Purpose and Goal: CNEP #2000

  • Understand the therapeutic benefits of probiotic supplements.
  • Identify the benefits of probiotic use in the NICU.

None of the planners, faculty or content specialists has any conflict of interest or will be presenting any off-label product use. This presentation has no commercial support or sponsorship, nor is it co-sponsored.

Requirements for successful completion:

  • Successfully complete the post-test.
  • Complete the evaluation form.

Date

  • February 2015 – February 2017

Learning Objectives

  • Describe the effects that probiotic supplements have on the gastrointestinal tract.
  • Identify at least two benefits of probiotic use in the NICU.

Introduction

  • Probiotic bacteria are live microbial supplements.
    • They colonize the gastrointestinal (GI) tract.
    • They improve the balance of gut microflora.
  • Probiotic supplements have been shown to benefit premature infants.
    • They reduce the incidence of necrotizing enterocolitis.
    • They reduce morbidity and mortality rates in the NICU.

Bacterial Colonization of the GI Tract

  • Prior to birth, the fetal intestine is sterile.
  • Colonization of the newborn gut begins at delivery.
    • Through contact with the mother
    • Through contact with the environment
    • Through contact with enteral feeds
  • A healthy breastfed newborn GI tract contains bacteria.
    • Two bacteria are most prevalent.
      • Bifidobacterium
      • Lactobacillus
    • These normal bacteria support immune function.
      • Antimicrobial activity
      • Anti-inflammatory activity
      • Inhibitory activity
    • A healthy GI tract reaches adult bacteria levels by 2 years.
    • A healthy adult GI tract contains >500 species of bacteria.

Definition of Probiotic Bacteria

  • Probiotic bacteria are food supplements.
  • They are live bacteria that improve gut flora.
  • Probiotic bacteria are nonpathogenic bacteria.
    • They colonize the GI tract.
    • They adhere to intestinal mucosa.
    • They influence immune protection.
    • They influence metabolic activity.
    • They produce antimicrobial substances.

Mechanism of Probiotic Protection

  • There are several species of probiotic bacteria.
  • Two bacteria have been extensively studied.
    • Bifidobacterium
    • Lactobacillus
  • Both are gram-positive anaerobic bacteria.
  • Both live in the normal healthy GI tract.
  • Both have several mechanisms of action.
    • They metabolize into acetic and lactic acids.
    • They lower gut pH to provide antimicrobial action.
    • They produce antimicrobial compounds.
    • They produce antibacterial compounds.
    • They produce antitoxin compounds.
    • They stimulate immunomodulatory cells.
    • They compete with pathogens for binding sites.
    • They enhance mucosal barrier protection.

Therapeutic Probiotic Use

  • Studies show that probiotic bacteria treat or prevent:
    • Allergic reactions
    • Infectious diarrhea
    • Inflammatory bowel disease
    • Necrotizing entercolitis (NEC)
  • The reduction of NEC has been an ongoing goal.
    • NEC prevention strategies
    • Evidence-based interventions
  • The use of probiotic bacteria continues to gain interest.

Definition and Incidence of NEC

  • NEC is a common GI emergency in the NICU.
  • It is caused by abnormal bacterial colonization.
  • It is characterized by ischemic necrosis of gut mucosa.
  • Ischemic necrosis is associated with:
    • Inflammation of the GI tract
    • Invasion of gas forming organisms
    • Perforation of the GI tract
  • 90% of NEC occurs in premature infants.
  • NEC occurs in 1–8% of all NICU admissions.

Pathophysiology of NEC

  • The pathology of NEC is due to intestinal infarction.
  • The premature GI tract is colonized with pathogenic bacteria.
  • There is low variability and diversity of normal bacteria.
  • Additionally, the premature GI tract and premature immune system predispose premature infants to NEC.
    • Immature mucosal barrier
    • Increased intestinal permeability
    • Increased bacterial penetration
    • Immature bowel motility
    • Immature bowel function
    • Immature local host defenses
    • Diminished concentrations of:
      • Secretory IgA
      • Mucosal enzymes

Mechanisms of Probiotic Protection from NEC

  • 22 studies have shown probiotic use reduces NEC.
  • Evidence shows that probiotic bacteria
    • Reduce inflammatory reactions
    • Regulate composition of mucosal barriers
    • Improve intestinal integrity
  • Evidence shows that probiotic bacteria prevents NEC by:
    • Encouraging competitive colonization
    • Competing for pathogen binding sites
    • Producing organic acids that lower pH
    • Producing bacteriocidins
    • Increasing gut motility
    • Increasing barrier protection
    • Modulating immune responses
    • Stimulating IgA production
    • Producing anti-inflammatory cytokines
    • Enhancing enteral feeding tolerance

