest avoiding enteral
nutrition in hemodynamically unstable patients. Once
shock is controlled, low-dose enteral nutrition may be
started. Thus far, however, it is unknown whether a well
designed early parenteral nutrition would be superior to
the fasting state in patients with uncontrolled shock;
however, the potential benefits of parenteral nutrition
are yet not considered in these recommendations.
Enteral vs. parenteral nutrition in septic shock Kott et al.
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3. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
resuscitation. Patients were classified as intolerant
to enteral nutrition if they met any element of a
composite endpoint including increased gastric
residual volume, vomiting, abnormal findings on
abdominal imaging, or mesenteric ischemia; 38% of
the patients had sustained one or several of these
complications. The most common reason for enteral
nutrition intolerance was a gastric residual volume
more than 250 ml. No episode of mesenteric ische-
mia was reported. A multivariate analysis revealed
that patients with septic shock receiving enteral
nutrition within 48 h and requiring norepineph-
rine-equivalent doses of 0.14 mg/kg/min or less were
more likely to tolerate enteral nutrition. The authors
concluded that enteral nutrition can be adminis-
tered safely in such patients.
In a recent multicenter retrospective database
analysis from 2010 to 2016, Ohbe et al. [19] assessed
outcomes of early and delayed enteral nutrition in
patients with cardiogenic or obstructive shock
requiring veno-arterial extracorporeal membrane
oxygenation (VA-ECMO). Early enteral nutrition
was defined as a start of enteral nutrition 2 days
or less after initiation of VA-ECMO. The final analy-
sis included 1769 patients of whom 1549 (88%) had
received late enteral nutrition (defined as start of
enteral nutrition more than 3 days after initiation of
VA-ECMO) and 220 early enteral nutrition. Using a
marginal structural model to adjust for baseline and
time-dependent confounders, ‘early’ as compared
with ‘delayed’ enteral nutrition was associated with
reduced in-hospital and 28-day mortality. No
differences were found with regard to infectious
complications or gastrointestinal ischemic events.
Ohbe et al. [20] used the same database and
design for another study comparing outcomes
between early (2 days after initiation of mechanical
ventilation) and late enteral nutrition in mechani-
cally ventilated patients with shock requiring low-
dose (0.1mg/kg/min), medium-dose (0.1–0.3mg/
kg/min), and high-dose (0.3mg/kg/min) noradren-
aline. In a propensity score matched analysis includ-
ing 5969, 2162, and 477 patients in the low-dose,
medium-dose, and high-dose noradrenaline groups,
respectively, early as compared with late enteral
nutrition was associated with a significantly lower
28-day mortality in the low-dose and medium-dose
noradrenaline group, but with no significant in-
between group difference in the high-dose noradren-
aline group. However, these studies are subject to
substantial criticism, since they just compared a
severely hypocaloric nutrition (late) with a moder-
ately hypocaloric nutrition (early), where benefits of
‘early’ mayjust relate to a higher calorie intake during
the acute phase, and not to the route of nutrient
supply. Furthermore, there are no statistical techni-
ques yet available allowing the complete elimination
of an ‘indication bias’ in observational studies.
THE NUTRIREA-2 RANDOMIZED
CONTROLLED TRIAL
NUTRIREA-2 was a large, multicenter, randomized,
controlled, open-label parallel group trial assessing
the effect of early first-line enteral nutrition or
Table 1. Pros and cons of enteral and parenteral nutrition in patients with shock
Enteral nutrition Parenteral nutrition
Pros Attenuate catabolism and prevent iatrogenic malnutrition
Putative:
Maintain
- intestinal structure and function
- microbial diversity
Prevent bacterial translocation
Stimulate
- secretion of intestinal hormones
- gut-derived immune function
Lower risk of
- hypoglycemia
- moderate-to-severe gastrointestinal complications
Guaranteed substrate delivery
Individual dosing of macronutrients
Cons Gastrointestinal intolerance
Aspiration/regurgitation with risk of pneumonia
Diarrhea with skin breakdown and electrolyte abnormalities
Risk of bowel ischemia/obstruction
Mismatch between intestinal oxygen demand and supply
Uncertain absorption of nutrients
More prone to relative overfeeding with
- hyperglycemia
- hypercapnia
- azotaemia
Increased risk of (infectious) morbidity (central line)
Aggravation of inflammation by providing precursors for inflammatory leukotrienes and prostaglandins
Potential inhibition of autophagy
Modified from [17].
