Use of Probiotics in the NICU

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Use of Probiotics in the NICU

  1. 1. Use of Probiotics in the NICU <ul><li>Part 1 </li></ul>
  2. 2. <ul><li>Today there will be 1,367 babies born prematurely in the United States… </li></ul><ul><li>and human milk feedings offer prevention and benefit for all of these morbidities. </li></ul>Immunonutrition
  3. 3. Immunonutrition <ul><li>“ The interaction between the initially sterile gastrointestinal tract and the microbiota that colonize it after birth is increasingly being recognized as a crucial component of postnatal development.” </li></ul>Montgomery, RK (2008) Gastroenterology and Nutrition: Neonatology Questions and Controversies .
  4. 4. Immunonutrition <ul><li>Ontogeny of the Gut </li></ul><ul><ul><li>Microvilli and biofilm </li></ul></ul><ul><ul><ul><li>Appear at 16 weeks & develop to cover surface area </li></ul></ul></ul><ul><ul><ul><li>Cover the surface of intestinal enterocytes - form brush border </li></ul></ul></ul><ul><ul><ul><li>Significantly increases mucosal surface area </li></ul></ul></ul><ul><ul><ul><li>Site of terminal carbohydrate digestion </li></ul></ul></ul><ul><ul><ul><li>Functions as a massive immune surface preventing bacterial adhesion and penetration – bacterial translocation </li></ul></ul></ul>
  5. 5. Immunonutrition Bengt Björkst ė n, MD, PhD (2008) Probiotics: Facts, Fiction and Future NASPGHAN Body Surface Area Skin 2m 2 Lungs ~100 m 2 Airways 100m 2 Gut 300m 2 Lungs as Sheet Intestines as Sheet Skin as Box Parameter Number Seating Capacity of the OSU Stadium 102,329 Population of the United States (2011)* 311,077,408 World Population (2011)* 6,909,201,891 GDP of the United States (2010) 14,624,184,000,000 # of Mammalian Cells in your Body 10,000,000,000,000 # of Microbial Cells in/on your Body 100,000,000,000,000
  6. 6. Immunonutrition <ul><li>Distribution of Microbiome </li></ul>Total Bacterial Counts (cfu/ml) stomach 0-10 3 jejunum 0-10 5 ileum 10 3 -10 7 colon 10 10 -10 13 1. Harmsen HJ, et al. J Pediatr Gastroenterol Nutr 2000;30:61–67 2. Guarner F, Malagelada JR. Lancet 2003;361:512–519 3. Orrhage K, Nord CE. Acta Paediatr Suppl 1999;88:47–57 Infant ~ 10 10 organisms (10,000,000,000) About 60% of fecal mass Over 400 species
  7. 7. Immunonutrition <ul><li>Function of Commensal Organisms </li></ul><ul><ul><li>Protection from infection </li></ul></ul><ul><ul><ul><li>Competes with pathogens </li></ul></ul></ul><ul><ul><ul><li>Forms bacteriocins </li></ul></ul></ul><ul><ul><li>Metabolism </li></ul></ul><ul><ul><ul><li>CHO fermentation </li></ul></ul></ul><ul><ul><ul><li>Vitamins, SCFA </li></ul></ul></ul><ul><ul><ul><li>Procarcinogens </li></ul></ul></ul><ul><ul><li>Immunity </li></ul></ul><ul><ul><ul><li>IgA synthesis </li></ul></ul></ul><ul><ul><ul><li>Modulate inflammation </li></ul></ul></ul>
  8. 8. Immunonutrition <ul><li>Colonization of the Gut </li></ul><ul><ul><li>First Stage (birth to one week) </li></ul></ul><ul><ul><ul><li>Composition of infants evolving microbiota is initially defined by the mother </li></ul></ul></ul><ul><ul><ul><li>Role of ROM, l abor, SVD </li></ul></ul></ul><ul><ul><ul><li>Exposes infant to maternal GI flora </li></ul></ul></ul><ul><ul><ul><li>Leading to colonization of maternal flora </li></ul></ul></ul><ul><ul><ul><li>Changing clinical practices </li></ul></ul></ul><ul><ul><ul><ul><li>Role of mode of delivery </li></ul></ul></ul></ul><ul><ul><ul><ul><li>↑ Elective C/S without ROM & labor </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Hyper-hygienic measures </li></ul></ul></ul></ul><ul><ul><ul><ul><li>↑ Use of antibiotics for mother & infant </li></ul></ul></ul></ul><ul><ul><ul><li>&quot;Evolutionary Discordance&quot; </li></ul></ul></ul>
