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Brain Cooling: Does it really work?

Brain Cooling: Does it really work? . Lamia Soghier MD Assistant Professor of Pediatrics Attending Neonatologist AECOM - CHAM. No Financial Disclosure. Objectives:. Pathophysiology of HIE and current interventions Historical Origins of Neonatal hypothermia Evidence based Questions?

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Brain Cooling: Does it really work?

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  1. Brain Cooling: Does it really work? Lamia Soghier MD Assistant Professor of Pediatrics Attending Neonatologist AECOM - CHAM

  2. No Financial Disclosure

  3. Objectives: • Pathophysiology of HIE and current interventions • Historical Origins of Neonatal hypothermia • Evidence based Questions? • Bench to Bedside • Animal Studies • Clinical Trials • Meta-analysis • Unanswered Questions

  4. Brought to the NICU

  5. What are the consequences of HIE? • 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. Vannucci et al. Pediatrics 1997

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

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

  8. 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

  9. Secondary Energy Failure Hypoxia-ischemia Anaerobic Glycoglysis ATP Lactate Adenosine Glutamate Il- Tnf- Nmda Receptor Il- Tnf- Interferon  Hypoxanthine Intracellular Ca++ Xanthine Oxidase Activates Lipases Activates Nos Xanthine Free Fatty Acids O2 O2 Free RadicalsFree Radicals Nitric Oxide Papadoupoulous et al Neoreviews 2010 Slide Courtesy of Dr Orna Rosen

  10. NeuroprotectiveStrategies “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) Papadoupoulous et al Neoreviews 2010 Slide Courtesy of Dr Orna Rosen

  11. How Hypothermia Prevent HIE damage? • 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) Slide Courtesy of Dr Orna Rosen

  12. 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 BjornWestin in the 1950s developed a scientificrationale for the use of hypothermia in "asphyxia neonatorum” in first case series • Dropped out of favor after Silverman paper in Pediatrics 1958 (Wyatt et al.Pediatrics 1997)

  13. EB Question • Population: Infants ≥ 36 weeks gestational age with moderate to severe neonatal encephalopathy • Intervention: Brain cooling vs. conventional treatment • Outcome: • Death • Neurodevelopmental disability • Combined outcome

  14. Animal Studies • Multiple studies of fetal Sheep, neonatal Rats, newborn Piglets • Preservation of architecture in cortex of cooled fetal sheep Cooled Control Gunn et al J of Clin Inv 1997

  15. 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

  16. Inclusion Criteria for Brain Cooling Infant > 36 weeks’ gestation with at least ONE of the following: Apgar score of  5 at 10 minutes after birth Continued need for assisted ventilation, including endotracheal or bag/mask ventilation, at 10 minutes after birth Acidosis defined as either umbilical cord pH or any arterial pH within 60 minutes of birth <7.00 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)

  17. MODIFIED SARNAT’S STAGING Shankaran et al. NICHD trial NEJM 2005

  18. CEREBRAL FUNCTION MONITORINGNormal andAbnormal aEEG Tracings NORMAL aEEG TRACING Lower margin of band of aEEG activity above 7.5 mV MODERATELY ABNORMAL(Upper margin >10 mV & lower margin <5 mV) SEVERELY ABNORMAL (Upper margin <10 mV & lower margin <5 mV) SEIZURES (sudden increase in voltage, narrow band aEEG & period of suppression) Slide Courtesy of Dr Orna Rosen

  19. Positive Predictive Value of aEEG with clinical picture • Abnormal aEEG in asphyxiated infant has >70% PPV of death or severe CP (Hellstrom-Westas Arch.Dis.Child1995,Toet Arch Dis Child 1999) • Correlation between severe aEEG changes and poor outcome (CoolCap trial 2005)

  20. 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 Coagulopathywith 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. What is the difference between Whole body cooling and Selective head cooling? • WBC provides homogenous cooling to all structures of brain (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 Slide Courtesy of Dr Suhas Nafday, Director of Neonatal Cooling Program at CHAM

  22. Cool Cap Trial

  23. The Cool Cap Trial • 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 Slide Courtesy of Dr Suhas Nafday, Director of Neonatal Cooling Program at CHAM Gluckman P et al Lancet 365: 663, 2005

  24. Olympic Cool CapR System Cerebral function monitor

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

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

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

  28. The Cool CAP trial : Adverse Effects • 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 Gluckman P et al Lancet 365: 663, 2005 Slide Courtesy of Dr Suhas Nafday

  29. TOBY Trial – NEJM 2009

  30. NICHD trial

  31. What do the combined results show?

  32. 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

  33. 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

  34. 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

  35. 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 Eicher Trial 2005 Infants required one clinical sign and two neurologic findings of HIE

  36. Eicher Trial 05 • 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 Eicher D et al Pediatr Neurol 32: 11-34, 2005

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

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

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

  40. Meta-analysis of 3 major trials

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

  42. Hypothermia for Perinatal HIE Where should it be done and by whom? 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 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

  43. Hypothermia for Perinatal HIE Where should it be done and by whom? 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 Executive Summary of the NICHD Workshop on Hypothermia and Perinatal Asphyxia J Pediatr 2006;148

  44. 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

  45. Management in the Delivery Room Resuscitation of asphyxiated infants should be done according to NRP guidelines using 100% O2. 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

  46. 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

  47. 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

  48. 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

  49. 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

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