Metabolic support
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parenteral nutrition on mortality in 2410 critically
ill mechanically ventilated patients with shock,
defined as the use of vasoactive therapy (adrenaline,
dobutamine, or noradrenaline) for treatment of
shock [21
]. After enrollment, patients were ran-
domly assigned to receive exclusive enteral nutri-
tion or parenteral nutrition for a period of 7 days,
with a caloric target of 20–25 kcal/kg day from day 1
to 7, followed by 25–30 kcal/kg day from day 8 on to
extubation. For patients randomized to early enteral
nutrition, parenteral supplementation was not
allowed. The individual caloric target determined
the nutrient flow rate of patients in the enteral
nutrition group, whereas patients in the parenteral
nutrition group exclusively received nutrition via
the central venous line for at least 72 h. A switch to
enteral nutrition at the flow rate needed to achieve
the predefined calorie target was allowed after this
72-h period if patients were hemodynamically sta-
ble – defined as no vasopressor support for at least
24 h and arterial blood lactate concentration less
than 2 mmol/l. If hemodynamic stability persisted,
parenteral nutrition was continued for a maximum
of 7 days. At the latest on day 8, patients were
switched to enteral nutrition regardless of the
hemodynamic status. Baseline variables were well
balanced between groups, and a mean SOFA score
of 11 points, a mean lactate concentration of
3.8 mmol/l, and a median norepinephrine dose of
approximately 0.5 mg/kg/min (present in 80% of the
patients at baseline) reflected a high baseline disease
severity. Sepsis was the underlying cause of shock in
two thirds (62.5%) of the patients. MNT was started
early in both groups with a median of 16 h after
intubation while the median time of exposure to the
intervention was generally short (4 days in the
parenteral nutrition and 6 days in the enteral nutri-
tion group, cross-over of 4% of patients in the
parenteral nutrition group vs. 6% of patients in
the enteral nutrition group). The daily calorie intake
approached the 20–25 kcal/kg/day target in both
groups, whereas macronutrient intake was slightly
lower in the enteral nutrition group. After enroll-
ment of 2000 patients, the study was stopped pre-
maturely because the external safety board deemed
it unlikely that the inclusion of the remaining 854
patients would significantly alter the results. No
significant differences were found for 28-day mor-
tality as the primary outcome, and frequency of
infectious complications, duration of severity of
organ failure, length of life support, ICU or hospital
stay, and 90-day mortality as prespecified secondary
outcomes.
The authors concluded that early parenteral
nutrition is largely equivalent to early enteral nutri-
tion during the acute phase of critical illness, if initial
circulatory failure is only moderate. This result was
consistent with the findings from the CALORIES trial
published in 2014 in patients without shock [22].
Concern was raised, however, since enteral nutrition
increased the frequency of moderate gastrointestinal
complications including vomiting (34 vs. 24%) and
diarrhea (36 vs. 33%, P ¼ 0.009), and of severe gastro-
intestinal complications including bowel ischemia
(2 vs. 1%, P ¼ 0.007), and colonic pseudo-obstruction
(1 vs. 1%, P ¼ 0.04). Furthermore, significantly
more patients in the enteral nutrition group experi-
enced hypoglycemia (2 vs. 1%, P ¼ 0.01); initial lac-
tate concentrations were increased and comparable,
but normalized in less patients of the enteral nutri-
tionthanoftheparenteralnutrition groupduringthe
intervention period (62 vs. 66%, P ¼ 0.03). Frequen-
cies of both vomiting and hypoglycemia were also
significantly increased in the enteral nutrition group
in the CALORIES trial [22].
