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Jack, Leanne, Coyer, Fiona, Courtney, Mary, & Venkatesh, Bala(2010)Probiotics and diarrhoea management in enterally tube fed critically illpatients-What is the evidence?Intensive and Critical Care Nursing, 26(6), pp. 314-326.
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https://doi.org/10.1016/j.iccn.2010.07.001
Title: Probiotics and diarrhoea management in enterally
tube fed critically ill patients - What is the evidence?
Author: Leanne Jack
RN, BN, MN (Intensive Care), MRCNA.
Doctor of Philosophy Candidate,
Queensland University of Technology,
School of Nursing,
Queensland University of Technology,
Victoria Park Road,
Kelvin Grove. Queensland. 4059.
AUSTRALIA.
Telephone: 61 7 3138 3901
Email: [email protected]
Second Author: Dr Fiona Coyer
RN, RM, ENB100, PGCEA, PhD.
Senior Lecturer,
Postgraduate Course Coordinator,
School of Nursing,
Queensland University of Technology,
Victoria Park Road,
Kelvin Grove. Queensland. 4059.
AUSTRALIA.
Telephone: 61 7 3138 3895
Email: [email protected]
Third Author: Professor Mary Courtney
RN, PhD.
Assistant Dean – Research,
Faculty of Health,
2
Queensland University of Technology,
Victoria Park Road,
Kelvin Grove. Queensland. 4059.
AUSTRALIA.
Telephone: 61 7 3138 9639
Email: [email protected]
Fourth Author: Professor Bala Venkatesh
Department of Intensive Care,
Princess Alexandra and Wesley Hospitals,
Critical Care Endocrinology and Metabolism Research Unit,
The University of Queensland,
St Lucia. Queensland. 4072.
AUSTRALIA.
3
Abstract
Objective
The aim of this literature review is to identify the role of probiotics in the
management of enteral tube feeding (ETF) diarrhoea in critically ill patients.
Background
Diarrhoea is a common gastrointestinal problem seen in ETF patients. The
incidence of diarrhoea in tube-fed patients varies from 2% to 68% across all patients.
Despite extensive investigation, the pathogenesis surrounding ETF diarrhoea remains
unclear. Evidence to support probiotics to manage ETF diarrhoea in critically ill patients
remains sparse.
Method
Literature on ETF diarrhoea and probiotics in critically ill, adult patients was
reviewed from 1980 to 2010. The Cochrane Library, Pubmed, Science Direct, Medline
and the Cumulative Index of Nursing and Allied Health Literature (CINAHL) electronic
databases were searched using specific inclusion/exclusion criteria. Key search terms
used were: enteral nutrition, diarrhoea, critical illness, probiotics, probiotic species and
randomised clinical control trial (RCT).
Results
Four RCT papers were identified with two reporting full studies, one reporting a
pilot RCT and one conference abstract reporting an RCT pilot study. A trend towards a
reduction in diarrhoea incidence was observed in the probiotic groups. However,
4
mortality associated with probiotic use in some severely and critically ill patients must
caution the clinician against its use.
Conclusion
Evidence to support probiotic use in the management of ETF diarrhoea in
critically ill patients remains unclear. This paper argues that probiotics should not be
administered to critically ill patients until further research has been conducted to
examine the causal relationship between probiotics and mortality, irrespective of the
patient’s disease state or projected prophylactic benefit of probiotic administration.
5
Keywords
Enteral nutrition
Diarrhoea
Critical illness
Probiotics
Probiotic species
Randomised control trial.
6
INTRODUCTION
Nutritional support is widely accepted as standard care for critically ill patients
(Jolliet et al., 1999; Casse et al., 2000; Heyland, 2000). Approximately 60% of critically
ill patients receive enteral nutrition during their intensive care unit (ICU) stay (Lee and
Auyeung, 2003). A common gastrointestinal problem in enterally tube fed (ETF)
patients is diarrhoea (Whelan et al., 2001). Electrolyte imbalance, dehydration, perianal
skin breakdown, wound contamination, alterations in intestinal micro flora,
psychological embarrassment, sleep disturbances and increased health care costs may be
complications associated with ETF diarrhoea. Diarrhoea management strategies and
ETF practices vary widely between ICUs. This is evidenced by the disagreement seen in
diarrhoea management strategies including the administration of probiotics in some
critical care environments (Cole et al., 1998; Barbut and Meynard, 2000; Whelan et al.,
2001; Whelan et al., 2003; Weisen et al., 2006).
Background
Enteral Tube Feeding
The optimal time to start nutritional support in critical illness remains unclear. It
is widely accepted to commence ETF in the ICU as early as possible as ETF is
purported to preserve the gut’s immunological barrier, reduce bacterial translocation,
reduce rates of sepsis and multi organ failure and improve wound healing (Kennedy,
1997; Marshall and West, 2004; Davies and Bellomo, 2004; Lopez-Herce et al., 2008).
