Abstract of thesis entitled “An Evidence-based Guideline on Using Oral Probiotic to Prevent Late- onset Sepsis in Preterm Infants” Submitted by Chan Shuk Wa for the degree of Master of Nursing at The University of Hong Kong in July 2016 Late-onset sepsis is one of the most common problems in preterm infants. According to a study from the National Institute of Child Health and Human Development (NICHD), nearly 21% of preterm infants developed at least one or more episodes of blood culture-proven sepsis during hospitalization. It also leads to additional unpleasant events to the infants, their parents and medical staff, such as lengthen of hospitalization, repeated invasive diagnostic and therapeutic procedures like long line insertion, lumbar puncture and blood taking, increased risk of serious medical conditions, such as meningitis, seizure, increased mortality, medical expenses, parental anxiety and staff workload. In recent decades, the use of oral probiotic was suggested to be an effective way in preventing late-onset sepsis in preterm infants as it can strengthen the host natural immune responses by developing gastrointestinal colonization.
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Abstract of thesis entitled
“An Evidence-based Guideline on Using Oral Probiotic to Prevent Late-
onset Sepsis in Preterm Infants”
Submitted by
Chan Shuk Wa
for the degree of Master of Nursing
at The University of Hong Kong
in July 2016
Late-onset sepsis is one of the most common problems in preterm infants.
According to a study from the National Institute of Child Health and Human
Development (NICHD), nearly 21% of preterm infants developed at least one or more
episodes of blood culture-proven sepsis during hospitalization. It also leads to additional
unpleasant events to the infants, their parents and medical staff, such as lengthen of
hospitalization, repeated invasive diagnostic and therapeutic procedures like long line
insertion, lumbar puncture and blood taking, increased risk of serious medical conditions,
such as meningitis, seizure, increased mortality, medical expenses, parental anxiety and
staff workload.
In recent decades, the use of oral probiotic was suggested to be an effective way
in preventing late-onset sepsis in preterm infants as it can strengthen the host natural
immune responses by developing gastrointestinal colonization.
This dissertation is a translational research that aims to identify the effectiveness
and implementation potential of using probiotic in preterm infants in order to reduce
incidence rate of late-onset sepsis and develop an evidence-based practice (EBP)
guideline for healthcare professionals.
A systematic literature review on the stated topic was done in three electronic
bibliographical databases, including PubMed, Cochrane library and the British Nursing
Index. The quality of the 6 studies found was assessed regarding the randomization,
concealment method, blinding, validity and reliability of outcome measures, dropout
rate and intention to treat, and other biases. And the EBP guideline was generated
based on the synthesis from the retrieved studies. Implementation potential of the
proposed guideline in local neonatal intensive care unit and special care baby unit
setting was discussed by assessing its transferability, feasibility and cost-benefit ratio.
Finally, a detailed implementation plan, including the communication plan, the pilot
study plan and the evaluation plan was proposed.
An Evidence-based Guideline on Using Oral Probiotic to Prevent Late-
onset Sepsis in Preterm Infants
by
Chan Shuk Wa
BNurs (HKU); RN (HK)
A thesis submitted in partial fulfillment of the requirements for
the Degree of Master of Nursing
at The University of Hong Kong
July 2016
i
Declaration
I declare that this dissertation represents my own work, except where due
acknowledgement is made, and that is has not been previously included in a thesis,
dissertation or report to this University or to any other institution for a degree, diploma
or other qualifications.
Signed………………………………………………
Chan Shuk Wa
ii
Acknowledgement
I would like to express my sincere gratitude to my dissertation supervisor, Dr.
Veronica S. F. Lam for her insightful comments and unfailing support throughout the
master dissertation. Her kindness and patience are greatly appreciated.
I am also grateful to my dissertation group members for their active participation
in the group discussion which inspired me a lot of excellent ideas to my dissertation.
Last but not least, I would like to offer sincere thanks to my family and friends for
their support throughout these two years of my master program.
iii
Table of contents Declaration ........................................................................................................................................ i
Acknowledgement ............................................................................................................................ ii
Table of contents ............................................................................................................................. iii
Abbreviations .................................................................................................................................... v
Additional records identified through other sources
(n =2 )
Records screened (n = 56)
Records excluded (n = 43)
- 49 -
Appendix A: Search strategies (cont’d)
Keyword PubMed Cochrane library
British Nursing Index
S1: premature infant 74927 5481 596
S2: premature infants 77454 5481 595
S3: preterm infant 82936 5110 906
S4: preterm infants 82461 5110 906
S5: neonatal prematurity 77644 825 120
S6: prematurity 84466 2369 186
S7: S1 OR S2 OR S3 OR S4 OR S5 OR S6 96125 8789 1446
S8: lactoferrin 7216 296 3
S9: bovine lactoferrin 1665 61 1
S10: probiotic 15556 1820 138
S11: probiotics 13383 1930 138
S12: S8 OR S9 OR S10 OR S11 22713 2856 141
S13: neonatal sepsis 8513 636 86
S14: neonatal infection 21314 1009 425
S15: neonatal infections 26072 1009 425
S16: late onset sepsis 1278 119 18
S17: late onset infection 3430 217 27
S18: late onset infections 4042 217 28
S19: bacteremia 36616 1406 79
S20: S13 OR S14 OR S15 OR S16 OR S17 OR S18 OR S19
66500 5132 532
S7 AND S12 AND S20 124 67 9
Articles remained after limited to RCTs and within 10 years (2005-2015), full text
16 37 1
Articles remained after screening title and abstract
5 6 0
Articles remained after removal of duplicated with other databases
8
Articles remained after screening full paper
4
Manual search from the references of potential eligible studies
2
Total 6
- 50 -
Appendix B: Table of Evidence Lin, H., Su, B., Chen, A., Lin, T., Tsai, C., Yeh, T., & Oh, W. (2005). Oral probiotics reduce the incidence and severity of necrotizing enterocolitis in very low birth weight infants. Pediatrics, 115(1), 1-4 4p.
