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Indian Journal of Pediatrics, Volume 75June, 2008 621

Correspondence and Reprint requests : Prof. Sunit C. Singhi, Head,Department of Pediatrics, Advanced Pediatrics Center, PGIMER,Chandigarh, India-160012. Ph.: +91-172-2746699, 2755301, Fax: +91-172-2747099[Received February 29, 2008; Accepted February 29, 2008]

Symposium on Advances in Pediatric Intensive Care

Probiotic Use in the Critically l LLSunit C. Singhi and A. Baranwal

Department of Pediatrics, Advanced Pediatrics Center, Postgraduate Institute of Medical Education and Research,Chandigarh, India

ABSTRACT

Probiotics are live microbes which when administered in adequate amounts confer a health benefit to the host (FAO/WHO joint group). Their potential role in b io-ecological modification of pathological internal milieu of the cr itically ill is underevaluation. Probiotics are available as single microbial strain (e.g., Bacillus clausii, Lactobacillus) or as a mix of multiple strainsof Lactobacillus (acidophilus, sporogenes, lactis, reuteri RC- 14, GG, and L. plantarum 299v), Bifidobacterium (bifidum, longum,infantis), Streptococcus (thermophillus, lactis, fecalis), Saccharomyces boulardii etc. Lactobacilli and Bifidobacteria are gram-positive, anaerobic, lactic acid bacteria. These are normal inhabitant of human gut and colonize the colon better than others.Critical illness and its treatment create hostile environment in the gut and alters the micro flora favoring growth of pathogens.

Therapy with probiotics is an effort to reduce or eliminate potential pathogens and toxins, to release nutrients, antioxidants,growth factors and coagulation factors, to stimulate gut motility and to modulate innate and adaptive immune defensemechanisms via the normalization of altered gut flora. Scientific evidence shows that use of probiotics is effective in preventionand therapy of antibiotic associated diarrhea. However, available probiotics strains in currently used doses do not provide muchneeded early benefits, and need long-term administration to have clinically beneficial effects (viz, a reduction in rate of infection,severe sepsis, ICU stay, ventilation days and mortality) in critically ill surgical and trauma patients. Possibly, available strainsdo not adhere to intestinal mucosa early, or may require higher dose than what is used. Gap exists in our knowledge regardingmechanisms of action of different probiotics, most effective strains- single or multiple, cost effectiveness, risk-benefit potential,optimum dose, frequency and duration of treatment etc. More information is needed on safety profile of probiotics in immuno-compromised state of the critically ill in view of rare reports of fungemia and sepsis and a trend toward possible increase innosocomial infection. At present, despite theoretical potential benefits, available evidence is not conclusive to recommendprobiotics for routine use in the critically ill. [Indian J Pediatr 2008; 75 (6) : 621-627] E-mail: sunit.singhi@ gmail.com

Key words: Probiotics; Critically ill; Intensive Care unit; Children

Live microbes and fermented food-products are in use fortheir health-promoting effects since pre-Vedic and Vedicperiod. Moreover, Ayurveda recommended Dahi (curd)for its therapeutic effect in diarrheal patients much beforethe microbial existence was recognized. In modern times,Metchnikoff identified the possible health benefits of lacticacid bacteria (LAB) viz., Lactobacillus bulgaricus a ndStreptococcus thermophillus at the turn of the last century.Subsequently, the term probiotics was coined by Lilleyand Stillwell in 1965. 1 Recently, it has been defined by a

Joint Working Group of FAO/WHO as live microbes

which when administered in adequate amounts confer ahealth benefit to the host. 2 Development of target-specific

probiotics is the focus of current research. Their potentialrole in bio-ecological modification of pathological internalmilieu of the critically ill is under evaluation. This reviewwill examine current status of probiotics in care of thecritically ill as per available evidence, and will try toidentify direction for future research.