Both the NUTRIREA-2 and CALORIES trials were
markedly efficient in terms of achieving a compara-
bly high calorie intake via both routes early in the
study; calorie targets were almost reached on all
subsequent days without additional step-up of calo-
rie intake. Thus, the higher proportion of patients
experiencing moderate gastrointestinal complica-
tions during enteral nutrition may be explained
by the relatively high enteral macronutrient intake
in the early acute phase. The lower rate of lactate
normalization may have been the result of a mis-
match between mucosal oxygen supply (reduced by
the catecholamine-induced redirection of blood
flow) and oxygen demand (increased by the nutri-
ent-induced stimulation of oxygen-consuming
digestive reactions). Impaired enteral macronutri-
ent absorption due to gastrointestinal dysfunction
may have rendered patients more prone to hypogly-
cemia. In addition, septic hyperinflammation,
gastrointestinal tract edema, and redirection of
splanchnic blood flow may have caused severe
gastroparesis and reduced gastrointestinal tract
motility with subsequent vomiting.
META-ANALYSES
Three meta-analyses [23
] investigated the effect of
enteral nutrition or parenteral nutrition, or a com-
bination of both on the clinical outcome in adult
patients treated in the ICU. A detailed description of
these meta-analyses is presented in Table 2. Lewis
et al. [23
] assessed the effect of exclusive enteral
nutrition vs. exclusive parenteral nutrition, and of
exclusive enteral nutrition vs. a combination of
enteral nutrition and parenteral nutrition on mor-
tality, number of ICU-free days up to day 28, and
adverse events. Zhang et al. [24
] analyzed 23 studies
Enteral vs. parenteral nutrition in septic shock Kott et al.
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5. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Table
2.
Summary
of
recent
meta-analyses
on
the
comparison
of
enteral
and
parenteral
nutrition
in
the
critically
ill
Meta-analysis
Lewis
et
al.
[23
]
Lewis
et
al.
[23
]
Zhang
et
al.
[24
]
Shi
et
al.
[25
]
Intervention
Part
I:
Exclusive
EN
vs.
exclusive
PN
Part
II:
Exclusive
EN
vs.
combined
EN/PN
Exclusive
EN
vs.
exclusive
PN
Exclusive
EN
vs.
combined
EN/PN
Patient
population
Adult
trauma,
emergency,
and
postsurgical
critically
ill
patients
Adult
critically
and
noncritically
ill
patients
Adult
critically
ill
patients
Number
of
included
studies
and
patients
25
8816
23
6478
8
5360
Overall
mortality
N/A
N/A
‘No
significant
effect’;
OR
0.98,
95%
CI
0.81–1.18;
N
¼
6478,
23
studies
‘No
significant
effect’;
RR
0.91,
95%
CI
0.74–1.12;
N
¼
5360;
8
studies
In-hospital
mortality
‘Little
or
no
difference’;
RR
1.19,
95%
CI
0.80–1.77;
N
¼
361;
6
studies
‘Little
or
no
difference’;
RR
0.99,
95%
CI
0.84–1.16;
N
¼
5111;
5
studies
N/A
N/A
30-day
mortality
‘Little
or
no
difference’;
RR
1.02,
95%
CI
0.92–1.13;
N
¼
3148,
11
studies
‘Little
or
no
difference’;
RR
1.00,
95%
CI
0.86–1.18;
N
¼
4760;
2
studies
N/A
N/A
90-day
mortality
‘Uncertain’;
RR
1.06,
95%
CI
0.95–1.17;
N
¼
2461;
3
studies
‘Uncertain’;
RR
1.64,
95%
CI
1.06–2.54;
N
¼
409;
3
studies
N/A
N/A
Hospital
LOS
N/A
N/A
‘Significant
effect’;
MD
0.90
days;
95%
CI
1.63
to
0.17;
N
¼
2901,
8
studies
‘No
significant
effect’;
MD
1.10
days;
95%
CI
3.5–1.94;
N
¼
5005;
5
studies
Incidence
of
organ
failure
N/A
N/A
‘No
significant
effect’;
OR
0.87,
95%
CI
0.75–1.01;
N
¼
2866;
9
studies
N/A
GI
complications
N/A
N/A
‘Significant
effect’;
OR
2.00,
95%
CI
1.76–2.27;
N
¼
2778;
10
studies
