Influential Articles in Neonatal Resuscitation

1. Influential Articles in Neonatal Resuscitation Henry C. Lee, MD, FAAP Lucile Packard Children’s Hospital Stanford, CA Steven Ringer, MD, PhD, FAAP Brigham and Women’s Hospital Boston, MA

2. Faculty Disclosure Information In the past 12 months, I have no relevant financial relationships with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services discussed in this CME activity.I do not intend to discuss an unapproved/investigative use of a commercial product/device in my presentation.

3. Session objectives • Discuss recent articles on evolving topics surrounding neonatal resuscitation • Discuss recent articles that may impact future neonatal resuscitation guidelines and practice

4. Topics to be discussed: • Encephalopathy / hypothermia • Periviable birth • Oxygen concentration for resuscitation • Cord clamping timing • Term • Preterm

5. Encephalopathy / Hypothermia • Hypothermia increases chance of better outcomes • Need for awareness of identification, appropriate diagnosis, and prompt therapy • Neurologic care may be next frontier for neonatology

6. Executive summary: Neonatal Encephalopathy and Neurologic Outcome, Second Edition, Report of the American College of Obstetricians and Gynecologists’ Task Force on Neonatal Encephalopathy. OB&GYN, April 2014; 123(4):896-901. PMID: 24785633 • Definition of neonatal encephalopathy – clinical syndrome of disturbed neurologic function in the earliest days of life in an infant born at or beyond 35 weeks gestation • Subnormal level of consciousness or seizures • Often accompanied by difficulty with initiating and maintaining respirations and depression of tone and reflexes

7. Signs consistent with acute peripartum or intrapartum event • Apgar score ≤ 5 at 5 and 10 minutes • (≥ 7 – unlikely to be hypoxia-ischemia) • Umbilical artery blood gas pH < 7.0 or base deficit ≥12 mmol/L • (> 7.20 – unlikely that intrapartum hypoxia played role) • Multisystem organ failure consistent with hypoxic-ischemic encephalopathy

8. Contributing factors consistent with acute peripartum or intraparum event • Sentinel hypoxic or ischemic event immediately before or during labor and delivery(such as ruptured uterus, abruption…) • Fetal heart rate monitor patterns (such as patient presenting with Category I pattern converting to Category III)

9. Magnetic resonance imaging / spectroscopy preferred • Ideal timing is between 24 and 96 hours after delivery • (with repeat at day 10 or later) • Timing of injury still requires further research

10. Hypothermia and Neonatal Encephalopathy. Committee on Fetus and Newborn. Pediatrics 2014;133(6):1146-50. PMID: 24864176 • Update from 2005 workshop / COFN commentary • Summary of randomized controlled trials of hypothermia • 6 trials ~1200 infants, head or whole body cooling • > 35 or 36 weeks, < 6 hours of birth • Target temperature 33.5 to 34.5 degrees C for 72 hours • Moderate to severe encephalopathy

11. Summary of large trials: • Reduction in death or major neurodevelopmental disability at 18 to 24 months by 24% (RR 0.76, 95%CI 0.69-0.84) • Number needed to treat: 7 • Areas of uncertainty: • < 35 weeks • Cooling initiation prior to transfer to cooling center

12. “Because the majority of infants who have neonatal encephalopathy are born at community hospitals, centers that perform cooling should work with their referring hospitals to implement education programs focused on increasing the awareness and identification of infants at risk for encephalopathy, and the initial clinical management of affected infants.”

13. Effects of Hypothermia for Perinatal Asphyxia on Childhood Outcomes. Azzopardi et al. (TOBY Study Group). NEJM July 10, 2014; 371(2):140-9. PMID: 25006720 • United Kingdom, original enrollment 2002 to 2006 • 325 newborns > 36 weeks • Previous study showed reduced cerebral palsy at 18 months • Current study: evaluation at 6 to 7 years of age

14. Testing: • Wechsler Scale of Intelligence (general measure of IQ) • Other assessments of neuro / psychosocial function • 15% loss to follow-up; 30% died

17. Optimal therapy requires prompt identification and initiation of protocols. • Kracer JPEDS 2014; 165(2):267-273.

18. Changes You May Wish to Make in Practice • Educate others about hypothermia therapy for moderate to severe neonatal encephalopathy. • Develop procedures for identification and early clinical care for patients eligible for hypothermia.