Gut Microflora and their Significance

Gut represents a complex ecosystem with a delicate balance between the microflora and the host. Human gutcontains about 400 different species of microbes as

commensals; total estimated number being >10 times thenumber of eukaryotic cells in the human body. Theyconstitute about 60% of fecal solids. 3 Human gutmicroflora is principally comprised of obligate anaerobes(about 95%) and facultative anaerobes (1-10%). Obligateanaerobes include Bifidobacterium, Clostridium,Eubacterium, Fusobacterium, Peptococcus, Peptostreptococcusand Bacteriodes; and facultative anaerobes areLactobacillus, E. coli, Klebsiella, Streptococcus, Staphylococcusand Bacillus. Very small amounts of Pseudomonas

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S.C. Singhi and A. Baranwal

622 Indian Journal of Pediatrics, Volume 75June, 2008

aeruginosa is also there. Each human being has his ownunique microbial collection especially of lactic acid

bact er ia l (LAB) st ra in s, e.g., Bifidobacterium an dLactobacillus. Bifidobacteria are the predominant microbesrepresenting up to 80% of the cultivable fecal bacteria ininfants and 25% in adults. Peristaltic movement, secretionof gastric acid and bile salts check the overgrowth of microflora and helps to maintain a concentration gradientaway from proximal gut (Fig. 1). Majority of thesemicrobes have health promoting effects; a few species are,however, potentially pathogenic. The good microbesoutnumber potentially pathogenic bacteria and live insymbiosis with host, benefiting the later (Fig. 2). Theoptimal composition and function of the flora depends onthe supply of food destined for colonic bacteria(fermentable fibers, complex proteins, GI secretions) andfluctuates with antibiotic usage, diarrheal diseases andcritical illness.

and small bowel, 5 help in development of a competentgut-associated immune system 6 and maintain a chronicand immunologically balanced inflammatory response.

The gut microflora provide physical barrier againstinvading pathogens, the so called colonizationresistance. The mechanisms for barrier effects include (i)

competition for epithelial cell adhesion sites preventingepithelial invasion (ii) competition for available nutrientsaffecting survival of potential pathogens and (iii)production of anti-bacterial substances ( e.g., bacteriocins,lactic acid) making the get environment unsuitable forgrowth of potential pathogens. Microflora has nutritivefunctions as well. It produces several enzymes and

biochemical pathways for fermentation of non-digestibledietary residue and endogenously secreted mucus 7 andhelps in recovering lost energy in form of short chain fattyacids. They also play a part in synthesis of vitamins, 8 andin absorption of calcium, magnesium and iron. 9

Critical illness, Gut, Sepsis and rationale of Probiotic

useCritical illness and their care in the modern ICUs createhostile environment in the gut and alters the microfloratilting the balance to favor pathogens. The hostileenvironment is contributed by various physical andchemical changes namely broad-spectrum antibiotics,changes in nutrient availability, gut motility, pH, oxygenconcentration, redox state, osmolality and release of highlevels of stress hormones including catecholamines. 10 Infact, stress-release of nor-epinephrine from sympatheticnerve endings, which are in highest concentration in gutepithelium, reduces the good microbes. 11 In experimentalmodels of acute pancreatitis disappearance of beneficialLABs was seen after 6 to 12 hours. 12 Human studies havealso shown similar loss of LABs in the critically ill after ashort ICU-stay. 13 Reduction in LABs breaks down thecolonization resistance and leads to overcrowding of potential pathogens. With capability to sense their ownovercrowding, the potential pathogens adapt themselvesto express virulence genes for self-protection and invasionafter having achieved a critical biomass in face of otherwise limited resources during such opportunism oradversity. 14 Overgrowth of various potentially pathogeniccommensals like Salmonella, E. coli, Yersinia, P. aeruginosahave been shown to cause one or more of cytokinerelease, cell apoptosis, activation of neutrophils and

disruption in epithelial tight junction permeability.11

Gut,with loss of colonization resistance, is unable to preventthe translocation of pathogens and toxins across the gutwall into the blood stream. Overgrowth of pathogens andmicrobial translocation have been shown to occur within6-12 hours of inducing acute pancreatitis in experimentalstudies. 12,15,16 Not surprisingly, gut has been identified asorigin and promoter of nosocomial sepsis and multi-organ failure in the critically ill, 17 which is the majordeterminant of ICU outcome.

