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Accepted Manuscript Blurred Lines: Dysbiosis and Probiotics in the Intensive Care Unit Lee E. Morrow, MD, MSc, Paul Wischmeyer, MD PII:
S0012-3692(16)60775-4
DOI:
10.1016/j.chest.2016.10.006
Reference:
CHEST 747
To appear in:
CHEST
Received Date: 31 July 2016 Revised Date:
21 September 2016
Accepted Date: 3 October 2016
Please cite this article as: Morrow LE, Wischmeyer P, Blurred Lines: Dysbiosis and Probiotics in the Intensive Care Unit, CHEST (2016), doi: 10.1016/j.chest.2016.10.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Submitted for: Contemporary Reviews in Critical Care Medicine
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Blurred Lines: Dysbiosis and Probiotics in the Intensive Care Unit
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Lee E. Morrow, MD, MSc [email protected] Professor of Medicine, Professor of Pharmacy Practice Creighton University School of Medicine Division of Pulmonary, Critical Care and Sleep Medicine and Paul Wischmeyer, MD [email protected] Professor of Anesthesiology and Surgery Duke University Medical Center
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Correspondence to: Lee E. Morrow, MD, MSc ([email protected]) Professor of Medicine, Professor of Pharmacy Practice Creighton University School of Medicine Division of Pulmonary, Critical Care and Sleep Medicine 601 North 30th Street, Suite #3820 Omaha, Nebraska 68131
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Dr. Morrow has no conflicts of interest to disclose. Dr. Wischmeyer has no conflicts of interest to disclose. 1
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Abstract Clinicians have traditionally dichotomized bacteria as friendly commensals or harmful pathogens. However, the line separating the two has
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become blurred with the recognition that the intestinal microbiome is a
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complex entity wherein species can shift sides – from friend to foe and back
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again – based on crucial factors in their local environment. Significant
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disruptions in the homeostasis of the microbiome, a phenomenon called
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‘dysbiosis,’ is increasingly associated with a host of untoward effects.
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Intensive care unit patients are at high risk for dysbiosis given high rates of
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antibiotic use, acute changes in diet, and the stress of critical illness.
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Probiotics are living microbes of human origin that, when ingested in
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sufficient quantities, can colonize sites such as the oropharynx and
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gastrointestinal tract and provide benefits to the host. In recent years we
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have increasingly explored the utility of using probiotics to reverse the
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intestinal dysbiosis associated with critical illness, thereby reducing select
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intensive care unit complications associated with increased morbidity and
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mortality. While these preliminary efforts have demonstrated varying
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degrees of success, our present studies suffer from a host of limitations that
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hinder the strength of their conclusions and/or the generalizability of their
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results. Probiotic investigations have been further hobbled by current
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regulatory requirements, which were designed to serve as the framework for
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pharmaceutical research. While such measures are intended to ensure
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patient safety, they inadvertently impose barriers that stifle innovation
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regarding nutraceuticals. This review strives to summarize the current
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evidence regarding the efficacy and safety of probiotics in the intensive care
6
unit as well as to provide an overview of the obstacles probiotic researchers
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face going forward.
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Introduction Although we have long believed it is our cells that make us human,
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new data shows we are made up of as many bacterial cells as human cells
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(about a 1:1 ratio) [1]. These microbes primarily live in the gut where they
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form a robust and diverse ecosystem living symbiotically with their host.
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Historically, clinicians have shown interest in such microbes only when they
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caused infectious diseases. In such instances our efforts have focused
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primarily on eradicating the offending organism(s). However, it is
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increasingly apparent that the ‘microbiome’ – this collection of commensal
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organisms living on and within each of us – plays critical roles in the
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homeostasis of our daily physiology and metabolism as well as in our
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response to acute illness.
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We have also learned that a significant disruption in the homeostasis
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of the microbiome, a phenomenon called ‘dysbiosis’, may contribute to the
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development of various diseases such as inflammatory bowel diseases,
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diabetes, allergies, and obesity. Dysbiosis during acute illness appears to
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lead to complex disruptions in host immunity, priming the gut to act as a
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source of ongoing inflammation that acts as the ‘motor’ of multiple organ
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dysfunction syndrome [2]. This interconnectedness of the microbiome and
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the host’s well-being suggests that regulation of the microbiota is a potential
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avenue to prevent and/or treat select human illnesses [3]. As such, the line
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dichotomizing microbes as inherently good or bad has blurred. We must
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change the paradigm by accepting that the effects these microorganisms
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have on the host may change based on multiple environmental factors.
