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Recent Trials in Neonatology - Part II
Recent Trials in Neonatology - Part II
neonatology – Part II
Dr. Keshav Kumar Pathak
DM senior resident
Department of neonatology
Dr. RML Hospital, New Delhi
01/05/2022 1
TRIALS
1. ACTION I Trial (NEJM 2020)
2. ACTION II Trial (Lancet 2022)
3. Cochrane 2020 for ACS in preterm birth
4. ASTEROID Trial(Lancet 2019)
5. HYPOEXIT Trial (NEJM 2020)
6. REACT Trial (Lancet 2021)
7. I KMC (NEJM 2021)
8. IN-REC-SUR-E (Lancet 2020)
9. HELIX Trial (Lancet 2021)
10.ULTRASURF
01/05/2022
(Eu.J.paed- 2020) 2
ACTION-I (Antenatal Corticosteroids for
Improving Outcomes in Preterm Newborns) trial
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PICO
• P (population)- 2852 women having fetus between 26 week 0 days to
33 weeks 6 days of gestation at risk of preterm delivery
• I (intervention)- dexamethasone sodium phosphate 6 mg- 12hours
apart , total 4 doses
• C (control) - placebo
• O (outcomes)-
primary outcome - neonatal death
- still birth or neonatal death
- possible maternal bacterial infection
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Conclusion
• Dexamethasone reduced the incidence of neonatal death and
still birth or neonatal death without increasing the incidence of
maternal bacterial infection in study conducted in low resource
countries.
• Early neonatal deaths, severe respiratory distress, use of major
neonatal resuscitation and CPAP
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ACT vs ACTION trial
Act trial Action trial
• Cluster randomised • Randomised
• All levels of care • In low resource setting
• Inadequate care • With minimum standards of care
• Selected women based on LMP • Selected women GA verified by
USG
• 16% of babies exposed <5th centile
BW • >90% infants exposed born preterm
• Substantial overtreatment • Treatment received by the needed
• Inappropriate selection • Appropriate selection
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ACTION – II Trial
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PICO
• P(population)- pregnant women at risk of imminent preterm birth between 34
weeks 0 days to 36 week 0 days of gestation (782 women)
• I (intervention)- 6 mg of intramuscular dexamethasone – 4 doses 12 hours apart
• C(control)- Placebo
• O(outcome)-
Primary outcome
Neonatal deaths
Any baby death(still birth or neonatal death
Severe neonatal respiratory distress
Possible maternal bacterial infection
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Result
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Objectives
To assess the effects of administering a course of corticosteroids to women prior to anticipated
preterm birth (before 37 weeks of pregnancy) on fetal and neonatal morbidity and mortality,
maternal mortality and morbidity, and on the child in later life
Studies
27 studies ( ten trials- lower or middle resource settings)
Studies in only high resource settings were included in previous Cochrane 2017
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Primary outcomes
Neonatal/childhood outcome-
•Definite reduction
Maternal
Perinatal death- RR-0.85, CI (0.77-0.93) outcomes
Neonatal death-RR-0.78, CI (0.70-0.87)
RDS- RR-0.71, CI (0.65-0.78)
•No difference in
•Probable reduction Maternal death
IVH- RR-0.58, CI (0.45-0.75)
•Decrease in developmental delay in
Chorioamnionitis
childhood, RR-0.51, CI (0.27-0.97), no benefit Endometritis
in previous Cochrane review 2017
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Lancet Child Adolesc Health 2019 Published Online September 12, 2019, http://dx.doi.org/10.1016/
S2352-4642(19)30292-5
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AIMS and OBJECTIVES
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Results (primary outcome)
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Secondary outcomes
• No difference • Dexamethasone group
Respiratory morbidities has decreased risk of
Intraventricular Hypertension at age of 2
hemorrhage year
Periventricular Decreased number of
leukomalacia cesarean section
chorioamnionitis
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Conclusion
Antenatal dexamethasone and betamethasone use provided similar likelihoods
of survival free of neurosensory disability at age 2 years, and either can be
given to women at risk of preterm birth to improve infant and child health.
•Kangaroo mother care is among the most effective interventions for preventing death
•Cochrane review reported 40% lower mortality in infants with a birth weight of less
than 2.0 kg who were given KMC as compared with those who were given standard
5.3%; risk ratio (RR) 0.60, 95% confidence interval (CI) 0.39 to 0.92; eight trials, 1736
infants)
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Background
• For most studies, the median age at initiation of KMC was 3.2 to 24.5
days.
