1. Oxygen therapy in the preterm: Too much of a good thing? Keith J Barrington CHU Ste Justine Université de Montréal

2. Introduction Oxygen- essential to life Oxygen- essential to life Oxygen - given to more infants than any other medicinal product Oxygen - given to more infants than any other medicinal product but dosage remains controversial but dosage remains controversial

3. Oxygen may be bad for you Oxidation of flavoprotiens produces superoxide and peroxide

4. Oxygen may be bad for you Production of free radicals involving hypoxanthine

5. Haber-Weiss reaction

6. Cardiac Stun Ihnken Ihnken Cheung Cheung Saugstad Saugstad All demonstrate that resuscitation with 100% O2 rather than 21% causes dramatic oxidative stress that has immediate and serious effects on cardiac function, All demonstrate that resuscitation with 100% O2 rather than 21% causes dramatic oxidative stress that has immediate and serious effects on cardiac function,

7. Bronchopulmonary dysplasia Oxygen is toxic to developing lungs in animals 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 Free radicals cause PMN influx into lungs, which release inflammatory mediators setting up proteolysis, production of elastase, reduction of alveolarization

8. Outline: Background and rationale Background and rationale  early randomised trials of oxygen  The BOOST RCT  STOPROP SUPPORT SUPPORT COT COT BOOST2, UK BOOST2, UK BOOST2, AUSNZ BOOST2, AUSNZ

13. 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” “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”

14. Retinopathy is still important Rates very variable from one hospital to another Rates very variable from one hospital to another Surgery effective in reducing risk of retinal detachment Surgery effective in reducing risk of retinal detachment But: after surgery visual outcomes are poor (Cryo-Rop study results) But: after surgery visual outcomes are poor (Cryo-Rop study results) 22% detach despite treatment 22% detach despite treatment 44% worse than 20/200 vision 44% worse than 20/200 vision Is Avastin better in the long term? Is Avastin better in the long term?

15. 358 convalescing infants of <30 wk GA who were still O 2 dependent at 32 wks pma 358 convalescing infants of <30 wk GA who were still O 2 dependent at 32 wks pma masked targeting of Functional SpO 2 ranges: 91-94% (STANDARD) versus 95-98% (HIGHER) masked targeting of Functional SpO 2 ranges: 91-94% (STANDARD) versus 95-98% (HIGHER)

16. 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 SaO 2 93-96% Standard groupHigher group Masking the O 2 saturation target in BOOST (only the study oximeter was allowed)

17. BOOST Results STANDARD SpO2 91 - 94% versus HIGHER SpO2 95 - 98% in convalescing preterm infants from 32 wks 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

18. Stoprop Infants with prethreshold ROP in at least 1 eye monitored for > 4 hours with pulse oximetry. 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 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%

19. STOP-ROP Number Enrolled Conventional 325 Supplemental 324 Gestational age (wk) * * 25.4 ± 1.5 PMA (wk) * * 35.3 ± 2.635.4 ± 2.5 Weight at entry (g) * * 1538 ± 4451556 ± 442 Gender (% 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%

20. Conventional n = 325 Supplemental n = 324 Weight gain over the first 2 wk (g; mean ± standard deviation) 291 ± 137278 ± 143 PMA to achieve oral feeding ‡ (wk; mean ± standard deviation) ‡ 39.0 ± 3.538.9 ± 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% *

21. 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

22. Criteria for an upper limit of oxygenation Cerebral and retinal vasoconstriction are caused by high oxygen tension (partial pressure, mmHg). 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. 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. The upper limit of targeted SpO2 should be selected so that no infant is exposed to hyperoxia.

