1. March 5, 2007Manitoba NRP Advisory Group Use of Oxygen during Resuscitation of Neonates John Baier

2. March 5, 2007Manitoba NRP Advisory Group Objectives Review CPS recommendations regarding use of oxygen during resuscitation of newborn infants Review the normal postnatal changes in oxygen saturation during transition to extra-uterine life Review scientific evidence for oxygen being harmful during resuscitation Review clinical trials and experience with room air resuscitation Provide a practical approach to CPS recommendations

3. March 5, 2007Manitoba NRP Advisory Group CPS Recommendations Positive-pressure ventilation should be initiated with air (21% oxygen). Supplemental oxygen should be used if the baby remains cyanotic or heart rate is less than 100 bpm at 90 seconds of age. Blended gases should be available in the delivery room and during transport to the NICU. To avoid hyperoxemia pulse oximetry should be available in rooms designated for delivery of babies <33 weeks gestation. Even though, there is no clear definition of what is hyperoxia for preterm infant, it seems reasonable to avoid saturations above 95% when supplemental oxygen is used.

4. March 5, 2007Manitoba NRP Advisory Group Normal postnatal changes in oxygen saturation during transition to extra-uterine life

5. March 5, 2007Manitoba NRP Advisory Group Transitions Fetal PaO 2 is 20 mm Hg –SaO 2 ~60% At birth –Infant starts to breath –Lungs expand Pulmonary vascular resistance decreases Pulmonary blood flow increases –Removal of placental circulation Systemic vascular resistance increases –Fetal circulatory pattern starts to convert to normal extra-uterine pattern –PaO 2 increases

6. March 5, 2007Manitoba NRP Advisory Group Transitions How long does this take? How good are we at detecting cyanosis?

7. March 5, 2007Manitoba NRP Advisory Group Rabi et al J Pediatrics 2006 Normal postnatal change in oxygen saturation

8. March 5, 2007Manitoba NRP Advisory Group Normal postnatal change in oxygen saturation Rabi et al J Pediatrics 2006

9. March 5, 2007Manitoba NRP Advisory Group Normal postnatal change in oxygen saturation Kamlin et al J Pediatrics 2006

10. March 5, 2007Manitoba NRP Advisory Group Evidence that resuscitation with 100% oxygen may harm

11. March 5, 2007Manitoba NRP Advisory Group Abstracts on use of oxygen for Resuscitation at PAS-SPR

12. March 5, 2007Manitoba NRP Advisory Group Animal Models: Cardiovascular Variety of species and models Compared to RA resuscitation with 100% results in: –Increased pulmonary arterial contractility in vitro (newborn lambs) –Similar effects on pulmonary and systemic vascular resistances (piglet) –No difference in cardiac output (piglets) –No differences in regional blood flow (piglets) –Similar or less myocardial protection – troponin (piglets)

13. March 5, 2007Manitoba NRP Advisory Group Compared to RA resuscitation with 100% results in: –Increased time of apnea (rat) Slower resolution of acidosis (piglets) Similar resolution of acidosis (lambs) More rapid resolution of hyperlactatemia (piglets) –Increased evidence of pulmonary injury (lamb, piglet) Decreased anti-oxidant levels Increased lipid peroxidation Increased neutrophil activation (MPO) Increased MMP-2, MMP-9 Increased cytokines (IL-8) Increased gene expression (immunosupression) Animal Models: Pulmonary

14. March 5, 2007Manitoba NRP Advisory Group Animal Models: CNS Compared to RA resuscitation with 100% results in: –No changes in regional blood flow (rabbits) –Increased CNS lipid oxidation and worse neurological outcome (adult dogs) –Increase in CNS apoptosis –cell death (piglets) –Increased in CNS MMP-2 (piglets) –Increase in CNS IL-1  and TNF  (lambs) –No improvement in neurobehavioural outcomes or brain histology (rats) –No differences in brain pathology (piglets)

15. March 5, 2007Manitoba NRP Advisory Group Animal Models: Other effects Compared to RA resuscitation with 100% results in: –Increased platelet aggregation (piglets)

16. March 5, 2007Manitoba NRP Advisory Group Evidence of harmful effects of resuscitation with 100% oxygen in newborn infants

17. March 5, 2007Manitoba NRP Advisory Group Copyright ©2001 American Academy of Pediatrics Vento, M. et al. Pediatrics 2001;107:642-647 Anti-oxidant status in resuscitated infants

18. March 5, 2007Manitoba NRP Advisory Group RA resuscitation resulted in less oxidant stress (GSH/GSSG ratio) at 48 hours of life than did resuscitation with 100% oxygen Superoxide dismutase (SOD) activity was less in infants resuscitated with room air than with 100% oxygen Vento et al 2005 AJRCCM Anti-oxidant status in resuscitated infants **p < 0.01 versus control; #p <0.05 versus RAR. **p < 0.01 versus control; #p <0.05 versus RAR.