Fig. 1. Normal composition of gut microflora.

Fig. 2. Delicate balance in gut microflora favors the host.

The gut microflora is important for development of normal intestinal morphology. Studies on animals raisedin germ-free environment have hypoplastic intestinalepithelium, reduced gut immunity, and impairedperistalsis all of which improved when normal gut florawere introduced. 4 The gut microflora stimulate theepithelial cell proliferation and differentiation in the large

Pathogenic Effects Health -promoting Effects

Pathogenic

P. aeruginosa

Proteus

Staphylococci

Clostridium

Intestinalputrefaction

Exogenous &harmful Endogenousbacteria

ImmuneStimulation

Digestion ofNutrients &Minerals

Synthesis ofVitamins

10 2

10 4

10 8

10 11

Streptococci

Eubacteria

Bacteroides

Lactobacilli

Bifidobacteria

Number/gmof feces

10 6

Enterococci

E. coli

Gastric acidBile salts

Gut motility

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Probiotic Use in the Critically Ill


Reversing the pathological microfloral tilt withexogenous supply of new and effective flora (probiotics)with/without food for the flora (prebiotics) seems anattractive and non-invasive attempt to restore naturalflora and thus the colonization resistance. It is likely toprevent microbial translocation and subsequent systemicinflammatory response. Probiotics (especially LABs)represent a therapeutic effort to reduce or eliminatepotential pathogens and toxins, to release nutrients, anti-oxidants, growth factors, coagulation factors, to stimulategut motility 18 and to modulate innate and adaptiveimmune defense mechanisms 19 via the normalization of altered gut flora.

The appeal of probiotics in critical care setting isthreefold. First, the existing safety record renders themattractive over many of the more aggressive therapeuticoptions. Second, they represent a simple, non-invasiveattempt to recreate natural flora rather than a disruptionof the nature. Third, the proposed use is for prevention of disease in a select group of patients which is associatedwith high mortality.

Currently Available Probiotics and their Mechanism ofaction

The effectiveness of probiotics is related to their ability tosurvive in the acidic and alkaline environment of stomachand duodenum respectively, as well as their ability toadhere to the colonic mucosa and to colonize the colon.Some probiotics, e.g., Lactobacillus GG and L. plantarum299v are better able to colonize the colon than others.Saccharomyces boulardii are non-LA yeast and secret aprotease causing proteolysis of Toxin A and Toxin B of Cl.difficile responsible for antibiotic associated diarrhea(AAD). Bacillus clausii are gram positive spore-formingstrictly aerobic non-LAB and constitute less than 1% of gutmicroflora. B. clausii stimulate CD4 proliferation and

2. Flora-SB Lactobacillus acidophilus(75 mg)Lactobacillus rhamnosus (75 mg)Bifidobacterium longum (75 mg)Bifidobacterium bifidum (50 mg)Saccharomyces boulardii (50 mg)

3. Lactisyn Lactobacillus lactis(490 million)Lactobacillus acidophilus(490 millionspores)Streptococcus thermophillus (10 million)Streptococcus lactis (10 million)

4. Eugi Lactobacillus acidophilus(240 million)Lactobacillus rhamnosus (240 million)Bifidobacterium longum (240 million)Bifidobacterium bifidum (240 million)Saccharomyces boulardii(50 million)Streptococcus thermophillus (240 million)Fructo-oligosaccharides (300 mg)

