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Oxygen in Neonates: Past, present and future….
Rebecca Sherlock MD, FRCPC Neonatologist/ Head of Paediatrics
Surrey Memorial Hospital
Disclosures
Honorarium from Drager for this talk
Such a small, important molecule…
• But only in physiologic quantities… • Hyperoxia has deleterious consequences
on many organs in the premature infant…
– The lungs – The eyes
Oxidative stress
• “Reactive oxygen species” cause oxidative stress by overwhelming the available antioxidants and causing tissue damage
• At the cellular level, free radicals oxidize
lipids, proteins, polysaccharides and damage DNA molecules
• In the preterm newborn, eyes, lungs
Oxygen free radicals and the retina
Oxygen free radicals and the lungs
• Reactive oxygen species target the vascular endothelial cells and the epithelial cells of the alveoli
• Antioxidant activity in the lungs is developed concomitantly with surfactant synthesis by Type II pneumocytes
• Imbalance between these leads to molecular damage in the alveoli
Controversies
Oxygen use in: Resusc Ongoing use Appropriate
saturation goals
Oxygen: The past….
The problem with oxygen….
1960s “if a little is good, a lot should be better”
– ROP surge
1970s Incubators designed that no more than
40% O2 could be delivered – Increase in deaths, CP
Oxygen: The present
Current day fears……
• Contribution of hyperoxia to …. – ROP – BPD – CANCER
• “it has been suggested that the most efficient way to limit childhood cancer is to reduce oxygen exposure during resuscitation at birth”
Attempts to prevent hypoxic damage while at the same time avoiding hyperoxia…..
The pyramid of evidence
Oxygen in resuscitation: Term • Systematic reviews
Saugstad et al, Neonatology, 2012 3 studies identified that looked at neurodevelopmental
outcomes (n=678) No difference in long-term outcomes Davis et al, Cochrane, 2009 5 studies that looked at mortality (n=1302) (24% prem) Reduced mortality in room air group RR 0.71 (0.54,
0.94) NNT 20 (12, 100)
Oxygen in Resuscitation
RCTs Wang et al,
Pediatrics, June 2008 • 2-center RCT of 41
preterm infants 23-32 weeks GA
• Protocolized approach to oxygen use in preterm newborns
Room air resusc failed
to achieve target O2 saturations….
Evidence for oxygen use at resuscitation of preterms
Oxygen: Resuscitation
• From Systematic reviews and RCTs – Enough evidence to change “consensus
guidelines” – NRP reflects room air resuscitation
“The risk:benefit for premature infants has not
yet been determined”
Oxygen: Ongoing O2 Use
Questions remaining to be answered: Restricted vs. liberal oxygen exposure for
preterm infants Early vs late discontinuation of oxygen in
preterm infants Gradual vs. abrupt discontinuation of oxygen in
preterm infants Oxygen saturation targets for preterm infants
Restricted vs. liberal oxygen exposure for preterm infants
• Systematic review (Cochrane) – Meta-analysis of 5 studies – Unrestricted oxygen led to increased CLD and
increased oxygen duration
BAD
Early vs late discontinuation of oxygen in preterm infants
• Systematic review (Cochrane) – One trial, n=99 – No difference in mortality, ROP overall – The trial did not look at early mortality, CLD or
growth and development
EQUIVOCAL
Gradual vs. abrupt discontinuation of oxygen in preterm infants
• Systematic review (Cochrane) – One trial, n=51 – Gradual discontinuation associated with
decreased risk of ROP
EQUIVOCAL
Oxygen saturation limits? • SUPPORT trial
– N=1316, 24 to 28 weeks GA – 85-89% vs 91-95% – No significant decrease in ROP or death BUT
increased mortality – In a subgroup, found a higher rate of intermittent
hypoxemia in the lower sat group – 18 to 22 month follow-up data showed no diff in
neurodev outcomes
We currently have no evidence to support any of the limits that we are using!
Oxygen: The present
• What do we really know? – Resuscitate term infants in room air, with O2
available – Too much O2 is bad for prems based on
physiology and oxygen free radicals.... – Too little O2 is bad for prems due to increased
mortality BUT
• How to limit it, measure it and stop it is unknown!
Oxygen: The Future
As Cochrane reviews always say……
MORE RESEARCH IS NECESSARY TO RECOMMEND ONE APPROACH
OVER ANOTHER
Protocol on Cochrane
• To determine whether higher or lower initial oxygen concentrations then titrated according to oxygen saturation targeting during the resuscitation of preterm infants at birth lead to improved short and long term mortality and morbidity.
Davis et al, 2012
RCT Protocol
• Resuscitation of very preterm infants with 30% vs. 65% oxygen at birth – Primary outcome is survival without BPD – N=200, <32 weeks GA
Rook et al, Trials, 2012
Future
• Biochemical manipulation of the oxidative load?
• Ongoing research into more accurate and precise oxygen saturation at the cellular or end organ level?
• Prevention of preterm birth?
Thank you very much!