  9. 9. Immunonutrition <ul><li>Colonization of the Infant GI tract </li></ul><ul><ul><li>Second Stage (1-4 weeks) </li></ul></ul><ul><ul><ul><li>Role of infant ’s diet major factor </li></ul></ul></ul><ul><ul><ul><ul><li>Variation in microbiota and organisms seen between breast fed and formula fed infants </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Promotes growth of Lactobacillus & bifidobacterium species </li></ul></ul></ul></ul><ul><ul><ul><li>Role of human milk </li></ul></ul></ul><ul><ul><ul><ul><li>Human milk has lower buffering capacity </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Acidic milieu potentiates nonpathogenic bacterial growth </li></ul></ul></ul></ul><ul><ul><ul><li>Role of oligosaccharides </li></ul></ul></ul><ul><ul><ul><ul><li>Serve as prebiotics </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Support favorable/commensal bacterial populations </li></ul></ul></ul></ul>
  10. 10. Immunonutrition 0 10 20 30 40 50 60 70 g/L Lactose Fat Oligosaccharides Protein 1. Boehm G, Stahl B. J Nutr 2007;137 Suppl 2:847S–849S. 2. Coppa G, Bruni S, Morelli L, et al. J Clin Gastroenterol 2004;38 (2):S80-S83. 3. Chaturvedi P. Glycobiology 2001;11:5:365-372. 4. Erney R. J Pediatr Gastroenterol Nutr 2000;30:181-192. Oligosaccharides Large variety – well over 100 possible 3 >400 samples from women in 10 countries showed great variability 4 70 12 40 10 Third Largest Component of Human Milk 1,2
  11. 11. Immunonutrition <ul><li>Oligosaccharides </li></ul><ul><ul><li>Third largest component of human milk </li></ul></ul><ul><ul><ul><li>Nutritional function is to serve as prebiotics </li></ul></ul></ul><ul><ul><ul><ul><li>A carbohydrate molecule composed of 3-20 monosaccharides or simple sugars &quot;feed&quot; the bacteria </li></ul></ul></ul></ul><ul><ul><ul><li>Oligosaccharides in milk are not digestible </li></ul></ul></ul><ul><ul><ul><ul><li>Selectively fermented by the desirable gut microflora </li></ul></ul></ul></ul><ul><ul><ul><li>S timulate developing immune system responses </li></ul></ul></ul><ul><ul><ul><ul><li>Act as receptor analogues to prevent attachment of enteropathogens on the epithelial surface </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Support favorable/commensal bacterial populations </li></ul></ul></ul></ul>Nestle Nutr Workshop Ser Pediatr Program. 2008;62:205-18; discussion 218-22
  12. 12. Immunonutrition <ul><li>Insults Affecting the Premature Gut </li></ul><ul><ul><li>Immaturity </li></ul></ul><ul><ul><li>Mode of delivery </li></ul></ul><ul><ul><li>Luminal starvation </li></ul></ul><ul><ul><li>Hypoxic-ischemic reperfusion </li></ul></ul><ul><ul><li>Infection/inflammation </li></ul></ul><ul><ul><li>Antibiotic exposure </li></ul></ul><ul><li>Insults Result in </li></ul><ul><ul><li>Altered GI Colonization </li></ul></ul><ul><ul><li>Risk of Bacterial Translocation </li></ul></ul><ul><ul><li>Potential for Sespis </li></ul></ul>Neu J & Bernstein, H Update on host defense and immunonutrients Clinics in Perinatology 29(1); 2002.