However, ETF is not without complications including diarrhoea, abdominal distension,
pulmonary aspiration, hyperglycaemia, electrolyte derangement, dehydration and
secondary infections (Pancorbo-Hidalgo et al., 2001; Williams and Leslie, 2004; Lopez-
7
Herce et al., 2008). It is not uncommon for ETF to be delayed or ceased for these
reasons (Adam and Batson, 1997; Heyland et al., 2003).
Diarrhoea Epidemiology
The incidence of diarrhoea in ETF patients is suggested to vary between 2% to
68% (Bowling, 1995; Bowling, 1998; Cole et al., 1998; Bengmark, 2002; Whelan et al.,
2001; McNaught et al., 2005; Weisen et al., 2006;). However, the incidence of diarrhoea
is argued to vary more widely between 2% to 95% in critically ill patients (Cataldi-
Betcher et al., 1983; DeMao et al., 1998). The variability of diarrhoea incidence
reported in different subsets of hospitalised patients may be related to the
inconsistencies in diarrhoea definitions and the clinical application of these definitions
(Whelan et al., 2003; Weisen et al., 2006). Therefore, the prevalence of diarrhoea may
depend on the definition used (Lebak et al., 2003; Weisen et al., 2006).
Diarrhoea Pathogenesis
The pathogenesis of diarrhoea in critical illness remains unclear; however,
diarrhoea is thought to be caused by infectious and non-infectious aetiologies (Weisen
et al., 2006). The higher incidence of ETF diarrhoea in critical illness may be related to
(i) microbial contamination of the ETF formula; (ii) altered colonic responses to intra
gastric feeding; (iii) hypoalbuminaemia; (iv) increased use of antibiotic therapy; and (v)
medications such as stool softeners, prokinetics and histamine-2 agents (Bowling, 1995;
Cole et al., 1998; Casse et al., 2000; Heyland, 2000).
Diarrhoea management strategies
8
Diarrhoea management remains inconsistent between ICUs. The management of
diarrhoea includes diarrhoea management algorithms, rehydration, electrolyte
replacement, anti diarrhoeal medications, continuation of ETF and the administration of
metronidazole or glycopeptides for Clostridium difficile (Bowling, 1995). A new
addition to this debate is probiotics. In non-critically ill situations, probiotics have been
shown to exert a beneficial effect on the incidence and severity of diarrhoea (Barbut and
Meynard, 2000; Whelan et al., 2001; Lee and Auyeung, 2003). The place for regular
probiotic administration in diarrhoea management in critical illness is not yet fully
explored or understood.
Probiotics
Probiotics are defined as viable non-pathogenic micro-organisms which when
ingested, exert a beneficial effect and positive influence on the health and well-being of
the host (Marteau and Seksik, 2002; Fioramonti et al., 2003). Current evidence suggests
that probiotic effects are strain specific and the effects seen in one probiotic strain may
not be seen in a different probiotic strain (Cataldi-Betcher et al., 1983). Furthermore,
probiotic effects may be enhanced when prebiotic, probiotic or synbiotic preparations
are administered (defined in Table 1) (Bengmark, 2005; Watkinson et al., 2007;
Guarner et al., 2008). The most frequently administered probiotics include Lactobacilli,
Bifidobacilli and Saccharomyces (Thomas et al., 2003; Hammilton-Miller, 2004).
Probiotics are commercially available in the form of capsules, enriched yoghurts,
powders and fermented milk and cheese products (Whelan et al., 2001).
9
For reasons of safety and efficacy a probiotic should fulfil strict selection criteria
(Whelan et al., 2001). A probiotic must have the ability to resist gastric juices and
exposure to bile, be able to multiply and colonise the digestive tract and maintain safety,
effectiveness and potency for the duration of its shelf life (FAO/WHO, 2001;
FAO/WHO, 2002; Senok et al., 2005).
Mechanisms of action of probiotics
Although the role and beneficial effects of probiotic ingestion remains uncertain,
recent studies suggest that some probiotics have been used as an adjuvant in the
treatment and prevention of many diseases including diarrhoea, immuno stimulation,
urogenital health and cancer prevention (Gorbach, 2000; Klaenhammer, 2000;
Bengmark, 2002; Thomas et al., 2003; Hammilton-Miller, 2004; Broekaert and Walker,
2006; Manzoni, 2007). Several probiotic mechanisms of action have been suggested
including: 1) antagonistic activity; 2) stimulation of mucosal defence; and 3) nutrient
production in the intestine (Erickson and Hubbard, 2000; Fooks, 2002; Isolauri and
Salminen, 2004; Sulivan and Nord, 2005). Recent studies suggest that probiotics exert
their mechanism of action through chemical inhibition and stimulation, nutrient
competition, immune clearance and competition for adhesion receptors (Bengmark,
2002). It must be emphasised that the exact mechanisms by which probiotics achieve
their physiological effect(s) remain unclear (Bengmark, 2002; Baker and day, 2008;
Quigley, 2008).
