The role of prebiotics and synbiotics in critically ill patients
William Manzanaresa and Gil Hardyb
a
Department of Critical Care, School of Medicine,
Universidad de la República, Montevideo, Uruguay and
b
Institute of Food, Nutrition and Human Health,
Massey University, Auckland, New Zealand
Correspondence to William Manzanares, MD, Assistant
Professor, Department of Critical Care Medicine,
Hospital de Clı́nicas (University Hospital), Avenida Italia
s/n, Piso 14, CP 11600 Montevideo, Uruguay
Tel: +598 2 4806180; fax: +598 2 4877213;
e-mail: wmanzanares@adinet.com.uy
Current Opinion in Clinical Nutrition and
Metabolic Care 2008, 11:782–789
Introduction
Multiple organ dysfunction syndrome (MODS) and
severe sepsis are highly prevalent in the ICU and are
associated with high mortality [1]. Epidemiological
studies carried out in ICU suggest that serious infections
in critically ill patients are caused by gut-derived organ-
isms, particularly Enterobacteriaceae. The intestinal tract
has been referred to as an undrained abscess or the motor
of severe sepsis in ICU [2].
In a healthy individual, there is a homeostasis between
commensal intestinal microbiota and pathogenic bac-
teria. The composition of colonic microbiota is funda-
mental to gut barrier function. Anaerobic bacteria are the
predominant microorganisms in the gastrointestinal tract
preventing the overgrowth of pathogenic bacteria by a
phenomenon termed ‘colonization resistance’ [3]. When
this homeostatic mechanism is altered, ecological imbal-
ance occurs and gut-barrier function is impaired [4]. A
breakdown in gut-barrier function and immune dysfunc-
tion is associated with the onset of systemic inflammatory
response syndrome (SIRS) and MODS. In this context,
1363-1950 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Purpose of review
To examine current knowledge regarding the role of prebiotics in critical illness when
administered singly or in combinations with probiotics (synbiotics).
Recent findings
Recent experimental and clinical studies support the fact that bioecological intestinal
control with early enteral nutrition enriched with synbiotics may reduce systemic
inflammation, improve the immunological status of the intestinal mucosa and help
prevent infections in critically ill patients. Three prebiotics, oligofructose,
galactooligosaccharides and lactulose are able to modify the balance of intestinal
microbiota. It appears that treatment with synbiotics during critical illness should restore
the balance of microbial communities in a beneficial way with positive effects on
intestinal permeability and bacterial translocation. Only data from small trials are
currently available to support use of prebiotics and synbiotics in the treatment of
different clinical scenarios. However, in some critical conditions, this supplementation
has so far not been effective.
Summary
Numerous questions about the molecular mechanisms of action or clinical indications
of prebiotics remain unanswered. Large, randomized, multicentre trials are necessary to
precisely define the role of prebiotics as therapeutic agents in critical illness. These
trials must identify clinically significant improvements in relevant clinical endpoints
before any large-scale usage is advocated for critical illness.
Keywords
critically ill patient, fibre, prebiotic, synbiotic
Curr Opin Clin Nutr Metab Care 11:782–789
ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
1363-1950
symbiosis between host and flora may be improved by
prebiotics via enteral nutrition.
Prebiotics: the concept
In 1995, Gibson and Roberfroid [5] introduced the
concept of prebiotic as a nondigestible food ingredient
that beneficially affects the host by selectively stimulat-
ing the growth and/or activity of one or a limited number
of bacteria in the colon, and thus improves host health.
This original definition of prebiotic only considered
microbiological changes in the gut microbiota of humans
[5,6].
Our knowledge of prebiotics has been developed and
modified in recent years. This was nicely summarized
by Gibson et al. [6] who reviewed the original concept
in the light of research published until 2004. In particu-
lar, the three key aspects of the original definition were
updated: resistance to digestion, fermentation by the
large intestinal microbiota and a selective effect on
the microbiota that has associated health-promoting
effects.
DOI:10.1097/MCO.0b013e328312c4f9
 Prebiotics and synbiotics in critical illness Manzanares and Hardy 783
Subsequently, the concept was further defined as a
selectively fermented ingredient that allows specific
changes, both in the composition, activity or both in
the gastrointestinal microflora that confer benefits upon
host well being and health [7