  13. 13. <ul><li>Late Onset Blood Stream Infection </li></ul><ul><ul><li>An episode of blood stream infection after 72 hours of life </li></ul></ul><ul><ul><li>Associated with high mortality </li></ul></ul><ul><ul><li>Associated with high morbidity </li></ul></ul><ul><ul><ul><li>Acute respiratory failure </li></ul></ul></ul><ul><ul><ul><li>Hypotension </li></ul></ul></ul><ul><ul><ul><li>Thrombocytopenia/Anemia </li></ul></ul></ul><ul><ul><ul><li>Feeding intolerance </li></ul></ul></ul><ul><ul><li>Staphlococcus aureus & Gram (-) organisms </li></ul></ul><ul><ul><ul><li>Constitute 15% of late onset infections and have particularly high morbidity and mortality in the preterm population </li></ul></ul></ul>Immunonutrition
  14. 14. <ul><li>Long term morbidity of Late Onset Sepsis </li></ul><ul><ul><li>Bronchopulmonary dysplasia (BPD) </li></ul></ul><ul><ul><ul><li>No BPD: in room air by 28d PNA </li></ul></ul></ul><ul><ul><ul><li>Mild BPD: in oxygen at 28d PNA but in room air at 36 weeks PMS </li></ul></ul></ul><ul><ul><ul><li>Oxygen therapy at 36 weeks PMA </li></ul></ul></ul><ul><ul><li>Moderate BPD </li></ul></ul><ul><ul><ul><li>In oxygen but <30% or <100ml/min at 36 weeks PMA </li></ul></ul></ul><ul><ul><li>Severe BPD </li></ul></ul><ul><ul><ul><li>In oxygen >30% or >100 ml/min at 36 weeks PMA </li></ul></ul></ul><ul><ul><li>Associated morbidity </li></ul></ul><ul><ul><ul><li>Increased LOS, Periventricular leukomalacia (PVL) </li></ul></ul></ul>Immunonutrition
  15. 15. Immunonutrition <ul><li>Risk of NEC, Translocation and Sepsis </li></ul>
  16. 16. Immunonutrition <ul><li>“ Lack of breast </li></ul><ul><li>milk may be the commonest immunodeficiency </li></ul><ul><li>of infancy. ” </li></ul>Tarnow-Mordi W et al Adjunctive immunologic interventions in neonatal sepsis. In Clinics in Perinatology 37(2) (2010) Hanson LA. Session 1: Feeding and infant development breastfeeding and immune function. Proc Nutr Soc 2007; 66(3): 384-96. <ul><li>&quot;Adjunctive Immunologic Interventions in Neonatal Sepsis “ </li></ul><ul><li>Listed with major clinical strategies , immunologic & pharmacologic therapies </li></ul>
  17. 17. Immunonutrition <ul><li>Immunonutrition </li></ul><ul><ul><li>The modulation of the immune and inflammatory responses in critically ill patients with the use of enteral feedings enriched with immune-enhancing ingredients. </li></ul></ul>Neu J & Bernstein, H Update on host defense and immunonutrients Clinics in Perinatology 29(1); 2002.
  18. 18. <ul><li>Benefits of Probiotics </li></ul><ul><ul><li>Resistance to colonization </li></ul></ul><ul><ul><ul><li>Reduction in bacterial translocation </li></ul></ul></ul><ul><ul><ul><li>Production of antimicrobial substances </li></ul></ul></ul><ul><ul><li>Immunomodulation </li></ul></ul><ul><ul><ul><li>Modification of host response to microbial products </li></ul></ul></ul><ul><ul><ul><li>Modification of toxins or toxin receptors </li></ul></ul></ul><ul><ul><ul><li>Promote intestinal motor function </li></ul></ul></ul><ul><ul><ul><li>Inhibition of adhesion augmentation of IGA </li></ul></ul></ul><ul><ul><ul><li>Anti-inflammatory signaling within the epithelium </li></ul></ul></ul>Immunonutrition
  19. 19. Immunonutrition <ul><li>Lin et al (2005). Oral Probiotics Reduce the Incidence and Severity of Necrotizing Enterocoloitis in Very Low Birth Weight Infants. Pediatrics, 115:1-4 </li></ul><ul><li>Probiotics and NEC </li></ul><ul><ul><li>Prospective, masked, randomized trial </li></ul></ul><ul><ul><li>367 VLBW ( < 1500g) with similar demographic & clinical variables were enrolled then randomized </li></ul></ul><ul><ul><li>Study group (180) fed Infloran ( Lactobacillus acidophilus & Bifodobacterium infantis ) with BM bid </li></ul></ul><ul><ul><li>Controls (187) fed BM alone </li></ul></ul><ul><ul><li>Both groups followed until discharge </li></ul></ul><ul><ul><li>Primary outcome: death or NEC ( ≥ stage 2) </li></ul></ul>