The aims of this review
The aim of this literature review is to identify the role of probiotics in the
management of enteral tube feeding (ETF) diarrhoea in critically ill, adult patients.
10
Search strategy
The studies included in this review were identified through the Cochrane
Library, Pubmed, Science Direct, Medline and the CINAHL databases for English
language sources published from 1980 to 2010. Key search terms used were: enteral
nutrition, diarrhoea, critical illness, probiotics, probiotic species and randomised clinical
control trial. Studies were included if they used a RCT design examining probiotics and
ETF in critically ill, hospitalised patients experiencing diarrhoea. Combinations of
critically ill and general ward patient studies were included. Studies were excluded if
they: (i) did not employ an RCT design; (ii) patients were not hospitalised; and (iii)
patients were not receiving ETF and probiotics. Reference lists of retrieved papers were
manually checked and abstracts were reviewed by one reviewer. Papers were selected
with reference to the aims of this review paper.
Results
The limited availability of research examining probiotic efficacy in the
management of ETF diarrhoea in critically ill adult patients was demonstrated with only
four RCT papers two reporting full studies (Heimburger et al., 1994; Bleichner et al.,
1997), one reporting a pilot RCT (Alberda et al., 2007) and one conference abstract
reporting an RCT pilot study (Chaboyer et al, 2007) (see Table 2). The design and
methodologies of these studies are presented in Table 2.
Discussion
This review has highlighted inconclusive evidence to support probiotic
administration in critically ill, ETF patients who experience diarrhoea. The larger, multi
11
centre study by Bleichner et al (1997) demonstrated a significant reduction in the
percentage of diarrhoea days in patients receiving Saccharomyces boulardii
(S.boulardii) from 18.9% to 14.2%. However, the three smaller studies (Heimburger et
al., 1994; Alberda et al., 2007; Chaboyer et al., 2007) showed only a trend towards less
diarrhoea in the probiotic groups.
The absence of a statistically significant difference might be related to a lack of
power in the studies reviewed. Although statistical significance was not found in the
smaller studies, a small treatment effect was observed (Heimburger et al., 1994; Alberda
et al., 2007; Chaboyer et al., 2007). This suggests that probiotics may be beneficial in
the treatment of ETF diarrhoea; however, larger, adequately powered studies are
required to support this trend.
There are a number of other identified issues arising from the studies which
were not reported (Heimburger et al., 1994; Bleichner et al., 1997; Alberda et al., 2007;
Chaboyer et al., 2007). The infrequent resiting of feeding tubes may directly influence
bacterial colonisation and potential development of infectious diarrhoea. Although stool
cultures were reported as a non-significant cause of diarrhoea in two RTCs (Heimburger
et al., 1994; Bleichner et al., 1997) it was not reported on in the two pilot studies
(Alberda et al., 2007; Chaboyer et al., 2007).
The ETF preparation and administration techniques, and infection control
practices were inadequately reported on (Heimburger et al., 1994; Bleichner et al., 1997;
Alberda et al., 2007; Chaboyer et al., 2007). Only one study reported ETF
12
administration methods. It is known that infection control practices may vary between
research sites (Alberda et al., 2007). Contamination of ETF is a known cause of
diarrhoea, particularly in critically ill patients (Marshall and West, 2004. It is possible
that contamination of ETF formulae may have occurred; however, this was not reported.
Combinations of ICU and ward patients were used by Heimburger et al (1994)
and Bleichner et al (1997); however, Alberda et al (2007) and Chaboyer et al (2007)
used ICU patients only (Table 2). Confounding of the treatment effect due to variability
in patient acuity may limit the generalisation of study findings in critically ill patients.
Patient demographics were not statistically significant between the groups
(Heimburger et al., 1994; Bleichner et al., 1997; Alberda et al., 2007; Chaboyer et al.,
2007). Severity of illness scores such as APACHE and Sepsis-related Organ Failure
Assessment scores were inconsistently reported. These recognised and validated scores
may have provided valuable data to benchmark the severity of critical illness and
therefore patient acuity.
Severity of illness scores and mortality rates and causes differ between subsets
of critically ill patients. Probiotics were reported as a non-significant mortality risk
factor in only one study (Alberda et al., 2007). Mortality was not associated with
probiotics in the studies reviewed (Heimburger et al., 1994; Bleichner et al., 1997;
Alberda et al., 2007; Chaboyer et al., 2007). It may be concluded that the scientific
weaknesses of probiotics such as their mechanisms of action have not been fully
understood when exploring diarrhoea, ETF, and mortality in critically ill patients.
13
Diarrhoea and Enteral Formulae
Diarrhoea is frequently defined by the number of loose stools passed each day
(Pancorbo-Hidalgo et al., 2001; Lebak et al., 2003; Thomas et al., 2003; Whelan et al.,
2003; Elia et al., 2008). Definitions of diarrhoea that rely on a subjective assessment of
stool consistency and frequency or by the summed daily score of stool frequency,
consistency and volume unreliably measure diarrhoea in the critical care environment
(Hart and Dobb, 1988; Duncan et al., 1997; Pancorbo-Hidalgo et al., 2001; Thomas et
al., 2003; Manley et al., 2007; Elia et al., 2008). Disparity of diarrhoea definitions was
noted in all studies. Diarrhoea was identified by the duration of diarrhoea monitoring.