Study type Sample characteristics Intervention Control Outcome measure(s) Result: (p=p-value)
Lin et al.(2005)/ RCT (1+)
neonates
Birth weight <1500g
Started to fed enterally
mean birth weight (g):
(1104/ 1071 : probiotic
/control)
mean gestational age
(wks): (28.5/ 28.2 :
probiotic /control)
Exclusion criteria:
Died or had NEC before
7th day of life
Probiotic: (n=180)
Placebo: (n=187) Primary measure(s)
1. number of infants with sepsis
(culture proven):
a. probiotic: 22 (12.2%)
b. control: 36 (19.3%)
2. number of infants with NEC≥
stage 2:
a. probiotic: 2 (1.1%)
b. control: 10 (5.5%)
3. mortality:
a. probiotic: 7 (3.9%)
b. control: 20 (10.7%)
1. number of infants with
sepsis (culture proven):
a. probiotic Vs control:
p=0.03, RRR=36.2%
2. number of infants with
NEC≥ stage 2:
a. probiotic Vs control:
p=0.04, RRR=81.3%
3. mortality:
a. probiotic Vs control:
p=0.009, RRR=63.6%
1. Probiotic group: combination
Lactobacillus acidpphilus and
Bifidobacterium infantis 125mg/kg
per dose mixed with breast milk
2. Control group: breast milk or
donor milk only
3. Probiotics mixed with breast milk
or donor milk before feeding
4. Feeding was started when the
infant had stable vital signs, active
bowel sound without abdominal
distension, no bile or blood from
the nasogastric tube, and no
indwelling umbilical artery or
umbilical venous catheter for at
least 24 hours.
Duration:
twice per day until discharge
- 51 -
Samanta, M., Sarkar, M., Ghosh, P., Ghosh, J., Sinha, M., & Chatterjee, S. et al.(2009). Prophylactic probiotics for prevention of necrotizing enterocolitis in very low birth weight newborns. Journal of Tropical Pediatrics. 55(2): 128–131.
Study type Sample characteristics Intervention Control Outcome measure(s) Result: (p=p-value)
Samanta et al.(2008)/ RCT (1+)
Inclusion criteria:
Born < 32 completed
weeks gestation
Birth weight <1500g
Started feed enterally
mean birth weight (g):
(1172/ 1210 : probiotic
/control)
mean gestational age
(wks): (30.12/ 30.14 :
probiotic /control)
Exclusion criteria:
Died before 2nd day of
life
had major congenital or
gastrointestinal
anomalies
infants expired due to
other neonatal illnesses
Probiotic: (n=91)
Placebo: (n=95) Primary measure(s)
1. days reached full enteral
feeding (SD):
a. probiotic: 13.76 2.28
b. control: 19.2 2.02
2. length of hospital stay (days)
(SD):
a. probiotic: 17.17 3.23
b. control: 24.07 4
3. mortality:
a. probiotic: 4 (4.4%)
b. control: 14 (14.7%)
4. number of infants with NEC≥
stage 2:
a. probiotic: 5 (1.1%)
b. control: 15 (15.8%)
5. number of infants with sepsis
(culture proven):
a. probiotic: 13 (14.3%)
b. control: 28 (29.5%)
1. days reached full enteral
feeding:
a. probiotic Vs control:
effect size= -2.39;
p=<0.001
2. days of hospital stay:
a. probiotic Vs control:
effect size= -2.14;
p=<0.001
3. mortality:
a. probiotic Vs control:
p=0.032, RRR=70.1%
4. number of infants with
NEC≥ stage 2:
a. probiotic Vs control:
p=0.042, RRR=93.0%
5. number of infants with
sepsis (culture proven):
a. probiotic Vs control:
p=0.020, RRR=51.5%
1. Probiotic group: mixture of
Bifidobacteria infantis,
Bifidobacteria bifidum,
Bifidobacteria longum and
Lactobacillus acidophilus, each2.5 x
109 CFU in breast milk, 125g/kg
2. Control group: breast milk only
3. Feeding was started when the
infant had stable vital signs, active
bowel sound without abdominal
distension, no bile or blood from
the nasogastric tube.
Duration:
4. Twice daily until discharge
CFU: colony-forming units
- 52 -
Manzoni, P., Rinaldi, M., Cattani, S., Pugni, L., Romeo, M. G., & Messner, H., et al. (2009). Bovine Lactoferrin Supplementation for Prevention of Late-Onset Sepsis in Very Low-Birth-Weight Neonates: A Randomized Trial. Journal of American Medical Association.302(13):1421-1428.
