The Oxygen Controversy Why can t Neonatologists get it Correct?

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1 The Oxygen Controversy Why can t Neonatologists get it Correct? Richard A. Polin M.D. Morgan Stanley Children s Hospital Columbia University

2 Cyanophobia Blue

3 Objectives To review the benefits and risks of oxygen during resuscitation. Identifying the ideal target saturation range

4 Oxygen Must be Good!

6 Oxygen Can t be Good!

7 Oxygen Can t be Good! Heterocephalus glaber Where does the truth lie?

Discovery of Oxygen Michał Sędziwój (Michael Sendivogius) (1566

By heating saltpetre, he discovered that air is not a single

8 Discovery of Oxygen Michał Sędziwój (Michael Sendivogius) ( ) was a Polish scientist, physician and alchemist. By heating saltpetre, he discovered that air is not a single substance but contains a life-giving food of life substance ( oxygen ). Saltpetre (KNO 3 )

Discovery of Oxygen John Mayow (1641-1679) When a small animal and a lighted candle were

animal died. However, if there was no candle present the animal lived twice as long.

9 Discovery of Oxygen John Mayow ( ) When a small animal and a lighted candle were placed in a closed vessel full of air the candle first went out and soon afterwards the animal died. However, if there was no candle present the animal lived twice as long. He concluded that this constituent of the air (spiritus nitro-aereus) is absolutely necessary for life.

important observation that a flame would go out when lighted in a sealed container.

10 Discovery of Oxygen Carl Wilhem Scheele ( hard luck Scheele ) re-discovered oxygen in 1772 Joseph Priestly (an ordained priest) re-discovered oxygen in 1774 Priestly made the important observation that a flame would go out when lighted in a sealed container. Similarly a mouse in the container would die from lack of air. Carl Wilhelm Scheele Joseph Priestly

The gas that was emitted was 5-6x as good as common air.

11 Discovery of Oxygen Putting a green plant in the jar would refresh the air-- allowing the candle to burn and the mouse to live. On August 12, 1774, he focused sunlight in a lump of mercuric oxide in an inverted glass container. The gas that was emitted was 5-6x as good as common air. Who can tell but that in time, this pure air may become a fashionable article in luxury. Hitherto only two mice and myself have had the privilege of breathing it. (dephlogisticated air)

12 Francoise Chaussier ( ) Pioneer in neonatal resuscitation First physician to oxygen to a neonate in (1780)

13 Use of Supplemental Oxygen Wilson (1942) reported that premature infants breathed with a more regular pattern if they were nursed in 70% oxygen. We have no proof that the regular type of respiration, which we believe is normal is better for a premature infant than the periodic type of breathing

14 In the 1940s incubators were designed to provide high concentrations of O 2. In 1948, the American Academy of Pediatrics recommended 40-50% oxygen for all premature infants immediately after birth to be continued for a period from 12 hours to as long as one month. ROP (Terry 1942)

15 Multicenter trial of restricted and unrestricted oxygen therapy in infants weighing less than 1500 grams Oxygen group # infants Blood vessel Scarring RLF changes RLF Routine Oxygen 47 70% 17% Curtailed Oxygen 42 31% 5% Incubators were redesigned with a red plastic flag on the back that had to be raised to deliver oxygen concentrations > 40%. (1960s) Following restricted oxygen use there was an increase in mortality in infants with RDS and cerebral palsy in preterm infants (16 infants died for every infant spared of blindness).

16 Case: Room Air or Oxygen for Resuscitation A 3.2 kg infant is born following a 37 week gestation. There were late decelerations prior to delivery and clinical signs compatible with an abruptio placentae. There is no meconium. The infant is apneic and has a slow (90 BPM) heart rate at one minute of life. Your team dries the infant and clears the airway. Ventilation with a T-piece resuscitator is begun immediately. Should you use 100% oxygen or 21% oxygen to ventilate the infant? Which concentration of oxygen would you use if the heart rate is 40?

17 Oxygen saturation trends immediately after birth When neither O 2 nor PPV is used the median time to reach a saturation of 90% ranges from 5-8 minutes. 100 * * 90 * * SpO * * * Vaginal delivery 50 * Cesarean delivery Minutes Rabi et al J Pediatr ( 35 weeks)

18 SaO 2 % Oxygen saturation trends immediately after birth Changes in SaO 2 After Birth Min. After Birth Rabi et al 2006 Kamlin et al 2006 Saugstad et al 2005 Rao et Ramji 2001 House et al 1987 Dimich et al 1991 Tooth et al 2002 ELBW with 100% Oxygen Fetal SpO 2 Room Air Resus ELBW Adapted from Saugstad J Peds 2006

