Oxygen in the delivery room: how much?

Ola Didrik Saugstad, MD, PhD

Department of Pediatric Research

University of Oslo

Norway

Oxygen Therapy of the Newborn

between

Skylla and Karibdis

Σκύλλα

Χάρυβδις

SaO2

FiO2 FiO2

PaO2

SaO2

SaO2

SaO2

Disclosure

OD Saugstad has received:

• An unrestricted grant from Chiesi Pharma AB

• Reseach grants from Laerdal Medical

World Map Before 1998Resuscitation of Newborn Infants

100% O2

Before

1998

1998: Resair 2 . Pediatrics 1998WHO Basic Newborn Resuscitation:Use air

Neonatal Mortality after 21% or 100% O2 resusctiation

10 studies incuding 2134 infants

Saugstad, Ramji, Soll, Vento. Neonatology 2008

Fetus Birth 1 5 10 min 7d 14d 28d Childhood

21% O2

PaO2

100% O2

PaO2

100% O2 free

radicals

Cerebral vasoconstriction

and brain inflammation

↑ pulmonary vascular reactivity

Myocardial damage

Acute renal injury

Childhod leukemia

21% O2 free

radicals

Lakshminrushimha S, Saugstad OD, J Perinatol 2016

Oxygen Management in the Delivery Room Has Changed Over 10 Years

• <2000: FiO2 100%

• 2000: FiO2 100%, RA if O2 is not available

• 2005: Air CAN be used for term infants

• 2010: Air SHOULD be used for term infants, oxygen should be used judiciously in preterm infants

• 2010: FiO2 should be adjusted to meet target preductal SpO2

Ressucitation World Map 2010-11?Term or Near term Infants

Low oxygen approach

ILCOR October 18th 2010

Unresolved question:

how to resuscitate very small babies?

Vento al, 2009

0,00

0,10

0,20

0,30

0,40

0,50

0,60

0,70

0,80

0,90

1,00

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 20 30

Time after birth (min)

FiO

2

60

100

140

180

220

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 20 30

Time after birth (min)

Heart

rate

(b

pm

)

Lox Hox

FIO2

HEART RATE

******

**

**

Esriq, Vento et al, 2009

High: 0.9Low: 0.3

< 29 weeks

Wang CL et al Pediatrics 2009

Resuscitation of preterm neonates <32 w using 21% or 100% oxygen.

High versus low iFiO2 preterm infants< 32 w GA

Updated review & meta-analysis.

High: 60-100% O2

Low: 21-30% O2

Relative risk meta-analysis plot (random effects)

0.01 0.1 0.2 0.5 1 2 5 10 100

Kapadia, 2013 0.77 (0.16, 3.59)

Aguar, 2013 0.44 (0.15, 1.26)

Kumar, 2012 0.39 (0.00, 3.96)

Rook, 2012 0.57 (0.22, 1.45)

Rabi, 2011 0.71 (0.10, 4.69)

Vento, 2009 1.48 (0.39, 5.61)

Wang, 2008 1.28 (0.14, 11.72)

See, 2008 0.80 (0.09, 7.35)

Lundstrøm, 1995 0.34 (0.08, 1.37)

combined [random] 0.62 (0.37, 1.04)

relative risk (95% confidence interval)

Mortality

Saugstad, Aune, Aguar, Kapadia, Finer, Vento, Acta Paediatr, 2014; 103:744-51

Oei JL, Ghadge A, Coates E, Wright IM, Saugstad OD, Vento M,Buonocore G, Nagashima T, Suzuki K, Hosono S, Davis PG, Craven P, Askie L, Dawson J, Garg S, Keech A, Rabi Y, Smyth J, Sinha S, Stenson B, Lui K, Hunter CL, Tarnow Mordi W; HOLISTIC (Higher Or Lower oxygen and Infant Saturation Targeting: International Collaboration) Study Group.

Acta Paediatr. 2016 Sep;105(9):1061-6

Clinicians in 25 countries prefer to use lower levels of

oxygen to resuscitate preterm infants at birth

Oei J et al Acta Paediatr. 2016 Sep;105(9):1061-6

Archives Dis Child Fetal and Neonatal Ed 2017

Starting FiO2 Levels Do not Influence Death in Preterm Infants

Hospital Death RR 0.99 95% CI 0.52-1.91)

Ju-lee Oei et al Archives Dis child Fetal and Neonatal Ed 2017

Secondary outcomes.

Ju Lee Oei et al. Arch Dis Child Fetal Neonatal Ed 2017;102:F24-F30

High or Low Oxygen for Delivery Room Resuscitation of Preterm

Infants below 29 weeks Gestation – a meta-analysis and systematic review

Updated metaanalysis

* Trend to increased mortality when iFiO2 21%

in the smallest babies

Oei JL, Vento M, Rabi J, Wright I, Finer N, Rich W, Kapadia V, Aune D, Rock D, Tarnow-Mordi W, Saugstad OD

ADCFN 2017;102:F24-F30

TORPIDO Patient recruitment.