Percentages of diarrhoea days or proportions of diarrhoea free days were inconsistently
reported (Heimburger et al., 1994; Bleichner et al., 1997; Alberda et al., 2007; Chaboyer
et al., 2007). The absence of a single agreed diarrhoea definition will continue to
influence research outcomes and generalisation of study results in the critical care
environment.
Enteral tube feeding is often cited as a diarrhoea risk factor. Putative factors
associated with diarrhoea and ETF include fibre enriched ETF, hyper-osmolality and
contamination of the ETF (Pancorbo-Hidalgo et al., 2001; Whelan et al., 2001; Lebak et
al., 2003; Whelan et al., 2003; Weisen et al., 2006). Clinical trials examining the effects
of fibre containing ETF formulae on GIT function show variable results (Thomas et al.,
2003.
14
The various ETF formulae used in the studies reviewed were inconsistently
reported (Heimburger et al., 1994; Bleichner et al., 1997; Alberda et al., 2007; Chaboyer
et al., 2007) (see Table 2). Diarrhoea was found to be inconsistently associated with the
type of ETF formulae administered. The unpredictability of these results might be
associated with the ETF formulae, duration of ETF, probiotic species administered,
inadequately powered sample sizes, or other confounding physiological or
pharmacological reasons not reported. Interestingly, a trend to continue ETF in the
presence of diarrhoea was observed in the studies reviewed (Heimburger et al., 1994;
Bleichner et al., 1997; Alberda et al., 2007; Chaboyer et al., 2007).
It is important to note that the faecal intestinal flora of study participants was not
examined for changes to normal GIT microbiota in the four RCTs (Heimburger et al.,
1994; Bleichner et al., 1997; Alberda et al., 2007; Chaboyer et al., 2007). It would be
beneficial to explore microbial changes at an individual patient level prior to
administering probiotics. Should alterations to the individual’s intestinal flora occur,
then it might be appropriate to consider probiotics as an adjuvant to diarrhoea
management.
Probiotics
Dissimilarity between probiotic species, dose and frequency of administration
was evident between the studies (refer to Table 2) (Heimburger et al., 1994; Bleichner et
al., 1997; Alberda et al., 2007; Chaboyer et al., 2007). Although little is understood
regarding the therapeutic dose(s) of probiotic species, a minimum of 5 x 106 colony
forming units (cfu) is suggested to guide the clinical benefits in most diarrhoeal and
15
disease states (Sartor, 2004). The disparity between probiotic species and concentrations
of the studies reviewed (100,000 0007, 500mg
8, 9 x 10
11 bacteria
9, 450 billion
10 cfu)
may attribute to the inconclusive findings.
The principle of using harmless bacteria to overcome pathological intestinal
pathogens has been acknowledged for many years (Montrose and Floch, 2005. Probiotic
ingestion by definition infers that the host will receive a physiological and therapeutic
benefit (Isolauri and Salminen, 2004; Chaboyer et al., 2007). The risk of morbidity must
be balanced against the sparse evidence supporting probiotic efficacy in the
management of ETF related diarrhoea in critically ill patients.
S.boulardii is a yeast used to treat antibiotic and ETF diarrhoea in critically ill
adults at a dose of 1-2 g/day. Seven cases of fungaemia were observed in critically ill,
mechanically ventilated patients who were treated with broad spectrum antibiotics and
had central venous catheter access between June 1996 and October 1998 (Lherm et al.,
2002). Six of these patients were treated with S.boulardii. Complications associated
with fungaemia in critically ill and immunocompromised patients have been
increasingly reported since the 1990s. Lherm et al (2002) argue that S.boulardii should
not be administered to critically ill or immunocompromised patients. Surprisingly, the
largest study by Bleichner et al (1997) did not report any cases of fungaemia in the
S.boulardii treated group.
Most research to date has focused on the mechanisms by which pathogenic
bacteria exert their effect (Rolfe, 2000; Fioramonti et al., 2003; Fedorak and Madsen,
16
2004). A better understanding of probiotics mechanism of action will result in more
efficacious application to the symbiotic relationship between the host and gut barrier
function.
The scientific weaknesses of probiotics have been inadequately examined and
cautious use is recommended in critically ill patients. Commonly noted scientific
weaknesses of probiotics which may explain the absence of a significant reduction in
diarrhoea includes:
Numerous and often inadequately described probiotic genera, species and strains
with varying effects at varying endpoints in the GIT;
Inadequate understanding of probiotic species and strain dosages and the
efficacious window of opportunity of administration; and
Inconsistent or inadequately stored probiotic cultures may result in reduced
bacterial viability (Guarner et al., 2008).
Why might probiotics be harmful?