Study type Sample characteristics Intervention Control Outcome measure(s) Result: (p=p-value)
Manzoni et al.(2009) / prospective RCT (1++)
Inclusion criteria:
1500g
younger than 3 days
mean birth weight (g):
(1142/1138/1109 :
BLF/BLF+LGG/control)
mean gestational age
(wks): (29.6/29.8/29.5:
BLF/BLF+LGG/control)
Exclusion criteria:
Parental consent lacking/
refused
Ongoing antifungal
prophylaxis
Early onset sepsis (before
day 3 of life)
Liver failure (APT, ALP -
glutamyl transferase and
DB 3-fold higher than
reference range)
BLF alone
(n=153)*
BLF+LGG (n=151)
Placebo: (n=168) Primary measure(s)
1. Incidence of late-onset sepsis
(culture proven):
a. BLF: 9 (5.9%)*
b. BLF+LGG: 7 (4.6%)
c. Control: 29 (17.3%)
2. Mortality attributable to sepsis
(culture proven):
a. BLF: 0 (0%)*
b. BLF+LGG: 1 (0.7%)
c. Control: 8 (4.8%)
Secondary measure(s)
3. NEC≥ stage 2
a. BLF: 3 (1.9%)*
b. BLF+LGG: 0 (0%)
c. Control: 10 (6.0%)
1. Incidence of late-onset
sepsis (culture proven):
a. BLF Vs control:
p=0.002, RRR=65.9%*
b. BLF+LGG Vs control:
p<0.001,RRR=73.4%
2. Mortality attributable to
sepsis (culture proven):
a. BLF Vs control:
p=0.008, RRR=100%*
b. BLF+LGG Vs control:
p=0.04, RRR=85.4%
3. NEC≥ stage 2
a. BLF Vs control: p=
0.09 (not significant),
RRR=68.3% *
b. BLF+LGG Vs control:
p=0.002,RRR=100%
1. BLF group: BLF (100mg/d)* or
2. BLF + LCC group: BLF (100mg/d) +
LGG (6x 109 CFU/d)
3. Control group: 2ml of 5% glucose
solution
4. Begin in 3rd day of life
5. 1 daily dose
6. Diluted in milk
7. Neonates not feeding in the first 48
hours received the drug(s) or
placebo by oro-gastric tube
Duration:
Start form 3rd of life
6 weeks (birth weight <1000g)
4weeks (birth weight 1001-1500g)
VLBW: very low birth weight; APT: aspartate aminotransferase; ALP: alanine aminotransferase; DB: direct bilirubin serum; BLF: bovine lactoferrin; LGG: Lactobacillus rhamnosus GG; late-onset sepsis: occurs more than 3rd of life and before discharge; * The BLF only group is not our focus in this dissertation
- 53 -
Demirel, G., Erdeve, O., Celik, I. H., & Dilmen, U. (2013). Saccharomyces boulardii for prevention of necrotizing enterocolitis in preterm infants: randomized, controlled study. Acta Paediatrica, 102(12), e560-e565.
Study type Sample characteristics Intervention Control Outcome measure(s) Result: (p=p-value)
Demirel et al.(2013)/ RCT (1+)
neonates
Birth weight 1500g
Born 32 completed
weeks gestation
Started to fed enterally
mean birth weight (g):
(1164/ 1131 : probiotic
/control)
mean gestational age
(wks): (29.4/ 29.2 :
probiotic /control)
Exclusion criteria:
With major congenital
malformations
Died within 7th day
after intervention started
(exclude from analysis)
Probiotic: (n=135)
Placebo: (n=136) Primary measure(s)
1. number of infants with NEC≥
stage 2:
a. probiotic: 6 (4.4%)
b. control: 7 (5.1%)
2. mortality:
a. probiotic: 5 (3.7%)
b. control: 5 (3.7%)
Secondary measure(s)
3. number of infants with sepsis
(clinical):
a. probiotic: 47 (34.8%)
b. control: 65 (47.8%)
4. number of infants with sepsis
(culture proven):
a. probiotic: 20 (14.8%)
b. control: 21 (15.4%)
Primary measure(s)
1. number of infants with
NEC≥ stage 2:
a. probiotic Vs control:
p=1.0 (not
significant),,
RRR=14.3%
2. mortality:
a. probiotic Vs control:
p=1.0 (not
significant),,
RRI=0.770%
Secondary measure(s)
3. number of infants with
sepsis (clinical):
a. probiotic Vs control:
p=0.03, RRR=41.7%
4. number of infants with
sepsis (culture proven):
a. probiotic Vs control:
p=0.906 (not
significant),,
RRR=4.76%
1. Probiotic group: Saccharomyces
boulardii 125mg/kg per dose
mixed with breast milk or formula
milk
2. Control group: breast milk or
formula milk
3. Probiotics mixed with breast milk
or donor milk before feeding
4. Feeding was started when the
infant had stable vital signs, active
bowel sound without abdominal
distension, no bile or blood from
the nasogastric tube.