23. Criteria for a lower limit of oxygenation lower limit- consider how much oxygen is being delivered to the tissues. lower limit- consider how much oxygen is being delivered to the tissues. Function of blood flow, Hb concentration and oxygen saturation. 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… 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…

24. Chow, Wright, Sola et al Pediatrics 2003 Cedar Sinai Medical Center, Los Angeles Cedar Sinai Medical Center, Los Angeles Reported outcomes following a change in protocol for infants < 1000 g in 1998 in Reported outcomes following a change in protocol for infants < 1000 g in 1998 in Old protocol: Target SpO2 90% - 98% Old protocol: Target SpO2 90% - 98% New Protocol: Target SpO2 83% - 93% New Protocol: Target SpO2 83% - 93% Compared results with the Vermont Oxford Network Compared results with the Vermont Oxford Network

27. J Perinatol. 2004 Mar;24(3):164-8. Anderson et al J Perinatol. 2004 Mar;24(3):164-8. Surveyed 142 US NICUs Surveyed 142 US NICUs

28. Anderson et al

30. 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

31. 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)

32. Medical Illustration © South Cleveland Hospital 0 10 20 30 40 50 60 70-9084-9485-9588-98 Alarm limits for O 2 saturation (%) One year survival rate (%) ONE YEAR SURVIVAL IN BABIES BORN BEFORE 28 WEEKS

33. 0 10 20 70-9084-9485-9588-98 C.P. amongst survivors (%) Alarm limits for O 2 saturation (%) 15 5 CEREBRAL PALSY AMONGST SURVIVORS IN BABIES BORN BEFORE 28 WEEKS

34. 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

35. Medical Illustration © South Cleveland HospitalSummary Significantly lower incidence of severe ROPSignificantly 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

36. Results of the trials won’t be available until 2012: earliest What shall we do while we wait? What shall we do while we wait? Assuming continued use of pulse oximeters as primary monitoring strategy for the preterm Assuming continued use of pulse oximeters as primary monitoring strategy for the preterm Remember their limitations! Remember their limitations! Accurate within 5%, 95% of the time. 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. A pulse oximeter saturation of 95% could mean a true saturation of 99% and a PaO2 of over 200. It happens. It happens.  Why don’t we all just switch to lower saturation targets now?

37. 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 (SpO 2 ) with simultaneous PaO 2.

38. Cust et al In order to prevent 95% of hyperoxic episodes (PaO 2 > 90 mmHg), the upper alarm limit was 95% Similarly, to prevent 95% of hypoxic episodes (PaO 2 < 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 PaO 2 values between 40 and 90 mmHg, an appropriate alarm range of 94-97% SpO 2 (90% sensitivity, 28% specificity) was established. Triangle = sensitivity for hypoxia Circle = sensitivity for hyperoxia

39. What to do for babies right now So severe hyperoxia can be reduced with the use of pulse oximetry So severe hyperoxia can be reduced with the use of pulse oximetry As long as false alarms are accepted, which can be frequent As long as false alarms are accepted, which can be frequent Upper limits are set which are appropriate for the device you are using Upper limits are set which are appropriate for the device you are using Alarms are responded to! Alarms are responded to! Commonest response to frequent alarms is to turn off the alarm! Commonest response to frequent alarms is to turn off the alarm!

40. Castillo 2008

41. Low saturation limit? A saturation limit below 90% will on occasion be associated with very low PO2. A saturation limit below 90% will on occasion be associated with very low PO2. In a non-transfused baby with 100% fetal HgB, 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 We do not know if this is safe

42. What to do for babies outside of a trial Most important: 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. Train nurses and other caregivers that high sat just as important as low. Reinforce importance of reducing O2 exposure. Reinforce importance of reducing O2 exposure.  Throughout training: all taught O2 is essential to life, less emphasis that O2 is toxic.

43. Early results of the SpO2 limit RCTs SUPPORT SUPPORT BOOST2 UK BOOST2 UK BOOST2 AUSNZ BOOST2 AUSNZ

44. Support

46. What now? Suggestion: avoid 85 to 89 Suggestion: avoid 85 to 89 Maintain high alarms at 95% Maintain high alarms at 95% Target range 88 to 92% ??? Target range 88 to 92% ???

47. 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). 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).

48. Hyperoxia in full term infants Animal data showing that resuscitation with 100% increases pulmonary vascular responsiveness Animal data showing that resuscitation with 100% increases pulmonary vascular responsiveness And decreases the response to NO And decreases the response to NO Avoid hyperoxia in full term babies also. Avoid hyperoxia in full term babies also.