19 Oxygen saturation, % Third, 10th, 25th, 50th, 75th, 90th, and 97th SpO 2 percentiles for all infants with no medical intervention after birth Minutes after birth 3rd 10th 25th 50th 75 th 90 th 97th Dawson, J.A. et al. Pediatrics 2010; 125:e1340-e1347

21 Use of Oxygen for Resuscitation of Infants with Perinatal Depression The Hypothesis Sudden reintroduction of O 2 may result in free radical formation. Free radicals can disturb the recovery of hypoxic cells through lipid peroxidation of membranes & oxidation of proteins

22 PaO2 (kpa) Resuscitation with 21% O 2 vs 100% O % O % O day old piglets were ventilated with 8% O 2 until they became bradycardic or hypotensive. (randomized for resuscitation with 21% O 2 or 100% O 2 for 20 minutes) Mean duration of hypoxemia was > 90 minutes Time (min) Rootwell T & Saugstad et al Pediatr. Res. 32: 107, 1992

23 MAP (mmhg) Resuscitation with 21% O 2 vs 100% O % O % O No significant differences in base deficit, hypoxanthine levels or histopathological brain injury Time (min) Rootwelt T & Saugstad et al Pediatr. Res. 32: 107, 1992

24 Laser Doppler flow in cortex (% of baseline) Hypoxia ischemia model: 8% O 2 (20 min.) and temporary occlusion of the common carotid arteries % O 2 100% O Time (min) HI Reoxygenation-reperfusion

25 The Goals of Resuscitation Restoration of systemic blood flow/cerebral blood flow Lessening production of reactive oxygen species and other neurotoxic substances

26 The benefits of 100% oxygen depends on whether the systemic circulation is in a state of collapse.

Ipsilateral Hemisphere Air O 2 60 40 20 250 Rear Paw At 24 hours of reperfusion 30 200 150

27 Changes in blood flow (%) of baseline Cerebral Blood Flow & Peripheral blood Flow During Reoxygenation Following Cerebral Ischemia (with preserved systemic blood flow) 80 Ipsilateral Hemisphere Air O Rear Paw At 24 hours of reperfusion Air O Hypoxia-Ischemia Reoxygenation 35 Min 0 Air n = 16 O 2 n = 14

Changes in Cerebral Blood flow in response to HI and re-oxygenation (%) Cerebral Blood Flow During Reoxygenation with 21% or 100% O 2 Following Complete Circulatory Collapse

28 Changes in Cerebral Blood flow in response to HI and re-oxygenation (%) Cerebral Blood Flow During Reoxygenation with 21% or 100% O 2 Following Complete Circulatory Collapse Hypoxia Re-oxygenation 21% O 2 Mitochondrial ROS production assay 50 % 0 % 20 min 5 min Time (min) 100% O 2 21% O 2 Mitochondrial ROS production assay 50 % 0 % 20 min 5 min Time (min)

29 Mortality with resuscitation using 21% or 100% O 2 Study or subgroup Treatment events total Control events total Weight Risk Ratio M-H, fixed,95% Cl Risk Ratio M-H, fixed,95% Cl Randomized Trials Toma, 2006 (15) Not estimable Toma, 2006 (16) Not estimable Toma, 2006 (17) % 0.43 (0.04, 4.51) Vento, 2001 (09) % 0.11 (0.01, 0.91) Vento, 2003 (10) % 0.46 (0.04, 4.96) Vento, 2003 (13) % 0.65 (0.13, 3.13) Subtotal (95% Cl) % 0.32 (0.12, 0.84) Total events 5 15 Heterogeneity: c 2 = 1.87, d.f.=3 (p=0.60%), I 2 =0% Favors tx Favors control Test for overall effect: Z = 2.30 (p=0.02)

30 Achievement of Targeted Oxygen Saturation Values Resuscitated with Room Air or 100% Oxygen RCT of preterm infants resuscitated with 21% or 100% O 2 (n = 41). The FiO 2 was adjusted every few minutes for a goal SpO 2 of 80-85% at age 5 minutes,. Every infant in the room air group met rescue criteria. Wang et al Pediatrics 121: 1083, 2008

31 SpO 2 percent Achievement of Targeted Oxygen Saturation Values Resuscitated with Room Air or 100% Oxygen * * * * * * * * O 2 Group Room Air Group * p < * Minutes from Birth Wang et al Pediatrics 121: 1083, 2008

32 Heart Rate Achievement of Targeted Oxygen Saturation Values Resuscitated with Room Air or 100% Oxygen Minutes from Birth Wang et al Pediatrics 121: 1083, 2008 O 2 Group Room Air Group

