overview of hypothermia in perinatal...
TRANSCRIPT
2013-03-11
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Overview of Hypothermia In
Perinatal Asphyxia
IPOKRATES – Cracow, Poland
Jerome Y. Yager MD Professor of Pediatric Neurosciences
Director of Research Department of Pediatrics
Stollery Children’s Hospital University of Alberta
• Historical Background • Support in Research • Overview of Clinical Trials • Mechanisms of Improvement
• Future Directions
Objectives
Take Home Messages
§ Hypothermia is currently the only accepted and proven effective therapy for hypoxic-ischemic brain injury
§ However, it is incompletely effective and incompletely understood
§ Future directions are clearly moving towards combination chemotherapy (Cocktails & Ice)
§ What about Hypothermia and….. § Prematurity? Neonatal Stroke?
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Historical Background
• Very Old Idea – 300 years ago, John Floyer suggested that babies might fare better if they were a little cold after birth.
• Modern hypothermia in clinical practice began in the
30’s and 40’s with the recognition of the successful resuscitation of near drowning victims.
• Deep hypothermia became standard of care in neurosurgical and cardiovascular procedures (aneurysm repair, CHD repair).
Historical Background • In the newborn – studies in the 50’s and 60’s,
particularly in preterm infants, who were exposed to cold environments for prolonged periods resulted in • Increased mortality • Cardiovascular compromise • Coagulation Defects
• This resulted in the promotion of thermoregulation and the maintenance of ‘normal’ temperatures.
Historical Background • Resurrection of mild hypothermia as a neuroprotectant
arose in adult animal models of stroke which showed that:
• Reductions of temperature by 2-4C during hypoxia-ischemia was profoundly neuroprotective.
• Post-ischemically – • Brief post-ischemic hypothermia provides
transient brain protection • Prolonged post-ischemic hypothermia
provides permanent protection, and • Hypothermia may be delayed for between 6
and 24 hours in the adult animal.
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Background • In the newborn animal model, early studies showed
complete neuroprotection following mild reductions in temperature of 1-3C during hypoxia-ischemia
Mild Hypothermia
Background • Post-Ischemically mild hypothermia for brief periods did
not provide permanent neuroprotection, for mild injuries and no protection for severe injuries
1 Week Neuropathology
0
5
10
15
20
25
Mea
n Ra
nk S
core
Thirty-One Thirty-Four Thirty-Seven
Temperature
180 Min Hypoxia-Ischemia
90 Min Hypoxia-Hypoxia
0
10
20
30
Mea
n Ra
nk S
core
Thirty-One Thirty-Four Thirty-Seven
Temperature
180 Min Hypoxia-Ischemia
90 Min. Hypoxia-Ischemia
3 Week Neuropathology
*
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Background • Post-Ischemically mild hypothermia for prolonged
periods of 12 or 24 hours did provide permanent neuroprotection in moderate HIE not Severe
0
5
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Mea
n R
ank
Scor
e
28 31 34 37
* *
Temperature (C)
0
5
10
15
20M
ean
Ran
k Sc
ore
28 31 34 37
Temperature (°C)
Moderate Severe
Background • Similar results have been found in other species of
animals, particularly the piglet and sheep.
Background • Post-ischemic Delayed Hypothermia may also be
effective, though this has not yet been proven
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Background
Pabello NG 2010
• Post-ischemic Delayed Hypothermia may also be effective, though this has not yet been proven
Background • Pre-ischemic hypothermia is not effective in preventing
injury, but hyperthermia is.
Mild Hypothermia
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Hypothermia Trials
Systematic Review
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Hypothermia Trials
Hypothermia Trials
Hypothermia Trials
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Hypothermia Trials
Adverse Events Associated with Hypothermia
Systemic vs Focal Hypothermia
(Inder et al. 2004)
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(Rutherford et al. 2005)
Systemic vs Selective Hypothermia
(Sarkar and Barks - 2012)
Systemic vs Selective Hypothermia
(Rutherford et al 2010)
MRI Predictability
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Predictability of Hypothermia Success?
(Perlman et al – 2010)
Predictability of Hypothermia Success?
(Sarkar et al – 2012)
§ Effective § More complete in the Moderate Group of HIE § Still some question regarding Severe Group of HIE
§ Definitely Standard of Care
Hypothermia
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Mechanisms of Hypothermic Protection
Mechanisms of Hypothermic Protection
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Mechanisms of Hypothermic Protection
Post-HI Energy Metabolism
0.000
0.500
1.000
1.500
2.000
2.500
3.000
3.500
0 0.25 0.5 1 4 24 48 72 120
ATP
(m
Mo
les/
Kg
)
Time post HI (h)
Hypothermia ATP
28° 37° with dam 37° Sham
Post-HI Energy Metabolism & Inflammation
A
B
C
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Hypothermia and Apoptosis
Normothermic Hypothermic
Core Core
Penumbra Penumbra
Ψ
ψ
*
AIF
Hypothermia and Apoptosis
Hypothermia and Apoptosis
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Future Thoughts
0
5
10
15
20
Mea
n Ran
k Sco
re
Control Deferoxamine Allopurinol Glutathione Flunarazine N-acetylcysteine
Thirty-Seven
Thirty-Four
Thirty-One
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Cocktails and Ice - Phenobarbital
(Barks et al. 2010)
Cocktails and Ice - Phenobarbital
(Sarkar and Barks et al. 2012)
Cocktails and Ice - Topirimate
(Liu and Barks et al. – 2004)
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Cocktails and Ice - Xenon
(Hobbs and Thoresen – 2008)
Cocktails and Ice - NAC
(Jutana and Jenkins et al. – 2006)
Cocktails and Ice – Caspase – 2 Inhibition
(Hagberg et al – 2001: 2012)
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Cocktails and Ice – Erythropoietin
(Ferriero et al: 2012) (Fan et al: 2012)
Hypothermia & Stem Cells
(Kaneko et al. 2012)
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Future Questions and Research
§ Cocktails and Ice
§ Is Delayed Hypothermia in the NB effective?
§ Can Hypothermia be used for Neonatal Stroke?
§ Can Hypothermia be used for other Neonatal Injury? § Ie. NEC, Sepsis, Meningitis
§ What about Premature Infants?
Conclusions § Mild Hypothermia Definitely has a role to Play in
Perinatal Neuroprotection: 1. Brief hypothermia provides only transient neuroprotection 2. Prolonged hypothermia provides permanent neuroprotection
to those babies with moderate encephalopathy 3. Babies with severe encephalopathy remain at risk for injury?
§ Hypothermia is safe § Hypothermic neuroprotection is incomplete. § There may be differences between WBC and SBC
regarding the pattern of brain injury.
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Acknowledgements
Students/Research Assistants/PDF Edward A. Armstrong Joanne Asselin Amy Black Avril Keller Scott Hess Sandra Wright Alireza Karimipour
Collaborators Deborah Saucier PhD Ashfaq Shuaib MD James Thornhill PhD Bernhard Juurlink PhD Kathryn Todd PhD Sandra Davidge PhD