Professor Sunil Sinha MD PhD FRCP FRCPCH

Professor of Paediatrics & Neonatal Medicine

University of Durham
James Cook University Hospital
Middlesbrough, U.K.
Outline
• Introduction
• Fetal oxygen saturation
• PaO2 v Oxygen saturation
• Pulse oximetry and outcomes in <28 weeks
• Other Trials (STOP-ROP, BOOST, others)
• The way forward
 Introduction

Oxygen
• one of the most commonly used drugs
in the neonatal intensive care unit

• an integral part of all the respiratory

support
 Introduction

Goal of Oxygen therapy:

• to achieve adequate delivery of oxygen
to the tissues without creating oxygen
toxicity
Acid-Base Haematological Data (Fetus)

Mean CI
pH 7.338 7.317 – 7.359
pO2 (kPa) 3.26 2.71 – 3.81
(mm Hg) 24.5 20.2 – 28.5
pCO2 (kPa) 5.55 5.04 – 6.06
Base(mmol/l) -3.4 -13 – 0

Nicolini et al. Lancet 1990;336:768-72

 Oxygen tension (mm Hg)

Fetal
haemoglobin
(HbF)

Adult
haemoglobin
Oxygen saturation (%)

(HbA)

Oxygen tension (kPa)

Oxyhaemoglobin dissociation curve for fetal and adult haemoglobin

 Oxygen Monitoring
• Continuous (Non-invasive)
- Transcutaneous PO2
- Pulse Oxygen Saturation
• Continuous (Invasive)
- Intra-arterial Monitoring
- PaO2
- Blood gas (Paratrend)
• Intermittent
A cohort study of transcutaneous oxygen
tension and the incidence and severity of ROP
Flynn JT, Bancalari E, Snyder ES, et al. N Engl J Med 1992;
326 : 1050-54.

• Observational study
• 101 premature infants (b.w. 500-1300g)

• Conclusion: association between the incidence

and severity of ROP and the duration of exposure
to arterial oxygen levels of 80 mmHg or higher,
measured transcutaneously
Hay et al 1987
Hay et al 1987
 Comparison of 125 paired
measurements of transcutaneous
arterial oxygen saturation (Stca02)
and arterial oxygen tension
(PaO2). The fitted mean curve
±2SD is shown

Whitelaw et al 1987
 Pulse oximetry, severe retinopathy,
and outcome at one year in babies of
less than 28 weeks gestation
Tin W, Milligan DWA, Pennefather PM, Hey E
Arch Dis Child 2001; 84: F106-110
 ALARM LIMITS FOR OXYGEN SATURATION
vv
THRESHOLD
THRESHOLD R.O.P.
R.O.P.
50%

Proportion of 40%
babies developing
threshold
retinopathy (and 30%
95% confidence
intervals)
20%

10%

0%
70% 80% 90% 100%
Limits within which oxygen saturation was allowed to vary
ONE YEAR SURVIVAL IN BABIES BORN BEFORE 28 WEEKS

60

50

One year 40
survival
rate
30
(%)

20

10

0
70-90 84-94 85-95 88-98
Alarm limits for O2 saturation (%)
CEREBRAL PALSY AMONGST SURVIVORS IN BABIES
BORN BEFORE 28 WEEKS

20

15
C.P.
amongst
survivors
(%) 10

0
70-90 84-94 85-95 88-98
Alarm limits for O2 saturation (%)
Comparison between one year survivors
Patient characteristics

Oxygen saturation limits 88- 98% 70 - 90%

Number of one year survivors 65 64

65
Gestation (weeks ) - median 26.4 27.1
- I.Q.R. 25.8 - 27.3 26.2 - 27.3

Birth weight - median 910 940

- I.Q.R. 810 - 1018 855 - 1074
Male sex % 55 46
 TARGET RANGE FOR OXYGEN SATURATION
vv
THRESHOLD
THRESHOLD R.O.P.
R.O.P.
50%

Proportion of 40%
babies developing
threshold
retinopathy (and 30%
95% confidence
intervals)
20%

10%

0%
70% 80% 90% 100%
Limits within which oxygen saturation was allowed to vary
 ALARM LIMITS FOR OXYGEN SATURATION
vv
VENTILATION
VENTILATION
100