]. Thus, inulin-type fruc-
tans (b 2-1 linear fructans) are properly defined as pre-
biotics, and clearly attain prebiotic status in terms of
nondigestibility, fermentation and selectivity [8
].
Products that combine prebiotic and bioactive lactic acid
bacteria (probiotics) are called synbiotics [9]. The supplies
of one or more prebiotic and one or more probiotic strains
appear to have synergistic and additive effects in stimulat-
ing the immune system and reinforcing the gut-barrier
functions [9–18]. The current targets for prebiotic use are
Lactobacilli and Bifidobacteria [7

]. Likewise, on the
basis of current knowledge, it is apparent that other micro-
organisms could be fortified by prebiotics [7

,8
]. The
hypothesis is that probiotics and prebiotics have a potential
role to play in maintaining gut-barrier function in critically
ill patients susceptible to gut-derived sepsis [9,19

,20].
Recently, the concept of a prebiotic index has been
defined as the increase in the number of new Bifidobac-
teria colony forming units per gram (CFU/g) of faeces
divided by the daily dose (in g) of prebiotic ingested [7

].
Structure and mechanisms of action of prebiotics
Prebiotics are short-chain carbohydrates (oligosacchar-
ides, 2–20 saccharide units) [13]. Inulin-type fructans
are polymers of D-fructose joined by b (2-1) bonds with a
(1–2) linked D-glucose at the terminal end of the
molecule; molecules polymerized between carbons 3
and 10 are referred to as oligofructose and between
carbons 10 and 65 are named inulin [8
]. Inulin-type
fructans are resistant to hydrolysis by human small
intestine enzymes because of the beta configuration of
the anomeric C2 in their fructose monomer from b 2-1
glycosides linkages [8
,19

