The Role of Probiotics in Preventing NEC: Should This Therapy be Standard of Care? Maryland Patient...

The Role of Probiotics in Preventing NEC: Should This

Therapy be Standard of Care?

Maryland Patient Safety CenterPerinatal/Neonatal Learning Network

June 11, 2015

Ravi Mangal Patel, MD, MScAssistant Professor of PediatricsDivision of [email protected]

Children’s Healthcare of Atlanta | Emory University

Disclosure statement

• I will be discussing the use of various probiotic preparations, none of which have been approved by the Food and Drug Administration for use in preterm infants and none of which I am specifically endorsing.

• I have no other relevant conflicts of interest.


Hypothetical case

• You are caring for a 27 week gestation female infant, who is currently 4 weeks old.

• She initially needed mechanical ventilation, but is currently in room air doing well. She is receiving enteral feedings by a feeding tube.

• The parents are encouraged by the progress their daughter has made in the NICU.


Hypothetical case

• The following day, the baby develops emesis, bloody stools and abdominal distention.


Hypothetical case

• An abdominal radiograph shows NEC with portal gas.


Hypothetical case

• An exploratory laparotomy is performed and 45cm of affected small bowel is resected.

• Short gut syndrome discussed with the family

Neu and Walker, NEJM. 2011

The parents search the internet and findsome studies that show probiotic therapy

reduces NEC.

They ask you why their daughter did not receive this therapy?


Learning objectives

At the end of this talk, you should know: • The current evidence regarding the risks and benefits

of probiotic therapy in preterm infants including:– Probiotic effects on NEC and mortality– Probiotic effects on sepsis– Differences in effect between various probiotic strains

• Strategies for implementation, including:– Selection of appropriate probiotic, including dose/duration– Considerations before implementation– Use of quality improvement principles


Necrotizing enterocolitis (NEC)

• Characterized by intestinal inflammation and necrosis although the exact pathogenesis is unknown

• Leading cause of mortality in very low birth weight infants with case fatality rates of 20-30%• Up to 50% of infants requiring surgery die

• Deaths from NEC have increased among extremely preterm infants from 2000 to 2011

Lin PW and Stoll BJ, Lancet. 2006

Patel RM et al. NEJM. 2015


Pathophysiology of NEC multifactorial

Premature birth- Propensity towards gut inflammation- Impaired intestinal barrier function - Decreased intestinal motility

- Decreased commensal flora- Increased pathogenic bacteria- Prolonged antibiotic therapy- Acid suppression medications

- Formula feeding

- Abnormal gut vascular regulation- RBC transfusion- Anemia

NEC

Patel RM and Denning PW.

Pediatric Research, 2015


Abnormal bacterial colonization

Patel RM and Denning PW.

Clinics in Perinatology, 2013


Probiotics: How do they work?

Patel and Denning. Clinics in Perinatology, 2013


Probiotics: What is the evidence?

AlFaleh K, Anabrees J. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane

Database of Systematic Reviews 2014, Issue 4.

Twenty of 24 randomized trials evaluatedTotal of 5529 infants studied

Effect of probiotics on definite NEC (Bell’s Stage 2-3)

<1500g

Probiotics significantly decrease the risk of NECPooled relative risk – definite NEC = 0.43 [0.33, 0.56]Analysis limited to <1500g infants = 0.41 [0.31, 0.56]

AlFaleh K, Anabrees J. Cochrane Database of Systematic Reviews 2014.

Effect of probiotics on mortality

NEC-related mortality

Probiotics significantly decrease mortalityPooled relative risk – all cause mortality = 0.65 [0.52, 0.81]

Pooled relative risk – NEC-related mortality = 0.39 [0.18, 0.82]


What about the risks of sepsis?


Probiotics do not increase or decrease the risk of sepsis(however, more heterogeneity among studies)

Pooled relative risk = 0.92 [0.81, 1.04]

What about the risk of sepsis in the smallest infants <1000g?

Lin HC, et al. Pediatrics. 2008


Culture proven sepsis <1000g

Although of potential concern, there is no clear evidence that the risk of sepsis from probiotic

therapy is increased among infants <1000g at birth

Do benefits vary by strain of probiotics?Is a combination better than a single

strain?


Differences by strain (genus)

Effect on risk of NEC Stage II+ by strain:• Lactobacillus: RR 0.45 (0.27-0.75)• Bifidobacterium: RR 0.48 (0.16-1.47)• Sacchromyces boulardii: RR 0.72 (0.34-1.55)• Combination (2 or more): RR 0.37 (0.25-0.54)

Test for subgroup differences: P=0.48



Differences by strain

Wang et al. J Pediatr Surg, 2012


What is the external validity of the probiotic trials?

(i.e. have the benefits of probiotics been demonstrated in routine clinical practice)


Cohort study in Canada

• All infants <32wk GA treated with first feeding and continued until 34wk postmenstrual age

• Florababy (combination probiotic) 0.5g in 1ml daily

Janvier et al. J Peds 2014

P<0.05

P<0.02

OR (95% CI) adjusted for GA, SGA, female No difference between groups among infants <1000g at birth

NEC: pre=17% vs. post=10%Sepsis: pre=35% vs post=30%


Cohort study in Germany

• Study of VLBW at 46 German NICUs (n=5351)• Infloran (Lactobacillus acidophilus/ Bifidobacterium

infantis) equivalent of 1 capsule per day

Hartel et al. J Peds 2014

Are probiotics ready for primetime?Should we start using routinely?