N/A
Vomiting
‘Uncertain’;
RR
3.42,
95%
CI
1.15–10.16;
N
¼
2525;
3
studies
N/A
N/A
N/A
Aspiration
‘Uncertain’;
RR
1.53,
95%
CI
0.46–5.03;
N
¼
2437;
2
studies
N/A
N/A
N/A
Pneumonia
or
respiratory
infections
‘Little
or
no
difference’;
RR
1.10,
95%
CI
0.82–1.48;
N
¼
415;
7
studies
‘Uncertain’;
RR
1.40,
95%
CI
0.91–2.15;
N
¼
205;
2
studies
N/A
‘Significant
effect’;
RR
1.13;
95%
CI
1.01–1.25;
N
¼
5270;
5
studies
Sepsis
‘May
reduce’;
RR
0.59,
95%
CI
0.37–0.95;
N
¼
361;
7
studies
N/A
N/A
N/A
Bloodstream
infections
N/A
N/A
‘Significant
effect’;
OR
0.59,
95%
CI
0.43–0.82;
N
¼
3093;
14
studies
N/A
CI,
confidence
interval;
EN,
enteral
nutrition;
LOS,
length
of
stay;
N,
number;
N/A,
not
analyzed;
OR,
odds
ratio;
PN,
parenteral
nutrition;
RR,
relative
risk.
Metabolic support
344 www.co-criticalcare.com Volume 25 Number 4 August 2019

6. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
(including both the NUTRIREA-2 and the CALORIES
trial) assessing the overall effect of exclusive enteral
nutrition vs. exclusive parenteral nutrition in criti-
cally ill patients on mortality (primary outcome)
and several clinical secondary outcomes. Shi et al.
[25
] studied the effect of a combination of enteral
nutrition and parenteral nutrition vs. exclusive
enteral nutrition in critically ill patients on hospital
mortality (primary outcome) and also various
secondary outcomes.
In essence, only the meta-analyses by Lewis et al.
[23
] and Zhang et al. [24
] directly compared exclu-
sive enteral nutrition with exclusive parenteral nutri-
tion (thereby analysing the ‘true’ effect of the route).
Both metaanalyses did not find an effect on mortality
endpoints. Although Lewis et al. [23
] concluded that
there is insufficient evidence suggesting that the
route of nutrient supply is important for secondary
outcomes, Zhang et al. [24
] reported that enteral
nutrition reduced the frequency of bloodstream
infections (BSI) and hospital length of stay, but con-
comitantly increased the risk of gastrointestinal com-
plications. Findings for example, on the frequency of
BSI, however, are heavily biased; to analyse the latter
outcome variable, the authors included 14 studies of
which three had been performed in patients after
severe head injury, one had tested an immunonu-
trition in patients after major elective surgery, and
two had provided almost twice as much calories
during parenteral nutrition; individual studies show-
ing significant effects had either been performed in
patients with severe burns in Vietnam (average calo-
rie intake 40 kcal/kg day), or in patients with severe
acute pancreatitis in China (calorie intake 30–
35 kcal/kg day); no study was blinded, and 11 studies
were single center studies randomizing less than 100
patients. The latter three characteristics are known to
cause a significant additive overestimation of the
effect size (ranging from 10 to 25% each) [26–28].
In light of these limitations we conclude that
the route of nutrition has no effect on mortality.
Although exclusive parenteral nutrition is associ-
ated with less moderate-to-severe gastrointestinal
and metabolic adverse events, beneficial effects of
the enteral route on infectious morbidity remain
inconclusive; rather, they appear to be associated
with the intensity of macronutrient intake, but not
with the route (as already shown by an earlier meta-
analysis [29]). All of the above metaanalyses per-
formed predefined subgroup analyses, but none
specifically adressed patients with (septic) shock.