  20. 20. Immunonutrition <ul><li>Lin et al (2005). Oral Probiotics Reduce the Incidence and Severity of Necrotizing Enterocoloitis in Very Low Birth Weight Infants. Pediatrics, 115:1-4 </li></ul><ul><li>Incidence o f death or NEC ( ≥ stage 2) </li></ul><ul><ul><li>Significantly lower in study group (2 of 180 vs 10 of 187 controls) </li></ul></ul><ul><ul><li>Six cases of severe NEC (Bell stage 3) in the control group </li></ul></ul><ul><ul><li>No cases of severe NEC in the study group </li></ul></ul><ul><ul><li>No positive blood cultures for Lactobacillus or Bifidobacterum </li></ul></ul>Probiotics Control P value Death, n% 7 (3.9) 10 (10.7) .009 Death or NEC cases, n (%) 9(5) 24(12.8) .009 NEC, stage 2 or 3, n(%) 2(1.1) 10(5.3) .04 Sepsis, n(%) 22(12.2) 36(19.3) .03 NEC or sepsis, n(%) 24(13.3) 46(24.6) .03 NEC, sepsis or death, n(%) 31(17.2) 60(32.1) .009
  21. 21. Immunonutrition <ul><li>Probiotics in the NICU </li></ul><ul><ul><li>Three separate meta-analyses of probiotics on the reduction of NEC in premature infants were published in 2010 </li></ul></ul><ul><ul><li>All three meta-analyses found probiotic supplementation significantly reduced the incidence of NEC and overall mortality </li></ul></ul><ul><ul><li>Based on the robust evidence from their data, Deshpande, Rao, Patole, and Bulsara stated probiotic supplementation should be routinely used in the NICU and additional placebo studies would be unethical </li></ul></ul>
  22. 22. Immunonutrition <ul><li>2010 Recommendations for Probiotics </li></ul><ul><ul><li>In their meta-analysis, Guthmann et al found </li></ul></ul><ul><ul><ul><li>Studies using a multi-strain probiotic had the best results compared to the studies using a single-strain probiotic </li></ul></ul></ul><ul><ul><li>American Academy of Pediatrics </li></ul></ul><ul><ul><ul><li>Suggest more research is needed to determine the appropriate probiotic species and dosing in this population with an emphasis on the extremely low birth weight infants </li></ul></ul></ul><ul><ul><ul><li>Lack of heterogeneity of the probiotic organisms used </li></ul></ul></ul><ul><ul><ul><li>Lack of FDA regulation on probiotics </li></ul></ul></ul><ul><ul><ul><li>Insufficient evidence for safety in infants <1000 grams </li></ul></ul></ul><ul><ul><ul><li>Although probiotic supplementation is not without absolute risk, the overwhelming evidence of its benefits may outweigh the risks </li></ul></ul></ul>
  23. 23. Immunonutrition <ul><li>Deshpande G, Rao S, Paole S & Bulsara M Updated Meta-analysis of Probiotics for Preventing Necrotizing Enterocolitis in Preterm Neonates. Pediatrics published online Apr 19, 2010. DOI: 10,1542/peds.2009-1301 </li></ul><ul><li>Probiotics </li></ul><ul><ul><li>A meta-analysis of 11 randomized, controlled trials that involved 2176 infants treated with oral probiotics </li></ul></ul><ul><ul><ul><li>Significant reductions in all-cause mortality and NEC are reported </li></ul></ul></ul><ul><ul><ul><li>Risk of NEC (typical relative risk: 0.35 [95% confidence interval: 0.23– 0.55]) </li></ul></ul></ul><ul><ul><ul><li>Death (typical relative risk: 0.42 [95% confidence interval: 0.29–0.62]) </li></ul></ul></ul><ul><ul><li>Results reflect on the growing body of evidence that probiotics are effective in the preterm patient population. </li></ul></ul>
  24. 24. Immunonutrition <ul><li>Deshpande G, Rao S, Paole S & Bulsara M Updated Meta-analysis of Probiotics for Preventing Necrotizing Enterocolitis in Preterm Neonates. Pediatrics published online Apr 19, 2010. DOI: 10,1542/peds.2009-1301 </li></ul><ul><li>Number Needed to Treat </li></ul><ul><ul><li>The number needed to treat with prophylactic probiotics to prevent 1 case of NEC in this population is 25 </li></ul></ul><ul><ul><li>Determined by all three separate meta-analyses in 2010 </li></ul></ul><ul><ul><li>The potential benefits of probiotic supplementation in premature infants should be seriously considered by NICU staff </li></ul></ul>

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