5. Prowell Lactobacillus acidophilus (5000 CFU)Bifidobacterium bifidum (5000 CFU)Bifidobacterium longum (5000 CFU)Bifidobacterium infantis (5000 CFU)Fructo-oligosaccharides

6. Biogut Lactobacillus acidophilus(300 million)Lactobacillus rhamnosus (300 million)Lactobacillus paracasei (300 million)Lactobacillus sporogenes (1200 million)Bifidobacterium longum (300 million)Saccharomyces boulardii(600 million)Inulin (200 mg)Fructo-oligosaccharides (200 mg)

7. Bifi lin Lactobacillus acidophilus(500 million)Lactobacillus rhamnosus (500 million)Bifidobacterium bifidum (500 million)Bifidobacterium longum (500 million)Streptococcus thermophillus (250 million)Saccharomyces boulardii(250 million)Fungal Amylase (200 mg)Fructo-oligosaccharides (100 mg)

8. Binifit Streptococcus fecalis(30 million)Clostridium butyricum (2 million)Bacillus mesentricus JPC (1 million)Lactobacillus sporogenes (50 million)

9. Ecoflora Lactobacillus rhamnosusGR-1 (1000million CFU)Lactobacillus reuteriRC-14

10. Flora-SB Lactobacillus acidophilus (40 mg)Lactobacillus rhamnosus (40 mg)Bifidobacterium bifidum (25 mg)Bifidobacterium longum (40 mg)Saccharomyces boulardii(25 mg)Fructo-oligosaccharides (100 mg)

11. Diacowin Saccharomyces boulardii (141.25 mg)Lactic Acid Bacilli (50 million)

TABLE 1. Commercially Available Probiotic Preparations inIndian Market.

No. Products Composition

Single strain probiotics1. Cynobac Tender/ Lactobacillus sporogenes(60 million

Baclac/Lactra/ spores/Tab)Rexflora kid tab/Oraflora

2. Cynobac/ Lactobacillus sporogenes(180 millionRexflora Cap spores/Tab or Cap)

3. Econorm/Biogit/ Saccharomyces boulardii(250 mg/ Sachet)Stibs4. Laviest Saccharomyces cerevisiae P(10 million

cells/Cap)5. Enterogermina Bacillus clausii (200 million spores/5 ml)

Multi-strain probiotics1 . Bifilac Lactobacillus sporogenes(50 million

spores)Streptococcus fecalis (30 million)Clostridium butyricum (2 million)Bacillus mesentricus (1 million)

lymphocytic activity in Peyers patches. It also lead to

increase in IgA-positive lymphocytes and HLA-DRpositive T lymphocytes. Bifidobacteria are gram-positiveanaerobic LAB, colonize the colon within days of birthand its population remains stable until advanced age.Lactobacilli are gram-positive, facultative anaerobic LABand are normal inhabitant of human gut. L. plantarum299v adheres to intestinal mucosa to re-inforce its barrierfunction, thus prevents attachment of pathogens to theintestinal wall. Lactobacilllus GG was found to eradicate Cl.difficile in patients with relapsing colitis. L. plantarum ST31

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being studied. In developing economies , majo rity of critically ill children have various infectious diseases asindication for PICU admission, and usually stay forrelatively shorter period. For example, only 28% of surviving patients with disseminated staphylococcaldisease stayed in PICU for >7 days in our experience. 35Thus, despite theoretical potential benefits, availableevidence is not conclusive to recommend it for routine usein the critically ill. 36,37

Probiotic in Antibiotic Associated Diarrhea (AAD):Available Evidence

With frequent use of broad spectrum antibiotics in criticalcare setting, AAD is frequently observed among criticallyill children. Decrease in population of microbes having

bene fi ci al me ta bo li c fu nc ti on s an d ov ergrowth of pathogens contribute to the osmotic and invasive diarrhearespectively. 38 A meta-analysis of 9 placebo-controlledRCTs (conducted during 1966-2000, including 2 pediatricRCTs) revealed probiotics to be effective in prevention of AAD; S. boulardii and lactobacilli having the bestpotential. 39 Another meta-analysis of 6 pediatric placebo-controlled RCTs (till 2005, n=766) have shown reducedincidence of AAD in probiotic treated patients. Furtheranalysis revealed that if 7 patients are going to developdiarrhea out of all patients receiving antibiotics, one can

be prevented if all of them received probiotics along withantibiotics. 40 Obviously, with the available preparationscost-benefit ratio of AAD-prevention does not seem to beclinically favorable.

