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Randomized Trial of Oxygen Saturation Targets in Premature Infants - the SUPPORT Trial

Randomized Trial of Oxygen Saturation Targets in Premature Infants - the SUPPORT Trial. NICHD. The SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network.

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Randomized Trial of Oxygen Saturation Targets in Premature Infants - the SUPPORT Trial

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  1. Randomized Trial of Oxygen Saturation Targets in Premature Infants - the SUPPORT Trial NICHD The SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network Randomized Trial of Early CPAP With Limited Ventilation Versus Surfactant and Conventional Ventilation in Extremely Preterm Infants - The SUPPORT Trial The SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network

  2. Background • Surfactant treatment at less than 2 hours of life significantly decreases death, air leak, and death or bronchopulmonary dysplasia (BPD) in preterm infants - but not BPD alone • However, no surfactant studies had a comparison group who received early CPAP • Retrospective cohort studies demonstrated that the early use of CPAP in very preterm infants with respiratory distress may decrease mechanical ventilation without increased morbidity and without surfactant

  3. Permissive Hypercapnia: Background - Rationale • Maintenance of normocapnia in some patients with severe respiratory failure necessitates high ventilatory support • Compensated respiratory acidosis is generally well tolerated and may reduce lung injury • Clinical studies show trend or significant benefits of a limited ventilation strategy with permissive hypercapnia

  4. Hypothesis Early CPAP with a limited ventilator strategy would reduce the incidence of death or survival with BPD at 36 weeks compared to early surfactant

  5. Method – Patients • Inborn infants of 240/7 to 276/7 weeks gestation for whom a decision had been made to provide full resuscitation were eligible • Antenatal Parental consent was obtained • Enrollment from February 2005 to February 2009 • Randomization was stratified by center and by gestational age (24 and 25 weeks; 26 and 27 weeks)

  6. Factorial Design Infants also randomized to 2 ranges of SpO2 using purpose-built blinded oximeters

  7. CPAP Intervention • In the delivery room, CPAP at 5 cm H2O was provided until NICU admission using a T-piece resuscitator, a neonatal ventilator, or an equivalent methodology • Intubation only for infants who required intubation for resuscitation based on standard NRP indications, not performed for the surfactant administration • Intubated infants given surfactant

  8. Methods

  9. Methods: Extubation CriteriaWithin 24 hrs of meeting all criteria Ventilator rate < 20 bpm Hemodynamically stable

  10. Methods – Duration of Intervention • The criteria for both arms were in effect for the first 14 days of life, following which the infant was treated as per NICU standard practice. • For both arms, intubation could be performed at any time for the occurrence of repetitive: 1. apnea requiring bag and mask ventilation 2. clinical shock 3. sepsis, and/or 4. the need for surgery

  11. Methods – BPD Definitions • For the primary outcome, BPD was defined using the physiologic definition: - receipt > 30% oxygen at 36 weeks - need for positive pressure support - if FiO2 < 30%, oxygen withdrawal performed • Pre-specified secondary outcomes included the evaluation of BPD defined by the receipt of oxygen at 36 weeks.

  12. Methods – Sample Size Estimate • Baseline rate of BPD/Death of 50% • Absolute risk difference of 10% • Increased by 1.12 to allow for multiples randomized to same treatment • Increased by 1.17 to adjust for attrition • Increased further to minimize Type I error using a conservative 2% level of significance • Final sample size was 1310 infants

  13. Methods – Data Analysis • The primary and categorical outcomes were analyzed using Poisson regression implementation in a Generalized Estimating Equation (GEE) model to obtain adjusted relative risk and 95% CI • Continuous outcomes were analyzed using mixed effects linear models to produce adjusted means and standard errors • Adjustment was performed for pre-specified stratification (center and GA) and for familial clustering as multiple births were randomized to the same treatment arms

  14. 3546 Infants were assessed for eligibility (3127 pregnancies)* • 235 Did not meet eligibility criteria • Personnel/Equipment not available • 699 Eligible but consent not sought • 344 Parent unavailable for consent • Consent denied by parent or guardian • 11 Excluded for other reasons • 68 Consented but not randomized 1316 Underwent randomization 663 Were assigned CPAP 653 Were assigned Surfactant 94 Died before discharge 569 Survived to discharge, transfer one year of life 114 Died before discharge 539 Survived to discharge, transfer or one year of life 320 No BPD Physiologic 223 BPD Physiologic 346 No BPD Physiologic 219 BPD Physiologic

