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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

10

15

20

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