Titrating oxygen needs in the delivery room in extremely preterm infants.
Máximo Vento MD PhD Professor of Pediatrics
Division of Neonatology & Health Research Institute University and Polytechnic Hospital La Fe
(Valencia; Spain)
XIX International Symposium on Neonatology (Sao Paulo 2013)
Scheme
• Basic concepts:
– Oxygen & oxidative stress & biomarkers
– Arterial oxygen saturation
• Oxygen in the fetal life & in the fetal-to-neonatal transition.
• Is it feasible to use lower FiO2 in preterm infants?
• Defining a reference range for postnatal SpO2.
• High versus low iFiO2: updated review & meta-analysis.
• Optimizing oxygenation in the DR in preterm.
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Basic concepts
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Glucose PEP
PYRUVATE
PYR
AcCoA
2ATP
TCA
SDH
CIII
CV
CI C IV UQ
C
CO2
CO2 H+
ADP
36ATP ATP synthase
NADH
NADH NAD+
H+ H+ H+
O2 H2O
Δψm
Fatty acids
Amino acids
PDH
LACTATE
Mitochondria
Cytoplasm 4 SAO PAULO 2013
Glucose (C6) Palmytic acid (C16)
Glycolysis 2 0
Krebs’ Cycle 2 8
Electron Transport Chain
32-34 121
TOTAL ATP formed 36-38 129
Aerobic vs. Anaerobic Metabolism: energetic balance
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+ + +
+
+ + +
+
+ + +
+
+ + +
+
Ground state di-Oxygen
Dröge W Physiol Rev 2002 6 SAO PAULO 2013
·O· ·O·
O2¯•
H2O2
OH•
O2
e¯
e¯
e¯
e¯
Superoxide
Hydrogen peroxide
Hydroxyl
Stepwise reduction of di-oxygen
4e¯
Adopted from Maltepe E et al Pediatr Res 2009
NO•
ONOO¯
Peroxynitrite
Fe++
7 SAO PAULO 2013
H2O + O2 GPx; CAT; PRx
PRx
GSH; TRx; CysSH
SOD
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Free radicals
Signaling molecules -Smooth muscle relaxation -Immunological function -EPO and HIF factors -Control of respiration
Damage cell constituents -DNA/RNA -Lipids -Proteins -Glycids Redox regulation
(GSH/GSSG) (L-cys/Cys-SS)
TRX-SH/TRX-SS
Oxygen saturation as measured by arterial pulse oximetry (SpO2)
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Wavelength absorption and transmission for Hb and HbO2
Sola A et al An Pediatr 2005
Absorption of light when passing through tissue. Without motion the only variable
light absorption is by the arterial pulsatility
How does pulse oximeter function?
10
SAO PAULO 2013 Richmond & Goldsmith Clin Perinatol 2006
Relationship between paO2 and SpO2
11
Pulse oximetry
• CONCEPTS
– Arterial oxygen saturation (SpO2) represents the amount (g) of available Hb which are carrying O2.
– O2 content in blood: % O2Sat x [Hb/g] x 1.36 (ml/dl)
– Supply of O2 to tissue depends also on cardiac output and regional blood flow.
– Confidence limits of SpO2 is ±3% for SpO2>70% and greater for SpO2
Pulse oximetry
• OPTIMIZING FUNCTIONALITY
– Adequate training
– Connecting the probe first to the patient and then to the oximeter (O’Donnell C et al 2007)
– Using shorter averaging intervals (2 sec), maximal sensitivity, and PO’s with motion artifact rejection (Rich W et al Clin Perinatol 2010)
– Setting the probe on the right wrist (pre-ductal)
– Protecting the probe from the light
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Oxygen in utero and in the fetal-to-neonatal transition
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8 10 12 14 16 20 24 28 32 36
100%
80%
60%
40%
20%
50%
Inte
rvill
ou
s o
xyge
n t
ensi
on
(m
m H
g)
Gestational age (weeks)
Oxygen saturation in utero during fetal development
Schneider H. Respir Physiol Neurobiol 2011
0
2
4
6
8
10
12
14
16
Non laboring Laboring
Veno-arterial difference (ml/dl) Fetal oxygen delivery (ml/min/kg)
Fetal oxygen uptake (ml/min/kg)
Umbilical cord analysis of parameters of oxygen metabolism
Acharya G et al SJOG 2009
NS
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Forkner et al Anesthesiology 2007
Maternal oxygen administration: fetal response
p
Khaw KS et al BJ Anaesth 2002
Maternal oxygen administration: fetal response.