Alterations to intestinal micro flora during critical illness lend the intestine
vulnerable to pathogenic microorganisms. Factors influencing this pathogenic
environment include gut dysmotility, changes in nutrient availability, pH balance,
oxygen supply/demand, increased release of stress hormones such as catecholamine,
osmolality of ETF, medications, and antibiotics (Singhi and Baranwal, 2008).
Theoretically, probiotics are responsible for four types of side effects including
1) systemic infections; 2) injurious metabolic activities; 3) undue or excessive immune
17
stimulation; and 4) gene transfer (Hammilton-Miller, 2004; Yan and Polk, 2006; Elia et
al., 2008).
Several studies did not meet the inclusion criteria of this review paper as
diarrhoea was not identified as an outcome measure (Rayes et al., 2002; Falcao et al.,
2004; Kotzampassi et al., 2006; Spindler-Vesel et al., 2007; Besselink et al, 2008;
Forestier et al., 2008) (see Table 3). However, it is important to discuss the efficacy of
probiotics in relation to critical illness. A number of clinical trials have reported
significant reduction in infection acquisition rates, systemic inflammatory response,
sepsis, ICU and hospital lengths of stay, early return of bowel function, reduced
mechanical ventilation days, decreased intestinal permeability and mortality rates in the
probiotic groups (Rayes et al., 2002; Kotzampassi et al., 2006; Alberda et al., 2007;
Spindler-Vesel et al., 2007; Forestier et al., 2008; Klarin et al., 2008). Conversely, some
studies found no increase in infection acquisition rates or mortality (Besselink et al.,
2008) in the probiotic treated patients. These findings may be because of the small
sample sizes, incongruence’s between severity of illness scores, heterogeneity of
participant populations, variations between probiotic/synbiotic species and doses, and
inadequate pre-trial testing of probiotic combinations.
Mortality and probiotic trials have been infrequently reported on for reasons
including inadequate sample sizes and mortality not cited as a study endpoint. Besselink
et al (2008) demonstrated a significant mortality rate which is in contrast to many other
study findings (Heimburger et al., 1994; Bleichner et al., 1997; Falcao et al., 2004;
Kotzampassi et al., 2006; Alberda et al., 2007; Chaboyer et al., 2007).
18
In the Besselink et al (2008) study, a six species, powdered probiotic preparation
was administered enterally or orally, twice daily for twenty-eight days. Baseline group
characteristics were similar. Infectious complications occurred in 30% (n=46) of the
probiotics and 28% (n=41) of the placebo patients. Probiotic group mortality was 16%
(n=24) compared to placebo group mortality of 6% (n=9). Bowel ischaemia was
diagnosed at autopsy in nine probiotic group patients (eight fatal) and no placebo group
patients (p=0.004).
Of particular note in the Besselink et al (2008) study was the significant bowel
ischaemia and mortality findings in the probiotic group. These findings may be
potentially related to the following study limitations:
Organ failure rates were significantly higher in the probiotic (n=20) versus the
placebo (n=7) group (p<0.02) on the day of randomisation;
There was inadequate pre-trial testing of the combined probiotic preparation;
Higher probiotic bacterial loads may have increased oxygen demand resulting in
cumulative gut ischaemia;
Injection of probiotics directly into the jejunum bypassing the acid environment
of the stomach might have led to an increased bacterial concentration in the
small bowel;
The ETF formulae combined with probiotic bacteria and fibre might have
resulted in an accelerated fermentation process;
19
Delayed upper GIT peristalsis seen in pancreatitis may have increased exposure
to the probiotic;
Many patients had previous exposure to alcohol misuse, were potentially
immunocompromised and then exposed to a bacterial, probiotic load. These
combined factors may have exacerbated intestinal permeability often seen in
pancreatitis patients (Marteau, 2008; Bjarnason et al., 2008; Reddy and MacFie,
2008; Reid et al., 2008).
The study by Besselink et al (2008) raises many questions. Does probiotic
therapy require additional oxygen requirements that cannot be met in a critically ill
patient with reduced splanchnic blood flow? Is it possible that multiple organ failure
associated with sepsis or infection affects the intestine’s 1) epithelial lining; 2)
homeostatic environment; 3) regulation of microbial environment; and 4) modifies
commensal bacteria? Does the site of probiotic administration such as intra gastric or
jejunal, affect splanchnic oxygen consumption and GIT permeability in critical illness?
Are the results of Besselink et al (2008) study only evident in acute pancreatitis patients
who are at an increased risk of intestinal permeability or are these results similar in
other subsets of critically ill patients? The answers to these physiological questions
require further research.