Probiotic Treatment Guidelines

  • The use of probiotic bacteria in the NICU is supported by:
    • The American Academy of Pediatrics
    • The American Society for Parenteral and Enteral Nutrition
    • The Canadian Paediatric Society
    • The World Gastroenterology Organization
  • Guidelines for use have been published in 2011 and 2014.
  • The use of at least two strains of bacteria appear most effective.
    • Lactobacillus acidophilus
    • Lactobacillus casei
    • Lactobacillus rhamnosus
    • Bifidobacteria bifidum
    • Bifidobacteria infantis
  • Several commercial products are available in the U.S.
  • The U.S. FDA has recognized these products as safe.
  • Only 2 products have undergone a safety peer review.
    • Culturelle
      • From ConAgra
      • Contains Lactobacillus rhamnosus
    • Probioplus DDS
      • From UAS Laboratories
      • Contains Lactobacillus acidophilus
      • Contains Bifidobacteria longum
      • Contains Bifidobacteria bifidum
      • Contains Bifidobacteria lactis
  • Probiotics are not stable in all formulations.
    • Freeze-dried tablet, capsule or loose powder
      • Must be kept cool and dry.
      • Viability is limited.
    • Liquid formulations are very unstable.
    • Only viable probiotic products should be used.
  • Specific products have not been licensed for NICU use.
    • Probioplus DDS has been recommended in U.S. studies.
    • BD Lactinex has also been recommended in the literature.
      • From Becton, Dickinson, and Company
      • Contains Lactobacillus acidophilus
      • Contains Lactobacillus bulgaricus
      • Each 1-gram packet contains 100 million colony forming units (CFU) at time of manufacture.
       

Probiotic Use in the NICU

  • Probiotic use is generally limited to VLBW infants.
    • Infants <32 weeks gestation
    • Infants >1000 grams
  • Probiotic bacteria use should be used cautiously in:
    • ELBW infants <1,000 grams
    • Clinically unstable infants
    • Infants with:
      • Perinatal depression
      • Congenital heart defects
      • Structural GI abnormalities
      • Short gut syndrome
      • History of GI surgery
      • History of NEC
      • Umbilical lines (controversial)
  • Probiotic bacteria should be started:
    • When an infant is stable
    • When an infant has a benign abdominal exam
    • When an infant is ready to start enteral feeds
    • Within the first week of life if possible
  • A combination of probiotic bacteria strains is ideal.
  • An annual quality control review should be done.
    • To ensure accurate ingredients
    • To ensure reliability of manufacturer
  • Dosing range is 0.056 to 6 x 107 to 109 CFU/day.
  • Probiotic bacteria should be administered daily.
    • Single daily dose
    • For 4–6 weeks
      • Until 36 weeks' gestation
      • Until hospital discharge
  • Storage and handling instructions are critical.
    • Refrigeration at 20º – 80º C or per manufacturer
    • Daily temperature quality should monitored.
  • Aseptic technique should always be used.
  • Probiotics should be mixed with 3 ml of breast milk.
    • Some studies used up to 10 ml breast milk.
    • Preparations should be used within 6 hours.
    • All studies to date have used breast milk.
    • It remains unclear if formula is beneficial.

Risks Associated with Probiotic Bacteria

  • There are possible side effects with probiotic use.
  • Rare cases of infection have been reported.
    • Sepsis
    • Meningitis
    • Endocarditis
    • Pneumonia
  • Infants should be closely monitored for:
    • Lactic acidosis
    • Sepsis
    • Meningitis
    • Diarrhea
    • Emesis
    • Abdominal distension
  • No studies have investigated long-term effects.
    • Probiotic sensitivity
    • Probiotic hypersensitivity
    • Probiotic allergies

Summary

  • Survival rates for VLBW premature infants have improved.
  • NEC remains an important cause of morbidity and mortality.
  • Studies show reductions in NEC with the use of probiotic bacteria.
  • The use of probiotic bacteria in the NICU should be considered.

References

  1. Anderson, S. 2015. Probiotics for Preterm Infants: A Premature or Overdue Necrotizing Enterocolitis Prevention Strategy? Neonatal Network, 34 (2), p, 83-101.
  2. Parker, R. 2014. Probiotic Guideline for Necrotizing Enterocolitis Prevention in Very Low-Birth Weight Neonates. Advances in Neonatal Care, 14 (2), p. 88-95.
  3. Janvier, A., Malo, J, and Barrington, K. 2014. Cohort Study of Probiotics in a North American Neonatal Intensive Care Unit. The Journal of Pediatrics, 164 (5), p. 980-985.
  4. Patel, R.M. & Denning, P.W. 2013. Therapeutic Use of Prebiotics, Probiotics, and Postbiotics to Prevent Necrotizing Enterocolitis: What is the Current Evidence? Clinics in Perinatology, 40 (1), p. 11-25.
  5. Gaul, J. 2008. Probiotics for the Prevention of Necrotizing Enterocolitis. Neonatal Network, 27 (2), p. 75-80.
  6. Bell. S. G. 2007. Immunomodulation, Part V: Probiotics. Neonatal Network, 26 (1), p. 57-60.

Evaluation

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