A meta-analysis of 7 RCTs (n=881) revealed beneficialtherapeutic role of probiotics in AAD. 41 To address the

issue in children, meta-analysis of 6 RCTs (n=707) wereperformed. It revealed beneficial effect; however the samecould not withstand intention-to-treat analysis. 42 Thus itwas opined to have large well-designed trials to look intothe cost of and need for routine use of probiotics inAAD. 39 While all these studies had tried to address theissue of probiotic use for AAD in non-critical care setting,AAD in the critically-ill has not received similarattention. 43

Safety Issues

Though probiotics do not seem to pose a significant risk of infection, 44 thorough understanding of risks and benefitsis imperative while beneficial effects are being evaluated.In 28 critically ill children, use of L. casei shirota was safeand has led to neither colonization nor bacteremia. 22 Useof probiotics was found to be safe in surgical 45 a ndcritically ill patients. 24 However, there are rare reports of fungemia and sepsis in immunocompromised patients 46aswell as in the critically ill 47,48 with use of S. boulardii.Recently, use of L. rhamnosus GG in PICU patients wasshown have a statistically nonsignificant trend toward anincrease in nosocomial infection. 30 Other theoretical safetyconcerns are genetic transfer of antibiotic resistance,

deleterious metabolic activities and excessive immunestimulation in susceptible individuals, 2 and need to beaddressed.

Well-designed, large and detail studies are required toaddress the risk-benefit potential of therapeutic usage.The risk and morbidity of probiotic-induced sepsis need

to be weighed vis--vis its preventive potential againstsepsis in the critically ill. The European Society of Pediatric Gastroenterology, Hepatitis and Nutrition(ESPGHN) committee on nutrition recently summarizedits approach to probiotics as follows Probiotics so farused in clinical trials can be generally considered as safe.However, surveillance for possible side effects, such asinfection in high-risk group ( read, critically-ill group), islacking and is needed. 49

Future Research Direction for Critical Care Use

Probiotics represent promising advance in the field of prophylaxis and therapy, however much more need to bedone as far as its use in the critically ill is concerned.Following are the areas for further research:

It is important to achieve tight adherence of probioticonto the intestinal mucosa, which may be difficult incritical illness. Higher doses of existing strains or searchfor different strains may be required.

Most of strains colonized the intestine, but did so afterone week of consumption. What we need is early andeffective mucosal adherence, preferably within 48hours, to prevent multi-organ dysfunction in septicpediatric patients.

Search for clinically beneficial probiotic strains which

have ability to eliminate unwanted antibiotic-resistantgut pathogens, to prevent sepsis and to reduce SIRS.

More research is needed for better understanding of pharmacokinetics, mechanism of action and selectionof specific probiotic (single-strain or multi-strain) forspecific critical care conditions.

It is known that probiotic preparations are highlyheterogeneous with difference in composition,

biolog ical ac tivi ty and cl in ical ly beneficial dose .Research is needed in areas like appropriate dose,administrative regimens and probiotic interactions.

Properties of different probiotic species vary and are

strain-specific. Therefore, the effects of one probioticstrain cannot be generalized to others withoutconfirmation in separate studies.

Though probiotics are proven to be safe in healthychildren, more information is needed on their safetyprofile in immunocompromised state of the criticallyill.

Significance of additional use of prebiotics need to bedefined.