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Intestinal dysbiosis is heavily driven by antibiotic consumption. The use of antimicrobial agents to treat infections inflicts inherent collateral
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damage on the numerous health-promoting microbes of the microbiota.
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Such changes in the commensal flora, coupled with potential overgrowth of
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more virulent species, often result in acute and dramatic alterations in the
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microbiome. The net result is a combination of potentially harmful local
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manifestations (increased gut permeability, reduced anti-inflammatory
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regulatory T cells) and distant effects (impaired immunity, systemic
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inflammation) [2,4].
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The intensive care unit (ICU) is a prime setting for intestinal dysbiosis
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given the frequency of antibiotic prescription in the critically ill
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superimposed on alterations in nutrition and the stress of acute illness.
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Large, multi-center studies have shown that 60-70% of ICU patients receive
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antibiotic therapy during their stay [5,6]. This is an ominous observation as
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dysbiosis, diagnosed via culture based techniques, in ICU patients has been
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associated with increased incidence of sepsis and death [7]. Given
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international concerns regarding increasing antimicrobial resistance and the
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rise of so-called ‘superbugs,’ it is not surprising that modulation of the
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microbiome to reverse dysbiosis has garnered significant attention. While
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multiple other modalities are available to alter the intestinal flora (i.e.,
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selective digestive decontamination, prebiotics, stool transplants) this review
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will focus on the use of probiotic-containing therapies in the ICU.
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The Probiotic Concept
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Probiotics are defined as living microbes of human origin that, when ingested in sufficient quantities, provide beneficial health effects to the host.
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Given the recent explosion of products claiming to contain probiotics (See
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Table 1), many clinicians think the probiotic concept is a relatively new
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phenomenon. In reality, 2016 marks the centenary of the death of Elie
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Metchnikoff, the father of innate immunity and Nobel Prize winner who
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hypothesized in 1904 that Belgian peasants’ heavy consumption of cultured
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yogurt may somehow account for their remarkable health and longevity [8].
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Basic science studies have shown that probiotic administration leads
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to numerous beneficial effects including augmented release of antimicrobial
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peptides, stimulation of mucus and IgA production, suppression of immune
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cell proliferation, reduced gut apoptosis, and anti-oxidative activity among 6
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others [2,9]. Because treatment for many ICU conditions remains primarily
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supportive, these observations have been too appealing to resist, ultimately
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translating into numerous clinical trials applying the probiotic concept to the
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dysbiosis of the critically ill population.
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Interest in probiotics has been further fueled by the success of fecal transplantation, a related strategy to therapeutically manipulate the
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microbiota. With this intervention, best studied in patients suffering from
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Clostridium difficile-associated diarrhea, presumably normal flora from
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healthy stool donors is used to repair the microbiome of affected patients.
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Fecal transplants demonstrate yet another blurred line as the method of stool
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transplant delivery determines whether or not it is a probiotic therapy. Our
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current strict definition of probiotics specifically requires that the agent is
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ingested. As such, a stool transplant given via pill form would be considered
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probiotic while a stool transplant administered via endoscopy would not.
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Disease States and Evidence Because probiotics are commercially available in the United States
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(US) as nutritional supplements or dietary aids they have not routinely been
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subjected to the same rigorous evaluation and oversight that the US Food
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and Drug Administration (FDA) requires of pharmaceuticals. As a direct 7
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result, the data supporting probiotic therapy is limited in scope, quality and
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quantity. Systematic reviews and/or meta-analysis techniques have often
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been used in an attempt to combine the fragmented primary data and to
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provide more meaningful estimates of the common effects of probiotics
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across a variety of clinical settings (See Table 2).
ICU-Acquired Infection: Probiotics have been shown to reduce the
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risk of ICU-acquired infections in aggregate. An early analysis that pooled
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data from 11 clinical trials found reduced ICU infections with probiotic
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administration (OR 0.82, 95% CI 0.69 to 0.99) [10]. A recently published
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updated meta-analysis of 14 randomized controlled trials (RCT) found that
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probiotic therapy significantly reduced the incidence of infectious
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complications in the ICU (RR 0.80, 95% CI 0.68 to 0.95, p = 0.009) [11].