A recent systematic review (Whelan and Myers, 2010) identified 72 articles
examining probiotic safety in enterally tube fed patients. Of these articles, 20 were case
reports of adverse events in 32 patients and 52 were articles that reported 53 trials in
which 4131 patients received probiotics. Notably, the majority of trials reported either
20
no effect of a positive effect related to the outcome measure of safety (mortality and
infection). An increase in patient complications was reported in only three trials. These
complications were predominantly non-infectious and in specific cohorts of patients
including transplant and pancreatitis patients. Probiotics were administered via a post-
pyloric tube in two of these three trials. Whelan and Meyers (2010) recommend that 1)
safety trials be conducted when a probiotic or combination of probiotics is administered
in a disease state for the first time; 2) efficacy trials should include a data monitoring
committee to monitor adverse events; 3) probiotics associated with an increased risk of
adverse events in specific disease states should not be administered to those particular
patients; and 4) administer probiotics cautiously in high risk patients such as critically
ill patients and patients with a central venous line insitu. A notable recommendation by
Whelan and Meyers (2010) is that probiotics should not be with held in high risk
patients or research as the potential benefits outweigh the potential risks. In this
situation, a risk-benefit analysis and surveillance monitoring is required for individual
patients to detect early adverse events.
Recommendations
This literature review has identified a number of areas that require further
attention. The definition and efficacy of probiotics in severely and critically ill patients
requires cautious application. Clearly, probiotics are not beneficial to the host when
mortality is observed in severely ill pancreatitis patients. Mechanisms of actions of
probiotics may be linearly affected by the probiotic species, dose, frequency and method
of administration in specific disease states such as diarrhoea, constipation and
infections. Future research must examine morbidity and mortality causes in critically ill
21
patients who receive probiotics. Intestinal flora changes must be examined at an
individual patient level prior to the addition of probiotics as adjuvant treatment in
critical illness.
Conclusion
From the evidence reviewed, it would appear that probiotics do not conclusively
reduce the incidence of ETF related diarrhoea in critically ill patients. An increased
incidence of mortality in probiotic patients, on the basis of one study must lend caution
to their use in critically ill patients. Further in-vivo and animal studies are required to
confirm the mortality findings in severely and critically ill patients. Only then, can
probiotics be safely administered to critically ill patients to manage enteral tube feeding
diarrhoea. In conclusion, as clinicians, we need to challenge the theoretical approach
that probiotics are beneficial to the critically ill patient?
22
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Table 1 Definitions
Prebiotic Non-digestible substances that beneficially effect the host
through selectively stimulating the growth and/or activity of
indigenous bacteria.
Probiotic Viable, non-pathogenic micro-organisms which when
ingested exert a beneficial effect and positive influence on
the health and well-being of the host.
Synbiotic Products combining both probiotic and probiotic. Synbiotics
provide a beneficial synergistic effect to the host.
(Cataldi-Betcher et al., 1983;Marteau and Seksik, 2002; Fioramonti et al., 2003)
Table 2 Probiotic and Diarrhoea Studies published between 1980 and 2008
Author Methodology Setting Participants
Aim Intervention Results
Heimburger et al (1994)
Prospective, randomised, double-blind, placebo controlled trial
Multi centre: ICUs and general wards teaching and general hospitals between September 1988 and February 1991. Participants: ETF critically ill adult patients
Assess whether 1) antibiotics, hypoalbuminaemia or hypertonic ETF is associated with diarrhoea; 2) determine the frequency of ETF related diarrhoea; 3) does Lactobacillus reduce the incidence of ETF diarrhoea
L acidophilus & L. bulgaricus 1g (n=18) vs placebo (n=23) TDS. Study duration not identified ETF: Osmolite HN, Isocal or Sustacal to maximum 10 days ICU patients (N=25): Probiotic group (n=13) vs placebo group (n=12) Randomisation: Stratified random assignment with regard to 3 putative risk factors: 1. Antibiotics; 2. Serum albumin ≤25 or
≥25 g/L; 3. ETF osmolality ≤ 350 or
≥350 mosmol/kg 3 diarrhoea risk factors: 1. Antibiotics 2. Hypoalbuminaemia 3. ETF osmolality
Diarrhoea defined as the excretion of >200g of stool in 24 hours;
34 patients completed 5 days of ETF without diarrhoea
Diarrhoea developed in 17% (n=7) of patients
Lactobacillus did not alter risk of diarrhoea
No statistical significance identified in the incidence of diarrhoea between the 2 groups
31
Bleichner et al (1997)
Prospective, randomised, double-blind, placebo controlled trial
Multi centre (11) ICUs in teaching and general hospitals between April 1992 and June 1993 Participants: Adult ICU patients expecting ETF > 6 days
Assess prophylactic effect of S.boulardii on diarrhoea in ETF critically ill patients