19. Periviablebirth • What is the appropriate minimum gestational age for attempting resuscitation?

20. Does GA affect neurodevelopmental outcomes for ventilated infants who survive to discharge home?

21. 199 infants at one NICU between 23 to 28 weeks GA • Limited to infants who required mechanical ventilation

22. Outcomes did not vary by GA for those who survived

23. “In the US… resuscitation of infants born at 24 weeks or below is considered optional. Our data suggest that these policies make sense only if “trying and failing” in the NICU is deemed to have no moral worth.”

24. JAMA 2011;306(21) • Previous trials on antenatal steroids have been limited in addressing the most preterm infants (22 to 25 weeks) • Should steroids be given prior to birth before 24 weeks?

25. NICHD Neonatal Research Network • 1993 to 2009 • Born between 22 to 25 weeks, BW 401-1000 grams • 1848 total infants

27. At 18 to 22 month f/u – death or neurodevelopmental impairment was less frequent when exposed to antenatal steroids: • Odds ratio 0.60 (95% CI 0.53-0.69)

29. Overall intact survival low even with steroids (35.8%) • Limitation – observational study – could be biased by intentions of parents / clinicians • Higher rate of BPD for those exposed to antenatal steroids

30. Periviable BirthExecutive Summary of a Joint Workshop by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, American Academy of Pediatrics, and American College of Obstetricians and Gynecologists – May 2014 • “periviable period” • 20 0/7 weeks – 25 6/7 weeks • Purpose: guide management and counseling issues

33. “When counseling parents, it is appropriate to present the data regarding the rate of survival and long-term disabilities separately, since the parents’ perspectives and the importance they give these may be different. Physicians should recognize that the parents’ views on what is “severe” disability may be different from those of the researchers or clinicians…”

34. “Because most newborns at 24-25 weeks of gestation will survive if resuscitated, efforts to prolong pregnancy, intrapartum interventions for fetal benefit, and neonatal resuscitation should generally be offered, if appropriate.”

36. Letter to EditorJeffrey Perlman, MB, ChBObstetrics & Gynecology Sept 2014 • “… concern – Table 3 particularly troubling … omission of a parent representative group, a critical stakeholder.” • “All studies referenced raise serious concerns for risk of bias for all outcomes…”

37. Dr. Perlman – • “… fetal outcomes at 23 to 23 6/7 weeks are distinctly different from those of larger fetuses. • Two possible recommendations: • Recommend against routine administration of interventions for 23 – 23 6/7 weeks except under special circumstances • All interventions may be considered (low quality of evidence) in accordance with parent preferences) • Recommend GRADE (Grading of Recommendations Assessment, Development and Evaluation) process rather than expert opinion.

38. Dr. Keith Barrington’s Neonatal Research blog • “Executive Summary… overall a reasonable reflection of our discussions, but… some disagreement.” • Table 3 – cesarean delivery is not recommended for fetal indications up to and including 22 weeks and 6 days, but then suddenly becomes recommended at 23 weeks and 0 days.

39. Dr. Keith Barrington • We do not know exact GA (except in IVF) • “This recommendation must be nuanced and take into account the particular clinical circumstances of the mother, and her values and desires.”

41. Changes You May Wish to Make in Practice • Discuss issues surrounding periviable birth with a multi-disciplinary team. • Be able to counsel parents before and after extremely preterm birth.

42. What is the correct oxygen concentration to initiate resuscitation for preterm infants? • 21% • 30% • 60% • 90% • 100%

43. NRP 5th ed. 2005/2006 • Preference of 100% O2 with vigilance and adjustment down • Allowance of less O2 ok • Recommend pulse oximetry • NRP 6th ed. 2010/2011 • Titrate O2 to achieve saturation goals similar to term infants • No specific oxygen concentration recommended (probably not 100%, probably not 21%)

45. Kapadia VS, Chalak LF, Sparks JE, Allen JR, Savani RC, Wyckoff MH. Resuscitation of preterm neonates with limited versus high oxygen strategy. Pediatrics 2013;132(6):e1488-96. PMID: 24218465 • Testing initial FiO2 of 21% vs 100% and titrating by 10% every 30 seconds to meet NRP goals • Primary outcome: total hydroperoxide(TH), biological antioxidant potential (BAP), BAP/TH

46. Protection Against Oxidative Stress and “IGF-I Deficiency Conditions” Munoz Biochemistry, Genetics and Molecular Biology 2012

47. Eligible infants 24 to 34 weeks GA • Due to equipoise, antenatal consent not needed as long as consent obtained subsequently • Treatment failure: HR < 60 despite 30 seconds of effective PPV  100% FiO2

49. Total hydroperoxide higher in high oxygen group at first hour after birth