1. Meltem Seli M.D. Division of Perinatal Medicine Yale University TJOD 2015

2.  Perinatal Asphyxia or Neonatal encephalopathy is a clinically defined syndrome of disturbed neurologic function in the earliest days of life in an infant born at or beyond 35 weeks of gestation, manifested by a subnormal level of consciousness or seizures, and often accompanied by difficulty with initiating and maintaining respiration and depression of tone and reflexes.

3.  A. Apgar Score of Less Than 5 at 5 Minutes and 10 Minutes  B. Fetal Umbilical Artery Acidemia <7.0  C. Neuroimaging Evidence of Acute Brain Injury Seen on Brain Magnetic Resonance Imaging or Magnetic Resonance Spectroscopy Consistent With Hypoxia–Ischemia  D. Presence of Multisystem Organ Failure Consistent With Hypoxic–Ischemic Encephalopathy

4. Maternal: –Cardiac arrest –Asphyxiation –Severe anaphylaxis –Status epilepticus –Hypovolemic shock Uteroplacental: –Placental abruption –Cord prolapse –Uterine rupture –Hyperstimulation with oxytocic agents Fetal: –Fetomaternal hemorrhage –Twin to twin transfusion –Severe isoimmune hemolytic disease –Cardiac arrhythmia

5.  Appearance of hypoxic-ischemic encephalopathy on axial diffusion-weighted magnetic resonance imaging. A, A normal brain in a term newborn with no areas of restricted diffusion. B, Severely restricted diffusion in the basal ganglia and thalami, posterior limb of the internal capsule, and white matter. C, Focal restricted diffusion in the putamen and optic radiations.

6.  A Category I or Category II fetal heart rate tracing when associated with Apgar scores of 7 or higher at 5 minutes, normal umbilical cord arterial blood (± 1 standard deviation), or both is NOT consistent with an acute hypoxic–ischemic event.

7.  A category II fetal heart rate pattern lasting 60 minutes or more that was identified on initial presentation with persistently minimal or absent variability and lacking accelerations, even in the absence of decelerations, is suggestive of a previously compromised or injured fetus.

8.  The patient who presents with a Category I fetal heart rate pattern that converts to Category III as defined by the Eunice Kennedy Shriver National Institute of Child Health and Human Development guidelines is suggestive of a hypoxic–ischemic event.

9. What are the consequences of HIE?  HIE contributes nearly ¼ of neonatal deaths and major morbidity  10-15 % of babies with Hypoxic Ischemic Encephalopathy will die  25–30% of HIE survivors will have long-term neurodevelopmental disabilities that include cerebral palsy, seizure disorder and mental retardation.  Currently there are very few treatment options for HIE and few clinical trials of new modalities are underway. Lancet 2005; 365:1147-1152

10.  Developmental Outcome is Spastic Quadriplegia or Dyskinetic Cerebral Palsy  Other subtypes of cerebral palsy are less likely to be associated with acute intrapartum hypoxic– ischemic events.

11. Systemic Complications of HIE Acute renal failure in up to 20% of asphyxiated term infants Myocardial dysfunction and hypotension in 28-50% of term infants Elevated LFTs in 80-85% of term infants Coagulation impairment is relatively common in severely asphyxiated infants Supportive care required!!

12. Multi Organ Injury Hypoxia Diving Reflex Shunting of blood -> Brain Adrenals & Heart Away from lungs, kidney gut & skin Slide Courtesy of Dr Orna Rosen

14. Phases of Cerebral Injury 2 phases to injury Initial insult at birth Secondary failure starts within 6-24 hours of birth Therapeutic window of 6 hours Slide Courtesy of Dr Suhas Nafday, Director of Neonatal Cooling Program at CHAM

16.  Lowering the body temperature from standard 37 to 33.5-34 degrees using cooling wraps or cap  Core temperature measured via rectal or esophageal probes  After 72 hours, core temperature is slowly increased to 37 degrees over 24 hrs.

