Transcript Neonatal Neuroprotection

Neonatal Neuroprotection
Shannon E. G. Hamrick, MD
Assistant Professor
Divisions of Neonatology and Cardiology
Department of Pediatrics
Emory University
Disclosure
•
I have no relevant financial relationships with the manufacturer(s) of any
commercial product(s) and/or provider(s) of commercial services discussed
in this CME activity.
•
I do not intend to discuss an unapproved/investigative use of a commercial
product/device in my presentation.
Neonatal Neuroprotection:
Learning Objectives
• Discuss the pathogenesis of neuronal injury in the setting
of perinatal hypoxia-ischemia.
• Describe why the immature brain is uniquely susceptible
to hypoxic-ischemic injury and how this impacts
treatment options.
• Explain strategies for neuroprotection, and specifically
the efficacy of hypothermia.
Overview
• Mechanisms of neonatal brain injury
– Term hypoxia-ischemia
– Preterm and other high-risk groups
• Treatment Strategies
– Clinical Standards
– Neuroprotection with Hypothermia
Cerebral energy
Membrane depolarization
Neurotransmitter release
Ca++
Free radicals
Neuronal damage
Reperfusion
Free radicals
necrosis
Cell death
apoptosis
Why is the immature brain particularly susceptible?
Basal Ganglia
1.
2.
3.
4.
5.
6.
Intervascular
Boundary Zone
Increased requirement for oxidative metabolism
Increased amounts of excitatory amino acid receptors
Immature vascular regulation
Response to inflammation
Selective cell type vulnerabilities
Maturational differences in free radical management
O•2
Superoxide
Dismutase
GSH
H2O2
Glutathione
peroxidase
Catalase
H2O
Fe++
GSSG
H2O
OH-
1. Immature brain has altered balance of antioxidants
2. The iron rich neonatal brain is vulnerable
Fe2+ + H2O2
Fe3+ + HO. + OH-
Patterns in Neonatal Hypoxia-Ischemia
Term
Deep Grey Nuclei
Preterm & Cardiac
Periventricular White Matter
Take-Home Points: pathogenesis
• Key to the cascade of injury:
– ATP, glutamate, calcium, free radicals
• Injury evolves over time
• Immature brain has unique susceptibilities
• Patterns of brain injury depend on maturational
state of the brain
– Term = injury to basal ganglia, intervascular boundary
zones
– Preterm = injury to periventricular white matter
– Heart disease = blurs this distinction
Overview
• Mechanisms of neonatal brain injury
– Term hypoxia-ischemia
– Preterm and other high-risk groups
• Treatment Strategies
– Clinical Standards
– Experimental Neuroprotection
Clinical Standards
• Secure airway; maintain
normal ventilation and
oxygenation parameters
– Severe hyperoxygenation
(paO2 >200) and hypocarbia
(pCo2 <20) associated with
worse outcomes in HIE infants
• Maintain systemic circulation
to maintain cerebral
perfusion
• Cerebral edema maximal
between 36-96 hours
– Antiedema agents not helpful
• Control seizures, use
EEG to monitor for
subclinical seizures
• Evaluate and treat
electrolyte
disturbances- avoid
hypoglycemia
• HYPOTHERMIA
• Avoid hyperthermia
Hypothermia:
potential mechanisms
•
•
•
•
•
Decreased metabolism/ATP preservation
Inhibition of glutamate release
Decreased free radical generation
Decreased apoptosis
Decreased inflammatory response
• Prolongation of therapeutic window?
Hypothermia eligibility criteria
•
•
•
•
•
≥ 36 weeks gestational age
≤ 6 hours of age
History of perinatal event
Apgar score < 5 at 10 minutes
Cord pH or any postnatal blood gas pH within 1 hour
of birth ≤ 7.0.
• Base deficit on cord gas or any postnatal blood gas
within 1 hour of birth ≥16 mEq/L.