• The impact of the KMC intervention could have been much larger had it
been initiated immediately after birth.
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AIM :
To evaluate the safety and efficacy of continuous KMC initiated immediately
after birth for neonates with a birth weight of 1.0 to less than 1.8 kg
compared with initiating KMC after stabilization in improving survival
Study design:
Multi-country, multi-center, non-blinded RCT
Conducted in five tertiary level hospital in Ghana, India, Malawi, Nigeria
and Tanzania between November 30,2017, and January 20, 2020;
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PICO
Patient /population All infants born alive in the participating hospitals with
a birth weight from 1.0 to less than 1.8 kg, regardless of
their gestational age
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Outcomes
Primary outcome
Secondary outcomemeasures:
measures
Hypothermia (any axillary temperature <36°C)
Neonatal deaths between enrollment and 72 h of age measured
Hypoglycemia (any blood glucose level of <45 mg per deciliter, measured
through vital status records every 12 h during hospital stay
when clinically indicated)
Suspected sepsis
Neonatal deaths between enrollment and 28 days of age
Time to clinical stabilization
measured through vital status records every 12 h during hospital
Exclusive breast-feeding (only by suckling) at the time of discharge
stay andbreast-feeding
Exclusive at a home at visit on day
the end of the29 of age.
neonatal period (at 28 days of age)
Maternal satisfaction with care
Maternal depression
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Conclusion
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HypoEXIT
Hypoglycemia–Expectant Monitoring versus Intensive
Treatment Trial
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Background
Tin W. Defining neonatal hypoglycaemia: a continuing debate. Semin Fetal Neonatal Med 2014.
Hawdon JM. Definition of neonatal hypoglycaemia: time for a rethink? Arch Dis Child Fetal Neonatal Ed 2013.
Cornblath M, Hawdon JM, Williams AF, et al. Controversies regarding definition of neonatal hypoglycemia: suggested operational thresholds. Pediatrics
01/05/2022 30 2000.
Aim of the study
• Aim of this RCT was to generate evidence for cut off threshold for management
by comparing 2 accepted threshold glucose values (as yet unsupported by
evidence) for treatment of asymptomatic moderate hypoglycemia (defined as
plasma glucose concentrations of 36 to 46 mg per deciliter [2.0 to 2.5 mmol per
liter]) in four high-risk subgroups of healthy newborns.
study design- multicenter, randomized, noninferiority trial involving 689 otherwise healthy
newborns
Settings: 17 academic and teaching hospital in Netherlands
Time period- October 2007 to April 2011
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PICO
• P(population)- Newborns at risk (Late preterm, SGA, LGA, IDM) with
plasma glucose less than 47 mg/dL, > 36mg/dL
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Secondary outcomes
• Fewer glucose measurements were performed in the lower threshold group than in the
traditional-threshold group (mean difference of −0.7 measurements, or 9% less)
• Fewer newborns in the lower threshold group received treatments for hypoglycemia.
• The durations of hospital stay of the newborns and of their mothers were similar in the
two groups, as were health care costs.
The NNT to save 1 newborn from intravenous glucose administration was 7, to save 1 newborn
from tube feeding was 12, and to save 1 newborn from supplemental oral feeding was 5.
