Oxygen therapy in the preterm:
Too much of a good thing?
Keith J Barrington
CHU Ste Justine
Université de Montréal
Introduction
 Oxygen-
essential to life
 Oxygen - given to more infants than
any other medicinal product
 but
dosage remains controversial
Oxygen
may be
bad for
you
Oxidation of
flavoprotiens
produces
superoxide and
peroxide
Oxygen
may be bad
for you
Production of free
radicals involving
hypoxanthine
Haber-Weiss reaction
Cardiac Stun
Ihnken
 Cheung
 Saugstad


All demonstrate that resuscitation with
100% O2 rather than 21% causes dramatic
oxidative stress that has immediate and
serious effects on cardiac function,
Bronchopulmonary dysplasia
Oxygen is toxic to developing lungs in
animals
 Free radicals cause PMN influx into lungs,
which release inflammatory mediators
setting up proteolysis, production of
elastase, reduction of alveolarization

Outline:

Background and rationale
early randomised trials of oxygen
 The BOOST RCT
 STOPROP





SUPPORT
COT
BOOST2, UK
BOOST2, AUSNZ
Askie, Henderson Smart: Cochrane
Library
 “It
is possible that the difference in
retrolental fibroplasia rates seen in
survivors may be influenced by the
trend towards excess deaths caused
by the restricted oxygen policy”
Retinopathy is still important
Rates very variable from one hospital to
another
 Surgery effective in reducing risk of retinal
detachment
 But: after surgery visual outcomes are poor
(Cryo-Rop study results)
 22% detach despite treatment
 44% worse than 20/200 vision
 Is Avastin better in the long term?

BO
S T T ria l
2
B en efits O f O x y g en S a tu ra tio n T a rg etin g

358 convalescing infants of <30 wk GA who
were still O2 dependent at 32 wks pma

masked targeting of Functional SpO2 ranges:
91-94% (STANDARD) versus
95-98% (HIGHER)
Masking the O2 saturation target in
BOOST
(only the study oximeter was allowed)
Study oximeter adjusted to display either
2% above or 2% below actual saturation value
Target display with study
oximeter SaO2 93-96%
Actual target 91-94%
Actual target 95-98%
(2% below displayed value)
value)
(2% above displayed
Standard group
Higher group
BOOST Results

STANDARD
HIGHER
SpO2 91 - 94% versus
SpO2 95 - 98%
in convalescing preterm infants from 32 wks
 Continued for entire duration of the oxygen need

NO DIFFERENCE in one year outcomes
16 days shorter duration of oxygen dependency with
STANDARD SpO2 91 - 94%
 1 pulmonary death in Standard Sat group and 6 in
High Sat group, p=NS

Stoprop
Infants with prethreshold ROP in at least 1
eye monitored for > 4 hours with pulse
oximetry.
 Candidates excluded if median pulse
oximetry > 94% saturation while breathing
room air
 O2 sats, in the target range of either 89% 94% or 96% - 99%

STOP-ROP
Number Enrolled
Conventional
Supplemental
325
324
*
25.4 ± 1.5
Gestational age (wk) 25.4 ± 1.5
35.3 ± 2.6
35.4 ± 2.5
PMA (wk)*
*
1538 ± 445
1556 ± 442
Weight at entry (g)
53.9%
60.5%
Gender (% male)
Pulmonary status
Pulmonary score*
.53 ± .36
.56 ± .37
Ventilator
46 (14%)
57 (18%)
CPAP or hood
57 (18%)
55 (17%)
Nasal cannula
210 (64%)
203 (63%)
No oxygen
12 (4%)
9 (3%)
Medications
Methylxanthines 68.6%
72.5%
Diuretics
52.3%
57.1%
†
CLD steroids
28.1%
30.6%
Conventional Supplemental
n = 325
n = 324
Weight gain over the first 2 wk (g; mean ±
standard deviation)
291 ± 137
278 ± 143
39.0 ± 3.5
38.9 ± 3.6
25 (29)
38 (51)
26 (36)
30 (33)
Remained hospitalized¶(%)
6.8%
12.7%
Remained on oxygen (%)
37.3%
46.8%
Remained on diuretics (%)
24.4%
35.8%
PMA to achieve oral
standard deviation)
feeding‡
(wk; mean ±
*
Infants with pneumonia/CLD events (total
events)§
#
of
Infants with apnea/bradys triple baseline
(total #events)
Outcomes at the 3-month corrected age window‖
Outcomes at 3 months' corrected age examination n = 301
n = 302
All deaths, n (pulmonary cause of death,n)
7 (3)
9 (5)
Room air saturations too low to test, n (%)
17 (6%)
35 (12%)
Room air oxygen saturation for those tested,
mean ± standard deviation
95.3 ± 4.7% 94.6 ± 7.7%
Cumulative rate curves demonstrating the differences in both the proportion and timing of
adverse (A) and favorable (B) ophthalmic outcomes by study arm.
Pediatrics 2000;105:295-310
Criteria for an upper limit of
oxygenation

Cerebral and retinal vasoconstriction are caused
by high oxygen tension (partial pressure, mmHg).

In setting a maximum upper limit of oxygenation,
it is therefore important to prevent excessively
high oxygen tension.

