Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03706586 |
| Other study ID # |
00084090 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
November 1, 2018 |
| Est. completion date |
March 31, 2019 |
Study information
| Verified date |
September 2021 |
| Source |
University of Alberta |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Preterm birth, or birth before 37 weeks' gestation, is increasingly common, occurring in 8%
of pregnancies in Canada. Preterm birth is associated with many health complications,
particularly when the birth happens before 29 weeks' gestation. At this gestational age, the
lungs are not fully developed and it is not uncommon for infants to have problems breathing
at the time of birth. One complication that can arise is when an infant stops breathing and
needs to be resuscitated. When preterm babies need to be resuscitated doctors must take
special care because of the small infant size and the immaturity of the brain and lungs.
Oxygen is used to resuscitate babies who need it, but unfortunately there is disagreement
about the best oxygen concentration to use. Oxygen concentration is important because both
too much and too little oxygen can cause brain injury. Our research aims to fill this
knowledge gap by participating in an international clinical trial to compare the effects of
resuscitating babies less than 29 weeks' gestational age with either a low oxygen
concentration or a high oxygen concentration. The oxygen concentrations have been selected
using the best available knowledge. During the first 2 months of the clinical trial we will
treat all babies less than 29 weeks' gestation who need resuscitation with the oxygen
concentration we are randomly assigned. Then in the next 2 months, we will treat babies using
the other oxygen concentration. After the trial, we will determine whether the babies
resuscitated with low oxygen or those resuscitated with high oxygen have better survival and
long-term health outcomes. Our research fills a critical knowledge gap in the care of
extremely preterm babies and will impact their survival both here in Canada and
internationally.
Description:
Purpose: Over the last 10 years, recommendations regarding the ideal level of oxygen for
resuscitation in preterm infants have changed from 100%, down to low levels of oxygen (<30%),
up to moderate concentration (30-65%). In addition, in 2010, oxygen saturation targeting was
recommended as standard of care and this contributed to a change in clinical practice as
clinicians were more likely and comfortable to start resuscitation at either 21% (room air)
or titrated levels of oxygen such as 30-40%. When the guidelines were again revised in 2015,
the International Liaison Committee on Resuscitation (ILCOR) acknowledged that a critical
knowledge gap continued to exist for the resuscitation of the preterm infants <37 weeks,
highlighting the need to provide more concrete guidelines. This leaves clinicians in a
challenging position. Despite the advances that have been achieved in perinatal and neonatal
care, neonates are still vulnerable to the consequences of the oxidative effects from
hyperoxia as well as the deleterious effects from hypoxia. A large, multi-centre
international trial of sufficient sample size that is powered to look at safety outcomes such
as mortality and adverse neurodevelopmental outcomes is required to provide the necessary
evidenced to guide clinical practice with confidence.
Hypothesis: the null hypothesis for this study is that the incidence of mortality or abnormal
neurodevelopmental outcomes at 18-24 months corrected age will be no different by using
either higher initial oxygen concentration of 60% compared to using lower initial oxygen
concentration of 30% for resuscitation of preterm infants of 23 0/7- 28 6/7 weeks gestation.
Justification:
The use of supplementary oxygen may be crucial, but also potentially detrimental to premature
infants at birth. High oxygen levels may lead to organ damage through oxidative stress, while
low oxygen levels may lead to increased mortality. Excess oxygen exposure during the early
post-birth period is associated with many complications and morbidities of preterm birth.
Preterm infants have lower levels of anti-oxidant pathways consistent with their expected
fetal environment of low oxygen exposure. Excess of oxygen free-radicals in infants
intrinsically deficient in enzymatic antioxidants and non-enzymatic antioxidants may
contribute to these morbidities. Pulmonary oxygen toxicity, through the generation of
reactive oxygen and nitrogen species in excess of antioxidant defenses, is believed to be a
major contributor to the development of bronchopulmonary dysplasia (BPD). Using lower oxygen
concentrations at birth results in decreased oxidative stress markers and a decrease risk of
developing BPD compared to higher oxygen concentrations. Other organs that may be damaged by
such oxidative stress include kidneys, myocardium and the retina.
There is equally growing evidence that using lower oxygen concentrations will lead to lower
oxygen saturation levels and bradycardia, which may lead to increased rates of mortality in
this vulnerable group of infants. An individual patient analysis of clinical trials reported
that 46% of preterm infants resuscitated with initial low oxygen concentration did not reach
SpO2 of 80% at 5 min. This was associated with increased risk of major intraventricular
hemorrhage (IVH), and an almost five times higher risk of death in this vulnerable group of
infants. These data provide a warning note for the use of higher vs. lower initial oxygen
concentration during delivery room resuscitation. As we proceed in determining a safe range
for resuscitation of ELBW/ELGA infants, it is highly likely that the optimum level of oxygen
concentration is likely between the two extremes of 21% and 100%.
Objectives: To determine whether initial resuscitation of preterm neonates with 60% versus
30% oxygen in the delivery room is feasible.
Research Method/Procedures: This will be a cluster crossover design, unmasked randomized
controlled trial (RCT) comparing two oxygen concentrations at initiation of resuscitation.
Infants will be placed on the resuscitation table with the initial steps of resuscitation
carried out as per standard of care at each centre which usually follows current
resuscitation guidelines. All centres will make every effort to establish adequate lung
expansion using CPAP or positive pressure ventilation as needed. Enrolled infants will have a
pulse oximeter sensor placed on the right arm in the first minute of life. Their
resuscitation will be initiated with an oxygen concentration of 30% or 60% depending on the
randomization sequence at the centre at the given time. Infants in the 30 % group will remain
in 30% oxygen until 5 min of age unless the infant's heart rate (HR) remains 100/min or less
and does not show a tendency towards progressive increase before reaching 5 min of age or
infant needs chest compression and/or epinephrine. No alteration in oxygen concentration will
be made for an infant who is responding to resuscitation efforts with HR progressively
increasing as minutes go by. At 5 min of age, the clinical team will assess oxygen
saturation. If the saturation is less than 85%, oxygen should be increased by 10-20% every 60
sec to achieve saturations of 85% or greater or a saturation of 90-95% at 10 min of age. If
saturations are greater than 95% at or before 5 min of age, oxygen should be decreased
stepwise (every 60 sec) with an aim to maintain saturations of 85% or greater during 5-10 min
of age or 90-95% at and beyond 10 min of age. The procedure for infants in the 60% group will
be identical. The intervention duration for the trial will be the first 5 min after birth
followed by initial monitoring/action for the next 5 min where titration in oxygen
concentration will be made to achieve stability making a total of 10 min for study
intervention. Titration of oxygen before 5 min after birth will only be made if the infant
remains bradycardic (HR less than 100) and does not show a tendency towards a sustained
increase in HR or if the oxygen saturation exceeds 95%. If the infant does not respond to
ventilation with increasing HR in the first 5 min after birth, steps to ensure effective
ventilation should be done before oxygen is titrated.
Plan for Data Analysis:
Data will be analysed as intention-to-treat. Data will be compared using Student's t-test for
parametric and Mann-Whitney U test for nonparametric comparisons of continuous variables, and
Fisher exact for categorical variables. The data will be presented as mean (standard
deviation (SD)) for normally distributed continuous variables and median (interquartile range
(IQR)) when the distribution will be skewed. P-values will be 2-sided and p<0.05 will be
considered statistically significant. Statistical analyses will be performed with SPSS
Statistics for Macintosh, Version 27.0 (Armonk, NY: IBM Corp).