17. Inclusion Criteria for Brain Cooling Infant > 35 weeks’ gestation with at least ONE of the following: 1.Apgar score of  5 at 10 minutes after birth 2.Continued need for assisted ventilation, including endotracheal or bag/mask ventilation, at 10 minutes after birth 3.Acidosis defined as either umbilical cord pH or any arterial pH within 60 minutes of birth <7.00 4.Base deficit  16 mmol/L on an umbilical cord blood gas sample or any blood sample within 60 minutes of birth (arterial or venous blood) AND moderate to severe encephalopathy with or without seizures OR the presence of one or more signs in 3 of 6 categories on the chart (Modified Sarnat Score)

18. Exclusion Criteria Infants expected to be > 6 hours of age at the time of cooling cap placement. Major congenital abnormalities, such as diaphragmatic hernia requiring ventilation, or congenital abnormalities suggestive of chromosomal anomaly (Trisomy13, 18) or other syndromes that include brain dysgenesis Imperforate anus (since this would prevent rectal temperature recordings) Evidence of neurologically significant head trauma or skull fracture causing major intracranial hemorrhage. Subgaleal bleeding is a relative contraindication; the infant should be fully stabilized before cooling is initiated Coagulopathy with active bleeding Severe PPHN/ possible need for ECMO Infants < 1,800g-birth weight Infants “in extremis” (those infants for whom no other additional intensive management will be offered)

21. Historical Origins of Cooling Babies!!  Hippocrates  John Floyer in1679 used a tub of ice to revive an infant who was not crying at delivery  James Miller and Bjorn Westin in the 1950s developed a scientific rationale for the use of hypothermia in "asphyxia neonatorum” in first case series  Dropped out of favor after Silverman paper in Pediatrics 1958-comments on heat loss (Wyatt et al.Pediatrics 1997)

22. Animal Studies  Multiple studies of fetal Sheep, neonatal Rats, newborn Piglets  Preservation of architecture in cortex of cooled fetal sheep ControlCooled Gunn et al J of Clin Inv 1997

23. Animal Data  Cooling needs to be started within ~ 6 h after birth (and earlier is better)  It needs to be continued for at least 24 h (72 h is better)  The brain needs to be cooled to 32 to 34ºC  Prolonging the duration of hypothermia improves neuroprotection

24.   Metabolic rate of Brain  Slows depolarization of brain cells   Accumulation of excitatory amino acids   Release of free radicals  Keeps integrity of brain cells membranes   Apoptosis (not necrosis)

25. Question  Population: Infants ≥ 35 weeks gestational age with moderate to severe neonatal encephalopathy  Intervention: Brain cooling vs. conventional treatment  Outcome: ◦ Death ◦ Neurodevelopmental disability ◦ Combined outcome

26. Cool Cap Trial -2005

27. TOBY Trial – NEJM 2009

28. NICHD trial-2005

29. Less Mortality in Hypothermia group RR 0.78, 95% CI 0.66 to 0.93, P=0.005

30. Meta-analysis of 3 major trials

31. Survival with normal neurological function at 18 months Edwards et al. BMJ 2010 Relative risk 1.53, 95% CI 1.22 to 1.93, P<0.001

32. Death or Severe Disability at 18 months Edwards et al. BMJ 2010 Total RR 0.81, 95% CI 0.71 to 0.93, P=0.002

33.  Cooling was safe and did not result in serious side- effects, which included: ◦ slightly lower baseline heart rate (RR 5.96, 95% CI 2.15– 16.49; RD 0.07, 95% CI 0.04–0.11), ◦ a marginally significant increase in the need for blood pressure support (RR 1.17, 95% CI 1.00–1.38; RD 0.08, 95% CI 0.00–0.17), ◦ more babies with a platelet count below 150 X 109 /litre (RR 1.55, 95% CI 1.14–2.11; RD 0.09, 95% CI 0.03–0.15). WHO policy statement on Cooling for newborns with hypoxic ischaemic encephalopathy 2014

34. Standard of Care - 2014 Data from large randomized clinical trials indicate that therapeutic hypothermia, using either selective head cooling or systemic cooling, is an effective therapy for neonatal encephalopathy. Infants selected for cooling must meet the criteria outlined in published clinical trials. The implementation of cooling needs to be performed at centers that have the capability to manage medically complex infants.