Um
bili
cal v
eno
us
paO
2 (
kPa)
8
7
6
5
4
3
10 20 30 40 50
Maternal arterial pO2 (kPa)
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Khaw KS et al BJ Anaesth 2002
Maternal oxygen administration: fetal response
MDA 8-ISOPROSTANES
19 SAO PAULO 2013
Is it feasible to use use lower initial iFO2 in extremely low birth weight
infants?
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PILOT STUDIES USING LOWER OXYGEN IN PRETERM (n= 506)
Reference Year Design N iFIO2 Aim Conclusions
Harling AE et al 2005 RCT; < 31 wks.
No blender; no P-Ox
No TSpO2
52 50 vs. 100% Reduce lung
inflammation
No differences in lung
inflammation. Feasible to
resuscitate with lower FIO2
Dawson JA et al 2007 Cohort study; < 30
wks
Blender; P-Ox;
TspO2
43 21% vs. 100% Feasibility study O2 supplementation needed
in room air group. Feasible
to resuscitate with lower
FIO2 if titrated.
Stola A et al 2009 Cohort vs practice
plan
< 1500 g.
Blender; P-Ox;
TSpO2
100 Variable vs.
100%
Feasibility study
Reduce paO2 at
admission to NICU
Feasible to initiate with
lower FIO2 if titrated.
Change associated with
lower paO2 at admission to
NICU.
Rabi J et al 2009 RCT; < 32 wks.
Blender; P-Ox;
TSpO2
106 100 % vs.
100% + titrated
vs. 21% +
titrated
Feasibility study
Target SpO2 85-92%
Both groups needed similar
FIO2 to attain targeted
saturation.
Escrig R et al
Vento M et al
2008
2009
RCT; ≤ 28 wks.
Blender; P-Ox;
TSpO2
120 30% vs. 90% Feasibility study
Target SpO2 85%
Oxidative stress
Inflammation
Feasible to initiate with
lower FIO2 with less
oxidative stress and
inflammation.
Wang CL et al 2008 RCT; < 32 wks.
Blender; P-Ox;
TSpO2
41 21% vs. 100% Feasibility study
Target SpO2 70-80%
No feasible to initiate with
room air; O2 supplements
needed.
Ezaki et al 2009 RCT; ≤ 29 wks.
Blender; P-Ox;
TSpO2
44 Titrated vs.
100%
Oxidative stress Increased oxidative stress in
100% group.
Vento M JNPM 2010 21 SAO PAULO 2013
Relevant features of oxygen studies in preterm
• Use of preductal pulse oximetry
• Target saturation at specific postnatal timing
• Use of air/oxygen blender to adjust FiO2 according to SpO2 readings.
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Resuscitation Pilot Studies in Extremely Preterm Infants Neonatal Research Group HUiP La Fe (Valencia)
• 2 randomized controlled clinical trials (nT =120
• Inclusion ≤ 28 weeks gestation needing active maneuvers to achieve successful adaption.
• DR management
– Blender randomly assigned to FiO2 30% or 90%
– Preductal pulse oximetry
– Adjustments according to HR, SpO2, reactivity
– Ventilation strategies according to S.E.N. guidelines 2007
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Low Oxygen
(n=56)
High Oxygen
(n=64)
Gestational age (weeks) , mean ± standard deviation 26.0 ± 1.5* 26.3 ± 1.3*
Birth weight (grams), mean ± standard deviation 854.7 ± 170.1* 901.7 ± 195.4*
Gender, n
Male
Female
14
23
18
23
Multiple birth, n 11 9
Prenatal corticosteroid therapy (full schedule), n (%) 36 (97.2%) 38 (92.7%)
Type of Delivery, n
Vaginal (percentage)
Cesarean section (%)
18 (48.6%)
19 (51.4%)* 17 (41.4%)
24 (58.6%)*
Cord blood pH at birth 7.05 ± 0.9* 7.09 ± 1.1*
Apgar score median (interquartile range)
1 min
5 min
5 (2-7)* 8 (5-9)
6 (2-8)* 8 (5-9)
Received supplementary oxygen during resuscitation, n (%) 32 (86.5%)** 34 (82.9%)**
Tracheal intubation in the Delivery Room, n (%) 21 (56.7%)** 25 (60.9%)**
Breathing 21% Oxygen at arrival to the NICU, n (%) 28 (75.6%)* 23 (56.0%)**$
POPULATION & DR MANAGEMENT
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FIO2 HEART RATE