S.boulardii 500mg (n=64) vs placebo (n=64) QID for 21 days or withdrawal of ETF ETF: Intact protein diet without fibre of lactose for minimum 6 days Randomisation: Stratified blocks of 4 random assignment with regard to hospital
15 risk factors studied 5 independent risk
factors: 1. Previous TPN; 2. Malnutrition; 3. Hypoalbuminaemia <26
g/l; 4. Infection site; 5. Hyper/hypothermia
Diarrhoea measured as number of days a patient experienced diarrhoea and volume and consistency of stool
Frequency of diarrhoea days 18.9% (placebo) vs 14.2% (S.boulardii) (p=0.0069)
Diarrhoea days reduced by 25%
Risk factor adjustment showed diarrhoea days reduced 42% vs 25% = 52% reduction
32
Alberda et al (2007)
Double-blind, placebo controlled pilot RCT;
Single centre ICU Participants: ETF critically ill adult pts
Do viable and non-viable probiotics modulate intestinal permeability and immune function and prevent MODS onset in critically ill patients; Do bacterial sonicates with bacterial DNA have similar effects as viable bacteria
Ix: ProbioticsVSL#3 BD for 7 days. Each sachet = 9 10
11 bacteria viable
probiotic n=10; sonicate (n=9); Control: placebo (n=9) ETF: Jevity plus within 48 hrs for all groups Randomisation: Random assignment, method of assignment not discussed
Higher incidence of diarrhoea in placebo vs probiotic and sonicate groups (23% vs 14% vs 12%). Not statistically significant;
Improved immune activity, decreased intestinal permeability & MODS in probiotic group
Chaboyer et al (2007)
Prospective, randomised, double-blind, placebo controlled trial
Single centre ICU Participants: Adult, ICU patients
Evaluate the efficacy of probiotics to reduce diarrhoea in ETF critically ill patients
VSL#3 (n=25) BD vs placebo (n=20) BD ETF: Not reported Randomisation: Method not identified
Diarrhoea measured using validated King’s College Stool Chart
Study duration 8.5 to 12.4 days
Risk factors adjusted for include: 1. Albumin; 2. Duration of EN
Liquid stool volume reduced by 50% in the VSL#3 treated group (p=0.05)
No adverse events were observed
33
Table 3 Probiotics in Critical Illness
Author Methodology Setting Participants
Aim Intervention Results/Limitations
Rayes et al (2002)
Prospective, randomized, double-blinded, placebo-controlled trial
Single centre ICU Participants: Adult patients undergoing liver transplantation
To examine three different treatment strategies on the incidence of early post operative infection following liver transplantation. Group 1: early enteral nutrition (fibre-free) with selective bowel decontamination (SBD); Group 2: fibre-enriched formula plus live Lactobacillus plantarum 299 (L. plantarum); Group 3: heat inactivated (placebo) L. plantarum 299.
EEN started within 24 hr of operation and continued until day 12 post operatively
Group1: SBD of 80 mg Tobramycin, 500 mg Amphotericin B, 100 mg colistin sulphate QID for 6 weeks post operatively (n=32); Group 2: Nutrison Fibre plus L. planatrum 10
9 cfu BD for 12 post
operative days (n=31); Group 3: heat-killed L. planatrum plus oat fibre BD for 12 post operative days (n=32) Randomisation: Stratified randomisation by sealed envelope
Serum albumin higher, shorter ICU and hospital LOS and earlier return of bowel function (not significant) in group 2;
Significantly less infections in group 2 (p=0.017);
Limitations: Statistical significance
poorly identified and discussed;
Small sample size; Extrapolation of results
to include probiotic administration to the donor is unsubstantiated
34
Falcao et al (2004)
Prospective RCT Blinding of participants not identified
Single centre ICU Participants: ETF brain injured CI pts Age 16 – 50
Evaluate the effects of EEN with glutamine against infectious complications, LOS ICU, time spent mechanical ventilation
Intervention: Glutamine 30g (administered as a bolus), 240 ml fermented milk with probiotic Lactobacillus johnsonii (La 1) (n=11); Control: Standard polymeric diet (n=12) Randomisation: Method not identified
No mortality observed;
Higher infection rate in control group (p=0.03);
Infections per patient higher (p<0.01), ICU LOS (p<0.01) and days mechanically ventilated (p=0.04) higher in control group
Limitations: ICU LOS included
ICU and ward days; Small sample size; Low statistical power
of 80% sought
35
Kotzampassi et al (2006)
Prospective, randomized, double-blind, placebo-controlled, pilot trial This study is an interim analysis at 60% recruitment into the RCT
Multi centre (5) ICU Participants: Mechanically ventilated, severe poly trauma, adult ICU patients with expected ICU LOS >15 days
To examine the benefits (infection rates, duration of mechanical ventilation, mortality) of combination treatment (synbiotics) with pre- and probiotics in critically ill, long term ventilated patients.
Intervention: synbiotic formulae consisted of 1) four probiotics (10
11
cfu each) Pediococcus pentosaceus, Leuconostoc mesenteroides, Lactobacillus plantarum, Lactobacillus ssp paracasei; and 2) prebiotics of insulin, oat bran, pectin, resistant starch. Dose of 12g daily for 15 days (n=35); Control: placebo (n=30) Randomisation: Random assignment
Synbiotic treated patients developed less infection (p=0.01), SIRS/sepsis (p=0.02), mortality, and reduced days under mechanical ventilation (p=0.001);
Trend toward normalization of upper GIT motility in synbiotic group
36
Spindler-Vesel et al (2007)
Prospective, randomized, controlled trial. Participant blinding to study investigators not identified.