]. Bifidobacteria are able
to break down and utilize inulin-type fructans by
the action of the b-fructofuranosidase enzyme. The
mechanisms of action of prebiotics are complex and so
far not yet well known or understood. These mechanisms
are summarized below [8
,12,21–28].
(1) Sources of carbon and energy for bacteria growing in
the large bowel [precursors of short-chain fatty acids
(SCFA): acetate, propionate and butyrate] by sac-
charolytic fermentation [12,21,23].
(2) Immunological effects:
(a) activate leukocytes in the gut-associated lym-
phoid tissue (GALT) system [24–26];
(b) increase cell numbers in Peyer’s patches [25];
(c) enhance production of bacteriocins [27];
(d) enhance IgA levels in the small intestine and
caecum [28].
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
(3) Improve gut-barrier function [25,26].
(4) Acidify intestinal contents (# faecal pH).
(5) Improve bioavailability of calcium and magnesium
[20,21].
(6) Foster absorption of water and sodium [22].
ICU and surgical patients are now thought to have a high
risk of bacterial translocation [29] resulting in a worsening
of the disease state. Lactic acid-producing bacteria can
inhibit endogenous pathogens from multiplying and can
block invasion of pathogens from the resident microbiota
or from outside the body [30]. In this respect, inulin and
oligofructose have the potential to improve the barrier
function of the intestine by their prebiotic action [25,26].
In the case of synbiotics, it is important that probiotics
adhere tightly onto the intestinal mucosa to achieve any
possible positive effect on the epithelium cells. In vitro,
several prebiotics such as fructooligosaccharides and inu-
lin have been shown to enhance the growth of probiotic
strains [31] and in an in-vivo murine model prebiotics
enhanced survival and prolonged the retention period of a
specific probiotic [32]. Kları́n et al. [33] investigated nine
critically ill patients treated with broad-spectrum anti-
biotics that received an oatmeal formula fermented with
Lactobacillus plantarum 299. The histological analysis of
the rectal mucosa showed that in the treated patients
none were colonized at ICU admission, but three patients
had L. plantarum 299 adhering to the mucosa from the
second or third biopsy and in subsequent samples. The
authors concluded that when probiotics are associated
with prebiotic fibre they could survive the passage from
the stomach to the rectum and be able to adhere onto the
rectal mucosa in critically ill, antibiotic-treated patients.
Additionally, prebiotics improve the bioavailability of
calcium and magnesium [20,21]. Inulin type fructans
acidify the intestinal contents, which solubilizes these
minerals and enhances their absorption. Hypocalcaemia
and hypomagnesaemia are highly prevalent in ICU, thus
prebiotics could help to correct or prevent these electro-
lyte disorders in critically ill patients.
These protective effects of prebiotics, probiotics and
synbiotics are encouraging. However, the critically ill
are a very heterogeneous group of patients and the results
of these different clinical studies may not necessarily be
extrapolated to every acute and critical condition.
The present review includes an analysis of clinical stu-
dies with prebiotics or synbiotics performed in critically
ill patients with sepsis and multiple trauma injury, severe
acute pancreatitis (SAP), liver transplantation, burn
injury, enteral-tube-feeding diarrhoea and antibiotic-
associated diarrhoea (AAD). The potential benefits of
prebiotic and synbiotic supplementation in elective
gastrointestinal surgery have not been reviewed.
 784 Functional foods
Polyvalent ICU
Jain et al. [34] investigated the effect of a synbiotic
preparation with a multistrain probiotic TREVIS (Chr
Hansen Biosystem, Denmark) that contains Lactobacillus
acidophilus La-5, Bifidobacterium lactis BB-12, Streptococcus
termophilus and Lactobacillus bulgaricus, and oligofructose
prebiotic vs. placebo. The synbiotic effect on gut-barrier
function was assessed by measurement of intestinal per-
meability (urinary lactulose/rhamnose test) and culture
of nasogastric aspirate. Ninety critically ill patients pre-
dominantly with diagnosis of peritonitis, intestinal
obstruction, pancreatitis, pneumonia or postoperative
complications were enrolled. After 1 week of therapy,
patients in the synbiotic group (n ¼ 45) had a significantly
lower incidence of pathogenic bacteria in their nasogas-
tric aspirates than in controls (43 vs. 75%, P ¼ 0.05).
There were no significant differences between groups
in intestinal permeability, septic complications or
mortality. Thus, administration of synbiotics in critically
ill patients altered the microbial composition of the upper
gastrointestinal tract, but had no effect on intestinal
permeability and was not associated with significant
clinical benefits [34]. Rayes et al. [35] in a prospective
randomized study evaluated the effect of early enteral
nutrition with fibre and L. plantarum 299 (synbiotic
group) vs. oat fibre and heat sterilized Lactobacillus vs.
parenteral nutrition in 3  30 patients undergoing
abdominal surgery. The results showed that fibre-supple-
mented groups had significantly fewer infections in
relation to the parenteral nutrition group (6/60 patients,
10% vs. 9/30, 30%, respectively; P < 0.001). Furthermore,
a larger difference between groups was observed when
gastric resection and pancreatic resection patients
were analysed.
Another study performed in Slovenia by Spindler-Vesel
et al. [36
] investigated the influence of synbiotics on
intestinal permeability in critical illness by lactulose/