** ** **
** **
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□ Low Oxygen (initial FiO2 : 30%)
▲High Oxygen (initial FiO2: 90%)
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◊ Low Oxygen (initial FiO2 : 30%) ▲High Oxygen (initial FiO2: 90%)
**
##
#
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O-tyr/Phenyl ratio 8oxdG/2dG ratio
**
**
**
**
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■ Control ; □ Hox; ▲ Lox
Isofurans
**
**
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◊ Control ; □ Hox; ▲ Lox
HYPEROXIA DERIVED OXIDATIVE STRESS MARKERS ASSOCIATED WITH BPD
0
40
80
120
160
BPD NO BPD
GSSG day 3 Iso F day 7
12.0
9.0
6.0
3.0
GS
SG
(n
g/m
l)
Iso
Fu (n
g/m
g d
e c
rea
tinin
e)
** **
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HYDROXYL RADICAL DERIVED OXIDATIVE STRESS MARKERS
ASSOCIATED WITH BPD
0
5
10
15
20
BPD NO BPD
O-tyr/phenyl day 7 8oxodG/2dg day 7
40.0
30.0
20.0
10.0
O-t
yr/
Ph
en
yl 8
-ox
od
G/2
dG
** **
31 SAO PAULO 2013
Defining the reference range for SpO2 in term and preterm infants
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25
50
75
100
Term fetal-to-neonatal transition: Arterial partial pressure of oxygen (paO2)
IU TRANSITION POST-NATAL
Vento M et al J Pediatr 2003
33
mmHg
Pulse oximetry in the first minutes of life (term newborn)
Vento M & Saugstad OD 2010
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0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16 18 20
Time after birth (min)
Pre
du
ctal
Sp
O2
(%
) SpO2 in ELGA neonates ≤ 28 weeks gestation (n=29)
Vento M & Saugstad OD SFN M 2010.
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SpO2 polynomial adjustment curve (± std) in “control” ELGA neonates (≤ 28 weeks gestation) (n=29).
Vento M, Saugstad OD SFNM 2010 SAO PAULO 2013
36
Data acquisition system
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Method
• Combined pulse oximetry data from three data sets
• Dawson JA (unpublished) n=230
• Kamlin et al J Pediatr 2006 n=175
• Vento M (unpublished) n=20 (≤ 28 weeks gestation)
• Pre-ductal sensor location
• 2 second averaging, maximum sensitivity
• Masimo Radical®
Dawson JA et al Pediatrics 2010 SAO PAULO 2013
38
JA Dawson O Kamlin (and Jr!)
Data set characteristics
160 (34%) 308 (66%)
Dawson Ja et al Pediatrics 2010 SAO PAULO 2013
39
01
02
03
04
05
06
07
08
09
01
00
Oxyge
n s
atu
ratio
n (
%)
1 2 3 4 5 6 7 8 9 10minutes from birth
10-90th centile median
Term Neonates > 37 weeks gestation
Dawson Ja et al Pediatrics 2010 SAO PAULO 2013 40
01
02
03
04
05
06
07
08
09
01
00
Oxyge
n s
atu
ratio
n (
%)
1 2 3 4 5 6 7 8 9 10minutes from birth
10-90th centile median
Preterm < 37 weeks gestation
Dawson Ja et al Pediatrics 2010 SAO PAULO 2013
41
Use of centiles in the delivery room
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How could SpO2 centiles be used to inform decision making in the DR?
• To date centile chart provides the best target range during resuscitation.
• For any given centile (e.g.: 50%) this percentage of normal babies (50%) will have an SpO2 below this level.
• If the centile chosen as target is too high, a great percentage of babies will unnecessarily receive oxygen supplementation.
• If the centile chosen is too low, babies could easily be exposed to hypoxemia.
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Suggested level for administration of oxygen0
10
20
30
40
50
60
70
80
90
100
Oxyg
en
sa
tura
tio
n(%
)
0 1 2 3 4 5 6 7 8 9 10
Minutes after birth
10th 25th 50th 75th 90th
How could SpO2 centiles be used to inform decision making in the DR?