Oei JL, Saugstad OD et al. Pediatrics 2017;139:e20161452

©2017 by American Academy of Pediatrics

Infants <32 w GA Randomized toAir or 100% O2

No difference in mortality for all babies

< 28 w Mortality RA: 17% 100% O2: 6%

RR 3.9 (95%CI 1.1-13.4)

Hospital OutcomesAir

(n = 144)100% O2 (n = 142)

P/OR (95% CI)

Respiratory support (days)*

11 (3, 39) 22 (5, 48) 0.01

O2 (days)* 18 (2, 55) 28 (2, 61) 0.54

BPD 34 (24%) 40 (28%) 1.3 (0.7-2.2)

Dexamethasone 8 (6%) 8 (6%) 1.0 (0.4-2.8)

ROP (>grade 3) 4 (3%) 8 (6%) 2.1 (0.6-7.2)

PDA 37 (27%) 40 (29%) 1.1 (0.71-1.9)

IVH>grade 3 2 (1%) 6 (4%) 3.2 (0.6-15.9)

NEC 5 (4%) 1 (1%) 0.2 (0.02-1.7)

*median, 1st and 3rd quartiles, exclude diseased infants. Abbreviations: HFOV: high frequency oscillatory ventilation, BPD: bronchopulmonary dysplasia, ROP: retinopathy of prematurity, PDA: patent ductus arteriosus, IVH: intraventricular hemorrhage, NEC: necrotizing enterocolitis

Oei JL, et al, Pediatrics 2017

POST HOC- Hypothesis Generating OnlyNeonatal and Hospital Mortality

• There was an unexpected increase in neonatal and hospital mortality in infants < 28 w GA who were initially resuscitated with air.

All infants <28 weeks 28-31 weeks

RA 144

100% O2142

RA46

100% O253

RA98

100%O289

Neonatal death 12 (8%) 5 (4%) 8 (17%) 3 (6%) 4(4%) 2 (2%)

POR (95%CI)

0.130.40 (0.14-1.17)

0.110.28 (0.07-1.15)

0.690.54 (0.09-3.02)

Hospital death 15 (10%) 5 (4%) 11 (24%)

3 (6%) 4 (4%) 2 (2%)

POR (95%CI)

0.030.32 (0.11-0.89)

0.0180.19 (0.05-0.74)

0.680.54 (0.09-3.02)

Oei JL, et al, Pediatrics 2017

Gestational age weeks

OR

/RR

0

10

20

> 31 28-31 < 28

0.69(0.54-0.88)

1.9(0.33-11.1)

5.3(1.35-20)

High Vs Low FiO2 for Newborn ResuscitationOR/RR vs Gestational Age

Saugstad OD, 2016

1-

OR/RR < 1 favours air

OR/RR > 1 favours supplemental oxygen

Soraisham AS et al. J Perinatol 2017;00:1-7

Soraisham AS et al. J Perinatol 2017;00:1-7

Adjusted OR for Outcome - Room Air as reference

Outcome Intermediate 100% O2

Primary Death or NDI 1.01 (0 .77-1.34) 1.03 ( 0.78-1.35)

Death or severe NDI 1.14 (0.82-1.58) 1.22 (0.90- 1.67)

SecondaryDeath 1.03 (0.68 -1.56) 0.93 ( 0.63-1.37)

NDI 1.00 (0.74- 1.35) 1.08 (0.81-1.45)

Severe NDI 1.22 (0.78-1.91) 1.57 (1.05-2.35)

Language score < 70 1.54 (0.89-2.67 1.73 (1.02-2.91)

No significant differences: CP, Cognitive score < 85, Cogntive score < 70, Visual impairmen , Hearing impariment

Soraisham AS et al. J Perinatol 2017;00:1-7

Use of 100% oxygen at the initiation of DR resuscitation was associated with increased odds of severe NDI at 18-21 months CA among survivors

The correct oxygen concentration to initiate resuscitation of extremely preterm infants has yet to be determined and future randomized trials should focus on the assessment of long-term neurodevelopmental outcomes.

Soraisham AS et al. J Perinatol 2017;00:1-7

Canadian network 2017

Oei, J L, Finer N, Saugstad OD, Wright I, Rabi Y, Tarnow-Mordi W, Rich, W, Kapadia V, Rook D, Vento M. Pediatrics, 2017

Oie J et al Archiv Dis Childhood FN Ed in prep

Outcomes of Babies Who Do Not Reach SpO2 80% at 5 minutes

OR 4.5 (2.1-9.8)OR 2.4 (1.3-4.4)

• Almost 50% of infants < 32 weeks do not reach SpO2 study targets at 5 minutes of age

• Those who do not reach SpO2 80% by 5 minutes are at increased risk of death and IVH

• Larger well designed controlled studies of outcomes of infants randomized to different targets are needed to review current oxygen management strategies

Recommendations of FiO2 and Resuscitation of Newborns

Term and near term infantsOR for mortality 0.69 ( 0.54-0.88) in favour of air

Start with air - adjust according to SpO2

Preterm 28-31 weeks GA

OR for mortality 1.9 (0.33- 11.1)Start with 21-30% - adjust according to SpO2

Preterm < 28 weeks GA

OR for mortality 5.3 (1.35-20) Don’t start with 21%

Start with 30% - adjust according to SpO2

Until more data are available from randomized studies

Aim at a SpO2 of 80-85% within 5 min

OD Saugstad 2017

Thank you so much for your attention!