33 The Goals of Resuscitation Restoration of systemic blood flow/cerebral blood flow Lessening production of reactive oxygen species and other neurotoxic substances

34 Use of 30% or 90% Oxygen During Delivery Room Resuscitation of infants weeks Gestation Clinical Outcome: Death or BPD (need for O 2 at 36 weeks) Targeted SaO 2 values were 75% at 5 minutes and 85% at 10 minutes Every seconds the FiO 2 was increased (if the infant was still bradycardic) or decreased if the saturation values were > 85%. Vento et al Pediatrics 124: e439, 2009

35 Use of 30% or 90% Oxygen During Delivery Room Resuscitation BPD 31.7% % 15.4% Low Oxygen High Oxygen Vento et al Pediatrics 124: e439, 2009

36 Use of 21% or 100% Oxygen During Delivery Room Resuscitation of infants weeks Gestation Primary Outcome: To determine if a low oxygen strategy (LOX) or high oxygen strategy (HOX) during resuscitation decreased oxidative stress. 44 infants randomized to each group: (mean gestational age 30 ± 3 weeks) Infants in the LOX group spent less time with a SpO 2 > 94% and had less evidence of oxidative stress. Use of LOX decreased ventilator days, the need for rescue HFOV and BPD. 4% vs. 23% (physiologic definition) & 7% vs. 25% (oxygen need at 36weeks) Kapadia et al Pediatrics e , 2013

37 Take Home Messages The 2015 NRP recommend starting with an FiO2 of,21 in term infants and 0,21-0,30 in preterm infants (class 1 LOE B-R) Starting with an FiO2 >.65 is not recommended. (class 1II LOE B-R) When the systemic circulation is collapsed (cardiac arrest or severe bradycardia (< 60 BPM & not increasing), use of 100% oxygen restores cerebral and systemic blood flow more quickly. 100% oxygen should be weaned as quickly as possible to decrease production of reactive oxygen species It is difficult to maintain infants at a specified saturation range.

38 A final thought In a retrospective, observational cohort study from Canada, the outcomes of 2326 preterm infants ( 27weeks gestation) resuscitated with100% O 2 were compared with those receiving < 100% O 2 (usually 21%-40% and titrated). The adjusted odds ratio for the primary outcome (severe neurologic injury or death was higher in infants resuscitated with < 100% oxygen (AOR 1.36 (CI ). In the To2rpido study published only in abstract form (comparing resuscitation with 100% O2 to room air resuscitation) mortality was 16.2% in the room air group and 6.2% in the 100% oxygen group Rabi et al Resuscitation 2015

40 Toxic Effects Reactive Oxygen Species Free radicals contribute to brain injury in hypoxia-ischemia. The developing retina is prone to ROS-mediated injury leading to retinopathy of prematurity. Epithelial and endothelial cell in the lung may be damaged by by ROS, leading to impaired lung development.

41 What Should the Target PaO 2 or SaO 2 Be? Prevention of ROP Avoidance of BPD Lessening CNS injury Lessening mortality

42 Oxygen Saturation Targets & Outcomes SUPPORT COT BOOST II (UK, Australia and New Zealand)

44 From: Oxygen Saturation Target Range for Extremely Preterm Infants: A Systematic Review and Meta-analysis JAMA Pediatr. 2015;169(4): doi: /jamapediatrics Figure Legend: Date of download: 11/15/2015 Copyright 2015 American Medical Association. All rights reserved.

45 Pulse Oximeter Recalibration A design anomaly in the oximeter was noted part way through the trials, which thought to result in less separation of the saturation groups. In the BOOST II (Australia and UK) and COT trials the oximeter algorithm was changed to correct that artefact. After the algorithm revision in the BOOST II trial, infants in the lower target group spent approximately ~ 30% longer in their intended saturation range.

46 Death or Disability Original software SUPPORT 2012 COT 2013 BOOST NZ 2014 BOOST AUS 2016 BOOST UK 2016 N=3003 RR=1.00 (0.94, 1.07) Revised software COT 2013 BOOST UK 2016 BOOST AUS 2016 N=1681 RR=1.13 (1.02, 1.24) N=4684 RR=1.04 (0.98, 1.10)

47 Death by months Original software SUPPORT 2012 COT 2013 BOOST NZ 2014 BOOST UK 2016 BOOST AUS 2016 N=3087 RR=1.05 (0.91, 1.2) Revised software COT 2013 BOOST UK 2016 BOOST AUS 2016 N=1716 RR=1.38 (1.13, 1.68) N=4803 RR=1.16 (1.03, 1.30)