Duration:
once per day until discharge
- 54 -
Jacobs, S. E., Tobin, J. M., Opie, G. F., Donath, S., Tabrizi, S. N., & Pirotta, M., et al. (2013). Probiotic Effects on Late-onset Sepsis in Very Preterm Infants: A Randomized Controlled Trial. Pediatrics: 132(6): 1055-1062.
Study type Sample characteristics Intervention Control Outcome measure(s) Result: (p=p-value)
Late onset sepsis: culture proven (blood/ CSF) after 2 days of life treated with antibiotics ≥ 5days
- 55 -
Oncel, M. Y., Sari, F. N., Arayici, S., Guzoglu, N., Erdeve, O., & Uras, N., et al.(2014). Lactobacillus Reuteri for the prevention of necrotizing enterocolitis in very low birthweight infants: a randomized controlled trial. Arch Dis Child Fetal Neonatal Ed. 99: F110-F115.
Study type Sample characteristics Intervention Control Outcome measure(s) Result: (p=p-value)
Oncel et al.(2014)/ RCT (1+)
Inclusion criteria:
Born 32 completed
weeks gestation
Birth weight 1500g
Survived to fed enterally
mean birth weight (g):
(1071/ 1048 : probiotic
/control)
mean gestational age
(wks): (28.2/ 27.9 :
probiotic /control)
Exclusion criteria:
had major congenital
malformations
lacks of parental consent
infants died within the
1st week of life (would
not have had
opportunity to benefit
from the intervention)
Probiotic: (n=213)
(n=200, analyzed)
Placebo: (n=211)
(n=200, analyzed)
Primary measure(s)
1. number of infants with
NEC≥ stage 2:
a. probiotic: 8 (4.0%)
b. control: 10 (5.0%)
Secondary measure(s)
2. number of infants with
culture proven sepsis:
a. probiotic: 13 (6.5%)
b. control: 25 (12.5%)
3. days required full enteral
feeding (SD):
a. probiotic: 9.1 3.2
b. control: 10.1 4.3
4. length of hospital stay
(days):
a. probiotic: 38
b. control: 46
1. number of infants with
NEC≥ stage 2:
a. probiotic Vs control:
p=0.63(not
significant),
RRR=20.0%
Secondary measure(s)
2. number of infants with
culture proven sepsis:
a. probiotic Vs control:
p=0.041, RRR=48.0%
3. days required full enteral
feeding
a. probiotic Vs control:
(effect size = -0.3125;
p= 0.006)
4. length of hospital stay
a. probiotic Vs control:
p= 0.022
1. Probiotic group: oil-based suspension
containing 1 x 108 CFU/day (5 drops)
of lyophilized Lactobacillus reuteri
2. Control group: oil-based suspension
3. Feeding was started when the infant
had stable vital signs, active bowel
sound without abdominal distension,
no bile or blood from the nasogastric
tube.
4. Started with the first feed of the
infants
5. Suction of oral secretions
6. 5 drops of study powder in oil-based
will be placed in the posterior
oropharynx of the infants
7. For infants without per oral feeds, 5
drops of study substance will be
administered through a gastric tube
followed by a flash of 0.5 ml of sterile
water
8. Follow by breast milk or formula milk
Duration:
Once daily until discharge
- 56 -
Appendix C: Summary or studies results Lin (2005) Samanta (2009) Manzoni (2009) Demirel (2013) Jacobs (2013) Oncel (2014)
Inclusion criteria
1. <1500g 2. Started enteral
feeding
1. <1500g 2. <32 weeks 3. Started enteral
feeding
1. 1500g 2. Younger than 3 day of
life
1. 32 weeks
2. 1500g 3. Started enteral
feeding
1. <32 weeks 2. <1500g 3. Younger than 3 day of
life
1. 32 weeks
2. 1500g 3. Started enteral
feeding
Exclusion criteria
1. Died or had NEC before 7th day of life
1. Died before 2nd day of life
2. With major congenital and GI anomalies
1. Ongoing antifungal prophylaxis
2. Had sepsis before 3rd of life
3. Liver failure
1. With major congenital malformations
2. Died within 7th day after intervention started (exclude from analysis)
1. With major congenital or chromosomal anomalies
2. Died before 3rd of life 3. Mother taking
nondietary probiotic supplements
1. With major congenital malformations
2. Died before 7th day of life (exclude from analysis)
Study identification (Include author, title, year of publication, journal title, pages)
Guideline topic: Key Question No: Reviewer:
Before completing this checklist, consider:
1. Is the paper a randomised controlled trial or a controlled clinical trial? If in doubt, check the study design algorithm available from SIGN and make sure you have the correct checklist. If it is a controlled clinical trial questions 1.2, 1.3, and 1.4 are not relevant, and the study cannot be rated higher than 1+
2. Is the paper relevant to key question? Analyse using PICO (Patient or Population Intervention Comparison Outcome). IF NO REJECT (give reason below). IF YES complete the checklist.
Reason for rejection: 1. Paper not relevant to key question 2. Other reason (please specify):
SECTION 1: INTERNAL VALIDITY
In a well conducted RCT study… Does this study do it?
1.1 The study addresses an appropriate and clearly focused
question.
