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
39 week born to a 20 yr old G1P0 bleeding. Crash C-section. Limp baby. Requiring intubation , chest compressions, 2 rounds of epi . UVC placed in DR and saline bolus given- blood ordered.
Brought to NICU. Notice Limp, non responsive, intubated, UVC, drips running.
Similar scenario seen with Mec, cord accidents, cord prolapse, shoulder dystocia, abnormal FHR tracings.

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.
NO way to treat HIE or prevent it.
Vannucci et al. Pediatrics 1997

6. Pathophysiology Multi Organ Injury Diving Reflex
Hypoxia
Diving Reflex
Shunting of blood -> Brain Adrenals & Heart
Away from lungs, kidney gut & skin
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
In the evolution of brain injury that occurs with hypoxic-ischemic encephalopathy, a certain amount of brain damage occurs at the initial insult. However, additional brain damage occurs due to cell death generated from secondary energy failure [I really wouldn’t go into the details of necrotic and apoptotic cell death here, if I were you]. Based on animal studies, it is believed that there is a therapeutic window of opportunity of approximately six hours during which hypothermic intervention can decrease the amount of cell death resulting from the secondary energy failure. Specifically, if you begin cooling the brain during that 6h time window and keep it cool for the duration of the secondary energy failure stage (>48 hours) you can have a significant effect on the severity of the secondary cell death. Animal studies have also shown that if you can start sooner (< 3hours) you can do even better. The message being that the earlier you cool, the better chance you have of helping the infant.
Slide Courtesy of Dr Suhas Nafday, Director of Neonatal Cooling Program at CHAM

9. Anaerobic Glycoglysis
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
Mechanisms of brain damage
1)Energy failure resulting in release of excitatory amino acids receptor over-activation which increases intracellular calcium accumulation leading to necrosis and cell death
2) Stimulating apoptosis causing delayed cell death
3)neuronal nitric oxide which also increases intracellular calcium
4) Lipid peroxidation, reactive oxygen species, caspase-mediated cell death and inflammatory lipid mediators (leukotrienes and platelet-activating factor (PAF)
Aikasu trial 2003 found hypothermia suppresses PAF formation even moderate hypothermia 36degrees and may inhibit inflammation and glutamate activity.
Activates
Nos
Xanthine
Free Fatty Acids O2 O2
Free Radicals Free Radicals
Nitric Oxide
Papadoupoulous et al Neoreviews 2010
Slide Courtesy of Dr Orna Rosen

10. “Main Players” Neuroprotective Strategies
 cerebral metabolic rate (Hypothermia*)
Excitatory Amino Acid Antagonists
Oxygen Free Radical Inhibitors / Scavengers*
Prevention of Nitric Oxide Formation
Growth Factors (apoptosis inhibition)
Excitatory Amino Acids
Intracellular Calcium
Free Radicals
Inflammatory Mediators
Nitric Oxide Synthase
Xanthine Oxidase
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 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
(Wyatt et al.Pediatrics 1997)
Hippocrates: prolonged survival of exposed babies. Miller and Westin started in 1950 with animal studies, then 10 babies placed in ice with cold blood transfusion temp Then in late 1950’s treated 65 babies with cooling with 52/65 survival and minimal CP outcomes. Rationale was decreased cerebral metabolism protective. Continued to champion cooling into 1970’s until Silverman paper with 150 premature infants nursed in hypothermic vs normothermic incubators with poor outcome for hypothermia.

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
Control
Cooled
Gunn et al J of Clin
Inv 1997
Preservation of architecture in cooled fetal sheep compared to control. Selective head cooling following occlusion of carotid arteries in utero.

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) 16

17. MODIFIED SARNAT’S STAGING
Shankaran et al. NICHD trial NEJM 2005
Need to have one or more signs in 3 of the 6 categories. To designate severity, if equal distribution between both you depend on the severity of the level of conciousness 17

18. CEREBRAL FUNCTION MONITORING Normal and Abnormal aEEG Tracings
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
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) 20

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 24

25. The Cool Cap Trial : Primary Outcomes Final Count Lost to Follow-up
234
Lost to Follow-up 16
18-Month
Primary Outcome
218
Cooled
108
218 babies – SHC to degrees x 72 hr with moderate to severe enceph- CFM +
Control
110
Favourable
49 (45%)
Unfavourable
59 (55%)
Favourable
37 (34%)
Unfavourable
73 (66%)
Slide Courtesy of Dr Suhas Nafday, Director of Neonatal Cooling Program
Gluckman P et al Lancet 365: 663, 2005