  15. Results – Patient Population *Mean ± Standard Deviation

  16. Results – Primary Outcome

  17. Results – Delivery Room

  18. Results – Other Pre-specified Outcomes * = p<0.05

  19. SUPPORT – Other Results No differences in the incidence of: • PDA, PDA requiring surgery • NEC, medical or surgical • Severe IVH/PVL • In the 24 to 25 weeks strata CPAP infants had a lower mortality than Surfactant infants: CPAP 23.9% vs Surfactant 32.1% Relative Risk difference 0.74 (0.57, 0.98)

  20. Causes of Death – 24-25 wk Strata

  21. SUMMARY • There was no significant difference for primary outcome of death or BPD • More CPAP infants were alive and off mechanical ventilation by day 7 (p=0.011) • CPAP infants received less postnatal steroids for BPD (p<0.001) and required fewer vent days (p=0.03) • CPAP Infants 24 to 25 6/7 weeks had a significantly lower mortality rate while hospitalized (p<.01) • CPAP infants did not have increased morbidities

  22. CONCLUSIONS • Early CPAP with a limited ventilator strategy for the extremely low birth weight infant is associated with decreased exposure to intubation and mechanical ventilation, decreased death in the most immature infants, without any increase in measured morbidities • All surviving infants will be followed to 18-22 months for a complete neurodevelopmental assessment

  23. What about other major trials of early CPAP/permissive hypercapnia?

  24. RCT of CPAP vs. Ventilation (COIN Trial): Methods Design: Multicenter RCT Subjects: 25 0/7 to 28 6/7 week infants, breathing at 5 min. Intervention: CPAP at 8 cmH2O vs. intubation/surfactant Intubation criteria for CPAP group pH< 7.25 PaCO2 > 60 mmHg; FiO2 > 0.60; and/or apnea Morley et al. NEJM 358; 700, 2008

  25. RCT of CPAP vs. Ventilation (COIN Trial) 610 subjects, 960 ± 215 gm, 94% got ANS CPAP Intubation RR CI p value N=307 N=303 BPD 28d/death 54% 65% 0.63 0.46 - 0.88 <0.05 BPD 36w/death 34% 39% 0.80 0.58 - 1.12 NS Pneumothorax 9% 3% <0.001 Days on ventilator 3 4 <0.001 Pneumothorax rate increased in the CPAP group (3 to 9%, p<0.003) Mortality, days of ventilatory support, days of O2, hospital stay, IVH ¾, PVL, NEC, PDA ligation, ROP, home O2 and steroid treatment did not differ between the groups Morley et al. NEJM 358; 700, 2008

  26. RCT of CPAP vs. Ventilation (CURCPAP Trial) Sandri et al. Pediatrics 125;31402, 2010

  27. RCT of CPAP vs. Ventilation (Rojas Trial) • 279 infants from 27 to 31 wks • Compared CPAP to intubation/surfactant and extubation within 1 hr of birth • CPAP group had lower BPD/death rates 54 vs 63% (NS) • Air leaks higher in CPAP – 9% vs 2% Rojas et al – Pediatrics 2009;123:137-42

  28. RCT of CPAP vs. Ventilation (VON Trial ) Soll et al PAS Vancouver 2010

  29. Early CPAP vs Surfactant in Very Low Birth Weight Infants J. Tapia. PAS 2010

  30. Results - Demographic Variables Minimal Vent Routine Vent p value (N=109) (N=111) Birth weight (gm) 742 ± 130 728 ± 135 NS Gestational age (wk) 25 ± 2 25 ± 2 NS Antenatal steroid (%) 74 75 NS Surfactant (%) 98 96 NS Male (%) 48 56 NS Race (%) B/W/O 46/39/15 48/43/9 NS Randomization age (hr) 6.5 ± 3.0 7.1 ± 2.8 NS Carlo et al. J Pediatr 41:370, 2002

  31. Results - Primary Outcome Measures SAVE Trial Minimal Routine Ventilation Ventilation RR CI (N=109) (N=111) Mortality or BPD (%) 63 68 0.93 (0.77-1.12) Mortality (%) 23 22 1.06 (0.65-1.74) BPD (%) 52 60 0.88 (0.67-1.14) Carlo et al. J Pediatr 41:370, 2002

  32. Results - Secondary Analyses SAVE Trial Minimal Routine Ventilation Ventilation RR CI NNT Ventilation at 36 wk (%) 1 16 0.09 (0.01-0.67)* 7 BPD or death in 501-750 gm (%) 68 86 0.79 (0.65-0.96)* 6 *p<0.05 Carlo et al. J Pediatr 41:370, 2002

  33. SAVE Trial Results - Long-term Follow-up Minimal Routine Ventilation Ventilation RR CI Death or NDI (%) 64 68 0.9 (0.8-1.2) NDI (%) 51 55 0.9 (0.7-1.3) CP (%) 11 20 0.55 (0.2-1.2) Carlo et al. J Pediatr 41:370, 2002