Yes
Can’t say
No
1.2 The assignment of subjects to treatment groups is randomised.
Yes
Can’t say
No
1.3 An adequate concealment method is used.
Yes
Can’t say
No
1.4 The design keeps subjects and investigators ‘blind’ about
treatment allocation.
Yes
Can’t say
No
1.5 The treatment and control groups are similar at the start
of the trial.
Yes
Can’t say □
No
1.6 The only difference between groups is the treatment
under investigation.
Yes
Can’t say
No
- 59 -
1.7 All relevant outcomes are measured in a standard, valid
and reliable way.
Yes
Can’t say
No
1.8 What percentage of the individuals or clusters recruited
into each treatment arm of the study dropped out before
the study was completed?
1.9 All the subjects are analysed in the groups to which they were randomly allocated (often referred to as intention to treat analysis).
Yes
Can’t say
No
Does not
apply
1.10 Where the study is carried out at more than one site, results are comparable for all sites.
Yes
Can’t say
No
Does not
apply
SECTION 2: OVERALL ASSESSMENT OF THE STUDY
2.1 How well was the study done to minimise bias? Code as follows:
High quality (++)
Acceptable (+)
Low quality (-)
Unacceptable – reject 0
2.2 Taking into account clinical considerations, your evaluation of the methodology used, and the statistical power of the study, are you certain that the overall effect is due to the study intervention?
2.3 Are the results of this study directly applicable to
the patient group targeted by this guideline?
2.4 Notes. Summarise the authors’ conclusions. Add any comments on your own
assessment of the study, and the extent to which it answers your question and mention
any areas of uncertainty raised above.
- 60 -
Appendix E: SIGN Methodological Quality Coding: levels of Evidence & Grading of Recommendations
LEVELS OF EVIDENCE
1++ High quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias
1+ Well-conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias
1- Meta-analyses, systematic reviews, or RCTs with a high risk of bias
2++ High quality systematic reviews of case control or cohort or studies High quality case control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal
2+ Well-conducted case control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal
2- Case control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal
3 Non-analytic studies, e.g. case reports, case series
4 Expert opinion
GRADES OF RECOMMENDATIONS
At least one meta-analysis, systematic review, or RCT rated as 1++, and directly applicable to the target population; or A body of evidence consisting principally of studies rated as 1+, directly applicable to the target population, and demonstrating overall consistency of results
A body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating overall consistency of results; or Extrapolated evidence from studies rated as 1++ or 1+
A body of evidence including studies rated as 2+, directly applicable to the target population and demonstrating overall consistency of results; or Extrapolated evidence from studies rated as 2++
Evidence level 3 or 4; or Extrapolated evidence from studies rated as 2+
Good practice points
Recommended best practice based on the clinical experience of the guideline development group
- 61 -
Appendix F: Summary of quality of studies
Lin (2005) Samanta
(2009) Manzoni (2009)
Demirel (2013)
Jacobs (2013)
Oncel (2014)
1.1 The study addresses an appropriate and clearly focused question.
Yes Yes Yes Yes Yes Yes
1.2 The assignment of subjects to treatment groups is randomised.
Yes Yes Yes Yes Yes Yes
1.3 An adequate concealment method is used.
Yes Not
mentioned Yes Yes
Not mentioned
Yes
1.4 The design keeps subjects and investigators ‘blind’ about treatment allocation.
No Not
mentioned Yes Yes Yes
Not mentioned
1.5 The treatment and control groups are similar at the start of the trial.
Yes Yes Yes Yes Not
mentioned Yes
1.6 The only difference between groups is the treatment under investigation.
Yes Yes Yes Yes Yes Yes
1.7 All relevant outcomes are measured in a standard, valid and reliable way.
Yes Yes Yes Yes Yes Yes
1.8 What percentage of the individuals or clusters recruited into each treatment arm of the study dropped out before the study was completed?
0% 0% 2.6% 2.86% 2.72% 6.1%
1.9 All the subjects are analyzed in the groups to which they were randomly allocated (often referred to as intention to treat analysis).
NA NA Yes No Yes No
1.10 Where the study is carried out at more than one site, results are comparable for all sites.
Appendix G: Summary of quality of studies (Supplementary information) Section 1: Internal validity 1.2 The assignment of subjects to treatment groups is randomised.
Lin (2005) By a random-number table sequence
Samanta (2009) By a random-number table sequence
Manzoni (2009) By computer-generated randomization lists; Lactoferrin : lactoferrin and probiotic: control is 1:1:1 ratio using computer-generated randomization lists; Randomization was stratified by centers
Demirel (2013) By computer-generated sequential numbers
Jacobs (2013) By computer-generated randomization lists; Randomization was stratified by center with 1:1 ratio, Infants from multiple births were randomized individually
Oncel (2014) By computer-generated randomization lists
1.3 An adequate concealment method is used.
Lin (2005) The allocations were contained in opaque, sequentially numbered, sealed envelopes
Samanta (2009) The concealment method was not mentioned
Manzoni (2009) All doses including placebo were diluted in prepared milk to maintain blinding
Demirel (2013) The allocations were contained in opaque, sequentially numbered, sealed envelopes
Jacobs (2013) The concealment method was not mentioned
Oncel (2014) The allocations were contained in opaque, sequentially numbered sealed envelopes