88 - 98%, mean 27 d
70 - 90%, mean 14 d
75
Proportion
still being
ventilated
(%) 50

25

1 2 3 4 5 6 7 8 9 10
Duration of ventilation (weeks)
 ALARM LIMITS FOR OXYGEN SATURATION
vv
OXYGEN THERAPY
OXYGEN THERAPY
100

Proportion 88 - 98%, mean 78 d

still 75 70 - 90%, mean 44 d
requiring
additional
02 (%)
50

25

0 2 4 6 8 10 12 14 16 18 20 22 24
Duration of oxygen therapy (weeks)
 CHANGE
CHANGE IN
IN WEIGHT
WEIGHT CENTILE
CENTILE FOR
FOR BABIES
BABIES OF
OF 23-25
23-25
WEEKS
WEEKS GESTATION
GESTATION BETWEEN
BETWEEN BIRTH
BIRTH AND
AND DISCHARGE
DISCHARGE
FROM
FROM HOSPITAL
HOSPITAL
2.5 2.5 2.5 2.5
99th C
2 2 2 2

1 1 1 90th
1 C
Weight as a
standard
deviate score 0 0 0 0 C
50th

-1 -1 -1 -1
10th C

-2 -2 -2 -2
1st C
-3 -3 -3 -3

-4 B D -4 -4 B D -4
Oxygen saturation limits 70 - 90% Oxygen saturation limits 88 - 98%
Early oxygen exposure and outcome at 10 years in
babies of less than 28 weeks gestation
Bradley S, Anderson K , Kelly T, Fritz S and Tin W (PAS 2004)

Aim:
• To compare the cognitive, adaptive and
behavioural performance in two groups

Low Saturation v High Saturation

Target 80-90% Target 94-98%
 Results

• Number of survivors - 124

• Health & Education information - 123 (99%)

• Full assessment - 119 (96%)

 “Unfavourable” Visual Outcome at 10 years

“Low” Saturation “High” Saturation

Target Target

Proportion of 3/6 (50%) 16/36 (44%)

“Treated” Eyes

Proportion of “All” 3/120 (2.5%) 16/126 (12.7%)

Eyes*
*p=>0.05
 Summary of outcome at 10 years

“Low” target “High” target

WISC Full Scale <2nd.C 23.2% 35.0%

Reading < 2nd. C 9.3% 23.3%
Numeracy <2nd. C 21.8% 36.7%
Vineland <2nd. C 36.3% 36.7%
Vineland Motor Skill < 6 yr. eq. 24.6% 25.0%

Child behaviour check list

Total problems >95th.C 12.7% 14.0%
 STOP – ROP Trial
Supplemental Therapeutic Oxygen for Prethreshold
Retinopathy of Prematurity.A Randomized Controlled Trial
STOP-ROP Multicenter Study Group. Pediatrics 2000; 105: 295-310

BOOST Trial
Oxygen saturation targets and outcomes in extremely preterm infants
Askie LM, Henderson-Smart DJ, Irwig L, Simpson JM. N Engl J Med
2003; 349: 953-961.
 STOP-ROP Trial (Results)
• No significant reduction in the number of infants requiring
peripheral ablative surgery (41% v 48%): benefit seen in
post hoc, sub group analysis

• No differences in Growth and Developmental milestones.

• Pneumonia and/or exacerbations of CLD occurred in more

infants in supplemental arm (13.2% v 8.5%).

• At 50 weeks PMA, more supplemental infants remained

hospitalised ( 12.7 v 6.8%), on oxygen (46.8% v 37%),
and on diuretics (35.8% v 24.4%).
 Benefit of Oxygen Saturation Targeting
(BOOST) Trial
Primary Aim
• Does maintaining oxygen saturation at a higher
versus standard level among oxygen dependent,
preterm infants improve long term growth and
development?