35. Woodbridge, CT winter 2015

37. European neo.nEURO.network trial (Simbruner 08)  Multicenter trial (n=129) terminated prior to completion in 2006  Whole body cooling x 72 hours  Differs from other trials ◦ Uses Griffiths General Quotient for neurodevelopmental assessment and Palisano score ◦ Included infants with moderate or severe aEEG or EEG changes ◦ Used Morphine for both control and hypothermia groups

38. Eicher Trial 2005  Clinical signs  Cord pH ≤ 7.0 or BE ≥ 13  Initial postnatal pH < 7.1  Apgar score < 5 at 10 min  Need for resuscitation after 5 min  Fetal bradycardia (< 80 bpm x 15 min)  A postnatal hypoxic-ischemic event  Neurological signs  Hypothermic infants were cooled with plastic bags filled with ice and then placed on a cooling blanket servo-controlled at 33.5 ± 0.5° C  Normothermic infants were kept at 37 ± 5° C Pediatric Neurology 2005 ; 32: 1 11-17

39. Potential pathways for brain injury after hypoxia- ischemia. Perlman J M Pediatrics 2006;117:S28-S33 ©2006 by American Academy of Pediatrics Perlman J M Pediatrics 2006;117:S28-S33 ©2006 by American Academy of Pediatrics

40. ● 234 infants studied ◦ 75% U.S. sites ◦ 25% UK, Canada, New Zealand ● Safety reviews at 25, 50 and 75% enrolment revealed no major concerns ● Follow up available on 218 (93%) infants ◦ 8 cooled and 8 control infants lost to follow up The Cool Cap Trial Gluckman P et al Lancet 365: 663, 2005 Slide Courtesy of Dr Suhas Nafday, Director of Neonatal Cooling Program at CHAM

41. Final Count 234 Lost to Follow-up 18-Month Primary Outcome Cooled 108 Control 110 Favourable 49 (45%) Unfavourable 59 (55%) Favourable 37 (34%) Unfavourable 73 (66%) 16 218 The Cool Cap Trial : Primary Outcomes Gluckman P et al Lancet 365: 663, 2005 Slide Courtesy of Dr Suhas Nafday, Director of Neonatal Cooling Program

42. A priori defined group excluding infants with severely abnormal aEEG w/seizure n=172 Cooled 84 Control 88 Favourable 44 (52%) Favourable 30 (34%) Unfavourable 58 (66%) Fisher’s exact p=0.02: logistic regression, OR: 0.42 (0.22, 0.80), p=0.009 Unfavourable 40 (48%) The Cool Cap Trial: If you exclude severely abnormal aEEG Gluckman P et al Lancet 365: 663, 2005 Slide Courtesy of Dr Suhas Nafday,

43. Intermediate aEEG group – cooled vs control odds ratio 0·47 95% CI 0·26–0·87, p=0·021

44. ● No increase in severe hypotension despite full volume and inotrope support: 3 cooled vs. 3 non-cooled infants (p=1.00) ● Scalp edema common (32 cooled and 1 control infant, p<0.0001), but transient ● One case of scalp damage under the cap in an infant dying of severe hypotension and coagulopathy ● Sinus bradycardia, without hypotension, was very common during cooling and reversed on rewarming The Cool CAP trial : Adverse Effects Gluckman P et al Lancet 365: 663, 2005 Slide Courtesy of Dr Suhas Nafday

45. What is the difference between Whole body cooling and Selective head cooling? WBC provides homogenous cooling to all structures of nervous system (peripheral and central) Laptook et al Pediatrics 2001 SHC combined with some body cooling provides cooling to the peripheral structures but minimizes temperature gradients across the brain (Thorensen et al. Ped Res 2001) SHC may have less adverse side effects than WBC cooling

47. Insult (~ 30 min) Reperfusion Hypoxic depolarization Cell lysis Excitotoxins Calcium Entry Latent ( 6-15h) Recovery of oxidative metabolism Apoptotic cascade 2° inflammation Calcium Entry Secondary (3-10d) Failing oxidative metabolism seizures Cytotoxic edema Excitotoxins Final cell death Intervention needed NEURO TOXIC CASCADE IN HIE – Ferriero, 2008

48. “ Main Players” Excitatory Amino Acids Intracellular Calcium Free Radicals Inflammatory Mediators Nitric Oxide Synthase Xanthine Oxidase  cerebral metabolic rate (Hypothermia*) Excitatory Amino Acid Antagonists Oxygen Free Radical Inhibitors / Scavengers* Prevention of Nitric Oxide Formation Growth Factors (apoptosis inhibition ) Neuroprotective Strategies Papadoupoulous et al Neoreviews 2010

