Evidence for Oxygen Use in Preterm Infants

Transcription

1 Evidence for Oxygen Use in Preterm Infants Michele Walsh, MD, MS Epi Professor of Pediatrics Case Western Reserve University Cleveland Ohio USA 1

2 Learning Objectives q Review the evidence for oxygen in the resuscitation and care of neonates. q Define the gaps in current evidence q Describe common misuses of oxygen. q Discuss evidence for the contribution of oxygen toxicity to the development of BPD. 2

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4 Oxygen q Priestly discovered oxygen in q First tested it on mice, who surprised him by surviving quite a while entrapped with the air, and then on himself. q Writing that it was "five or six times better than common air for the purpose of respiration, inflammation, and, I believe, every other use of common atmospherical air" Experiments and Observations on different kinds of air Quoted in Wikipedia. 4

5 Wilson, et al q Routine use of supplemental oxygen (>70%) overcame the irregular respiratory pattern of short gestation infants q Widespread use of unrestricted oxygen for small or sick infants in 1950s. Cooperative Trial q Hypothesis: Reduced oxygen will prevent retrolental fibroplasia q Randomized infants <1500g Routine oxygen >50% oxygen for 28 days. Curtailed oxygen- added oxygen at the clinician s discretion, but not > 40-50%. q Results interpreted as showing that oxygen therapy was safe, so long as FiO 2 not >40%. q Not until 1973 was it recognized by Cross that more infants may have died or been disabled in the curtailed oxygen arm. 5

6 Oxygen Therapy: 50 Years of Uncertainty Oxygen therapy must have been given to more infants than any other medicinal product in the last 60 years. Despite that, we still know very little about how much infants actually need, or how much it is wise to give.the depth of our ignorance is really quite embarrassing. W. Tin, Pediatrics 2002 How Might Oxygen be Harmful? q Free radical generation q Cytokine elaboration q Permanent disruption of alveolar development 6

7 Mechanisms of Oxygen Toxicity Superoxide Hydrogen Peroxide Hydroxyl free radical Singlet Oxygen Antioxidant Defenses Lipid: alter cell membranes DNA: breakage, cross linkage Protein: inactivate enzymes Permanently disrupt Alveolar architecture Brief oxygen exposure permanently disrupts type II alveolar cell development Panel A: Clara cell protein in red, Green colocalizing with pro-spc. Panel B: Red= pro- SP B. Yee M, et al. AJP lung 291: L1101;

8 Defenses Against Oxygen Toxicity q Glutathione peroxidase q Super Oxide Dismutase q Catalase q Alpha 1 Antitrypsin q Vitamin A, Vitamin E, β- carotene Maturation parallels surfactant system Late Gestational Changes in Anti- Oxidant Enzyme Activity % Change In Enzymes Rabbit Rat Hamster SOD Catalase GSH 8

9 Developmental lack of IL Time IL-8 Time IL-10 Term Preterm Jones, 1996 Phases of Neonatal Care- What is known about optimal oxygen? q Resuscitation q Acute Care of Respiratory Disease q Care of Convalescent Neonates 9

10 Resuscitation FIGURE 2 Proportions of newborn infants who were ventilated with room air at each time point after delivery in the low-oxygen (Lox) group (initial FIO2: 30%) and the highoxygen (Hox) group (initial FIO2: 90%) Escrig, R. et al. Pediatrics 2008;121: Copyright 2008 American Academy of Pediatrics 10

11 FIGURE 2 Mean SpO2 at each minute of life Wang, C. L. et al. Pediatrics 2008;121: Copyright 2008 American Academy of Pediatrics 2010 International Consensus q For infants < 32 wks, room air is not sufficient but 100% oxygen leads to hyperoxia. q Resuscitation with 30%-90% FiO2 AND titration to oxygen saturation is optimal. q For infants weeks, there is insufficient evidence to define the best strategy. Evidence = Level 2A Perlman et al. Circulation 2010: 122: S516-S538 11

12 Respiratory Distress Syndrome Oximetry Ranges and Outcome W Tin, et al. Arch Dis Child Fetal Neonatal Ed Tin, Arch Dis Child

13 Trials: q SUPPORT: NICHD NRN Oxygen saturation arm randomized to 88-92% versus 92-95%. Completed: NEJM q Australian Study: Enrolling Uses same saturation targets q European Study: Enrolling Uses same saturation targets SUPPORT: Saturation Arm q Does a lower saturation target (85-89%) compared to a higher saturation target (91-95%) lead to better outcomes in ELGAN? 13

14 Background q Retinopathy of prematurity (ROP) continues to be an important cause of blindness q Observational data suggest that saturations in the lower limits of common clinical practice (83 or 85%) may reduce ROP but not tested in RCTs q RCTs of oxygen restriction to reduce ROP conducted in the 1950s resulted in increased mortality in the lower oxygen group Hypothesis A lower O 2 saturation target range (85 to 89%) compared to a higher O 2 saturation target range (91 to 95%) reduces the incidence of the composite outcome of severe ROP or death among infants of 24 0/7 to 27 6/7 weeks gestational age 14