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Ventilator-Associated Pneumonia (VAP): Although this is one of the most frequently studied areas related to probiotics in the ICU, the use of
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probiotics to prevent VAP remains highly controversial. The first meta-
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analysis in this area, published in 2010, demonstrated reductions of VAP
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(OR 0.61, 95% CI 0.41 to 0.91) and ICU length of stay (-0.99 days, 95% CI
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-1.37 to -0.61) with probiotic administration [12]. A subsequent meta-
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analysis similarly found reductions in ICU-acquired pneumonia (OR 0.59,
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95% CI 0.42 to 0.79) and ICU length of stay (-1.49 days, 95% CI -2.12 to -
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0.87 days) [13]. Neither study showed a mortality benefit with probiotic
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use. In contrast, two separate groups of investigators – combining different
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primary studies into their analyses – were unable to confirm a significant
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effect of probiotic therapy on the incidence of VAP [10,14]. A subsequent
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Cochrane review of probiotic prevention of VAP found that although
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probiotic therapy was associated with a reduction in the incidence of VAP
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(OR 0.70, 95% CI 0.52 to 0.95), the quality of the evidence was low [15]. A
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more recent, updated meta-analysis of nine RCTs found that probiotic
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therapy resulted in a significant reduction in the incidence of VAP (RR 0.74,
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95% CI 0.61 to 0.90, p=0.002) [11]. Based on these data and the overall
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reduction in ICU infections as described above, the May 2015 Canadian
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Clinical Practice Guidelines (CCPG) state, “Based on 4 Level 1 studies and
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24 Level 2 studies, the use of probiotics should be considered in critically ill
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patients.” (Available at www.criticalcarenutrition.com.)
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Three RCTs have been published after the recent CCPG were
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published, two in adults and one in pediatrics [16-18]. Given that these
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studies show contradictory results – two positive and one negative – it is
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increasingly clear that further study is needed.
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Antibiotic-Associated Diarrhea (AAD): Prevention of AAD is the most heavily studied indication when considering probiotic therapy, leading
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to the most robust meta-analyses. When investigators combined 63 studies
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(>11,800 patients) they showed that probiotics reduced AAD risk by 42%
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(RR 0.58, 95% CI 0.50 to 0.68) [19]. A subsequent meta-analysis found
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considerable heterogeneity among the 30 RCTs meeting their more rigorous
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criteria which led them to perform subgroup analyses [20]. This resulted in
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a positive association between probiotic intake and reduced risk of AAD in
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the adult population (RR 0.47, 95% CI 0.40 to 0.56) but not in elderly
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patients (RR 0.94, 95% CI 0.76 to 1.15). While both of these meta-analyses
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are intriguing, each primarily included studies of non-ICU and ambulatory
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patients. Studies dedicated to the critically ill, while overwhelmingly
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favorable, suffer from small sample sizes or the study of specific ICU sub-
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populations (i.e., neonates, spinal cord injury) making generalizations
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challenging.
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Clostridium difficile-Associated Diarrhea (CDAD): CDAD represents
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a subset of AAD that disproportionately affects patients in the ICU or leads
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to ICU admission. One meta-analysis looking at probiotic use for the
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prevention of CDAD combined 23 studies and over 4,200 patients [21].
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These investigators found that probiotics reduced CDAD incidence 64% and 10
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mitigated the side-effects associated with the use of CDAD-specific therapy
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(abdominal cramping, nausea, fever, soft stool, dysgeusia, flatulence).
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Another recent meta-analysis combined 26 RCTs involving 7,957 patients
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and found that probiotics reduced the risk of CDAD (RR 0.40, 95% CI 0.29
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to 0.53) in both adults and children [22]. These findings appear congruent
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with studies demonstrating that fecal transplantation – another avenue for
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reversing dysbiosis – is effective in curing CDAD in >90% of cases. In
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another insightful meta-analysis, probiotics were effective as primary
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prevention of CDAD but did not appear to have efficacy as secondary
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prevention of CDAD [23].
Necrotizing Enterocolitis (NEC): Accumulating evidence suggests
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that perinatal antibiotic use and alterations in bacterial colonization play
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pivotal roles in the pathogenesis of NEC. The most current meta-analysis on
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this topic confirmed the findings of three prior meta-analyses, suggesting
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that while probiotics reduce the severity of NEC and reduce mortality, there
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was no convincing benefit regarding sepsis prevention [24]. These authors
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conclude that while there is insufficient evidence to routinely recommend
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probiotics, there is encouraging data which justifies further investigations – a
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recurring theme regarding probiotics in the critically ill.