1.4 The design keeps subjects and investigators ‘blind’ about treatment allocation.
Lin (2005) Single blinded; investigators were not blinded, only clinical staff remained unware of the randomization
Samanta (2009) Double blinded; Author didn’t mentioned which parties were blinded
Manzoni (2009) Double blinded; Clinical and research staff remained unware of the randomization
Demirel (2013) Double blinded; Clinical and research staff remained unware of the randomization
Jacobs (2013) Double blinded ; Apart from pharmacist, all staff and parents were blinded to the randomized allocation
Oncel (2014) Double blinded; Clinical staff were blinded but the author didn’t mention about whether investigators were blinded as well
1.5 The treatment and control groups are similar at the start of the trial.
Lin (2005) Author stated that the maternal clinical and infant’s clinical and demographic characteristics did not differ
- 63 -
between the 2 groups
Samanta (2009) Author stated that the maternal clinical and infant’s demographic and clinical characteristics were similar with p-values >0.05
Manzoni (2009) The demographic and nutritional characteristics were compared and p-values shown to be non-significant
Demirel (2013) Author stated that the maternal clinical and infant’s clinical and demographic characteristics did not differ between the 2 groups
Jacobs (2013) Author didn’t state that the demographic data of patients were similar and p values were not shown
Oncel (2014) Author stated that the maternal clinical and infant’s demographic and clinical characteristics were similar with p-values >0.05 except the duration of TPN with p=0.048
1.7 All relevant outcomes are measured in a standard, valid and reliable way.
Lin (2005) Sepsis: positive blood culture NEC ≥ Bell’s stage 2: 2 independent doctor Mortality: hospital data
Samanta (2009) Sepsis: positive blood or CSF culture taken beyond 5 days of age NEC: ≥ Bell’s stage 2 Mortality: hospital data Days required full enteral feeding: hospital data Length of hospital stay: hospital data
Manzoni (2009) Sepsis: occurred ≥ 72 hours of life. Detection of clinical signs by physician, presence of positive blood or CSF culture results NEC: ≥ Bell’s stage 2 Mortality attributable to sepsis: hospital data
Demirel (2013) Sepsis (clinical): C-reactive protein >4.82 mg/L and Interleukin-6 >4.82mg/L Sepsis (definite): 1 culture proven (blood/ CSF/ urine) NEC: ≥ Bell’s stage 2 Mortality: hospital data
Jacobs (2013) Definite sepsis: 2 separate cultures (blood/ CSF) of same species and treated with antibiotic ≥ 5 days Sepsis (clinical): CRP >10mg/L and /or immature-to-total neutrophil ratio>0.2 and treated with antibiotic ≥ 5days NEC: ≥ Bell’s stage 2
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Mortality caused by NEC” hospital data Days required full enteral feeding: hospital data Length of hospital stay: hospital data
1.9 All the subjects are analyzed in the groups to which they were randomly allocated (often referred to as intention to treat analysis).
Lin (2005) Author didn’t mention that intention to treat analysis was used
Samanta (2009) Author didn’t mention that intention to treat analysis was used
Manzoni (2009) Author used intention to treat analysis
Demirel (2013) Participants who discontinued intervention were not included into the analysis
Jacobs (2013) Author used intention to treat analysis
Oncel (2014) Participants who discontinued intervention were not included into the analysis
1.10 Where the study is carried out at more than one site, results are comparable for all sites.
Lin (2005) Carried at in the NICU of China Medical University Hospital in Taiwan
Samanta (2009) Carried out in the NCU of Medical College and Hospital, Kolkata, India
Manzoni (2009) Carried out at 11 tertiary Italian neonatal intensive care units
Demirel (2013) Carried in the NICU of Samsun Maternity and Child Health Hospital, Samsun, Turkey
Jacobs (2013) Carried out in 2 perinatal hospitals in Australia and 2 perinatal hospitals in New Zealand
Oncel (2014) Carried in the NICU of Zekai tahir Burak Maternity Teaching Hospital, Ankara, Turkey
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SECTION 2: OVERALL ASSESSMENT OF THE STUDY 2.4 Comments:
Lin (2005) Oral probiotics (Lactobacillus acidophilus and Bifidobacterium infantis) significantly reduces the incidence and severity of NEC, incidence of sepsis and mortality in very low birth weight infants. Potential bias The intervention was not masked to investigators and breast milk team
Samanta (2009) Oral probiotics (Bifidobacteria infantis, Bifidobacteria bifidum, Bifidobacteria longum and Lactobacillus acidophilus, each 2.5 x 109 CFU) significantly reduces the incidence of NEC, sepsis, mortality, days required full enteral feeding, length of hospital stay in very low birth weight infants, BUT NOT the severity of NEC.
Manzoni (2009) Oral lactoferrin (BLF) in combination with probiotic (LGG) decreased the incidence of late-onset sepsis NEC, and mortality attributable to sepsis in VLBW and ELBW infants.
Demirel (2013) It is statically significant in reducing the rate of clinical sepsis. All other outcomes, including definite sepsis, rate of NEC stage II or above can’t react statically significant.
