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!