mannitol (L/M) excretion ratio; 113 multiple injured
patients were prospectively randomized into four groups
(fermentable fibre, glutamine, peptide diet or standard
enteral nutrition with fibres combined with Synbiotic
2000 Forte). The synbiotic group was the only one in
which L/M ratio decreased from 0.148 (0.056–0.240)
on day 4 to 0.061 (0.040–0.099) on day 7, P < 0.05. In
addition, the synbiotic group exhibited significantly
fewer infections (P ¼ 0.003) and pneumonia (P ¼ 0.03)
in relation to the other three groups [36
].
In an interesting Greek study, Kotzampassi et al. [37]
randomized 65 critically ill, mechanically ventilated,
multiple trauma patients to receive a synbiotic formula
vs. maltodextrin as placebo for 15 days. Synbiotic-treated
patients exhibited a significantly reduced rate of infec-
tions (63 vs. 90%, P ¼ 0.01) and severe sepsis (17 vs. 40%,
P ¼ 0.04). Serum levels of procalcitonin and C-reactive
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
protein (CRP) as markers of systemic inflammation were
both lowered (P ¼ 0.05, ANOVA), whereas cytokines
TNF-a and IL-6 were significantly reduced in the syn-
biotic group, P ¼ 0.05). In addition, days of ICU stay and
days of mechanical ventilation were also significantly
reduced in relation to placebo (27.7  15.2 vs. 41.3 
20.5, P ¼ 0.01 and 16.7  9.5 vs. 29.7  6.6, P ¼ 0.001,
respectively) [37]. In contrast, an abstract by Gomersall
et al. [38] could not identify any benefit of synbiotic or
fibre on hospital mortality and MODS score as endpoints.
Severe acute pancreatitis
In SAP, a significant reduction of intestinal microbiota
with overgrowth of bacterial pathogens and the infection
of necrotic areas secondary to bacterial translocation are
two major clinical problems [39]. Currently, infected
pancreatic necrosis and severe sepsis are the most import-
ant predictors of poor prognosis. It is hypothesized that
prebiotics, probiotics and synbiotics exert an effect on
some mechanisms involved in bacterial translocation as a
rationale for synbiotic supplementation.
Oláh et al. [40] in their original randomized, controlled,
double-blind study evaluated synbiotic supplementation
in SAP. Patients (n ¼ 45) were randomly allocated to
receive either synbiotic (viable L. plantarum 299 and
oat fibre), (n ¼ 23) or heat-inactivated probiotics and
oat fibre (n ¼ 22) for 1 week by nasojejunal tube. Infected
pancreatic necrosis and abscesses occurred in one out of
22 patients (5%) in the synbiotic group compared with
seven out of 23 (30%) in the probiotics group (P ¼ 0.023).
Synbiotic supply was effective in reducing severe pan-
creatic sepsis and the number of surgical interventions
[40]. Because of this beneficial effect of synbiotic, treat-
ment was stopped at a scheduled interim analysis.
However, methodological shortcomings of this study
were criticized by Weale and Edwards [41] and Rahman
et al. [42]. More recently, in another randomized, double-
blinded study [43] the same Hungarian group evaluated
the role of ‘Synbiotic 2000’ in the treatment of SAP.
Nasojejunal feeding was commenced in both groups
within 24 h after admission and continued for at least 7
days. Synbiotic 2000 is a formulation that contains four
specific lactobacilli (Pediacoccus pentosaceus, Leuconostoc
mesenteroides, Lactobacillus paracasei sub sp. paracasei
and L. plantarum 2362) and a mixture of four bioactive
plant fibres: betaglucan, inulin, pectin and resistant starch
(2.5 g each). Sixty-two patients with SAP completed the
study. Patients in the control group received only pre-
biotics. A lower incidence of MODS, septic compli-
cations and mortality were detected in the treatment
group compared with the control, but the differences
were not statistically significant. Furthermore, the num-
ber of patients recovering from complications was sig-
nificantly less in the group receiving synbiotic therapy
compared with the control (P < 0.05). Finally, a lower rate
 Prebiotics and synbiotics in critical illness Manzanares and Hardy 785
of late MODS (over 48 h) was detected in the treatment
group vs. the control group (3.0 vs. 17.2%) [43]. The
results suggest that early nasojejunal feeding with syn-
biotics may prevent organ dysfunctions in the late phase
of SAP. In addition, the data also indicate that the
infection of pancreatic necrosis may be associated with
early phase organ failure [43]. However, single prebiotic
supplementation was not associated with better results
and did not improve the prognosis [44,45].
So far, the only randomized study that compared the
beneficial effects of early enteral nutrition with single
prebiotic fibre supplementation on the clinical course of
SAP with standard enteral nutrition was performed by
Karakan et al. [46
]. Thirty consecutive SAP patients on
nasojejunal enteral nutrition were randomized to receive
either a multifibre prebiotic supplement (24 g/day)
(n ¼ 15) or patients without any supplement as a control
group (n ¼ 15). The diets in the two groups were iso-
caloric and isonitrogenous. The results showed that naso-
jejunal enteral nutrition with prebiotic fibre in SAP
improves hospital stay (10  4 vs. 15  6 days, P < 0.05)
and the prognostic indices [mean duration of acute
physiology and chronic health evaluation II (APACHE
II) and CRP normalization] were shorter in the study
group, (P < 0.05). Furthermore, the study group had
fewer overall complications compared with the standard
enteral nutrition group [46
].
The Dutch Acute Pancreatitis Study Group has recently
published results of the PROPATRIA (PRObiotics in
acute PAncreatitis TRIAl) a double-blind, placebo-con-
trolled multicentre trial that enrolled 298 patients [47