UPDATED GUIDELINE
RECOMMENDATIONS
In 2016, the guideline by the Society of Critical Care
Medicine and the American Society for Parenteral
and Enteral Nutrition suggested (based on expert
opinion) that enteral nutrition should be withheld
until the patient is ‘fully resuscitated’, and that the
enteral route should not be used if there is hemody-
namic compromise or instability [30]. This recom-
mendation applies to patients with hypotension, in
whom vasopressor or inotropic support is being
initiated, or has to be increased to maintain an
adequate perfusion pressure or cardiac output. In
patients with a low and stable dose of vasopressor
support, enteral nutrition ‘may be provided with
caution’, but should immediately be withheld, if
there are early signs of gut ischemia (abdominal
distension, symptoms of paralytic ileus, vomiting/
increased gastric residuals, or acid base disorders
including lactic acidosis). Enteral nutrition should
be also withheld in patients with septic shock until
resuscitation is complete; exclusive parenteral nutri-
tion or a combination with enteral nutrition is not
recommended for patients in the acute phase of
septic shock. The Surviving Sepsis Campaign made
identical recommendations [31]. The European
Society of Intensive Care Medicine (ESICM) 2017
practice guideline for early enteral nutrition in criti-
cally ill patients recommended delaying initiation
of enteral nutrition in patients with uncontrolled
shock receiving vasopressors or inotropes and in
which perfusion goals are not met [32]. Low-dose
enteral MNT should be started as soon as shock is
controlled. As early enteral nutrition was the focus
of this guideline, no recommendation was made
concerning the comparison of enteral nutrition
with parenteral nutrition except for the suggestion
to use early enteral nutrition rather than early par-
enteral nutrition or delayed enteral nutrition in the
general critically ill population. Recently, the Euro-
pean Society of Clinical Nutrition and Metabolism
(ESPEN) updated their guideline on MNT in criti-
cally ill patients [33
]. The ESPEN guideline quotes
contraindications for enteral nutrition as defined by
the ESICM expert group including shock, uncon-
trolled hypoxemia, acidosis and bowels ischemia
amongst others. ESPEN suggests not using enteral
nutrition when ‘shock is uncontrolled and hemo-
dynamic and tissue perfusion goals are not reached’.
In accordance with the ESICM guideline, low-dose
enteral nutrition is only recommended if shock has
been controlled by fluids and vasoactive agents.
Emphasis is put on the need for a tight surveillance
of gastrointestinal function during enteral nutrition
to avoid missing signs and symptoms of bowel
ischemia. Formulation of the latter recommenda-
tion was probably stimulated by the results of the
NUTRIREA-2 trial. Significantly, ESPEN did not spe-
cifically address the role of (early) parenteral nutri-
tion as opposed to early enteral nutrition in patients
Enteral vs. parenteral nutrition in septic shock Kott et al.
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7. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
with shock. Table 3 presents an overview on the
relevant guideline recommendations concerning
MNT in patients with hemodynamic instability/
(septic) shock.