The upper limit of targeted SpO2 should be
selected so that no infant is exposed to hyperoxia.
Criteria for a lower limit of
oxygenation

lower limit- consider how much oxygen is being
delivered to the tissues.

Function of blood flow, Hb concentration and
oxygen saturation.

If blood flow and Hb are adequate, and oxygen
saturation is above fetal values, then O2 delivery
is above fetal levels. Is this enough? What about
pulmonary artery pressures…
Chow, Wright, Sola et al
Pediatrics 2003

Cedar Sinai Medical Center, Los Angeles

Reported outcomes following a change in protocol for
infants < 1000 g in 1998 in


Old protocol: Target SpO2 90% - 98%
New Protocol: Target SpO2 83% - 93%

Compared results with the Vermont Oxford Network
Anderson et al
J Perinatol. 2004 Mar;24(3):164-8.

Surveyed 142 US NICUs
Anderson et al
Anderson et al
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
TARGET RANGE FOR OXYGEN SATURATION
v
..
THRESHOLD R.O.P
50%
Proportion of 40%
babies developing
threshold
30%
retinopathy
(95% confidence
intervals)
20%
10%
0%
70%
80%
90%
100%
Limits within which oxygen saturation was allowed to vary
Medical Illustration ©
South Cleveland Hospital
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 (%)
Medical Illustration ©
South Cleveland Hospital
CEREBRAL PALSY AMONGST SURVIVORS IN
BABIES BORN BEFORE 28 WEEKS
20
C.P.
amongst
survivors
(%)
15
10
5
0
70-90 84-94 85-95 88-98
Alarm limits for O2 saturation (%)
ALARM LIMITS FOR OXYGEN SATURATION
vv
VENTILATION
100
88 - 98%, mean 27 d
75
70 - 90%, mean 18 d
Proportion
still being
ventilated
(%)
50
25
1
2
3
4
5
6
7
Duration of ventilation (weeks)
Medical Illustration ©
South Cleveland Hospital
8
9
10
Summary
••Significantly lower incidence of severe ROP
• Shorter duration of ventilation and oxygen
• No difference in long term survival rate
• No difference in rate of cerebral palsy
• No adverse effect on growth
Medical
Illustration
©
South
Cleveland
Hospital
Results of the trials won’t be
available until 2012: earliest






What shall we do while we wait?
Assuming continued use of pulse oximeters as
primary monitoring strategy for the preterm
Remember their limitations!
Accurate within 5%, 95% of the time.
A pulse oximeter saturation of 95% could mean a
true saturation of 99% and a PaO2 of over 200.
It happens.

Why don’t we all just switch to lower saturation targets
now?
Cust, AE, et al. Alarm settings for the Marquette
8000 pulse oximeter to prevent hyperoxic and
hypoxic episodes.Journal of Paediatrics and Child
Health 1999: 35 (2), 159-162.
Comparison of 322 pulse oximeter readings (SpO2) with simultaneous PaO2.
Cust et al
Triangle = sensitivity for hypoxia
Circle = sensitivity for hyperoxia
In order to prevent 95% of hyperoxic episodes (PaO2>
90 mmHg), the upper alarm limit was 95%
Similarly, to prevent 95% of hypoxic episodes (PaO2<
40 mmHg), the lower alarm limit was 95%
A sensitivity lower than 95% had to be accepted to develop an
alarm range which prevented both hyperoxic and hypoxic
episodes. To maintain PaO2 values between 40 and 90 mmHg,
an appropriate alarm range of 94-97% SpO2 (90% sensitivity,
28% specificity) was established.
What to do for babies right now





So severe hyperoxia can be reduced with the use
of pulse oximetry
As long as false alarms are accepted, which can be
frequent
Upper limits are set which are appropriate for the
device you are using
Alarms are responded to!
Commonest response to frequent alarms is to turn
off the alarm!
Castillo 2008
Low saturation limit?
A saturation limit below 90% will on
occasion be associated with very low PO2.
 In a non-transfused baby with 100% fetal
HgB,
 If the sat is reading 85%
 The true sat may be 80%
 The actual PaO2 could be 34 mmHg
 We do not know if this is safe

What to do for babies outside of a
trial

Most important:
High saturation alarms set for every
preterm baby receiving O2.
 Reduce FiO2 when high alarm rings.


Train nurses and other caregivers that high sat
just as important as low.

Reinforce importance of reducing O2 exposure.
 Throughout training: all taught O2 is essential
to life, less emphasis that O2 is toxic.
Early results of the SpO2 limit
RCTs
SUPPORT
 BOOST2 UK
 BOOST2 AUSNZ

Support
What now?
Suggestion: avoid 85 to 89
 Maintain high alarms at 95%
 Target range 88 to 92% ???

Oxygen may be toxic at term also!

Lakshminrusimha, 2006, pulmonary arteries isolated from 24-hold
lambs. Exposure to O2 during 1st 30 min of life (100%Res: ■, n = 5)
or for 24 h (100%24h: ▲, n = 5) (21%Res: ◇, n = 5).
Hyperoxia in full term infants
Animal data showing that resuscitation with
100% increases pulmonary vascular
responsiveness
 And decreases the response to NO


Avoid hyperoxia in full term babies also.