26. The Cool Cap Trial: If you exclude severely abnormal aEEG
A priori defined group excluding infants with severely abnormal aEEG w/seizure
n=172
Cooled 84
Control 88
Favourable
44 (52%)
Unfavourable
40 (48%)
Favourable
30 (34%)
Unfavourable
58 (66%)
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
WBC to degrees x 72 hrs in moderate to severe encephalopathy with seizures, used CFM for 30 min unlike Cool cap 20mn.
Enrolled 325 patients 163 cooled vs 162 controls. Randomized, not blinded for cooling, Blinded for neurodevelopment follow up. Had initiation of cooling during transport. Increased withdrawl of care in cooled group.

31. NICHD trial
239 infants some WBC and control over 3 years 102 cooled vs 106 controls. 72 hours similar inclusion criteria. No CFM monitor used. Outcome death or severe or moderate disability. Showed improvement in outcome. But no improvement in CP or blindness. Only trial that showed improvement. Average f/u was 19 months in hypothermia group vs 20mo for control

32. What do the combined results show?
Trial
RR of Death or Severe disability at 18 months
Confidence Interval
Cool Cap
(n=218)
0.82
TOBY
(n=325)
0.86
NICHD
(n=239)
0.72

33. 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
WBC- to for 72 hours with outcome of survival free of severe disability. Simple eligibility criteria (at least 2 –Apgar, resuscitation, gas) to identify infants at outside hospitals in Australia and cooling initiated soon after birth. Trial was stopped early 221/276 infants in 2007 and currently undergoing neurodevelopmental follow up. Includes infants that are more than or equal to 35wks and base deficit of 12 or more. Cooling done by turning off warmer with use of cold gel packs at 10 degrees on head back or across chest. Slow rewarming 0.5 degrees every 2 hours. Results: Majority outborn (70%), majority severe or moderate encephalopathy or seizures only 17% mild. Mortality reduced in hypothermia group

34. 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

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

36. 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
Infants > or equal to 35 wks or 2000g
Infants required one clinical sign and two neurologic findings of HIE 36

37. 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

38. Meta-analysis of all Trials
Recent Meta-analysis that updates Cochrane 2007 analysis and includes results of new trial. Approx 1320 infants included from 10 trials for mortality calculation infants from 3 major trials used for death or disability at 18months.
Edwards et al. BMJ 2010

39. 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

40. 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

41. Meta-analysis of 3 major trials

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

43. 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

44. 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

45. Regional Cooling Centers Consortium Referring Institutions
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

46. 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 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

47. 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)
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 ,
Slide Courtesy of Dr Suhas Nafday, Director of Neonatal Cooling Program at CHAM

48. 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

49. REQUESTS PRIOR TO TRANSPORT TEAM ARRIVAL
Transport consent should be obtained from parents. We would FAX the consent form. Please return the signed form
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

50. 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 50

51. 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 months?
Benefit of using combined treatment?
Animal studies suggest degrees

52. Hobbs et al used Rice vannuci model in rats with HIE found to improve long term neurodevelopmental outcome and histopathology when combined with cooling sacrificed at 10weeks.

53. What new combination treatments are under investigation?
Phenobarbitol – China- Lin J Perinat 2006
CT scan
Neonatal NBS
Lin – Study from China reported 2006 on SHC 32 vs 30 controls with phenobarb and dopamine (renal dose)- transferred from community hospitals with passive cooling. Looked at Neonatal behavioral score at 7-10 days. Long term results pending

54. 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
+ Topiramate
Rats were sacrificed at 35days of age
Silverstein’s lab. Used Vannucci model with Topiramate or PBS 3 hours after insult then hypothermia after 6 hours x 3 hours. Topiramate prevents seizures and good results from adult cerebral ischemia studies in rats.also modification of sodium- and/or calcium-dependent action potentials, enhancement of GABAmediated chloride fluxes into neurons, and inhibition of the AMPA/kainate type glutamate receptors. Protective for 1 month but damage may still be seen after that.

55. 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