Use of Oxygen during Resuscitation of Neonates John

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

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

Transitions • Fetal Pa. O 2 is 20 mm Hg – Sa. O 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 – Pa. O 2 increases March 5, 2007 Manitoba NRP Advisory Group

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

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

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

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

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

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

Animal Models: Pulmonary • 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) • • • March 5, 2007 Decreased anti-oxidant levels Increased lipid peroxidation Increased neutrophil activation (MPO) Increased MMP-2, MMP-9 Increased cytokines (IL-8) Increased gene expression (immunosupression) Manitoba 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 b and TNFa (lambs) – No improvement in neurobehavioural outcomes or brain histology (rats) – No differences in brain pathology (piglets) March 5, 2007 Manitoba NRP Advisory Group

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

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

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

Anti-oxidant status in resuscitated infants • 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 n**p < 0. 01 versus control; #p <0. 05 versus RAR. March 5, 2007 Manitoba NRP Advisory Group Vento et al 2005 AJRCCM

Renal injury in resuscitated infants • • March 5, 2007 Manitoba NRP Advisory Group 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 (Ox. R). *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

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) March 5, 2007 Manitoba NRP Advisory Group Vento et al 2005 AJRCCM

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

Time needed for the onset of a sustained respiratory pattern ** p<0. 01 vs. controls # p<0. 05 vs. the RAR group. Vento, M. et al. Pediatrics 2001; 107: 642 -647 Copyright © 2001 American Academy of Pediatrics March 5, 2007 Manitoba NRP Advisory Group

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

Saugstad et al 1998 • Multicenter Study • Entry criterion • Exclusion criteria • Quasi randomized • • 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% – Mainly in developing countries – apnea or gasping with heart rate <80 beats per minute at birth necessitating resuscitation – – – Birth weight <1000 g Lethal anomalies Hydrops cyanotic congenital heart defects Stillbirth – even dates were resuscitated with room air (room air group), and those born on odd dates were resuscitated with 100% oxygen (oxygen group) March 5, 2007 Manitoba NRP Advisory Group

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

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

Bajaj et al 2005 • 204 infants • Entry criterion • Exclusion criteria • Quasi randomized • • 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% – India – apnea or gasping with heart rate <100 beats per minute at birth necessitating resuscitation – Birth weight <1000 g – Lethal anomalies – Hydrops – Odd dates were resuscitated with room air (room air group), and those born on even dates were resuscitated with 100% oxygen (oxygen group) March 5, 2007 Manitoba NRP Advisory Group

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

Blood Gases March 5, 2007 Manitoba NRP Advisory Group

Overall Mortality in studies Number of Resuscitated Source March 5, 2007 Manitoba NRP Advisory Group Number Died Room Air Oxygen Ramji 1993 42 42 3 4 Saugstad 1998 288 321 40 61 Vento 2001 19 21 0 0 Vento 2001 16 1 14 6 Ramji 2003 210 221 26 40 Bajaj 2005 107 97 17 17 Vento 2005 17 22 2 4 Totals 657 683 99 128 15. 1% 18. 7%

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

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

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

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

Resuscitation using an Anesthesia Bag • Situation 1: Blended oxygen is available in delivery suite: • Bag is connected to a blender and Fi. O 2 turned to 21% • If no response, then Fi. O 2 is increased using blender. March 5, 2007 Manitoba 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 Fi. O 2 turned to 21% – If no response after 90 seconds, then Fi. O 2 is increased using the blender. March 5, 2007 Manitoba 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 March 5, 2007 Manitoba 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 March 5, 2007 Manitoba 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 Fi. O 2 March 5, 2007 Manitoba NRP Advisory Group

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

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

Titrating oxygen in infants < 33 weeks PPV with room air HR <100 or Sat<80 60 secs Increase Fi. O 2 to 0. 40 HR <100 or Sat<80 60 secs Increase Fi. O 2 to 0. 60 HR <100 or Sat<80 60 secs etc March 5, 2007 Manitoba NRP Advisory Group • Blended oxygen source • Titrate Fi. O 2 to saturation and heart rate – HR >100 – Slow increase to ~90% – Saturation <90%

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

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 March 5, 2007 Manitoba NRP Advisory Group