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626 Indian Journal of Pediatrics, Volume 75June, 2008

Available evidence suggest potential role of probioticin care of the critically ill. Recent ventures in metabolicengineering and heterologous protein expression haveenhanced the enzymatic and immunomodulatory effectsof probiotics and with time, may allow more activeintervention for its use in the patients underconsideration.

CONCLUSION

With increasing knowledge, eco-immunonutrition withprobiotics and synbiotics seem to be logical tools in care of the critically ill, however major gap exists in ourknowledge regarding mechanisms of action of differentprobiotics, most effective strains single or multiple, costeffectiveness, risk-benefit potential, optimum dose,frequency and duration of treatment. There is long way togo to have strain(s), which is clinically beneficial in thecritically ill. Optimally designed, well-powered,randomized, large clinical trials with reproducible resultsare required to define their preventive and therapeuticrole before routine use can be recommended.

REFERENCES

1. Lilly DM, Stillwell RH. Probiotics: growth promoting factorsproduced by micro- organisms. Science 1965; 147 : 747-748.

2. Joint FAO/WHO Working Group. Guidelines for the evaluationof probiotics in food. London, Ontario, Canada. 2002.

3. Guarner F, Malagelada JR. Gut Flora in health and disease.Lancet 2003; 361 : 512-519.

4. Noverr MC, Huffnagle GB. The microflora hypothesis of

allergic diseases. Clin Exp Allergy 2005; 35 : 1511-1520.5. O Sullivan GC. Probiotics. Br J Surg 2001; 88 : 161-162.6. Frankel WL, Zhang W, Singh A et al. Mediation of the trophic

effects of short-chain fatty acids on the rat jejunum and colon.Gastroenterology 1994; 106 : 375-380.

7. Roberfroid MB, Bornet F, Bouley C, Cummings JH. Colonicmicroflora: nutrition and health: summary and conclusions of an International Life Sciences Institute (Europe) workshopheld in Barcelona, Spain. Nutr Rev 1995; 53 : 127-130.

8. Conly JM, Stein K, Worobetz L, Rutledge-Harding S. Thecontribution of vitamin K 2 (metaquinones) produced by theintestinal microflora to human nutritional requirements forvitamin K. Am J Gastroenterol 1994; 89 : 915-923.

9. Younes H, Coudray C, Bellanger J et al. Effects of twofermentable carbohydrates (inulin and resistant starch) andtheir combination on calcium and magnesium balance in rats.

Br J Nutr 2001; 86: 479-485.10. Freestone PP, Haigh RD, Williams PH et al. Stimulation of bacterial growth by heat-stable, norepinephrine-induced auto-inducers. FEMS Micobiol Lett 1991; 172: 53-60.

11. Alverdy JC, Laughlin RS, Wu L. Influence of the critically illstate on host-pathogen interactions within the intestine: Gut-derived sepsis redefined. Crit Care Med 2003; 31 : 598-607.

12. Wang X, Andersson R, Soltesz V et al. Gut origin sepsis,macrophage function, and oxygen extraction associated withacute pancreatitis in the rat. World J Surg 1996; 20: 299-307.

13. Knight DJW, Ala Aldeen D, Bengmark S, Girling KJ. Theeffect of synbiotics on gastrointestinal flora in the critically ill.

(abstract). Br J Anaesth 2004; 92 : 307-308.14. Kinney KS, Austin CE, Morton DS et al. Nor-epinephrine as a

growth-stimulating factor in bacteria: Mechanistic studies.Life Sci 2000; 67: 3075-3085.

15. Leveau P, Wang X Soltesz V, Ihse I, Andersson R. Alterationsin intestinal permeability and micro flora in experimentalacute pancreatitis. Int J Pancreat 1996; 20 : 119-125.

16. Andersson R, Wang X, Ihse I, Leveau P. The influence of abdominal sepsis on acute pancreatitis in rats: a study onmortality, permeability,arterial blood pressure and intestinal bloo d flow. Pancreas 1995; 11: 365-373.

