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Oxygen therapy in the preterm: Too much of a good thing?
Keith J Barrington
CHU Ste Justine
Université de Montréal
Introduction
Oxygen- essential to lifeOxygen - 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 oxygenThe BOOST RCTSTOPROP
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?
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)
BO ST Trial2
Benefits Of Oxygen Saturation Targeting Trial
Actual target 91-94% Actual target 95-98%
(2% below displayed value) (2% above displayed value)
Study oximeter adjusted to display either 2% above or 2% below actual saturation value
Target display with study oximeter SaO2 93-96%
Standard group Higher group
Masking the O2 saturation target in BOOST
(only the study oximeter was allowed)
BOOST Results
STANDARD SpO2 91 - 94% versus HIGHER 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 EnrolledConventional325
Supplemental324
Gestational age (wk)* 25.4 ± 1.5 25.4 ± 1.5PMA (wk)* 35.3 ± 2.6 35.4 ± 2.5Weight at entry (g)* 1538 ± 445 1556 ± 442Gender (% male) 53.9% 60.5%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%
Conventionaln = 325
Supplementaln = 324
Weight gain over the first 2 wk (g; mean ± standard deviation)
291 ± 137 278 ± 143
PMA to achieve oral feeding‡ (wk; mean ± standard deviation)
39.0 ± 3.5 38.9 ± 3.6
Infants with pneumonia/CLD events (total # of events)§ 25 (29) 38 (51)
Infants with apnea/bradys triple baseline (total #
events)26 (36) 30 (33)
Outcomes at the 3-month corrected age window‖
Remained hospitalized¶(%) 6.8% 12.7%
Remained on oxygen (%) 37.3% 46.8%
Remained on diuretics (%) 24.4% 35.8%
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 alPediatrics 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 alJ 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
Medical Illustration © South Cleveland Hospital
50%
40%
30%
20%
10%
0%70% 80% 90% 100%
v THRESHOLD R.O.P.
TARGET RANGE FOR OXYGEN SATURATION
.
Limits within which oxygen saturation was allowed to vary
Proportion of babies developing threshold retinopathy (95% confidence intervals)
Medical Illustration © South Cleveland Hospital
0
10
20
30
40
50
60
70-90 84-94 85-95 88-98
Alarm limits for O2 saturation (%)
One year survival
rate (%)
ONE YEAR SURVIVAL IN BABIES BORN BEFORE 28 WEEKS
0
10
20
70-90 84-94 85-95 88-98
C.P. amongst survivors
(%)
Alarm limits for O2 saturation (%)
15
5
CEREBRAL PALSY AMONGST SURVIVORS IN BABIES BORN BEFORE 28 WEEKS
ALARM LIMITS FOR OXYGEN SATURATION
Medical Illustration © South Cleveland Hospital
v v
VENTILATION
Proportion still being ventilated
(%)
Duration of ventilation (weeks)
100
75
50
25
1 2 3 4 5 6 7 8 9 10
88 - 98%, mean 27 d
70 - 90%, mean 18 d
ALARM LIMITS FOR OXYGEN SATURATION
Medical Illustration © South Cleveland Hospital
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
•
• 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
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
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.
Triangle = sensitivity for hypoxiaCircle = sensitivity for hyperoxia
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.