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Postoperative Infections: Although not limited to ICU patients, a recent meta-analysis compared probiotic supplementation to standard of care
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in 20 studies totaling 1,374 patients undergoing abdominal surgeries [25].
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This investigation found that probiotics reduced surgical site infections (RR
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0.63, 95% CI 0.41 to 0.98) and urinary tract infections (RR 0.29, 95% CI
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0.15 to 0.57). Probiotic use did not affect adverse event rates, length of stay,
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or mortality. A related meta-analysis looked at the effect of probiotics on
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the rate of postoperative sepsis in gastrointestinal surgery patients [26].
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When 15 RCTs involving 1,201 patients comparing probiotics with placebo
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were combined, the investigators found that probiotic treatment reduced the
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risk of sepsis (RR 0.62, 95% CI 0.52 to 0.74).
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Urinary Tract Infections (UTI): A systematic review of probiotics in UTI found limited data (nine studies) with a small aggregate sample size
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(735 patients) [27]. Comparisons were further limited by fragmentation of
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the comparator: five studies compared probiotics with placebo; two
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compared probiotics with no therapy; and two compared probiotics with
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antibiotics. Although no significant benefit was demonstrated for probiotics,
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the authors cautioned that a benefit cannot be ruled out given the limited
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number of studies, the small sample size, and the studies’ inherent poor
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methodologic quality.
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Hepatic Encephalopathy (HE): Probiotics are hypothesized to reduce HE through a combination of reduced ammonia production and absorption
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through intraluminal reductions in pathogenic bacteria, reduced ororectal
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transit time, and improved barrier function. Our most current understanding
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of the role for probiotics in HE comes from two meta-analyses. The first
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study, looking at minimal HE, combined nine studies with subjects
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randomized to probiotics or lactulose and found that the rate of progression
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to overt HE was similar for the two therapies [28]. However, probiotics
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were better tolerated than lactulose. The second study, evaluating fulminant
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HE in patients with cirrhosis, combined six RCTs involving 496 patients
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[29]. Compared to placebo, treatment with probiotics was shown to reduce
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HE (OR 0.42, p=0.0007) but did not affect the constipation rate, serum
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ammonia level, or mortality rate. So, while probiotics appear to confer some
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benefit in HE, the mechanism(s) of benefit remain unclear.
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Pancreatitis: Up to 20% of patients with acute pancreatitis develop
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pancreatic necrosis, a risk factor for serious infections with an associated
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mortality rate approaching 30%. Multiple small studies suggested that
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probiotics reduced the rate of infectious complications, thereby minimizing
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the need for surgical intervention in these patients. Research in this specific
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subset of ICU patients came to an abrupt halt in 2009, with the publication 13
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of the PROPATRIA trial which reported increased mortality in probiotic-
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treated pancreatitis patients [30]. However, this study has been heavily
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criticized regarding its design, execution, data safety monitoring, and
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analysis, and is commonly viewed as an outlier in the field of probiotic study
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[31].
Sepsis and Multiorgan Dysfunction Syndrome (MODS): Given the
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collective general trend towards benefit with probiotics across all of the
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indications described to this point, probiotic therapy is appealing as a
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preventive strategy for patients at risk for sepsis or MODS. The largest
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study to date – an RCT of only 65 trauma patients – showed reduced
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infection rates overall, less severe sepsis, and reduced mortality [32].
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Similar findings have been seen in small, focused cohorts of patients
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including severe pancreatitis, following liver transplantation, and post-
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abdominal surgery.
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Limitations
As previously alluded to, our current comprehension of probiotics in
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the ICU is far from perfect. The majority of published data consists of
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woefully small studies performed within single centers, hindering both
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confidence and generalizability. Criticisms of research methods are plentiful 14
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with several common themes. First, clinical endpoints are variably defined.
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As an example, a review of probiotic prevention of VAP trials shows nearly
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as many definitions of the diagnosis of VAP as there are studies themselves.