CONCLUSION
The physiological rationale of enteral nutrition-
induced gut protection and subsequent avoidance
or attenuation of sepsis-induced organ dysfunction –
according to the phrase ‘use it (the gut) or loose it’ – is
largely based on experiments in rodents. This effect
has not been demonstrated by methodologically
sound and adequately powered controlled trials or
meta-analyses. The hypothesis that the positive tro-
phic effectsof anearly‘low-dose’ enteral nutrition are
superior to either fasting or to early parenteral nutri-
tion has yet to be tested. On the contrary, two large
multicenter trials in critically ill patients with or
without shock, respectively consistently showed that
the parenteral route – with the premise of an equal
and mildly hypocaloric macronutrient intake (80–
90% of calorie target) in the acute phase – offers
clinical advantage in terms of less metabolic and
gastrointestinal complications. So, are the enteral
and parenteral routes equivalent in patients with
septic shock? The answer to this question depends
on the targeted clinical endpoint. Although for mor-
tality the answer is ‘yes’, it is ‘no’ for certain morbid-
ities, with a clear advantage to the parenteral route
regarding metabolic (less hypoglycemia) and gastro-
intestinal endpoints, and inconsistent evidence to
Table 3. Summary of recommendations for nutrition in hemodynamically compromised patients from currently valid guidelines
Guideline and
year of publication Recommendation and grade
ASPEN 2016 [30] We suggest
- that in the setting of hemodynamic compromise or instability, EN should be withheld until the
patient is fully resuscitated and/or stable. Initiation/reinitiation of EN may be considered with
caution in patients undergoing withdrawal of vasopressor support. Expert consensus
- that critically ill patients receive EN therapy within 24–48 h of making the diagnosis of
severe sepsis/septic shock as soon as resuscitation is complete and the patient is
hemodynamically stable. Expert consensus
- not using exclusive PN or supplemental PN in conjunction with EN early in the acute phase
of severe sepsis or septic shock, regardless of patients’ degree of nutrition risk. Expert
consensus
SSC 2017 [31] We recommend
- against the administration of early parenteral nutrition alone or parenteral nutrition in
combination with enteral feedings (but rather initiate early enteral nutrition) in critically ill
patients with sepsis or septic shock who can be fed enterally. Strong recommendation,
moderate quality of evidence
- against the administration of parenteral nutrition alone or in combination with enteral feeds
(but rather to initiate IV glucose and advance enteral feeds as tolerated) over the first 7 days
in critically ill patients with sepsis or septic shock for whom early enteral feeding is not
feasible. Strong recommendation, moderate quality of evidence
We suggest
- the early initiation of enteral feeding rather than a complete fast or only IV glucose in
critically ill patients with sepsis or septic shock who can be fed enterally. Weak
recommendation, low quality of evidence
- either early trophic/hypocaloric or early full enteral feeding in critically ill patients with
sepsis or septic shock; if trophic/hypocaloric feeding is the initial strategy, then feeds should
be advanced according to patient tolerance. Weak recommendation, moderate quality of
evidence
ESICM 2017 [32] We suggest delaying EN if shock is uncontrolled and hemodynamic and tissue perfusion goals
are not reached, but start low-dose EN as soon as shock is controlled with fluids and
vasopressors/inotropes. Conditional recommendation based on expert opinion ¼ Grade 2D;
agreement 91.4% with the notion that there was concern applying EN when very high doses
of vasopressors (e.g., noradrenalin 1 mg/kg/min) are required and hyperlactatemia is
persisting or other signs of end organ hypoperfusion are present
ESPEN 2019 [33
] EN should be delayed if shock is uncontrolled and hemodynamic and tissue perfusion goals are
not reached, whereas low-dose EN can be started as soon as shock is controlled with fluids
and vasopressors/inotropes, while remaining vigilant for signs of bowel ischemia. Grade B –
strong consensus (100% agreement)
ASPEN, American Society for Parenteral and Enteral Nutrition; EN, enteral nutrition; ESICM, European Society for Intensive Care Medicine; ESPEN, European
Society for Clinical Nutrition and Metabolism; IV, intravenous; PN, parenteral nutrition; SSC, Surviving Sepsis Campaign.
Metabolic support
346 www.co-criticalcare.com Volume 25 Number 4 August 2019

8. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
support enteral nutrition with respect to the fre-
quency of infectious complications. Given this ‘shift
in paradigm’, we provide a clinically oriented algo-
rithm how to approach MNT in the acute phase of
patients with septic shock (Fig. 1). Finally, we
strongly believe that the amount and composition
of macronutrients and their exposure times (which
were relatively short in both the NUTRIREA-2 and
CALORIES trial) are clinically more relevant than the
route of nutrient supply. To be effective, MNT should
essentially respect the patient’s individual metabolic
tolerance in the acute phase of sepsis.
Acknowledgements
The article has been seen, reviewed, and approved by all
contributing authors.
Financial support and sponsorship
None.
Conflicts of interest
G.E. has received lecture fees and travel support from
Fresenius Kabi, Baxter and consulting fees and travel
support from Cardinal Health, Fresenius Kabi and
Nutricia. W.H.H. has received consulting fees and travel
support from Fresenius Kabi and Elly Lilly. M.K. has
declared no conflict of interest.
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