].
Patients with predicted SAP were randomized to receive
the study product Ecologic 641 (Winclove Bio Industries,
Amsterdam, The Netherlands), a multistrain of six viable
bacteria and cornstarch and maltodextrins as fibre or
placebo (cornstarch and maltodextrins) for 28 days. This
multispecies probiotic has demonstrated that it is capable
of inhibiting growth of a wide variety of pathogens
isolated from infected pancreatic necrosis [48]. Both
groups had a nasojejunal tube and received fibre-
enriched formula (49% prebiotic fibre inulin and oligo-
saccharides, Nutrison Multi Fibre, Nutricia Zoetermeer,
Netherlands). The primary endpoint was the rate of
infectious complications during admission and 90-day
follow-up. Infectious complications were higher in the
synbiotic group (30%) than in the placebo group (28%)
[relative risk (RR) 1.06, 95% confidence interval (CI)
0.75,1.51]. In addition, the finding of 15 excess deaths
(16 vs. 6%, RR 2.53, 95% CI 1.22–5.25) and the nine
bowel ischaemia cases in the synbiotic group (eight with
fatal outcome) compared with none in the placebo group
(P ¼ 0.004) are very worrying and dramatically different
from what was expected [47

,49]. Both groups were
supplied with the same dose of prebiotics and the only
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
difference was the probiotic supply. Therefore, it would
seem that the poor outcome is more likely to be attribu-
table to the probiotic than the prebiotic fibre supply.
However, the difference between the groups could be
due to lack of homogeneity at the time of randomization
and not due to the probiotic intervention.
For the moment, these results must serve as a warning
against using probiotic bacteria for ICU patients with
acute pancreatitis [49].
Liver transplantation
Rayes et al. [50] in a prospective randomized clinical trial
in 95 liver transplant patients that received postoperative
early enteral nutrition compared the incidence of post-
operative infections among three groups of patients. The
three groups were: A (n ¼ 32) selective digestive tract
decontamination with antibiotics four times daily for
6 weeks; B (n ¼ 31) received L. plantarum 299 as probiotic
and fermentable fibres (with Inulin) 15 g/day for 12 days
in the postoperative period; C (n ¼ 32) received heat-
inactivated probiotics (L. plantarum 299) and fermentable
fibres. The numbers of postoperative infections were
significantly higher in-group A (n ¼ 23) in relation to
group B (n ¼ 4) and group C (n ¼ 11). This study con-
cluded that administration of synbiotic with L. plantarum
299 and prebiotic including inulin was associated with a
lower incidence of postoperative infections in liver trans-
plantation patients [50].
Another prospective randomized, double-blind trial [51]
was performed by the same group in 66 liver transplant
recipients that received enteral nutrition immediately
postoperatively. The authors compared one group
supplemented with Synbiotic 2000 with another group
receiving only fibre. Both treatments started the day
before surgery and continued for 14 days. The incidence
of postoperative bacterial infections was significantly
reduced by synbiotic treatment; 48% (16/33 patients)
in the fibre-only group and 3% (1/33 patients) in the
synbiotic-treated group. Only one microbe (Enterococcus
fecalis) was isolated in the synbiotic-treated group in
contrast to 17 different types of microorganisms in the
fibre-only-treated group. In addition, total antibiotic use
was significantly less in the synbiotic-treated group.
These trials have shown that selected synbiotics have
positive immune enhancing effects in this population of
patients [51]. Currently, synbiotic supply to liver trans-
plantation patients seems to be an effective tool to reduce
inflammation and infections in the postoperative period
[52].
Burn injury
After burn injury, both intestinal and gastric permeability
increase significantly [53]. In this context, prebiotic
supplementation may contribute to normalize intestinal
 Table 1 Summary of the more important studies with prebiotics and synbiotics in ICU patients
Reference Prebiotic fibre Probiotic strain (CFU/day) Study population (n) Clinical endpoints Study design Results
daily dose (g)