48 Necrotizing Enterocolitis SUPPORT 2012 COT 2013 BOOST NZ 2014 BOOST UK 2016 BOOST AUS 2016 N=4929 RR=1.24 (1.05, 1.47) RD=0.02 (0.01, 0.04) I 2 =0% NNT=46

49 Treated Retinopathy of Prematurity SUPPORT 2012 COT 2013 BOOST NZ 2014 BOOST UK 2016 BOOST AUS 2016 N=4089 RR=0.72 (0.61, 0.85) RD=-0.04 (-0.06, -0.02) NNH=24

50 Oxygen dependency at 36 weeks SUPPORT 2012 COT 2013 BOOST NZ 2014 BOOST UK 2016 BOOST AUS 2016 N=4175 RR=0.87 (0.81, 0.94) RD=-0.06 (-0.09, -0.03) NNH=17

51 There were no differences in: Outcome Relative Risk or Mean Difference* (95% CI) PDA requiring treatment 1.00 [0.95, 1.06] Days of ETT ventilation* [-1.36, 1.17] Cerebral palsy 1.02 [0.79, 1.32] Severe hearing loss 1.02 [0.73, 1.43] Bayley III cognitive score* 0.55 [-0.91, 2.00] Bayley III language score* 0.20 [-2.03, 2.43]

52 Oxygen Saturation Targets and Mortality Compared survival rates and causes between SGA and AGA infants in SUPPORT by assigned target saturation groups using Kaplan Meier Survival Analyses. There were 237 deaths in SUPPORT; 35.8% of the SGA infant died, while 16.4% of the AGA infants died. Mortality for AGA infants did not differ between saturation groups (17.6% v. 15.2%) SGA infants had almost twice the mortality in the lower v. higher saturation target group (lower target 56.1% & higher target-25.5%). Severe ROP was reduced in the lower saturation group (8.5% v. 16.5%) Walsh, DiFiore, Marin, Carlo. Grantz and Finer JAMA Pediatrics 2016

53 Oxygen Saturation Targets and Mortality Walsh, DiFiore, Marin, Carlo. Grantz and Finer JAMA Pediatrics 2016

54 The Conundrum of Intermittent Hypoxia

55 Hypoxic events (n/week) Hypoxemic Events are Common, But Do They Matter? Number of Desaturation Episodes in a Cohort of weeks Gestation 1, Postnatal age (weeks) Number of Desaturation Episodes in a Cohort of weeks Gestation Martin R et al Neonatology 2011

56 Hypoxemic events: Do they matter? Association between intermittent hypoxemia or bradycardia and late death or disability in extremely premature infants This was a post hoc analysis of infants enrolled in the Canadian Oxygen Trial. Hypoxemia was defined as a S P O2 < 80% or bradycardia < 80 bpm for 10 seconds. Primary outcome was the composite outcome of death after 36 weeks PMA, motor impairment, cognitive or language delay, severe hearing loss or blindness at 18 months corrected age Poets et al JAMA 2015

57 Hypoxemic events: Do they matter? Hypoxemic events were associated with an estimated late risk of death or disability at 18 months of 56.5% in the highest decile of hypoxemic exposure vs. 36.9% in the lowest decile RR 1.53 (CI ) Poets et al JAMA 2015

58 Probability of Late Death or Disability, % Hypoxemic events: Do they matter? Adverse Outcomes by Time with Hypoxemia (SpO2 < 80%) Adjusted Risk Gradient P < Time with SpO2 <80%, Percent

59 One Target Saturation Range is not Appropriate for all Clinical Situations

60 Recommendations for Oxygen Saturation Targets Understanding the saturation ranges that are associated with increased morbidity of mortality is not synonymous with pinpointing safe and unsafe saturation levels. The ideal saturation level may be different for various organ systems at varying gestational/postnatal ages. Until the results of NEOPROM are know, it seems prudent to maintain the SaO2 at 91-95%, but that may result in higher rates of ROP* Maintaining an infant in a given saturation can be difficult *Manley et al J Pediatrics 2016; University of Melbourne

61 Thank You

STOP ROP The STOP-ROP Multicenter Study Group: Pediatrics 105:295, 2000 Progression to Threshold Conventional Sat 89-94% STOP ROP

STOP ROP The STOP-ROP Multicenter Study Group: Pediatrics 105:295, 2000 Progression to Threshold Conventional Sat 89-94% STOP ROP Hrs TcPO2 > 80 nnhg (weeks 1 4) OXYGEN TARGETS: HOW GOOD ARE WE IN ACHIEVING THEM Oxygen Dependency GA wks Eduardo Bancalari MD University of Miami Miller School of Medicine Jackson Memorial Medical Center