Transcript 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?
 Bench to Bedside
 Animal Studies
 Clinical Trials
 Meta-analysis
 Unanswered Questions
Brought to the NICU
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
Pathophysiology
Hypoxia
Diving Reflex
Shunting of blood ->
Brain Adrenals & Heart
Away from lungs, kidney
gut & skin
Multi Organ
Injury
Slide Courtesy of Dr Orna Rosen
Phases Of Cerebral Injury
Intervention needed
Insult
(~ 30 min)
Hypoxic
depolarization
Cell lysis
Excitotoxins
Latent
Secondary
(6-15h)
(3-10d)
Recovery of
oxidative
metabolism
Failing
oxidative
metabolism
Apoptotic
cascade
seizures
2°
inflammation
Calcium Entry
Calcium Entry
Reperfusion
NEURO TOXIC CASCADE IN HIE – Ferriero, 2008
Cytotoxic
edema
Excitotoxins
Final cell
death
Slide Courtesy of Dr Orna Rosen
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
Secondary Energy
Failure
Hypoxia-ischemia
Anaerobic Glycoglysis
ATP
Adenosine
Hypoxanthine
Glutamate
Nmda Receptor
Il-
Tnf-
Intracellular Ca++
Xanthine
Oxidase
Xanthine
O2
Free Radicals
Slide Courtesy of Dr Orna Rosen
Activates Lipases
Lactate
Il-
Tnf-
Interferon 
Activates
Nos
Free Fatty Acids
O2
Free Radicals
Nitric Oxide
Papadoupoulous et al Neoreviews 2010
“Main Players”
 Excitatory Amino Acids
 Intracellular Calcium
 Free Radicals
 Inflammatory Mediators
 Nitric Oxide Synthase
 Xanthine Oxidase
Neuroprotective
Strategies
  cerebral metabolic rate
(Hypothermia*)
 Excitatory Amino Acid
Antagonists
 Oxygen Free Radical Inhibitors /
Scavengers*
 Prevention of Nitric Oxide
Formation
 Growth Factors (apoptosis
Papadoupoulous et al Neoreviews 2010
Slide Courtesy of Dr Orna Rosen
inhibition)
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
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)
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
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
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
Inclusion Criteria for Brain Cooling
Infant > 36 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)
MODIFIED
SARNAT’S
STAGING
Shankaran et
al. NICHD
trial NEJM
2005
CEREBRAL FUNCTION MONITORING
Normal and Abnormal aEEG Tracings
NORMAL aEEG TRACING
Lower margin of band of aEEG activity
above 7.5 mV
SEVERELY ABNORMAL
(Upper margin <10 mV &
lower margin <5 mV)
Slide Courtesy of Dr Orna Rosen
MODERATELY ABNORMAL (Upper margin
>10 mV &
lower margin <5 mV)
SEIZURES
(sudden increase in voltage,
narrow band aEEG & period
of suppression)
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)
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
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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)
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
Cool Cap Trial
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
Olympic Cool CapR System
Cerebral function monitor
The Cool Cap Trial :
Primary Outcomes
Final
Count
234
Lost to
Follow-up
16
18-Month
Primary Outcome
218
Cooled
108
Favourable
49 (45%)
Unfavourable
59 (55%)
Slide Courtesy of Dr Suhas Nafday,
Director of Neonatal Cooling Program
Control
110
Favourable
37 (34%)
Unfavourable
73 (66%)
Gluckman P et al Lancet 365: 663, 2005
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
Favourable
44 (52%)
Unfavourable
40 (48%)
Control
88
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
Intermediate aEEG group – cooled vs control odds ratio 0·47
95% CI 0·26–0·87, p=0·021
The Cool CAP trial : Adverse Effects
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No increase in severe hypotension despite full
volume and inotrope support: 3 cooled vs. 3 noncooled 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
Slide Courtesy of Dr Suhas Nafday
Gluckman P et al Lancet 365: 663, 2005
TOBY Trial – NEJM 2009
NICHD trial
What do the combined results show?
Trial
Cool Cap
(n=218)
RR of Death or Confidence
Severe disability Interval
at 18 months
0.82
0.66 -1.02
TOBY
(n=325)
0.86
0.68 -1.07
NICHD
(n=239)
0.72
0.54 - 0.95
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
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
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
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
 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
min
 Fetal bradycardia (< 80 bpm x 15
min)
 Normothermic infants were
kept at 37 ± 5° C
 A postnatal hypoxic-ischemic
event
• Neurological signs
Infants required one clinical sign and two neurologic findings of HIE
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
Meta-analysis of all Trials
Edwards et al. BMJ 2010
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
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
Meta-analysis of 3 major trials
Less Mortality in Hypothermia
group
RR 0.78, 95% CI 0.66 to 0.93, P=0.005
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
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 followup 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
The Neonatal Brain Cooling Program at The
Children’s Hospital at Montefiore
Regional Cooling Centers
Consortium
 Children’s Hospital at Montefiore
 Presbyterian Hospital-Weill
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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
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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
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
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,
[email protected]
Slide Courtesy of Dr Suhas Nafday, Director of Neonatal Cooling Program at CHAM
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
REQUESTS PRIOR TO TRANSPORT TEAM
ARRIVAL
 Transport consent should be obtained from parents.
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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
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
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?
What new combination treatments are
under investigation?
 Phenobarbitol – China- Lin J Perinat 2006
 CT scan
 Neonatal NBS
What new combination treatments are
under investigation?
 Morphine- nEURO trial
 Topiramate + delayed hypothermia > 6 hours in neonatal
rats – Liu 2004
Hypoxia
+ PBS
Hypoxia
+ Topiramate
Rats were sacrificed at 35days of age
 Anti-inflammatory agents? Xanthine oxidase inhibitors?
Stem cells?
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