Suggested level for administration of oxygen0
10
20
30
40
50
60
70
80
90
100
Oxyge
n s
atu
ration
(%)
0 1 2 3 4 5 6 7 8 9 10
Minutes after birth
10th 25th 50th 75th 90th
Suggested level for administration of oxygen0
10
20
30
40
50
60
70
80
90
100
Oxyge
n s
atu
ration
(%)
0 1 2 3 4 5 6 7 8 9 10
Minutes after birth
10th 25th 50th 75th 90th
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The Transitional Oxygen Tracking System (TOTS)
NN Finer & W Rich & Tina A Leone (UCSD; San Diego; USA)
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25
35
45
55
65
75
85
95
0 2 4 6 8 10 12 14 16 18 20
Pre
du
cta
l S
pO
2 (
%)
Time after birth (min)
Titration of FiO2 against measured SpO2
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Courtesy of NN Finer & W Rich (San Diego; USA)
TRANSITIONAL OXYGEN TRACKING SYSTEM
50%
10%
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Courtesy of NN Finer & W Rich (San Diego; USA)
TRANSITIONAL OXYGEN TRACKING SYSTEM
Courtesy of NN Finer & W Rich (San Diego; USA)
FiO2 adjustments in 10% intervals according to oximeter readings
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Copyright ©2010 American Academy of Pediatrics
Kattwinkel, J. et al. Pediatrics 2010;126:e1400-e1413 No Caption Found
49 SAO PAULO 2013
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Oxygen saturation in preterm with CPAP + air Comparison with Dawson’s nomogram
Vento M et al ADC FNE 2012
What initial FiO2 is best for ELGA neonates in the delivery room?
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High vs. low iFiO2 : systematic review
• 6 Studies randomized or “quasi” randomized controled trials including 484 preterm newborn infants were identified.
• iFiO2 50%
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Brown JVE et al PLoS ONE 2012
• Primary outcomes
– Mortality before hospital discharge.
– Neurocognitive development at >12 m
– Disability classification and results of cognitive and educational evaluation at > 5 years of age.
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Brown JVE et al PLoS ONE 2012
High vs. low iFiO2 : systematic review
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Brown JVE et al PLoS ONE 2012
Study (year)
Place Method Participants Comparison
Harling 2005 Liverpool RU RC
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Brown JVE et al PLoS ONE 2012
High vs. low iFiO2 : systematic review
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Brown JVE et al PLoS ONE 2012
SECONDARY OUTCOMES N= assays (participants) RR
Tracheal intubation 3 (225) 0.97 (0.72, 1.29)
Surfactant reposition 3 (188) 1.03 (0.68, 1.58)
Reaching SpO2 at (min):
3 min 1 (106) 0.42 (0.10, 1.83)
5 min 2 (184) 0.94 (0.80, 1.11)
10 min 3 (231) 0.96 (0.84, 1.11)
EPC/DBP 3 (223) 0.86 (0.62, 1.18)
ROP 3 (199) 0.68 (0.24, 1.96)
NEC 3 (199) 1.74 (0.42, 7.20)
IPVH- GRADES III/IV 4 (240) 1.50 (0.71, 3.15)
High vs. low iFiO2 : systematic review
• CONCLUSIONS
– There is a tendency towards reduction in mortality (20%) in preterm with iFiO2
Optimizing oxygenation of ELBW infants in the delivery room:
practical approach!
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Optimizing oxygenation in ELBW infants
• Place preductal PO2 sensor (60-90 sec)
• Start in 21-40% FiO2 with adequate flow (4-8 l/min) and always use an air/oxygen blender.
• Aerate lungs to promptly achieve Functional Residual Capacity (FRC)
– Continuous positive pressure 4-6 cmH2O
– PIP 20-25 / PEEP 4-5 cmH2O
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SAO PAULO 2013 60 Fuchs H et al Neoreviews 2012
Vento M editor: Non-invasive ventilation in the DR: NeoReviews 2012
Optimizing oxygenation in ELBW infants
• At 90s review the infant’s HR, SpO2 and breathing efforts
– If the baby is breathing, or is well ventilated, and HR is rising, and SpO2 > 10th OXYGEN is not required.
– If O2 is needed, FiO2 should be titrated against SpO2 to be kept within established centiles.
– SpO2 < 10th and/or HR is not rising or continues to fall increase FiO2 until SpO2 fits within centiles.
– Wait at least 15 sec after each change and be sure the mask is well placed (use colorimetric assessment??)
– If SpO2 > 90th reduce FiO2.
• Continue titrating FiO2 according to infant’s response. SAO PAULO 2013
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PRETERM DELIVERY
Good responder
PROFILE >27 wks female
HR response +++ Cry +
Activity + A. Steroids +
Uncertain
PROFILE 25/0-26/6 wks/d
male/female HR delayed response Weak cry; high pitch Scarce movements
A. Steroids +
Bad responder
PROFILE
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Neonatal Research Group University & Polytechnic Hospital La Fe
(Valencia; Spain)