49. Meta-analysis of all Trials Edwards et al. BMJ 2010

50. What do the combined results show? TrialRR of Death or Severe disability at 18 months Confidence Interval Cool Cap (n=218) 0.820.66 -1.02 TOBY (n=325) 0.860.68 -1.07 NICHD (n=239) 0.720.54 - 0.95

51. Hypothermia during transport?  Infant cooling evaluation or ICE trial (Jacobs et al – Hot topics 2008)  Whole Body Cooling x 72 hrs started 2002  Differs from other trials ◦ Simple eligibility Criteria ◦ Included infants outborn (70%) ◦ Included infants 35 weeks or more ◦ Both passive and active cooling on transport  Decrease in mortality in cooled group  Awaiting neurodevelopmental outcomes

52. European neo.nEURO.network trial (Simbruner 08)  Results: Hypothermia group : ◦ More Survival free of severe disability Relative Risk 2.86 with CI (1.58-5.19) ◦ Severe Disability was less Relative Risk 0.34 with CI (0.2-0.57) ◦ Reduction in Cerebral Palsy ◦ Trend to reduction of cortical blindness, hearing loss ◦ Same held true for infants for both severe and moderate encephalopathy group

53. Eicher Trial 05 Eicher D et al Pediatr Neurol 32: 11-34, 2005 ● Enrolled 65 infants ● 33 hypothermia ● 32 control ● Outcome: incidence of abnormal neurodevelopmental scores by Bayley II (follow-up done on only 28 infants) at 12 months of age ● Death or severe neuromotor disability was 52% in the hypothermia group and 84% in the normothermia group (p=0.019) -- Mortality: 31% cooled & 42% controls

54. Guidelines To implement brain cooling, HIE should be defined by the rigorous criteria and published protocols (Body Cooling or CoolCap) and should be strictly adhered to Appropriate personnel need to be available day and night to implement the protocol Collection of appropriate data and assurance of follow-up after discharge to ascertain outcome for Perinatal HIE Hypothermia for Perinatal HIE Where should it be done and by whom? Executive Summary of the NICHD Workshop on Hypothermia and Perinatal Asphyxia J Pediatr 2006;148 Slide Courtesy of Dr Suhas Nafday, Director of Neonatal Cooling Program at CHAM

55. Guidelines Providers must be highly experienced in evaluating treatment candidates, knowledgeable in the techniques to administer hypothermia, and have a comprehensive follow- up program to determine neurodevelopmental outcome Large regional referral centers will be critical for providing this intervention, given that more than 40% of the patients in the Body Cool trial were out-born Need for longer follow-up of infants receiving hypothermia for Perinatal HIE Hypothermia for Perinatal HIE Where should it be done and by whom? Executive Summary of the NICHD Workshop on Hypothermia and Perinatal Asphyxia J Pediatr 2006;148

56. The Neonatal Brain Cooling Program at The Children’s Hospital at Montefiore Regional Cooling Centers Consortium  Children’s Hospital at Montefiore  Presbyterian Hospital-Weill Cornell Medical College  North Shore - Long Island Jewish Health System  NYU Medical Center  Mt. Sinai Medical Center  Westchester Medical Center  Morgan Stanley Hospital (Columbia University Medical Center)  Winthrop-University Hospital Referring Institutions  Montefiore North (Previously OLM)  Jacobi Medical Center  North Central Bronx Hospital  Lincoln Hospital and Mental Health Center  St. Barnabas Hospital  Flushing Hospital Medical Center Slide Courtesy of Dr Suhas Nafday, Director of Neonatal Cooling Program at CHAM

57. Management in the Delivery Room  Resuscitation of asphyxiated infants should be done according to NRP guidelines using 100% O 2.  The radiant warmer should be turned off as soon as adequate ventilation and heart rate are obtained  Maintain rectal temperature at 35 + 0.5 Cº range; if necessary use radiant warmer to prevent overcooling of the infant Slide Courtesy of Dr Suhas Nafday, Director of Neonatal Cooling Program at CHAM