5-10 years ago

For probiotics

Against probiotics

• Animal data supports biologic plausibility

• Several small single center RCTs in foreign countries

• Lack of a large, multicenter RCTs• Lack of implementation cohort studies• Insufficient evidence regarding

optimal strain• Concerns for sepsis amongst the

smallest infants• No FDA-approved preparation• Manufacturer quality control• Other strategies to reduce NEC risk

Today

For probiotics

Against probiotics

• Multiple RCTs with >5000 infants including the ProPrems trial shows consistent benefit in reducing NEC

• Subgroup analyses by strains shows similar treatment effects

• 2+ implementation cohort studies• Meta-analysis for <1000g shows no

increase in risk of sepsis• NEC remains a major cause of death

• Lack of FDA approved preparation• Manufacturer quality control • No long-term follow-up studies


Local NEC incidence may influence overall risk:benefit ratio at a center• For units with NEC incidence <5%, number needed to

treat (NNT) to prevent 1 case of NEC may be too highNEC NNT0.0% ---2.5% 675.0% 357.5% 2310.0% 1815.0% 12

NNT estimates based on point-estimate of relative risk 0.43 for Bell’s 2+ NEC (probiotic vs. control) from Cochrane analysis

Median NEC incidence in 2013 was 3.8%

(Q1, Q3: 0.0%, 7.1%)

Probiotic use in infants for 2013 was 10.5%

(Q1, Q3: 0.0%, 1.8%)

Compared to VON:

Which probiotic do I choose and how do I obtain it?

Brand Name Made in Type Strains Cost perdose

Culturelle Denmark Single-dose packet Lactobacillus rhamnosus GG $ 0.81

FloraBaby USA Multi-dose container Bifidobacterium & Lactobacillus & FOS $ 0.38

ProBiota USA Multi-dose container Bifidobacterium & Lactobacillus $ 0.50

FloraTummys USA Singe-dose packet Bifidobacterium & Lactobacillus $ 1.00

FlorastorKids USA Singe-dose packet Sacchromyces boulardii $ 0.78

VSL#3 Junior USA Singe-dose packet Bifidobacterium & Lactobacillus & Streptococcus $ 2.56

ABC Dophilus USA Multi-dose container Bifidobacterium and Streptococcus $ 0.48

Infloran* Switzerland Single-dose capsule Bifidobacterium & Lactobacillus

Probiotics used in prior studies: ProPrems trail (Au/NZ): ABC DophilusJanvier et al. (Canada): FloraBabyManzoni et al (Italy). LGG (similar to Culturelle)Hartel et al. (Germany): Infloran

Data from amazon.com 11/20/13 *Minimal data on Infloran available


ABC Dophilus – FDA Recall

36


Lactobacillus reuteri

• Some studies suggest benefit in reducing colic• Large recent negative trial for NEC

– Randomized trial of 400 infants – No difference in NEC, lower risk of sepsis

Oncel MY et al. Arch Dis Child Fetal Neonatal Ed 2014


Bifidobacterium breve

• PiPS trial: large multicenter trial in the UK• Enrolled 1315 infants less than 31 weeks gestation• Results not yet published but preliminary report

suggests no benefit

Costeloe KL et al. Arch Dis Child 2014;99(Suppl 2):A1–A620https://www.npeu.ox.ac.uk/pips

https://www.npeu.ox.ac.uk/pips

https://www.npeu.ox.ac.uk/pips

What dose per day?How long do we treat?

Desphande et al. Pediatrics 2010

Significant variability in dose and duration of treatment.Most studies initiate therapy within the first 24-72hr or with

initial feed and treat for at least 28 days, a few until discharge

Dose depends on preparationMost studies use a dose range of

1 - 5 x 109 CFU per day


Who should receive treatment?


Summary of inclusion criteria


Majority of studies included infants <1500g, Several added a gestational age inclusion (<30-35wk)

How do you start?

Nursing leadershipPharmacy

Infectious disease

expertise

Nutrition

Physicians

NNPs

Nursing educators

microbiology

Parents?


Our protocol


Apply QI principles

• “N of 1” tests-of-change before broad implementation• Things to consider?

– Where will the probiotic powder be prepared?– Does it need to be approved by your P&T committee?

• If so, will it be dispensed or prepared by pharmacy?• If not, will it be prepared by nursing staff or nutrition?

– Staff education regarding handling, preparation• Hand hygiene, CLABSI, clogging of feeding tubes

– Dosing frequency - CLABSI tradeoff– Approach for sepsis evaluation

• Type of culture medium, addition of empiric Ampicillin, genotyping

– Tracking of process and outcome data


Apply QI principles

• Key outcome measures (NEC, sepsis) will have some lag time and may have substantial common cause variation if measuring on monthly or even quarterly intervals– consider looking at number of cases as opposed to

proportion

• Focus on process measures– What proportion of eligible infants are receiving probiotic

treatment?– What proportion of eligible infants receive probiotics within

24 hours of initiating feeding?

Should we obtain parental consent?


Parental consent vs. opt-in/opt-out vs. informing parents•

Information sheet adapted from Sesham et al. Arch Dis Child Fetal Neonatal Ed. 2014

What if I want to wait for an FDA-approved preparation?


Clinical trial in US ongoing

• Estimated Phase Ib/IIa completion in December 2017• Study plans to enroll 400 infants at 6 US hospitals

Thank you. Questions?

[email protected]

The Role of Probiotics in Preventing NEC: Should This Therapy be Standard of Care? Maryland Patient...

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