19. March 5, 2007Manitoba NRP Advisory Group Renal injury in resuscitated infants NAG urine excretion expressed in IU/mmol creatinine, in the first 14 d of postnatal life in asphyxiated newborn infants resuscitated with room air (RAR) or 100% oxygen (OxR). *p < 0.05 versus RAR. Normal values for non asphyxiated control infants are below the limit of 10 IU/mmol creatinine Vento et al 2005 AJRCCM

20. March 5, 2007Manitoba NRP Advisory Group Relationships between oxidant status and injury biomarkers Both troponin (myocardial injury) and NAG (renal injury) were directly related to degree of oxidant stress (oxidized glutathione) Vento et al 2005 AJRCCM

21. March 5, 2007Manitoba NRP Advisory Group Clinical Trials and Experience with Room Air Resuscitation

22. March 5, 2007Manitoba NRP Advisory Group Clinical Trials comparing Resuscitation with room air and 100% oxygen Vento et al 1991 –Spain (40 infants) Ramji et al 1993 –India (84 infants) Saugstad et al 1998, 2003 –India and Europe (609 infants) Ramji et al 2003 –India (431 infants) Bajaj et al 2005 –India (204 infants) Vento et al 2005 –Spain (39 infants)

23. March 5, 2007Manitoba NRP Advisory Group Vento et al 1991 Term Infants (40) Clinical and biochemical signs of asphyxia (moderate) –hypotonia and apnea, which were nonresponsive to external stimuli –Apgar score at 1 minute in both groups ranged from 3 to 5 Resuscitating team was unaware of the type of gas (RA or 100%)

24. March 5, 2007Manitoba NRP Advisory Group Vento, M. et al. Pediatrics 2001;107:642-647 Time needed for the onset of a sustained respiratory pattern ** p<0.01 vs. controls # p<0.05 vs. the RAR group. Copyright ©2001 American Academy of Pediatrics

25. March 5, 2007Manitoba NRP Advisory Group Extended experience with Room Air Resuscitation (Vento 2001)

26. March 5, 2007Manitoba NRP Advisory Group Saugstad et al 1998 Multicenter Study –Mainly in developing countries Entry criterion –apnea or gasping with heart rate <80 beats per minute at birth necessitating resuscitation Exclusion criteria –Birth weight <1000 g –Lethal anomalies –Hydrops –cyanotic congenital heart defects –Stillbirth Quasi randomized –even dates were resuscitated with room air (room air group), and those born on odd dates were resuscitated with 100% oxygen (oxygen group) Not Blinded Infants in the room air group who had bradycardia (heart rate <80) and/or central cyanosis 90 seconds after birth was switched over to 100%

27. March 5, 2007Manitoba NRP Advisory Group Saugstad et al 1998 Treatment failure (ie cyanosis or HR<80 at 90 seconds

28. March 5, 2007Manitoba NRP Advisory Group Saugstad et al 1998 Primary outcome: Death within 1 week and/or presence of grade II or III HIE

29. March 5, 2007Manitoba NRP Advisory Group Bajaj et al 2005 204 infants –India Entry criterion –apnea or gasping with heart rate <100 beats per minute at birth necessitating resuscitation Exclusion criteria –Birth weight <1000 g –Lethal anomalies –Hydrops Quasi randomized –Odd dates were resuscitated with room air (room air group), and those born on even dates were resuscitated with 100% oxygen (oxygen group) Not Blinded Infants in the room air group who had bradycardia (heart rate <100) and/or central cyanosis 90 s after birth was switched over to 100%

30. March 5, 2007Manitoba NRP Advisory Group Bajaj et al 2005 Primary Outcome: HIE and/or death before discharge

31. March 5, 2007Manitoba NRP Advisory Group Blood Gases

32. March 5, 2007Manitoba NRP Advisory Group Overall Mortality in studies Number of ResuscitatedNumber Died SourceRoom AirOxygenRoom AirOxygen Ramji 199342 34 Saugstad 19982883214061 Vento 2001192100 Vento 2001161146 Ramji 20032102212640 Bajaj 20051079717 Vento 2005172224 Totals65768399128 15.1%18.7%

33. March 5, 2007Manitoba NRP Advisory Group Metanalysis of Trials: Death at 1 week Rabi et al 2007 (in press)

34. March 5, 2007Manitoba NRP Advisory Group Metanalysis of Trials: Death at 1 month Rabi et al 2007 (in press)

35. March 5, 2007Manitoba NRP Advisory Group Metanalysis of Trials: HIE

36. March 5, 2007Manitoba NRP Advisory Group Practical Considerations CPS Guideline: –Supplemental oxygen should be used if the baby remains cyanotic or heart rate is less than 100 bpm at 90 seconds of age.