Inclusion Criteria
• <30 weeks, oxygen dependent at 32 weeks p.m.a.
 Conclusion (BOOST Trial)
• No major effect of higher oxygen saturation
targeting in the SpO2 95-98% range on long
term growth and development

• Potential increase in health service costs

resulting from increased time on
supplemental oxygen and increased rates of
home oxygen
Do we really know what is the optimal
oxygen saturation for preterm babies?
Intensive oxygen therapy as a possible
cause of retrolental fibroplasia
Campbell K. The Med J Australia 1951;2:48-50

Conclusion:
• The normal oxygen environment of the
newborn full term infant is abnormal for the
premature infant
Restricted versus liberal oxygen exposure for preventing
morbidity and mortality in preterm or low birth weight infants
Askie L, Henderson-Smart DJ. In: The Cochrane Library, Issue 3, 2003. Oxford:
Update Software.
 ..... and 50 years later

We still do not know

How much is too little or too much
 Variations in oxygen saturation monitoring
(U.K.)

25
30 28
24

25 20

20 19
15
15 13 13
15 12
10 10
11 10 9
10
7
7
5 5 5
4
2 3
2
0 0 0 0
92 93 94 95 96 97 98 99 100 90 92 94 96 98 100

Walker S, Tin W 2001 Alsop E, Sinha SK 2004

 Other observational studies
- Relation of target SpO2 levels and clinical outcome
in ELBW infants on supplemental oxygen. Sun et al
2002

- Can changes in clinical practice decrease the

incidence of severe retinopathy in very low birth
weight infants?
Chow et al 2003

- Retinopathy of prematurity and pulse oximetry: A

national survey of recent practice.
Anderson et al 2004
 Retinopathy of prematurity (ROP): A comparison
between two centres aiming for different pulse
oximetry saturation levels. Poets C, Arand J, Hummler et al. Biol
Neonate 2003; 259-80.

- 2 centres, <31 weeks

Target range Target range
80-92% 92-97%
N=579 N=314
Survival % 92% 93%

ROP > stage 3 13%** 6%**

(% of survivors)
ROP needing laser Rx 6% 5%
 The way forward

• Randomised Controlled Trial

• Randomised Controlled Trial
• Randomised Controlled Trial
• Randomised Controlled Trial
• Randomised Controlled Trial
• Randomised Controlled Trial
• Randomised Controlled Trial
• Randomised Controlled Trial
 The Oxygen Trials
Masked Randomised Controlled Trials

• Benefit Of Oxygen Saturation Targeting

(BOOST - II) [Australia]

• BOOST - II [New Zealand]

• BOOST - II [U.K.]

• Canadian Oxygen Trial (COT) [Canada]

• Surfactant Positive Pressure and Pulse Oximetry Trial

(SUPPORT) [U.S.A.]
 Hypotheses (Oxygen Saturation Trials)
Compared with functional SpO2 of 91-95%, targeting
85-89% within 24 hours of birth, and until infant breathes air (or till 36 weeks
GA) is associated with:

• reduction in
- severe ROP
- duration of ventilation & supplemental oxygen

• without increasing
- mortality
- adverse neurodevelopmental outcome (at 18 months/2 years of age).
- NEC and Treated PDA
- adverse effect on growth through 2 years
 The Oxygen Trials
Global collaboration

Australia (BOOST-II) 1,200 Funded

New Zealand 320 Funded
USA (SUPPORT) 1,310 Funded
UK (BOOST-II) 1,200 Funded
Canada (COT) 1,200 Funded

USA (STOP-ROP) 1,200 Awaiting

funding
 The Oxygen Trials
Global collaboration

Prospective Meta-analysis**
Neonatal Oxygenation Prospective Meta-
analysis (NeOProM).
** Simes RJ. Prospective meta-analysis of cholesterol-lowering studies: the
Prospective Pravastatin Pooling (PPP) Project and the Cholesterol Treatment
Trialists (CTT) Collaboration. Am J Cardiol 1995;76:122-6.
 Summary (Oxygen Saturation Trials)
• First RCTs (masked) on effect of targeting
“low” v “high” SpO2
• Meaningful outcome measures
• High risk group, from early life
• Pragmatic design
• Simple data collection
• Prospective Meta-analysis
 Julius Comroe (1945)

• “The clinician must bear in mind that oxygen is a

drug and must be used in accordance with well
recognized pharmacologic principles; i.e., since it
has certain toxic effects and is not completely
harmless (as widely believed in clinical circles) it
should be given only in the lowest dosage or
concentration required by the particular patient.”