Jain et al. [34] Oligofructose (15 g) Lactobacillus acidophilus La5,
Bifidobacterium lactis Bb12,
Streptococcus thermophilus,
L. bulgaricus (TREVIS)
ICU patients, median Incidence of gastric colonization; Single, double- blind, Reduced gastric colonization
APACHE II score 11 intestinal permeability; SIRS; placebo- controlled in synbiotic group
(n ¼ 90) septic morbidity trial
786 Functional foods

(12  109)
Spindler-Vesel Inulin, oat bran, pectin, Pediococcus pentosaceus Multiple injured patients, Primary: intestinal permeability; Single, prospective, Synbiotic group: lower
et al. [36
] resistant starch 5–33 : 3, ISS > 18 (n ¼ 113) secondary: infections rate, randomized trial; intestinal permeability
(2.5 g of each) Leuconostoc mesenteroides mortality, ICU stay, days of four groups (P < 0.05) and less
32–77 : 1, L. paracasei spp. mechanical ventilation and infectious complications
paracasei 19, and L. plantarum incidence of MODS including pneumonia
2362 (Synbiotic 2000 Forte) (P < 0.03)
Kotzampassi Inulin, b-glucan, pectin, P. pentosaceus 5–33 : 3, ICU trauma patients Primary: infection rate, SIRS Randomized, double- Synbiotic group: lower
et al. [37] resistant starch L. mesenteroides 32–77 : 1, (n ¼ 65) and MODS development; blind, placebo- rate of: infections
(2.5 g of each) L. paracasei spp. paracasei secondary: mortality, ICU controlled trial (P ¼ 0.01); SIRS, severe
19, and L. plantarum 2362 stay and days of mechanical sepsis (P ¼ 0.02);
11
(10 of each) (Synbiotic ventilation ICU stay (P ¼ 0.01); days
2000 Forte) of mechanical ventilation
(P ¼ 0.001) and mortality
(P ¼ 0.12)
Oláh Oat fibre L. plantarum 299 (109) Acute pancreatitis within Synbiotic capacity to prevent Randomized, double- Synbiotic group: lower rate
et al. [40] (10 g twice daily) 48 h after the onset of gut colonization and blind, placebo- of pancreatic aspiration
symptoms (n ¼ 45) endotoxaemia controlled trial positive cultures (P ¼ 0.023)
and septic complications
requiring surgery (P < 0.05)
Oláh Inulin, b-glucan, pectin, P. pentosaceus 5-33 : 3, SAP (n ¼ 62) Synbiotic capacity to reduce Single, prospective, Synbiotic group: lower
et al. [43] resistant starch L. mesenteroides 32-77 : 1, the incidence of SIRS randomized, double- complications rate
(2.5 g of each) L. paracasei spp. paracasei and MODS blind, placebo- (P ¼ 0.049) and SIRS þ
19, and L. plantarum 2362 controlled trial MODS (P < 0.05)
(1010 of each, 40 billion of
lactobacillus per dose)
(Synbiotic 2000)
Karakan Multifibres (soluble or SAP (n ¼ 30) Prebiotic effect in severe Prospective, randomized, Prebiotic group: shorter
et al. [46
] prebiotic 0.7 g/l and pancreatitis double-blind, hospital stay (P < 0.05);
insoluble 0.8 g/l) controlled trial shorter duration of
APACHE II score and
normalization of CRP and
CT score (P < 0.05)
Besselink Soluble fibre (0.7 g/l L. acidophilus, L. casei, Predicted SAP Primary: infectious complications Multicentre, randomized, Multispecies probiotic group:
et al. [47

] of enteral formula) L. salivarius, Lactococcus (n ¼ 296) at admission and 90 days double-blind, placebo- higher incidence of
Nutricia Multi Fibre lactis, B. bifidum, B. lactis follow-up; secondary: mortality, controlled trial infectious complications
(ECOLOGIC 641) (1010) SOFA score, infected necrosis (P ¼ 0.08); bowel ischaemia
and need for surgical (P ¼ 0.004) and mortality
intervention, ICU and hospital (P ¼ 0.01).
stay, use of antibiotics,
abdominal complaints
and diarrhoea
CFU, colony forming units; CRP, C-reactive protein; CT, computed tomography; ISS, injury severity score; MODS, Multiple organ dysfunction syndrome; SAP, severe acute pancreatitis; SIRS, systemic
inflammatory response syndrome; SOFA, sepsis-related organ failure assessment.