58. Neonatal Hypothermia Program at CHAM  The time frame for neonatal therapeutic hypothermia is critical-Treatment must be administered within six hours of birth.  Neonatal patient 36 weeks or greater, and has suffered possible brain injury during birth, please call us immediately at (718) 904-4032  Upon arrival at the Weiler NICU, an aEEG and neurological assessment will determine if the therapeutic intervention is appropriate for the infant  Questions about Weiler’s Neonatal Therapeutic Hypothermia Program can be referred to Suhas Nafday, MD, at 718-904-4105, snafday@montefiore.org Slide Courtesy of Dr Suhas Nafday, Director of Neonatal Cooling Program at CHAM

59. Practical Tips for NICU’s: Transferring Newborns for Cooling  Educate staff, especially ‘off-hours’ personnel to recognize eligibility for cooling  Besides providing cardiorespiratory stability: ◦ IV glucose, ASAP ◦ Avoid Hyperoxia and Hyperthermia ◦ Use double lumen UV lines, low line OK for D10W ◦ Initiate transport call ASAP, don’t wait for lines/images/labs ◦ Discuss cooling but make no promise re: use and outcome Slide Courtesy of Dr Suhas Nafday, Director of Neonatal Cooling Program at CHAM

60. REQUESTS PRIOR TO TRANSPORT TEAM ARRIVAL  Transport consent should be obtained from parents. We would FAX the consent form. Please return the signed form ASAP @ 718-904-2649.  Clean the head and get a head circumference prior to arrival of the transport team to facilitate placement of the leads and the correct size of Cool Cap  Secure vascular access-placement of double/single lumen umbilical vein catheter and umbilical artery catheter prior to departure, if there is time  Ventilatory support is necessary during hypothermia treatment  Maintain skin temperature at greater than 36°C and less than 37 °C  Don’t treat with phenobarbital (prophylactic treatment) unless there is evidence of clinical seizures. Slide Courtesy of Dr Suhas Nafday, Director of Neonatal Cooling Program at CHAM

61. Special Considerations  Patients who clearly exhibit signs of severe HIE on early neurologic evaluation (Sarnat 3), but normal tracings on aEEG should be offered hypothermia treatment  Patients who have moderate HIE on neurologic exam with normal aEEG can be monitored with continuous aEEG recording up to 6 hours of life and treated with hypothermia if aEEG becomes abnormal  If these inclusion/exclusion criteria are met and infants are found eligible for cooling, the hypothermia treatment can be initiated  No informed consent is necessary (FDA approved devise), however parents would be given written information about the treatment Slide Courtesy of Dr Suhas Nafday, Director of Neonatal Cooling Program at CHAM

62. Unanswered Questions  What is the optimal ◦ Depth of hypothermia? ◦ Duration of hypothermia? ◦ Mode of delivery- Whole body vs.Selective? ◦ Impact of time of initiation? Starting at resuscitation? After 6hours?  Use of aEEG to target treatment to babies that are more likely to benefit?  Long term follow up more than 18-22 months?  Benefit of using combined treatment?

64. What new combination treatments are under investigation?  Phenobarbitol – China- Lin J Perinat 2006  CT scan  Neonatal NBS

65. What new combination treatments are under investigation?  Morphine- nEURO trial  Topiramate + delayed hypothermia > 6 hours in neonatal rats – Liu 2004  Anti-inflammatory agents? Xanthine oxidase inhibitors? Stem cells? Hypoxia + PBS Hypoxia + Topiramate Rats were sacrificed at 35days of age

66. Alistar Gunn – Hot Topics 2008 “ Cooling is An Evolving Therapy” There are too many unanswered questions for hypothermia to be a true “standard of care” But………….. We don’t need to wait for another 100 years to start cooling babies!!!! Randomization to normothermia is no longer reasonable

67. Pathophysiology The immature brain is in some ways more resistant to hypoxic-ischemic events compared to older children & adults –This may be due to: Lower cerebral metabolic rate Immaturity in the development of the balance of neurotransmitters Plasticity of the immature CNS

68. Pathophysiology Gestational age plays an important role in the susceptibility of CNS structures –< 20 weeks: Insult leads to neuronal heterotopia or polymicrogyria –26-36 weeks: Insult affects white matter, leading to periventricular leukomalacia –Term: Insult affects primarily gray matter

69. Management - Hypothermia Has become standard of care Whole-body and head-cooling available –Unclear if one regimen is superior to the other - currently either one is utilized, based on availability Aim to get core (rectal) temperature to 33-35º C for 72 hours –based on Cool Cap and NICHD Neonatal Research Network trials