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Second, most studies fail to document quality control of their probiotic
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products and/or that probiotic therapy altered the host flora – a cornerstone
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of the current probiotic concept. Finally, a wide variety of probiotic species,
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doses and routes of administration have been used in the clinical trials
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discussed. As such, no recommendation can be made for the ‘optimal’
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probiotic agent or its ideal dose.
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Advocates of probiotics posit that commensals have co-evolved with humans over tens of millions of years and thus, their safety should be
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considered well established. Skeptics of probiotics cite numerous potential
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(and very real) risks of probiotics including systemic infection by probiotic
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therapies, potential harmful metabolic activities, excessive immune-
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stimulation, gastrointestinal side effects, and harmful gene transfer among
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others. Indeed, safety outcomes are inconsistently reported and subject
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protections vary greatly among existing published studies.
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Based on case reports, it has been suggested that probiotics should be
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avoided in select subpopulations where the risks of adverse events may be
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increased. Cohorts of concern include patients with immune disorders 15
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(including poorly controlled diabetes), pregnancy, endovascular grafts,
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cardiac valve disease or prosthesis, recent tracheostomy placement, and
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intestinal injuries due to trauma or surgery. Although these limitations are
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well intended, clinical data question whether they might be over-stated. As
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contradictory examples, probiotics have safely been used in patients
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undergoing major abdominal surgeries (despite surgical intestinal injuries)
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and in patients receiving solid organ transplants (despite intense immune
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suppression) [33, 34].
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In 2011, the Agency for Healthcare Research and Quality (AHRQ)
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concluded that while current probiotic RCTs don’t suggest an increase in
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risk, “the current literature is not well equipped to answer questions on the
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safety of probiotics in intervention studies with confidence.” A systematic
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review of the safety of probiotics concluded that while the “overwhelming”
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evidence suggests that probiotics are safe, critically ill patients in ICUs are
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one of the most at-risk populations for adverse effects [35]. This is
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particularly true for Saccharomyces boulardii, a probiotic generally
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considered unsafe for use in critically ill patients given its association with
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iatrogenic infections.
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Probiotics are big business with worldwide sales exceeding $30
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billion. As previously mentioned, these products are commercially available 16
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in the US as dietary aids or nutritional supplements, thereby skirting FDA
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regulation. In so doing, however, we simultaneously limit the rigorous study
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needed to definitively establish probiotics as ‘nutraceuticals’ – nutritional
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products with well-established medical benefits. The line currently
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separating nutraceutical claims from general health claims – meaning those
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that do and those that do not require FDA regulation – is, to say at the least,
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blurry.
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Manufacturers have crossed this line, moving their product from
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supplement to nutraceutical, raising the ire of the FDA. In 2010, parent company Danone (operating as the Dannon Company in the US) advertised
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that probiotic-containing Activia® yogurt relieved irregularity and that
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probiotic DanActive® dairy drink helped people avoid catching colds or the
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flu – claims not substantiated by clinical studies. After challenges by the US
14
Federal Trade Commission, these deceptive claims were dropped from
15
subsequent marketing and Danone was fined over $21 million
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(www.ftc.gov/news-events/press-releases/2010/12/dannon-agrees-drop-
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exaggerated-health-claims-activia-yogurt).
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The current FDA process for an Investigative New Drug (IND) was
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developed and refined to meet the needs of bringing pharmaceuticals to
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market. However, this IND pathway fails nutraceuticals. Currently most 17
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INDs are brought forth by large pharmaceutical companies for proprietary
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chemical agents whose potential for financial reward justifies the inherent
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(and expensive) risk. However, patenting a natural probiotic product is
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controversial and fraught with potential legal hurdles. Without such
5
justifiable protections, the risk-to-reward balance is unpalatable and ‘big
6
pharma’ is extremely unlikely to pursue a nutraceutical IND. Because the
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IND process is both cost-prohibitive and beyond the capacity of most
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academic researchers, it is similarly unlikely that academia will persevere.
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In this complicated arena it is clear that we need a unique regulatory
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pathway that balances safety and efficacy concerns with expediency and
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practicality [36]. With increasing antibiotic resistance and a stagnating
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antibiotic pipeline, it is imperative that we creatively reconcile the protection
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of research subjects and patients without stifling innovation.
