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

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1 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 CARE OF THE SICK NEWBORN 2015 Postnatal age (weeks) Infants born at UM-JMH, GA 24-31w Years NONE MILD MODERATE-SEVERE Flynn J, Bancalari E, NEJM 1992 ROP Severity (N= 101) STOP ROP The STOP-ROP Multicenter Study Group: Pediatrics 105:295, 2000 Progression to Threshold Conventional Sat 89-94% Supplemental Sat 96-99% ALL 48% 41% Non plus disease OR 0.72 ( ) 46% 32% STOP ROP The STOP-ROP Multicenter Study Group: Pediatrics 105:295, 2000 Conventional Supplemental Pneumonia or Pulmonary Deterioration 8.5% 13.2% Hospitalized at 50 wks PMA 6.8% 12.7% On Oxygen at 50 wks PMA 37.0% 46.8% On Diuretics at 50 wks PMA 24.4% 35.8% 1

2 # of Desaturations (per week) BOOST TRIAL OUTCOME BPD (O2 at 36 weeks PMA) (%) Duration of oxygen therapy after randomization (Days /Median) Worst ROP (%) < Stage 3 Stage 3 or 4 Ablation Askie et al. NEJM Sept infants enrolled at 32 weeks PMA targets: vs Standard N=178 Bwt 918g High N=180 Bwt 916g 82 (46) 116 (64) < < (84) 28 (16) 20 (11) 158 (88) 22 (12) 11 (6) P Model Based Estimate of Desaturation Episodes in Infants with and without Laser Therapy for ROP Adjusted for gestational age, race, sex, multiples and SNAPPE-II Score LaserROP (n=16) No LaserROP (n=63) Postnatal Age (wks) p<.05 Mean± 95% confidence Interval J DiFiore, J Pediatr 2010 Lung tissue section (autopsy) from a term + 5 months child. Lung tissue section (biopsy) from an infant treated with prenatal steroids and postnatal surfactant born at 28 wks gestation and underwent an open lung biopsy 8-months after birth. Coalson JJ. Seminars in Neonatol, 2003; 8: Contrasting light microphotographs of lung parenchyma of RA and O 2 exposed rats. Shaffer SG et al. Pediatr Res, 1987; 21: Ten day old SD rats exposed to RA or O2 for 2-8 weeks Control RA OXYGEN AND THE BRAIN FiO2 0.8 Wilson WL et al. Pediatr Res, 1985; 19:

3 Distribution pattern, time, and age dependency of hyperoxia-induced apoptosis in infant rats Multivariate odds ratios for DCP with 95% CI and test of significance for risk factors Risk factor Model 1 (N=400) Model 2 (N=400) Model 3 (N=390) Model 4 (N=336) Cumulative hypocapnia 2.9 (1.6, 5.5) p= (1.1, 4.5) p= (1.0, 4.7) p= (1.1, 6.4) p= 0.03 Cumulative hyperoxemia 2.5 (1.3, 5.1) p= (1.1, 5.2) p= (0.9, 5.0) p= 0.10 Prolonged ventilation 2.9 (1.5, 5.6) p= (0.9, 5.9) p= (1.0, 8.9) p= 0.04 Gestational age 0.9 (0.6, 1.5) p= (0.7, 1.5) p= 0.59 Felderhoff-Mueser, U et al. Neurobiol Disease 2004; 17(2): From Collins, MP et al. Ped Res 2001; 50(6): Resuscitation of the Newly Born with Room Air or 100% O 2 Neonatal Death Term Preterm Odds Ratio Supplemental Oxygen for Preterm Infants: A Difficult Balancing Act CNS hypoxia-damage Multi organ/tissue hypoxia Pulmonary vasculature Ductus arteriosus Impaired growth Increased mortality? Lung injury-bpd Retinal damage-rop CNS damage Oxidative stress Increased mortality? Apgar score 1 min <4 Too Little Too Much Favoring 21% Favoring 100% Odds ratio and confidence intervals for neonatal death in term, preterm (>1,000g) and the most depressed infants (1-min Apgar <4). Odds ratio <1 indicates a favorable effect of 21% O2 compared with 100% O2. Saugstad OD et al. Biol Neonate 2005;87:27-34 SUPPORT Trial 1316 infants, weeks gestational age, O 2 saturation target 85%-89% vs 91%-95% ROP Lower O 2 Group n/n (%) Higher O 2 Group n/n (%) Adjusted Relative Risk (95% CI) Severe ROP 43/483 (8.9) 95/514 (18.5) 0.51 (0.37, 0.71) BPD (oxygen at 36 weeks) 203/540 (37.6) 265/568 (46.7) 0.82 (0.72, 0.93) BPD (physiologic) at 36 weeks 205/540 (38.0) 237/568 (41.7) 0.92 (0.81, 1.05) Death 130/654 (19.9) 107/662 (16.2) 1.27 (1.01, 1.60) SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network. N Engl J Med. 2010;362:

4 BPD NEC Mortality How good are we keeping oxygen targets? Achieved Versus Intended Pulse Oximeter in Infants Born Less Than 28wks The AVIOx Study Higher vs. Lower Arterial Oxygen s in Extremely Preterm Infants 14 Centers using different saturation targets Percent time Below target 16 (0-47) Within target 48 (6-75) Above target 36 (5-90) Hagadorn et al. Pediatrics 2006 Schmidt B et al. JAMA 2013; 309:

5 FiO2 SpO2 Why are we so bad in keeping oxygen targets? Blood oxygen level fluctuates constantly: Require continuous attendance and tight alarm settings Delayed response: Desensitization to frequent alarms Lack of buy-in by staff, unknown consequences of transient deviations More concern with hypoxemia than hyperoxemia Response not always appropriate for the mechanism of the hypoxemia Claure et al. J Pediatr 2009 Nurse: patient ratio and achievement of oxygen saturation goals in premature infants PaO 2 vs. SpO 2 Castillo et al, Pediatrics 2008 Quine et al, ADC FN Ed 2008 Sink DW, et al. Arch Dis Child Fetal Neonatal Ed (2010). Online First doi: /f2 of 6 adc How can maintenance of oxygen targets be improved? Develop clear unit guidelines for oxygen monitoring and targets Set alarms on target range Minimize factors that induce fluctuations in oxygenation Continuous education of medical and nursing personnel Proper nurse patient ratio Monitor incidence of pathologies associated with hyperoxia Automated systems for oxygen control Efficacy of Automated FiO2 Control % time within target Cl. loop Manual Type Beddis, 1979 Dugdale, 1988 Bhutani, 1992 Morozoff, 1992 Morozoff, 1993 Sun, 1997 Claure, 2001 Urschitz, 2004 Morozoff, 2009 Claure, 2009 Claure,

6 % of 24 hours Disclosure 50 Manual 40 Automated The University of Miami, Drs. Claure and Bancalari have a patent on the algorithm for automated adjustment of inspired oxygen and a licensing agreement with Carefusion Clio studies have been supported by Carefusion 10 0 < 75% < 87% 87-93% > 93% (@O2>21%) > 98% (@O2>21%) :p<0.001 Paired t-test (mean±sd) :p=0.003 Wilcoxon Signed Rank Test (median, IQR) SpO 2 Claure et al. PAS 2009 Prolonged episodes with SpO 2 below intended range Workload:FiO 2 adjustments SpO 2 < 85% (>120s) SpO 2 < 75% (>60s) Manual Automated Standard Automated :p<0.001 Paired t-test (mean±sd) :p<0.001 Paired t-test (mean±sd) :p=0.001 Wilcoxon Signed Rank Test (median and 25 th 75 th percentile) Claure et al. PAS 2009 Limitations Automated FiO 2 is dependent on pulse oximetry accuracy Observed differences in this study are relative to the effectiveness of the standard of care Automated FiO 2 should not substitute more appropriate interventions (e.g. in hypoventilation) Automated FiO 2 may give excessive sense of confidence and lead to reduce attentiveness 6

7 Oxygenation Targets: Can they be achieved? Surely can do better with oxygen targets, but Arterial oxygen levels fluctuate constantly in preterm infants and maintenance of targets is a tedious and demanding task Fluctuations can be produced by different mechanisms that require specific interventions While hypoxemic episodes are usually related to patient issues, hyperoxemia is always induced by excessive inspired oxygen Infants are seldom hyperoxic on room air Need to define the best targets and the short and long term consequences of fluctuations in oxygenation What oxygen targets should we use? Avoid hyperoxemia: Keep PaO2 <80 mmhg SpO2 under 95-97% Avoid hypoxemia: Keep PaO2>40mmHg SpO2 over 88-90% Keep higher SpO2 in infants with ROP or BPD? Keep in mind limitations of SpO2 in predicting PaO2 7