Jacobs (2013) It is statically significant in reducing late onset sepsis in infants≥ 28weeks but no those <28 weeks. It was also significant in reducing NEC≥ 2nd Bell’s stage. But the decrease in mortality, days required full enteral feeding and length of hospital stay were not supported.
Oncel (2014) Probiotic (Lactobacillus reuteri , 1 x 108 CFU/day) is not statistically significant in reducing culture proven late onset sepsis but is statistically significant in reducing NEC, days required full enteral feeding and length of hospital stay
However, in this study, infants who died before 7th day of life were excluded from analysis which downgraded its quality of study. The reason explained by the author is infants would not have had opportunity to benefit from the intervention if they died within 7 days of life.
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Appendix H: Estimated cost for the innovation annually
Estimated cost for the first year:
Items Price per unit (HKD) Quantity Amount (HKD)
Set-up cost:
Rooms for training 0 1 0
Chairs for training 0 15 0
Computer 0 1 0
Projector 0 1 0
Stationary 5 10 50
Hard copy guideline 5 6 30
Electronic copy guideline 0 1 0
Poster for promotion 20 5 100
Checklist for staff competency
1 60 60
Evaluation forms for staff satisfaction
1 60 60
Sub-total: 300
Material cost:
Probiotic 245/90 (one capsule)
140x60x2 45734
Salary of staff for training (30 minutes)
$300 0.5x55 8250
Salary of staff for milk preparation (15 minutes each day)
$300 0.25x 2x 365
54750
Sub-total: 108734
Total: 109034
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Appendix H: Estimated cost for the innovation annually (cont’d)
Estimated additional annual running cost in the subsequent year
Items Price per unit (HKD) Quantity Amount (HKD)
Set-up cost:
Rooms for training 0 1 0
Chairs for training 0 15 0
Computer 0 1 0
projector 0 1 0
Stationary (bought in the first year)
0 10 0
Hard copy guideline (printed in the first year)
0 6 0
Electronic copy guideline 0 1 0
Poster for promotion (printed in the first year)
0 5 0
Checklist for new staff competency
1 10 10
Material cost:
Salary of new staff for training (30 minutes)
$300 0.5x10 1500
Probiotic 245/90 (one capsule)
140x60x2 45734
Salary of staff for milk preparation (15 minutes each day)
$300 0.25x 2x 365
54750
Total: 101994
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Appendix I: Evidence-based practice guideline
Title
The title of the clinical guideline is named as “Evidence-based Guideline on Using
Oral probiotic to prevent Late-Onset Sepsis in Preterm Infants”
Background of clinical issue
Late-onset sepsis is a common problem in extremely preterm and very preterm
infants with delayed natural gastrointestinal colonization (Mshvidadze et al., 2010;
Schwiertz et al., 2003). The use of oral probiotic is shown to be effective in preventing
neonatal late-onset sepsis in different randomized controlled trial studies (Demirel et al.,
2013; Jacobs et al., 2013; Lin et al., 2005; Manzoni et al., 2009; Oncel et al., 2014;
Samanta et al., 2009). Besides that, the use of probiotic can also reduce incidence rate of
NEC≥ stage 2 (Jacobs et al., 2013; Lin et al., 2005; Manzoni et al., 2009; Oncel et al., 2014;
Samanta et al., 2009), infant mortality (Lin et al., 2005; Manzoni et al., 2009; Samanta et
al., 2009) and shorten length of hospitalization (Oncel et al., 2014; Samanta et al., 2009).
Aim
To develop an evidence-based guideline on using oral probiotic for preventing
late-onset sepsis in preterm infants
Objective
The objectives of this guideline are to:
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To summarize all available high level of evidences for the use of oral probiotic on
preterm infants
To formulate and evidence-based guidelines for NICU and SCBU nurses on using
oral probiotic on preterm infants
To streamline and standardize the clinical practice on using oral probiotic on
preterm infants
Target Users
This guideline is intended to provide instructions for NICU and SCBU nurses of all
level on the usage of oral probiotic in preterm infants.
Target group
Preterm infants who are admitted to NICU or SCBU with gestational age ≤ 32
weeks and/ or birth weight ≤ 1500 grams, excluding those with major congenital
anomalies.
Recommendations
The recommendations are graded according to Scottish Intercollegiate
Guidelines Network (SIGN).
Recommendation 1
1.1 The eligible population should include preterm infants with gestational week 32
weeks and/or with birth weight 1500 grams.
(Grade of recommendation: A)
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Evidences:
Infants with gestational age < 32 weeks [Samanta et al., 2009 (1+), Demirel et al.,
2013 (1+), Jacobs et al., 2013 (1+), Oncel et al., 2014 (1+)] and/ or birth weight < 1500g
[Lin et al., 2005 (1+), Samanta et al., 2009 (1+), Manzoni et al., 2009 (1++), Demirel et al.,
2013 (1+), Jacobs et al., 2013(1+), Oncel et al., 2014 (1+)] were eligible population to the
intervention.
1.2 Intervention should start when eligible population started enteral feeding.
(Grade of recommendation: A)
Evidences:
Four studies mentioned that oral probiotic should be used when infant started to
feed enterally [[Lin et al., 2005 (1+), Samanta et al., 2009 (1+), Demirel et al., 2013 (1+),
Oncel et al., 2014 (1+)].