37. March 5, 2007Manitoba NRP Advisory Group How much Oxygen???? How to switch between RA and Oxygen????

38. March 5, 2007Manitoba NRP Advisory Group How much Oxygen?? No Data –Clinical Trials switched back to 100% oxygen if poor response after 90 seconds of room air resuscitation

39. March 5, 2007Manitoba NRP Advisory Group How much Oxygen?? No Data –Clinical Trials switched back to 100% oxygen if poor response after 90 seconds of room air resuscitation CPS recommendation is to use 100% oxygen

40. March 5, 2007Manitoba NRP Advisory Group Resuscitation using an Anesthesia Bag Situation 1: Blended oxygen is available in delivery suite: Bag is connected to a blender and FiO 2 turned to 21% If no response, then FiO 2 is increased using blender.

41. March 5, 2007Manitoba NRP Advisory Group Resuscitation with Self Inflating Bag Situation 1: Blended oxygen is available in delivery suite: –Bag (with reservoir attached) is connected to blender and FiO 2 turned to 21% –If no response after 90 seconds, then FiO 2 is increased using the blender.

42. March 5, 2007Manitoba NRP Advisory Group Resuscitation with Self Inflating Bag Situation 2: Only 100% oxygen is available –Bag (with reservoir attached) is connected to 100% oxygen source and flow is turned off –If no response after 90 seconds, then flow is turned on

43. March 5, 2007Manitoba NRP Advisory Group What if there is no medical air in the delivery room? A compressor in the delivery room could be used to deliver room air –Still needs to be blended with 100% oxygen source

44. March 5, 2007Manitoba NRP Advisory Group What if there is no blender CPS Guideline: –Blended gases should be available in the delivery room and during transport to the NICU This means all deliveries. Not recommended but gases can be tee’d together to adjust effective FiO 2

45. March 5, 2007Manitoba NRP Advisory Group Blending gases without blender

46. March 5, 2007Manitoba NRP Advisory Group Additional Considerations Infants <33 weeks gestation Resuscitation in patients in NICU who are ventilated or already receiving oxygen

47. March 5, 2007Manitoba NRP Advisory Group CPS recommendation To avoid hyperoxemia pulse oximetry should be available in rooms designated for delivery of babies <33 weeks gestation. Even though, there is no clear definition of what is hyperoxia for preterm infant, it seems reasonable to avoid saturations above 95% when supplemental oxygen is used. How to titrate oxygen in preterm infants?

48. March 5, 2007Manitoba NRP Advisory Group Oxygen administration Pulse oximetry must be considered an essential component of resuscitation Should be placed as soon as possible in an infant who requires resuscitation or appears in need of supplemental oxygen Consider use of new technology signal extraction monitors that will perform adequately in low perfusion situations.

49. March 5, 2007Manitoba NRP Advisory Group Infants <33 weeks gestation Start resuscitation with room air as for term infants –If bradycardic/cyanotic at 90 sec increase oxygen incrementally Gradual increase in saturation to 90% Avoid saturation >95% How?

50. March 5, 2007Manitoba NRP Advisory Group Titrating oxygen in infants < 33 weeks Blended oxygen source Titrate FiO 2 to saturation and heart rate –HR >100 –Slow increase to ~90% –Saturation <90% PPV with room air Increase FiO 2 to 0.40 Increase FiO 2 to 0.60 etc HR <100 or Sat<80 HR <100 or Sat<80 HR <100 or Sat<80 60 secs

51. March 5, 2007Manitoba NRP Advisory Group Titrating oxygen in infants < 33 weeks Self inflating bag attached to 100% oxygen Endpoints –HR >100 –Slow increase to ~90% –Saturation <90% PPV with no reservoir and no flow Turn on flow (40%) Attach reservoir HR <100 or Sat<80 HR <100 or Sat<80 60 secs

52. March 5, 2007Manitoba NRP Advisory Group Infants who need resuscitation on ventilators or on oxygen Most likely have pulse oximetry already established Start with oxygen concentration patient was receiving before need for resuscitation occurred Example: Infant was on 30% oxygen for resolving HMD and has a severe apnea and profound bradycardia needing bag mask ventilation –Start at 30% and provide adequate ventilation for 90% before increasing oxygen