17. MacFie J, OBoyle C, Mitchell CJ, Buckley PM, Johnstone D,Sudworth P. Gut origin of sepsis: a prospective studyinvestigating associations between bacterial translocation,gastric microflora, and septic morbidity. Gut 1999; 45 : 223-228.

18. Bengmark S. Bio-ecology control of the gastrointestinal tract:The role of flora and supplemented probiotics and synbiotics.Gastroenterol Clin North Am 2005; 34: 13-36, viii.

19. Alberda C, Gramlich L, Meddings J et al. Effects of probioticstherapy in critically ill patients: a randomized, double-blind,placebo-controlled trial. Am J Clin Nutr 2007; 85: 816-823.

20. Meie R, Steuerwals M. Place of probiotics. Curr Opin Crit Care2005; 11: 318-325.

21. Gomes AMP, Malcata FK. Bifidobacterium spp. and Lactobacillusacidophilus: biological, biochemical, technological andtherapeutic properties relevant for use as probiotics. TrendsFood Sci Technol 1999; 10: 139-157.

22. Srinivasan R, Meyer R, Padmnabhan R, Britto J. Clinical safetyof Lactobacillus casei shirota as a probiotic in critical ill children. J Pediatr Gastroenterol Nutr 2006; 42: 171-173.

23. Mohan R, Koebnick C, Schildt J et al. Effects of Bifidobacteriumlactis Bb 12 supplementation on intestinal microbiota of preterm infants: a double-blind, placebo-controlled,randomized study. J Clin Microbial 2006; 44: 4025-4031.

24. Klarin B, Johansson ML, Molin G, Larsson A, Jeppsson B.Adhesion of the probiotic bacterium Lactobacillus plantarum299v onto the gut mucosa in critically ill patients: arandomized open trial. Crit Care 2005; 9: R285-293.

25. Manzoni P, Mostert M, Leonessa ML et al. Oralsupplementation with Lactobacillus casei subspecies rhamnosusprevents enteric clononization by Candida species in pretermneonates: a randomized study. Clin Infect Dis 2006; 42 : 1735-1742.

26. Jain PK, McNaught CE, Anderson AD, MacFie J, Mitchell CJ.Influence of synbiotic containing Lactobacillus acidophilus La5,Bifidobacterium lactis Bb12, Streptococcus thermophilus,Lactobacillus bulgaricus and oligofructose on gut barrierfunction and sepsis in critically ill patients: a randomizedcontrolled trial. Clin Nutr 2004; 23 : 467-475.

27. Mangell P, Lennernas P, Wang M et al. Adhesive capability of Lactobacillus plantarum 299v is important for preventing bacterial translocation in endotoxemic rats. APMIS 2006; 114:611-618.

28. Dani C, Biadaioli R, Bertini G, Martelli E, Rubaltelli FF.Probiotics feeding in prevention of urinary tract infection, bac ter ial sepsis and nec rot izing ent ero col it is in pre terminfants. A prospective double-blind study. Biol Neonate 2002;82: 103-108.

29. McNaught CE, Woodcock NP, Anderson AD, MacFie J. Aprospective randomized trial of probiotics in critically illpatients. Clin Nutr 2005; 24 : 211-219.

30. Honeycutt TC, El Khashab M, Wardrop RM 3rd et al.Probiotic administration and the incidence of nosocomialinfection in pediatric intensive care: A randomized placebo-controlled trial. Pediatr Crit Care Med 2007; 8: 452-458.

31. Watkinson PJ, Barber VS, Dark P, Young JD. The use of pre-

8/9/2019 0c96052a08a48e9c89000000 (1).pdf

7/7



pro- and synbiotics in adult intensive care unit patients:systematic review. Clin Nutr 2007; 26 : 182-192.

