JOURNAL CLUB

JUNE 2019
Dr Rino
Dr Sarita
Volume 56 – April 2019
EBM Pyramid
RCT
 Randomization:
Statistical procedure where subjects are randomly allocated
into groups called study/control, to receive or not to receive
a therapy/intervention

 Why randomize?
 Eliminate bias
 Allows comparability
 Matches for known and unknown confounding variables
 Likely to be more representative of population
Types of randomization
 Simple randomization

 Block randomization

 Stratified randomization
Simple randomization
 Flip a coin
 Even/odd
 Random number table

 Pros:  Cons
 Simple  Canresult in unequal no
 Easy to implement of participants in each
group
Block randomization
Stratified randomization
 Separate block randomisation schemes for
each combination of characteristics

 Eg 0-1 year, 1-5 year

Inappropriate randomization methods
 Assigning patients alternately to treatment group
is not random assignment

 Assigning the first half of the population to one

group is not random assignment

 Assignments by methods based on patient

characteristics such as date of birth, order of
entry into the clinic or day of clinic attendance,
are not reliably random
Indian Paediatrics

Volume 56 – April 2019

Background
 Aggressive enteral nutrition – risk factor for NEC
 Delayed enteral feeds in infants < 1250g
 Slow gradation of enteral feeds with parenteral nutrition
bridging the nutritional gap

 Prolonged parenteral nutrition

 Metabolic complications
 Blood stream infections
 NICU mortality
 Poor growth
 Poor neurodevelopmental outcome
Hypothesis

Will an aggressive feeding regimen in preterm infants

with birth weight 750 – 1250 g result in a lower
mortality and morbidity compared to conservative
feeding regimen?
Objective
To evaluate the impact of aggressive enteral feeding
on mortality and morbidity among preterm neonates
Study Design
Randomized controlled open label trial
Methodology
 Medical College affiliated hospital
 Period: April 2012 – June 2014
 Institutional IEC approved

 Inclusion criteria:
 All inborn neonates with birth weight 750 – 1250g

 Exclusion criteria:
 Gross congenital GI malformations
 Severe birth asphyxia (APGAR <3 at 1min)
 Could not establish enteral feeding within first 4 days
Outcomes
 Primary outcome: all-cause mortality during hospital
stay
 Secondary outcome:
 Blood culture proven sepsis
 NEC ≥ Stage II*
 Feed intolerance#
 Survival without major morbidity at discharge
 Time to reach full enteral feed (180 ml/kg/d)
 Average daily weight gain in NICU after achieving birth
weight (g/kg/day)
*Modified Bell’s staging
#≥1 of: distended/tense/tender abdomen, AG increase >2cm in 2 hr interval, hemorrhagic/bilious aspirate
Outcomes
 Secondary outcome:
 Survival without major morbidity at discharge
 Bronchopulmonary dysplasia*
 IVH grade III or IV#
 Cystic periventricular leukomalacia@
 ROP requiring treatment

*National Institute of Health consensus definition 2001

#Papile’s classification
@ De Vries classification
Methodology – Sample size
 Pilot observational study:
 Mortality among neonates with birthweight <1250g
was 80%

 Expected a 30% relative reduction in mortality with

aggressive feeding
Methodology – Sample size
For power of 80% and alpha error of 0.05,
sample size = 58 neonates in each arm
+
10% attrition

65 neonates in each arm

Methods
 Eligible to start enteral feeds:
 Not on ionotropic support
 If on mechanical ventilation:
 Mean Airway Pressure (MAP) < 14 mbar AND/OR
 FiO2 < 0.7

 Soft abdomen
 Study Design

Eligible
Informed neonates
written consent enrolled

Stratified Block Early Conservative

aggressive feeding
Randomization treatment (AR) regimen (CR)

Allocation concealment
No blinding
Study design

CR AR
750 – 1000 g
15 ml/kg/d 30 ml/kg/d
+ 15 ml/kg/d + 30 ml/kg/d
1000 – 1250 g
20 ml/kg/d 40 ml/kg/d
+ 20 ml/kg/d + 40 ml/kg/d
 Mothers milk (Preterm formula if unavailable)
 Parenteral nutrition till 100 – 120 ml/kg/d tolerated
Methods
 Baseline maternal, antenatal, intrapartum and
neonatal details recorded
 Monitored for NEC and feed intolerance
< 20% - increment
as assigned

↑ AG > 2cm OR Gastric residue 20 – 50%

tense/tender aspiration Continue without
abdomen increment x 24 hrs

> 50% - withhold 24

hrs or till abdominal
signs resolve (later)
Methods
 Withhold feeds if on ionotropes
 Culture data obtained and recorded in suspected
sepsis
 Statistical analysis

Categorical data Chi-Square test

Continuous data Student t-test
Mann-Whitney U test
Time to event analysis Kaplan-Meier curve

Test of significance: p value (<0.05)

results
Flow of participants
Results
Results
Strengths
 Enrollment of relatively smaller neonates
 Higher risk for morbidity
 Abnormal umbilical artery doppler and mechanical
ventilation requirement not excluded
 Findings can be generalized to sick and growth-
restricted neonates
Limitations
 Inability to mask intervention from caregivers and
investigator
 Inadequate power for primary outcome
Conclusion
 Early aggressive feeding regimen is well tolerated
with reduction in IVF duration and early
achievement of full enteral feeding.

 No significant reduction in all-cause mortality,

culture-positive sepsis or survival without major co-
morbidities during NICU stay.
CRITICAL ANALYSIS
Title
 Identified study design – RCT
 Population
 Intervention

 Outcome
Abstract
 Structured abstract
 Trial design
 Methods

 Results

 Conclusions
Introduction
 Scientific background
 Explained rationale
 Stated hypothesis

 Need for stratification and rationale not explained

Methods
Trial design RCT

Allocation ratio not mentioned

Participants Eligibility criteria
Inclusion, exclusion

Location of study
Interventions Well detailed
Outcomes Well defined primary and secondary outcomes
No changes made once trial started

Duration of hospital stay – criteria for discharge

Outcomes like feed intolerance, sepsis, NEC – time of
assessment or number
Methods
Sample size Mentioned

Nature of pilot study conducted

Mortality with conservative feeding was considered
Arbitary relative reduction by 30% for aggressive feeding
Inadequate power of study though calculated for 80% (actual
power – 32.5%)
Inadequate sample size  inconclusive results
Randomisation Sequence generation
Blocks and strata
Allocation concealment

Implementation
Blinding Not done
Statistical Mentioned
analysis
Results
Participant flow Depicted

No details on stratification and samples in each strata

Recruitment Period of study clearly defined
Baseline data Given
Numbers Overall as AR and CR
analysed
No details on stratification , numbers obtained or relevant analysis
Outcomes and Birthweight and gest age mean - ? Relevance of data for 750 –
estimation 1000g
?subgroups
Potential harms
or unintended
effects Not mentioned
Results
Participant flow Depicted

No details on stratification and samples in each strata

Recruitment Period of study clearly defined
Baseline data Given
Numbers Overall as AR and CR
analysed
No details on stratification , numbers obtained or relevant analysis
Outcomes and Birthweight and gest age mean - ? Relevance of data for 750 –
estimation 1000g
?subgroups
Potential harms
or unintended
effects Not mentioned
Discussion
 Mentioned limitations
 Applicability

 Potential bias – unequal distribution in each strata

?Details
Other information
 Registration number of trial

 Source of funding and support