1.3 The patient should be excluded from the innovation if they have major congenital
anomalies.
(Grade of recommendation: A)
Evidences:
Four studies exclude infants with major congenital anomalies. [Samanta et al.,
2009 (1+), Demirel et al., 2013 (1+), Jacobs et al., 2013(1+), Oncel et al., 2014 (1+)].
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Recommendation 2
2.1 Probiotic contains Lactobacillus and/or Bifidobacterium infantis species should be
used.
(Grade of recommendation: A)
Evidences:
Five studies use probiotic that contains Lactobacillus species [Lin et al., 2005 (1+),
Samanta et al., 2009 (1+), Manzoni et al., 2009 (1++), Oncel et al., 2014 (1+)] and/or
Bifidobacterium infantis species [Lin et al., 2005 (1+), Samanta et al., 2009 (1+), Jacobs et
al., 2013(1+)].
2.2 Probiotic mixture of Bifidobacteria infantis, Bifidobacteria bifidum, Bifidobacteria
longum and Lactobacillus acidophilus, each 2.5 billion CFU should be used.
(Grade of recommendation: B)
Evidences:
After comparing the effect on the incidence rate of late onset sepsis in all six
studies found, probiotic with mixture of Bifidobacteria infantis, Bifidobacteria bifidum,
Bifidobacteria longum and Lactobacillus acidophilus, each 2.5 billion CFU provided a 93%
of RRR significantly (p=0.020) [Samanta et al., 2009 (1+)].
2.3 The probiotic mixture should administrate according to infant’s body weight.
(Grade of recommendation: B)
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Evidences:
After comparing the RRR in the incidence rate of late onset sepsis in all six
studies found, probiotic used in Samanta et al. (2009) provided the highest RRR.
Samanta et al. (2009) suggested that the probiotic mixture should be administrated
according to infant’s body weight *Samanta et al., 2009 (1+)].
2.4 The probiotic mixture should be administrated at a dose of 125g/kg twice daily.
(Grade of recommendation: B)
Evidences:
After comparing the RRR in the incidence rate of late onset sepsis in all six
studies found, probiotic used in Samanta et al. (2009) provided the highest RRR.
Samanta et al. (2009) suggested that the probiotic mixture should be administrated
twice daily with the dosage being 125g/kg till discharge [Samanta et al., 2009 (1+)].
Recommendation 3
3.1 Intervention should start when infants started enteral feeding with stable vital
signs, active bowel sound without abdominal distension and no bile or blood aspirated
from gastric tube.
(Grade of recommendation: A)
Evidences:
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In four of the studies found, intervention should only start when infants started
enteral feeding with stable vital signs, active bowel sound without abdominal distension
and no bile or blood from gastric tube [Lin et al., 2005 (1+), Samanta et al., 2009 (1+),
Demirel et al., 2013 (1+), Oncel et al., 2014 (1+)]
3.2 Intervention should stop when signs of feeding intolerance were observed.
(Grade of recommendation: B)
Evidences:
Interventions were stopped in three of the studies found when signs of feeding
intolerance were observed in infants [Lin et al., 2005 (1+), Demirel et al., 2013 (1+),
Oncel et al., 2014 (1+)]
3.3 The intervention should end when infant discharge.
(Grade of recommendation: A)
Evidences:
In five of the studies found, intervention were ended when infants discharged
from hospital [Lin et al., 2005 (1+), Samanta et al., 2009 (1+), Demirel et al., 2013 (1+),
Jacobs et al., 2013(1+), Oncel et al., 2014 (1+)].
3.4 The probiotic should mix with breast milk or formula milk.
(Grade of recommendation: A)
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Evidences:
The probiotic was mixed with breast milk [Lin et al., 2005 (1+), Samanta et al.,
2009 (1+), Manzoni et al., 2009 (1++), Demirel et al., 2013 (1+), Jacobs et al., 2013(1+)]
or formula milk [Manzoni et al., 2009 (1++), Demirel et al., 2013 (1+)] before
administrate to infants.
3.5 The probiotic can be administrated orally or through oro-gastric tube.
(Grade of recommendation: A)
Evidences:
In the six studies found, five of them mentioned that the probiotic were
administrated orally [Lin et al., 2005 (1+), Samanta et al., 2009 (1+), Manzoni et al., 2009
(1++), Demirel et al., 2013 (1+), Jacobs et al., 2013(1+)] or through orogastric tube
[Manzoni et al., 2009 (1++), Jacobs et al., 2013(1+), Oncel et al., 2014 (1+)]. Oncel et al.
(2014) stated that suctioning oral secretions should be done before administrating
probiotic and the probiotic was placed in the posterior oropharynx of the infants. For
infants without per oral feeds, probiotic were administered through a gastric tube
followed by a flash of 0.5 ml sterile water [Oncel et al., 2014 (1+)].
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Appendix J: Schedule for implementation and evaluation Timeslot Phase Action
Week 1 Approval seeking
Hold meetings to explain the innovation Form the committee
Week 2 Get support and introduce the innovation to the staff
Hold briefing sessions to the intended users Introduce the innovation in the multi-disciplinary
team meeting Email details of innovations to all staffs in
department Provide hardcopy and electronic copy of