  34. Summary of Major Trials of Early CPAP and/or Permissive Hypercapnia BPD/Death CPAP/PHC Experimental Control ARR Carlo (2002) 63% 68% 5% Morley (2008) 34% 39% 5% Rojas (2009) 54% 63% 9% Soll (2010) 30% 36% 6% Finer (2010) 48% 51% 3% Neocosur/Tapia (2010) 15% 19% 4% CURPAP/Sandri (2010) 21% 22% 1%

  35. Summary of Major Trials of Early CPAP and/or Permissive Hypercapnia Preliminary meta-analysis SUPPORT, COIN, VON, Neocosur, CURPAP and Rojas BPD/Death CPAP/PHC Control 624/1568 (40%) 689/1538 (45%) RR 0.88 95% CI 0.81; 0.96

  36. Early CPAP vs Early Surfactant – ELBW Infants Death or BPD at 36 Weeks Study CPAP Surfactant OR (fixed) OR (fixed) or sub-category n/N n/N 95% CL 95% CL COIN NEJM 104/307 118/303 0.80 (0.58, 1.12) CURPAPS Peds 5/103 5/105 1.02 (0.29, 3.64) SUPPORT NEJM 323/663 353/653 0.81 (0.65, 1.00) VON 2010 68/223 138/425 0.91 (0.64, 1.29) Total (95%, CI) 39%/1296 41%/14860.83 (0.71, 0.97) Total events: 500 (CPAP), 614 (Control) Test for heterogeneity: ChF=0.48, df=3 (P=0.92), F=0% Test for overall effect: Z=2.28 (P=0.02) 0.1 0.2 0.5 1 2 5 10 Favours treatment Favours control Finer 2010.

  37. Early CPAP vs Early Surfactant – ELBW Infants Death at 36 Weeks Study CPAP Surfactant OR (fixed) OR (fixed) or sub-category n/N n/N 95% CL 95% CL COIN NEJM 20/307 18/303 1.10 (0.67, 2.13) CURPAPS Peds 11/103 9/105 1.28 (0.51, 3.22) SUPPORT NEJM 94/663 114/653 0.78 (0.68, 1.06) VON 2010 9/223 30/425 0.66 (0.26, 1.19) Total (95%, CI) 10%/1296 12%/1486 0.82 (0.64, 1.04) Total events: 134 (CPAP), 171 (Surfactant) Test for heterogeneity: ChF=2.78, df=3 (P=0.43), F=0% Test for overall effect: Z=1.64 (P=0.10) 0.1 0.2 0.5 1 2 5 10 Favours treatment Favours control Finer 2010.

  38. Early CPAP vs Early Surfactant – ELBW > 27 weeks – Death or BPD at 36 Weeks Study CPAP Surfactant OR (fixed) OR (fixed) or sub-category n/N n/N 95% CL 95% CL COIN NEJM 51/207 62/198 0.72 (0.46, 1.11) CURPAPS Peds 22/72 18/73 1.34 (0.65, 2.79) SUPPORT NEJM 144/378 165/373 0.78 (0.58, 1.41) VON 2010 68/223 138/425 0.91 (0.64, 1.29) Total (95%, CI) 32%/880 36%/1069 0.83 (0.69, 1.01) Total events: 285 (CPAP), 383 (Surfactant) Test for heterogeneity: ChF=2.59, df=3 (P=0.46), F=0% Test for overall effect: Z=1.86 (P=0.06) 0.1 0.2 0.5 1 2 5 10 Favours treatment Favours control Finer 2010.

  39. So What Should I Do In My Daily Practice? Suggestions for ELBW/ELGAN Infants • Use CPAP instead of intubation and surfactant as the mode of initial support • If intubated (FiO2 > 50%,PCO2 >65, pH < 7.20, others): give surfactant • Attempt to wean the ventilator if PCO2 < 55-65, pH > 7.20, FiO2 < 50%

  40. Thanks to the many parents, infants, and NICU staffSpecial Thanks to the Research Coordinators of the NRNStudy Funded by the NICHD and NHLBI

  41. NICHD Neonatal Research Network Centers (2005-2009) Brown University Case Western Reserve Univ Duke University Emory University Indiana University RTI International Stanford University Tufts Medical Center University of Alabama – Birmingham University of California – San Diego University of Cincinnati University of Iowa University of Miami University of New Mexico University of Rochester University of Texas, Southwestern – Dallas University of Texas – Houston University of Utah Wake Forest University Wayne State University Yale University

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