Single centre ICU Participants: Multiple trauma, adult, patients
To examine the relationship and extent of synbiotics, prebiotics, glutamine, peptide on 1) intestinal permeability (IP); and 2) infection rate, mortality, ICU LOS, days of mechanical ventilation and incidence of MOF
Group 1: Alitraq EN plus 1.55 g glutamine, 446 mg arginine, 154 mg α-linoleic acid per 100 ml; Group 2: Nova Source EN; Group 3: Nutricomp peptide EN; Group D; Nutricomp standard plus synbiotic (Pediococcus pentocsaceus 10
10,
Lactococcus raffinolactis 10
10, L. paracacsei sub
species paracasei 1010
, L. plantarum 10
10, and 4
fibres (β glucan, insulin, pectin, resistant starch) En started within 24 hrs
of ICU admission EN stopped x 6 hr over
night; Total patient sample:
N=113 Randomisation: Random allocation
Significant less combinations of infections in Group D (p=0.003);
Intestinal permeability decreased only in Group D from 0.148 (0.056-0.240) on day 4 to 0.061 (0.040-0.099) on day 7 (p < 0.05);
Total gastric retention volume higher in Group D (p <0.02)
Limitations: Patient numbers per group not identified
37
Forestier et al (2008)
Prospective, randomised, double-blind, placebo controlled pilot RCT
Single centre ICU Participants: ICU patients with LOS > 48 hrs and NGT
Investigate the effectiveness of an oral probiotic on gastric and respiratory colonization/infection with Pseuomonas aeruginosa (P. aeruginosa)
Intervention: Lactobacillus casei rhamnosus 10
9 cfu
BD from day 3 of ICU admission to discharge (n=102); Control: placebo (not identified) BD from day 3 ICU admission to discharge (n=106) Randomisation: Computer generated, equal random allocation through sealed envelopes
Delayed (11 vs 50 days) respiratory colonization of P. aeruginosa (p=0.01) in probiotic group;
Reduced P. aeruginosa VAP in probiotic group (not significant)
Klarin et al (2008)
Prospective, randomized, double-blind, placebo controlled RCT
Single centre ICU Participants: ICU patients with LOS > 3 days, >18 years of age, no previous positive C. difficile infection, commence ETF within 24 hours of ICU admission, no allergy to study protocol probiotics, not moribund
Investigate the effectiveness of enteral administration of Lactobacillus plantarum 299v on the prevalence of Clostridium difficile (C. difficile) infection in critically ill patients treated with antibiotics
Intervention: fermented oatmeal gruel with 8 x 10
8
cfu/mL of Lactobacillus plantarum 299v 100 ml bolus doses BD by 6 days, followed by 50 ml bolus doses BD ICU discharge. Control: Same gruel as the intervention group, less the Lactobacillus plantarum 299v. Lactic acid added to achieve same pH. Randomisation: Method not identified
No C. difficile colonisation in intervention group;
C. difficile in 19% of control group
No differences in frequency or consistency of bowel movements. Statistics not reported.
38
Besselink et al (2008)
Prospective, randomized, double-blinded, placebo-controlled trial
Multi ICU centre Participants: First episode of severe, acute, pancreatitis in adult patients
Assess the effects of probiotic prophylaxis on infectious complications in patients with severe, acute pancreatitis
Intervention: 6 strains of freeze-dried viable bacteria: L. acidophilus, L. casei, L, salivarius, Lactococcus lactis, Bifidobacterium bifidum, Bifidobacterium lactis to total of 10
10 bacteria plus
cornstarch and maltodextrins (n=152); Placebo: cornstarch and maltodextrins only (n=144) Probiotic or placebo administered BD and added to continuously infused fibre-enriched ETF (Nutrison Multi Fibre) or until oral intake resumed for 28 days. Randomisation: Computer generated permuted blocks of 4, balanced by admitting hospital and presumed cause of pancreatitis
Significantly higher mortality in probiotic group (p=0.01);
Bowel ischaemia higher in probiotic group 9 vs 0; p=0.004);
Early onset MOF in all probiotic patients who died
Limitations: Inadequate pre-trial
testing of probiotic combination (Ecological 641);
MOF rate on day of randomisation was significantly higher (p<0.02) in the probiotic (n=20) vs placebo (n=7) groups;
Pre-treatment MOF events closely correlate mortality rates (24 vs 9) and incidence of bowel ischaemia (9 vs 0);
Haemodynamic instability is a pre-cursor to MOF and non-occlusive bowel ischaemia in acute pancreatitis;
39
Hyper caloric ETF and inadequate gut function may explain bowel ischaemia;
High doses of probiotics (5 x 10
9 cfu
BD) untested; Probiotic bypassing of
gastric acid may have led to higher bacterial colonization in the jejunum;
Infectious complications (the aim of this study) poorly discussed
