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Oxygen therapy for the premature infantRetinopathy of prematurity (ROP)
Teaching Evidence-based Practise15th September 2015
Kenneth TanMonash Newborn
the RITCHIE CENTRE for baby health researchthe RITCHIE CENTRE for baby health research
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Objectives
•Preterm infants definitions
•Complications of preterm birth, including ROP
•Early trials oxygen
•NeoPROM collaboration trials
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Preterm infant
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Med J Aust. 1951;2(2):48-50
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Campbell 1951
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IIII
IIIIIIIIII
MaculaMacula
Optic discOptic disc
33 99
1212 1212
33
6666
99
Right eyeRight eye Left eyeLeft eye
Ora Ora serrataserrata
ROP - ClassificationROP - Classification
IIIIII IIIIII
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Classification of ROP
• Staging:5 stages - describe abnormal vascular response. Most severe stage is used to determine the stage of the eye as whole.
Stage 1: Demarcation line Stage 2: Ridge
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Classification of ROP
• Stage 3: Extaretinal Fibrovascular Proliferation
• Stage 4: Partial Retinal Detachment
4a - Extrafoveal
4b – Foveal• Stage 5: Total Retinal
Detachment
Major cause of childhood blindness in developed world
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Retinopathy of Prematurity
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Clinical trials in the 1950s confirmed that restricting oxygen reduced the risk of eye damage, then called Retrolental Fibroplasia (RLF), and blindness
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History of oxygen use in preterm neonates
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Children's Hospital, Buffalo, NYAccessed via http://www.nei.nih.gov/rop/photos.asp
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Side-effects of oxygen Therapy
• Preterm infants lack a fully functioning antioxidant defence system (Frosali 2004)
•Oxygen rich environment
•Antioxidant defences
•Glutathione peroxidase, superoxide dismutase
•Other diseases of the preterm neonate where oxidative stress plays a role:
Lungs - BPD (Davis, 2002) Brain - PVL (Kakita et al, 2009)
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Reduced oxygen Therapy
•Less inspired oxygen (to target SpO2 <90%) may increase
•patent ductus arteriosus•pulmonary vascular resistance•apnoea•impair survival and neurodevelopment
Newburger N Engl J Med 1984, 310:1495-1499.Skinner JR, Arch Dis Child Fetal Neonatal Ed 1999, 80: F81-F87.Subhedar Arch Dis Child Fetal Neonatal Ed 2000, 82:F243-F247.
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Cost of preventing ROP
• For each case of RFLP by oxygen restriction prevented about 16 infants died or had cerebral palsy
• Competing goals of treatment
Kenneth CrossLancet 1973;2(7835):954–956
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Monitoring of oxygenation
•Monitoring paO2
•Levels of pO2 that is damaging to the retina 80 mmHgFlynn JT et al N Engl J Med 1992, 326:1050-1054.
•tcpO2
•Arterialised capillary bed
•Disadvantage that it heats the skin up (40 C)
•SpO2
•Introduced in 1980s
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History of oxygen therapy in preterm infants
•After trials in 1950s, very little study on oxygen therapy (Silverman 1980)
•Northern Neonatal Network (North of England)
•Newcastle, Middlesbrough et al
•Centres with 4 different SpO2 targets policy
•Problem with this was a studyShows association cannot determine cause-effect relationship
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Outcomes – Northern Neonatal Network
Arch Dis Child Fetal Neonatal Ed. 2001 Mar;84(2):F106-10
What type of study is this?
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NeOProM
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Aim
• To determine whether, in infants < 28 weeks gestation, targeting SpO2 85 – 89% versus 91 – 95% when in supplementary oxygen leads to a lower rate of death or disability at two years
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Target 88 – 92%
Alarm limits: upper - 94%lower – 86%
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Primary Outcome
• Death or major disability at two years corrected for gestationon Bayley III scales
• Secondary outcomes:– Retinopathy, chronic lung disease, PDA,
NEC, Sepsis, Growth
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Actual target 85-89% Actual target 91-95% (3% below displayed value) (3% above displayed value)
Study oximeter adjusted to display either 3% above or 3% below actual saturation for values between 85% - 95%. Outside that range the true
values are displayed.
Staff are asked to target display with masked study oximeter SpO2
88-92%
Lower group Higher group
Masking O2 saturation in BOOST II
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SUPPORT Trial
SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research NetworkN Engl J Med 2010; 362:1959-1969
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What about the other RCTs?
• Continue or stop RCT
• Data and safety monitoring committee of BOOST- Aus ANZ
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Stopping the RCT
Stenson B et al. N Engl J Med 2011;364:1680-1682.
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BOOST-II• In December 2010, a joint safety analysis of survival at 36
weeks' postmenstrual age was undertaken– 2315 infants in the U.K., Australian, and New Zealand trials
with the 1316 infants in the SUPPORT trial
• Investigators be told the results if the difference in 36-week survival between groups for all infants, or for those recruited after introducing the new calibration algorithm, exceeded 3 SE (equivalent to 99.73% CI, with P=0.003) (UK BOOST protocol)
Stenson et al N Engl J Med 2011; 364:1680-1682
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Implications for practise
• Main question: should we change current practise from 88-92% targetting to 91-95%
• Two NICUs (USA, UK) have already implementation this
• Most NICUs in Australia have changed practise to higher SpO2 target
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Take home message
• Meta-analysis
• Odd ratios
• Cohort study
• Randomised control trial (double blind)
• Individual patient meta-analysis