15 Methods Intervention (1) q Infants were randomized to: lower saturation targeting (85 to 89%) or; higher saturation targeting (91 to 95%) q Oxygen saturations were monitored with electronically-altered Masimo Radical Pulse Oximeter Actual Median Oxygen Saturation (%) Percent of Infants (%) % oxygen saturation target 85-89% oxygen saturation target Percent of O 2 saturation (%) 15

16 Results Primary Outcome Lower Saturation Group N=654 Higher Saturation Group N=662 Adjusted Relative Risk (95% CI) Severe ROP/death 28.3% 32.1% 0.90 (0.76, 1.06) Severe ROP 8.6% 17.9% 0.52 (0.37, 0.73) NNT=11 Death 19.9% 16.2% 1.27 (1.01, 1.60) NNH=27 Survivor Function Estimate (%) Survival Curve for Mortality % oxygen saturation target 85 89% oxygen saturation target Survival Time in Days Hazard ratio 1.32 (CI 1.01, 1.72) p=

17 Results BPD and other pulmonary outcomes Lower Saturation Group N=654 Higher Saturation Group N=662 Adjusted Relative Risk (95% CI) BPD (O 2 use at 36 w) 37.6% 46.7% 0.82 (0.72, 0.93) BPD (O 2 use) or death, 36 w 48.5% 54.2% 0.91 (0.83, 1.01) BPD (phys), 36 w 38.0% 41.7% 0.92 (0.81, 1.05) BPD (phys) or death, 36 w 48.8% 50.0% 0.99 (0.90, 1.10) Pneumothorax 7.2% 6.5% 1.12 (0.74, 1.68) Any air leaks (14 days) 7.8% 6.3% 1.23 (0.83, 1.83) Postnatal steroids for BPD 9.6% 10.7% 0.91 (0.67, 1.24) Summary q O 2 saturation targeting in the range of 85-89% did not affect severe ROP/death q O 2 saturation targeting in the range of 85-89% resulted in a significant reduction in severe ROP (17.9 to 8.6%, NNT = 11) q However, mortality was significantly increased in the 85-89% target group (19.9 versus 16.2%, NNH = 27) 17

18 Care of the Convalescent Premature Infant Stop-ROP q Randomized infants with pre-threshold ROP Mean age at enrollment 35.4 weeks PMA q Saturation ranges: 88-94% vs 96-99% q No difference in progression of ROP q No difference in growth q Increased adverse pulmonary events at 3 months corrected age. Pediatrics. 2002;110:

19 3 Month Outcomes in STOP-ROP 89-94% 96-99% Hospitalized (%)* On oxygen (%)** Adverse pulmonary event * p=0.012, **p=0.02, +p=0.005 Pediatrics. 2002;110:540-4 BOOST Trial q Can higher oxygen saturation improve outcomes? q Preterm neonates < 30 wks q If still in oxygen at 2 wks of age, randomized to 91-94% vs 95-98%. q No difference in: Growth or neurodevelopment at 12 mos of age Askie, NEJM, Sept

20 BOOST Trial 88-94% 95-99% Duration of O 2 * 18 d 40 d O 2 at 36 wks* 46% 64% Discharge in O 2 * 17% 54% Askie, NEJM, Sept 2003 Physiologic Definition of BPD q Clinical definition of BPD problematic because it assumes that all MDs prescribe the same oxygen targets. q Wide variation in oxygen targets and threshold for oxygen treatment. Ellsbury DL, J Perinatol. 2004;24:

21 Physiologic Definition of BPD q Challenged selected infants <1250 gm at birth, still in <30% oxygen at 36 wks corrected age at 16 centers. q Calculated the effective FiO 2 q Weaned in stepwise increments to room air so long as saturation stayed >90%. Clinical vs Physiologic Definition: Clinical Definition Physiologic Definition BPD 559 (35%)* 397 (25%)* No BPD TOTAL * p <

22 Variation in Impact Among Sites 70 Frequency (%) Clinical Physiologic P < for variation among sites Why Does Oxygen Use Vary? q No standard definition of acceptable saturations. q Delivery of oxygen by nasal cannula led to enormous differences in practice between physicians and between centers. Clinicians overestimate oxygen delivered resulting in extra days equivalent to room air q Use of oxygen for extra-pulmonary indications: apnea promotion of growth retinopathy of prematurity 22

23 Evidenced Based Practice What can we do? q Resuscitate with targetted FiO 2 and saturation monitor q Transport on blended oxygen and pulse ox q Re-evaluate saturation targets In the NICU q CAUTION: may not be as simple as it seems to reset targets increased alarms increased frequency and severity of desaturation 23

24 What Saturation Target to Use q Target 85% to 95% q Await results of SUPPORT 2 year outcomes-? Is there developmental harm with lower sat? q Await results of European and Australian trials What can we do now? q Limit repeated hyperoxic exposures and question routine practices:?increased oxygen for desaturations?increased oxygen for suctioning?increased oxygen for hands on care 24

25 What Can We Do Today? q Create a NICU culture that is less comfortable with hyperoxia, more tolerant of brief desaturations. q Use pulse oximetry technology that generates a histogram of saturation to accurately reflect distribution of saturations. 25