01/05/2022 35
Lancet Child Adolesc Health 2021; 5: 265–73
Published Online February 9, 2021 https://doi.org/10.1016/ S2352-4642(20)30367-9
13 neonatal intensive care units in the UK, Spain, and the Netherlands
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Background
• Hyperglycaemia and hypoglycemia are common in preterm infants
• Hyperglycemia
Persistent osmotic diuresis
Metabolic acidosis
IVH
ROP Poor neurodevelopmental
outcome
• Hypoglycemia
• Occipito-parieto-temporal regions
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Background
• CGM
Could allow earlier detection and prevention of exposure to
extreme glucose concentrations in preterm
Real-time CGM has been used in adult and paediatric
intensive care units
Feasible in preterm infants
Aim
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PICOT
• Population: <33+6 weeks, < 1200g, <24 hours of life
• Intervention: Real time CGM
• Comparison : Standard clinical protocol
• Outcome:
• Primary : Proportion of time sensor glucose concentrations remaining
in target range (2·6–10 mmol/L) (~46.8-180 mg/dL)
• Secondary : Efficacy, acceptability and safety of CGM
• Time period: up to 7 days of age
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Trial outcomes
• The primary outcome is percentage of time SG in target range of 2.6–10mmol/L
(represents internationally, clinically most widely accepted target range )
• Secondary outcomes :
• Efficacy:
• Proportion of time sensor glucose concentrations within target range of 4–8 mmol/L
• Overall mean sensor glucose concentration
• Proportion of time that sensor glucose concentrations were in the severe
hyperglycaemic range (>15 mmol/L) (~270mg/dL)
• Safety :
• Incidence of hypoglycemia (any recorded blood glucose concentration of 2·2–2·6
mmol/L or any continuous episode of sensor glucose concentration of 1 h)
• Severe hypoglycemia (any recorded blood glucose ≤2·2 mmol/L) (~40mg/dL)
• Acceptability :
• Staff and parent questionnaire
• Prospective economic evaluation
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Primary outcome
• Proportion of time that sensor glucose concentrations were 2·6–10
mmol/L
Equivalent to an increase of 13 h (95% CI 5–21) within the target range during the first 6 days of
life
01/05/2022 46
Secondary outcome
Equivalent to 17 h
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Conclusion
01/05/2022 48
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Background
•IN-SUR-E (INtubate- SURfactant- Extubate)- lower incidence of need for mechanical ventilation, air
•Surfactant administration before recruitment -> Uneven surfactant distribution -> Reduced efficacy
01/05/2022 50
Aim
To study the safety and efficacy of IN-REC-SUR-E in comparison
with IN-SUR-E in terms of need for mechanical ventilation in first
72 hours of life in spontaneously breathing preterm infants
Study design
Multi-center randomized unblinded controlled trial.
November 2015 - September 2018
35 Neonatal intensive care units in Italy
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PICO
• Population- preterm 24+0 to 27+6 week of gestation ,breathing
spontaneously with only nasal CPAP support, and met nasal
CPAP failure criteria during first 24 hours of life.
• Intervention- recruitment before surfactant administration(IN-
REC-SUR-E)
• Comparison- no recruitment before surfactant
administration(IN-SUR-E)
• Outcome- the primary outcome was the need of mechanical
ventilation within first 72hrs of life
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Inclusion criteria
• Inborn with gestation of 24+0 to 27+6 weeks (and)
• Spontaneously breathing at birth but requiring respiratory
support (CPAP or O2) at 5 mins of life (and)
• Parental consent has been obtained (and)
• Failing CPAP during the first 24 hours of life.
• FiO2 > 30 % to maintain saturation 87-94% for 30 minutes or rapid
clinical deterioration
• Respiratory acidosis: pH <7.2 and pCO2 > 65 mmHg
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Trial Outcomes
Primary outcomes Secondary outcomes
conclusion
In this trial recruitment before surfactant administration decreased the need for
mechanical ventilation in first 72 hours of life compared with no recruitment.
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• Study design – Open Label multi-country RCT
• Study site – 7 sites (5 in India, 1 in Sri Lanka and Bangladesh each)
• Duration - August 15, 2015 to February 15, 2019
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Background
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Aim
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Inclusion Criteria
Neonates born 36 weeks, birthweight of 1·8 kg, admitted within 6 h of birth
with following two criteria:
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Primary outcomes
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Primary and secondary outcome
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Conclusion
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Randomized, non-blinded clinical trial conducted in the NICU of
Hospital Joan XXIII, Tarragona, in Spain, between January
2019 and March 2020
01/05/2022 65
Background
• In recent guidelines, early therapy with surfactant in RDS if patients
requires nCPAP of 6 cmH20 and an FiO2 over 0.3.
• This cut-off can be arbitrary, as current evidence is based on
observational studies - FiO2 requirements greater than 0.3 as a predictor
of respiratory failure and may not accurately reflect patient’s
oxygenation.
• It is challenging to identify newborns who will benefit from early
surfactant treatment (within the first 3 h of life), which is known to
decrease pneumothorax and BPD and to improve survival rates
01/05/2022 66
Aim of the study
To study if lung ultrasound allows an earlier surfactant therapy (within
the first 3 hours of life) compare to FiO2 and Chest X Ray
01/05/2022 69
Pie graph
representing the
proportion of
patients who
received early
surfactant
therapy
(within the first 3
h of life) in each
group
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Result
• Surfactant administration occurred earlier in the ultrasound group
than in the control group, with statistically significant differences: 1
h of life (IQR 1–2) vs. 6 h (IQR 4– 6.5), with p < 0.001.
• Patients in the ultrasound group had better oxygenation after
surfactant therapy, with lower FiO2 requirements and a better S/F.
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Conclusion
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Thank you
01/05/2022 73