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Future Horizons
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Because dysbiosis in the ICU increases susceptibility to nosocomial
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infections and increases down-stream mortality, perhaps we should
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proactively monitor the microbiome of ICU patients to identify this at-risk
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cohort [1]. Small pilot studies have successfully described strategies for
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monitoring the microbiome signature in critically ill patients [37,38]. In 18
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addition, a multicenter analysis of the effects of critical illness on the
2
microbiome – The ICU Microbiome Project – has recently been published
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[39]. These innovative studies show that we can successfully identify
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patients with dysbiosis in real-time and that changes in select flora correlate
5
with increased mortality. The ICU Microbiome Project demonstrated
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significant and rapid loss of health-promoting bacteria (i.e., Firmicutes)
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coupled with overgrowth of well-recognized pathogens such as Enterobacter
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and Staphylococcus. More specifically, this new data showed large
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depletions of organisms such as Faecalibacterium which are known to
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confer anti-inflammatory benefits [40]. This suggests that targeted repletion
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of beneficial bacteria lost during critical illness – the so-called ‘re-sodding’
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of the gut – may be a therapeutic avenue to pursue. What remains unknown,
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is the ideal probiotic or combination of probiotics needed to correct
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dysbiosis and what benefit(s) we can realistically expect to achieve.
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Conclusions
When it comes to probiotics, there is a blurred line separating two
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realities. First, current evidence has not convincingly established the
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therapeutic efficacy of probiotics and these agents cannot be definitively
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recommended for any ICU indication at present. Second, based on 19
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promising results from small studies and meta-analyses, some clinicians –
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frustrated by a lack of better options – are incorporating these agents into
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ICU care in a proverbially ‘off-label’ manner. Clinical researchers, federal
4
funding sources, industry experts and the FDA need to further the dialogue
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as to how we can stimulate clinical research and reconcile these two
6
realities. Better, larger RCTs with low risk of systematic and random errors
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are needed to rigorously evaluate the therapeutic effects and the safety of
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probiotics. Ideally, comparative efficacy studies of various probiotic species
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will similarly be undertaken to simultaneously define the optimal dose and
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duration of treatment.
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Figure 1. Representative Probiotic-Containing Products
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Commercially-Available in the United States Probiotics
Align Probiotic®
Bifidobacterium infantis
Blue Biotics®
Bacillus species (coagulans and
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Agent
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subtilis), Bifidobacterium species
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(breve, lactis and longum), Lactobacillus species (acidophilus,
casei, plantarum, rhamnosus and salivarius)
Florastor®
Lactobacillus rhamnosus GG
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Culturelle®
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Phillips’ Colon Health®
Bifidobacterium species (bifidum and longum), Lactobacillus gasseri Bifidobacterium animalis,
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TruBiotics®
Saccharomyces boulardii
Lactobacillus acidophilus
Ultimate Flora Critical Care®
Bifidobacterium species (breve, lactis and longum), Lactobacillus species (acidophilus, bulgaricus,
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casei, plantarum, paracasei, rhamnosus and salivarius)
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Figure 2. Overview of Recommendations Regarding the Use of
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Probiotic-Containing Products in ICU-Related Illnesses Overview
Antibiotic-associated diarrhea
Meta-analyses estimate 40-50%
(AAD)
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Disease State
reductions in AAD with probiotic
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therapy
Clostridium difficile
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Primary data include non-ICU studies Meta-analyses estimate ~60% reductions in rates of Clostridium difficile infection with probiotic use
Meta-analyses show limited benefit in
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Hepatic encephalopathy (HE)
Necrotizing enterocolitis
reducing hepatic encephalopathy progression in advanced liver disease patients given probiotic therapy
Meta-analyses consistently find that
(NEC)
probiotics reduce NEC severity and mortality but the magnitude of the effect size is varied
Nosocomial infections
Meta-analyses demonstrate ~20% 30
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reduction in ICU infections overall with probiotic therapy Limited primary data
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Pancreatitis
Probiotics were found to increase
mortality in one controversial trial
Meta-analyses found ~40% reductions
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Postoperative infections
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in operative site infections and sepsis with systematic probiotic use
Sepsis and multiple organ
Limited primary data
dysfunction syndrome (MODS) Probiotics consistently show reductions
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in sepsis and MODS rates in patients
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Urinary tract infections (UTI)
Ventilator-associated
given probiotic prophylaxis
Limited primary data
No meaningful benefits were demonstrated with probiotic use Meta-analyses suggest a 25-40%
pneumonia (VAP)
reduction in the rate of VAP in probiotic-treated patients
1
31

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