• Continued need for ventilation at 10 minutes
• Neurological exam consistent with moderate to
severe encephalopathy OR presence of seizures
before 6 hours of life
Hypothermia efficacy studies:
eligibility criteria- neuro exam
Moderate HIE Severe HIE
Category
need 3 of 6
consciousness
activity
posture
lethargic
stupor/coma
decreased
none
distal flexion, full
extension
decerebrate
tone
hypotonia or
hypertonia
flaccid
reflexes suck, Moro
autonomic
weak or incomplete
absent
constricted pupils,
bradycardia,
periodic breathing
dilated/non-reactive,
variable HR, apnea
pupils, heartrate,
respirations
Hypothermia efficacy studies, 2005
• Gunn et al- Lancet
– Head cooling, n= 234, used aEEG as additional criteria
– Overall no difference in death/severe disability, but subgroup analysis of
moderately affected infants showed positive effect: OR 0.42 (95% CI .22-.8, p
= 0.009).
• NICHD- NEJM
– Systemic cooling, n = 239
– 18% decrease in composite outcome with hypothermia (44% vs. 62%, RR .72,
95% CI .54-.95, p = 0.01)
– No significant difference in CP in survivors of either group
• Eicher et al- Pediatric Neurology
– Systemic cooling, n= 65
– Tested ability to initiate tx in referral hospitals
– Composite outcome 52% treated, 84% control, p= 0.019.
Hypothermia
• Summary in 2005:
– Short-term benefit (18 month follow-up) in
affected neonates using experimental
protocols
– Safe therapy
– Survey Oct. 05: 6.4% respondents offered,
mainly academic centers
Shah et al, 2007 Arch Pediatric Adol. Med Epub
Cochrane Review
• October 2007
– 8 RCT, 638 term infants, mod-sev HIE
– Composite outcome
• RR 0.76, 95% CI 0.65-0.89, NNT 7
• Mortality alone: RR.74 (.58-.94) NNT 11
• Disability alone: RR.68 (.51-.92) NNT 8
– Cooling reduces mortality without increasing disability,
benefits outweigh short-term adverse effects, but
review comprises data from less than half infants
currently randomized . . . So questions remained
Systematic Review 2010
• Up to 1440 patients
Shah, Semin Fetal Neonatal Med., 2010
Systematic Review 2010
Shah, Semin Fetal Neonatal Med., 2010
Systematic Review 2010
Shah, Semin Fetal Neonatal Med., 2010
Hypothermia: Questions Remain
• Is it effective in the severely affected?
• How late can you initiate cooling and still see an effect?
– 6-24 hour hypothermia trial underway
• What is the optimum degree and duration of cooling?
– optimizing cooling trial just begun
• Can we extend this protection down to the preterm
population?
– trial of hypothermia proposed for 33-35 wk GA
• Should the degree/duration of cooling be based on
cause, severity and stage of brain injury?
Overview
• Mechanisms of neonatal brain injury
– Term hypoxia-ischemia
– Preterm and other high-risk groups
• Treatment Strategies
– Clinical Standards
– Experimental Neuroprotection
• Developmentally appropriate
The Ideal Neuroprotectant
•
•
•
•
•
•
•
Cross the blood brain barrier
Accumulate at desired site of action
Act for appropriate duration of time
No drug interactions
No adverse side effects
Does not prevent normal maturation
Would work post-injury
HIE: Treatment Strategies
• Maintain energy stores to
reduce depletion of ATP
• Inhibit glutamate release
• Block Calcium entry
• Inhibit degradative enzymes
• Scavenge free radicals,
reduce Fenton chemistry
• Block apoptosis
• Modulate inflammation
Treatment Strategies in Hypoxia Ischemia
Cerebral blood flow
Hypothermia
Energy failure
Glutamate release
FBP
NMDA-2nd messenger
modulation
Calcium-dependent
‘excitotoxicity’
Apoptotic cell death
Necrotic cell death
Free radical injury
Caspase inhibitors
Anti-inflammitory agents
Repair
Neurotrophins
Antioxidants,
desferoxamine
Delayed cell death
Inflammation
Restoration
Stem cells
Plasticity & Recovery
Cocktail approach
Ferriero, D. M., N Engl J Med 2004
Take-Home Points: treatment
• Maintain “ABCs”
• Avoid hyperoxygenation, hypocarbia,
seizures, hypoglycemia, or hyperthermia
• Hypothermia now proven therapy for
moderate, ?severe HIE
• Additional hypothermia trials underway
– Late, “optimizing” and ??33-35 weekers
• Neuroprotection must not disrupt normal
maturational process
• Successes are possible