32. Kotzampassi K. Giamarellos-Bourboulis EJ, Voudouris A,Kazamias P, Eleftheriadis E. Benefits of a symbiotic formula(Synbiotic 2000Forte) in critically ill trauma patients: earlyresults of a randomized controlled trial. World J Surg 2006; 30:1848-1855.

33. Falcao de Arruda IS, de Aguilar-Nascimento JE. Benefits of early enteral nutrition with glutamine and probiotics in braininjury patients. Clin Sci (Lond) 2004; 106 : 287-292.

34. Bin-Nun A, Bromiker R, Wilschanski M et al. Oral probioticsprevent necrotizing enterocolitis in very low birth weightneonates. J Pediatr 2005; 147: 192-196.

35. Baranwal AK, Singhi SC, Jayashree M. A 5-year PICUexperience of Disseminated Staphylococcal Disease, Part 1:Clinical and Microbial Profile. J Trop Pediatr 2007; 53: 245-51.

36. Heyland DK, Dhaliwal R, Drover JW, Gramlich L, Dodek P;Canadian Critical Care Clinical Practice GuidelinesCommittee. Canadian clinical practice guidelines for nutritionsupport in mechanically ventilated, critically ill adult patients. J Parenter Enteral Nutr 2003; 27: 355-373.

37. Nathens AB, Curtis JR, Beale RJ et al. Management of thecritically ill patient with severe acute pancreatitis. Crit Care Med 2004; 32: 2524-2536.

38. Beaugerie L, Petit JC. Microbial-gut interactions in health anddisease: Antibiotic-associated diarrhoea. Best Pract Res ClinGastroenterol 2004; 18: 337-352.

39. DSouza Al, Rajkumar C, Cooke J, Bulpitt CJ. Probiotics inprevention of antibiotic-associated diarrhea: meta-analysis.BMJ 2002; 324: 1361.

40. Szajewska H, Ruszczynski M, Radzikowski A. Probiotics in

prevention of antibiotic-associated diarrhea in children: ameta-analysis of randomized controlled trials. J Pediatr 2006;149: 367-372.

41. Cremonini F, Di Caro S, Nista EC et al. Meta-analysis: theeffect of probiotic administration on antibiotic-associateddiarrhea. Aliment Pharmacol Ther 2002; 16: 1461-1467.

42. Johnston BC, Supina AL, Vohra S. Probiotics for pediatricantibiotic-associated diarrhea: a meta-analysis of randomizedplacebo-controlled trials. CMAJ 2006; 175: 377-383.

43. Wiesen P, Van Gossum A, Preiser JC. Diarrhoea in thecritically ill. Curr Opin Crit Care 2006; 12: 149-154.

44. Hammerman C, Bin-Nun A, Kaplan M. Safety of probiotics:comparison of two popular strains. BMJ 2006; 333: 1006-1008.

45. Sugawara G, Nagino M, Nishio H et al. Perioperative synbiotictreatment to prevent postoperative infectious complications in biliary cancer surgery: A randomized controlled trial . AnnSurg 2006; 244: 706-714.

46. Lestin F, Persehy A, Rimek D. Fungemia after oral treatmentwith Saccharomyes boulardiiin a patient with multiple Co-morbidities. Dtsch Med Wochensehr 2003; 128 : 2531-2533.

47. Munoz P, Bouza E, Cuenca-Estrella M et al. Saccharomycescerevisiaefungemia: an emerging infectious disease. Clin InfectDis 2005; 40: 1625-1634.

48. Hennequin C, Kauffman Lacroix C, Jobert A et al. Possible roleof catheters in Saccharomyces boullardiifungemia. Eur J Clin Micribiol Infect Dis 2000; 19: 16-20.

49. ESPGHAN Committee on Nutrition. Probiotic bacteria indietetic products for infants: a commentary by the ESPGHANcommittee on nutrition. J Pediatr Gastroenterol Nutr 2004; 38:365-374.

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