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 Prebiotics and synbiotics in critical illness Manzanares and Hardy 787
permeability and thus gastrointestinal gut-barrier function.
Olguin et al. [54] performed a randomized, double-blind,
controlled, clinical trial in burn patients who ingested
6 g/day of oligofructose (n ¼ 21) or placebo (n ¼ 20) for
15 days. Gastrointestinal permeability to sucrose and
L/M was evaluated before, during and after treatment.
Urinary excretion of sucrose and L/M ratio were five and
4.4-fold higher in burn patients than in controls. Thus,
intake of oligofructose did not improve gastrointestinal-
barrier function in burn patients [54]. To date, results are
negative with respect to prebiotics in critically ill burn
patients, and more studies are necessary before any defini-
tive recommendations can be made.
Enteral-tube-feeding diarrhoea
Enteral tube feeding (ETF) is used increasingly in the
ICU [55]. There is a high incidence of diarrhoea in
critically ill patients ranging from 2 to 95% and the
pathogenesis involves an interaction between antibiotic
prescription and intestinal ecological imbalance [56

]. So
far, there are only a few small trials that have investigated
the effects of prebiotics supply with ETF as preventive
or therapeutic agents and the implementation of
feeding formulae enriched with fibre have been mostly
unsuccessful.
In a small prospective double-blind, controlled study,
Rushdi et al. [57] evaluated the use of guar gum, a soluble
fibre in enteral feeds, to prevent diarrhoea and potential
health benefits in a small sample of ICU patients. The
results showed that the number of liquid stools in
response to a soluble fibre-enriched diet was 2.0  0.9
(day 1) vs. 1.0  0.7 (day 4) (P < 0.01). This study con-
cluded guar gum-enriched enteral nutrition correlated
with a decrease of diarrhoeal episodes in critically ill
patients with preexisting diarrhoea [57]. Spapen et al.
[58] performed a randomized, double-blind trial in severe
sepsis and septic-shock patients receiving enteral nutri-
tion supplemented with 22 g/l partially hydrolyzed guar
for a minimum of 6 days. The mean frequency of diar-
rhoea days was significantly lower in patients receiving
fibre than in those on standard enteral nutrition
(8.8  10.0 vs. 32.0  15.3%; P ¼ 0.001). Furthermore,
the enteral nutrition fibre patients had fewer days with
diarrhoea per total feeding days [16/148 days (10.8%) vs.
46/146 days (31.5%); P < 0.001] and a lower mean diar-
rhoea score (4.8  6.4 vs. 9.4  10.2; P < 0.001) [58]. Thus,
so far guar gum is a compound with promising, but
uncertain, prebiotic properties.
The effects of prebiotics on the colonic microbiota have
not been confirmed with studies in ETF patients [56

].
Studies that have been performed used enteral formulae
containing an unspecified quantity of fructooligosacchar-
ides fibre or have used compounds with ill-defined pre-
biotic characteristics Although fructooligosaccharides
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exhibit prebiotic effects in healthy individuals, their
ability to increase faecal bifidobacteria and reduce the
incidence of diarrhoea in patients receiving ETF has not
been demonstrated [56

,59].
Antibiotic-associated diarrhoea
AAD is an important cause of morbidity and mortality in
critically ill patients and a high percentage of patients
relapse after treatment. Probiotics clearly have a potential
role in the prevention or relapse of AAD [60]. As,
Saccharomyces boulardi has been shown to reduce the
incidence of AAD caused by the bacterium Clostridium
difficile [60], prebiotics could also be an effective resource
for prevention and treatment. In a study by Lewis et al.
[61] in 435 patients aged over 65 years, the authors
showed that administration of 12 g of oligofructose daily
did not reduce the risk of C. difficile-associated diarrhoea
(CDAD). However, in another randomized trial [62]
performed by the same group in 142 patients with CDAD
who were treated with metronidazole and vancomycin,
the authors showed that diarrhoea relapse was more
common in patients taking placebo (34.3 vs. 8.3%,
P < 0.001). In addition, length of hospital stay was also
reduced and bifidobacterial numbers increased signifi-
cantly with prebiotic therapy [62]. Thus, oligofructose
appears to be effective in the prevention or relapse of
CDAD. We nevertheless endorse the conclusions in a
recent comprehensive paper by de Vrese and Marteau
[63

] who concluded that ‘despite positive effects of
prebiotics on the intestinal microbiota the results of these
studies are not yet sufficient to give specific recommen-
dations for the use of prebiotics for the prevention or
treatment of diarrhoea’.
Posology of prebiotics and synbiotics in the ICU
The optimal doses of prebiotics and synbiotics in ICU
patients are uncertain and a high variability has been
reported. Data from healthy humans have shown that
inulin achieves a bifidogenic effect with a minimum daily
dose of 5–8 g/day [8
]. However, although doses up to
20 g/day have not shown adverse effects, too high a dose
of a prebiotic may compromise microbial selectivity and
risk generating gas with abdominal distension [8
]. The
same variability exists with reported doses of probiotics as
shown in Table 1.
Conclusion
Bioecological intestinal control through enteral nutrition
associated with prebiotics, probiotics and synbiotics is
capable of controlling superinflammation and gut-derived
sepsis [9,14,15,18]. Current evidence, suggests that pro-
biotics enhance the efficacy of prebiotic supplementation,
so should be given in combination. There is increasing
awareness of the potential benefits of prebiotics supple-
mentation and there is a growing body of data that suggest
 788 Functional foods
their usefulness in ICU [13,15,64]. However, most of the
data for these indications is from small clinical studies.
When examining these studies, it is not always possible to
distinguish clearly between the effects of prebiotics and
probiotics in synbiotic mixtures and thus determine the
appropriate place of prebiotics in critically ill patients.
Watkinson et al. [65] have performed the only systematic
review to compare enteral feeding with prebiotics, pro-
biotics and synbiotics vs. standard enteral nutrition in
critically ill adult patients. This review included eight
randomized controlled studies (n ¼ 999); the results
showed that prebiotics, probiotics and synbiotics did
not significantly reduce ICU stay (RR 0.03, 95% CI
0.44, 0.51), hospital mortality (RR 0.96, 95% CI
0.78,1.17) nor the incidence of ventilator-associated
pneumonia (RR 1.40, 95% CI 0.75,2.64).
The 2007 update of the Canadian Guidelines [66] based
on 1  level 1 and 6  level 2 studies concluded that there
are insufficient data to make a recommendation on the
use of prebiotics/probiotics/synbiotics in critically ill
patients. However, the authors indicate ‘there are prom-
ising results from recent studies on the use of Synbiotic
Forte 2000 but more conclusive data on clinical outcomes
is needed before a recommendation can be made’. Sim-
ilarly, the recent Guidelines on Enteral Nutrition from
the European Society of Parenteral and Enteral Nutrition
(ESPEN) [45] recommend that ‘a combination of differ-
ent fibres, probiotics and prebiotics should be studied
because of synergistic effects in different diseases’.
For the future, researchers must identify the best type,
the best combination of fibres for enteral nutrition or both
in ICU. Furthermore, a combination of different fibres,
prebiotics and probiotics should be studied because
additive or synergistic effects in different acute and
critical situations may exist.
The place of probiotics in the treatment and prevention
of infectious diarrhoea and for preventing AAD is well
defined, but the place of prebiotics is so far less clear.
Large, well designed, randomized, multicentre trials are
necessary to define the role of prebiotics and synbiotics as
preventive or therapeutic agents in ICU. These trials
must detect clinically significant reductions in relevant
clinical endpoints, such as infection rates or mortality,
prior to any large-scale usage in critical illness.
Until such additional research has been undertaken pre-
biotics in combination with probiotics should only be
supplied to critically ill patients with liver transplan-
tation, postoperative and AAD. However, in critically
ill patients with high risk of nonocclusive intestinal
ischaemia and in those with predicted SAP, synbiotics
can be harmful and are not recommended.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:

of special interest


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