Neuroprotection for
Neonatal Encephalopathy
Hannah C. Glass, MDCM, MAS Professor Neurology & Pediatrics University of California, San Francisco
February 2020
15th Hot Topics in Neonatal Medicine
Jeddah, Saudi Arabia
Hypothermia
Hypothermia optimization
Add-on therapies/alternate agents
Neurocritical care – “brain focused care”
Neuroprotective Strategies
Hypothermia
Hypothermia optimization
Add-on therapies/alternate agents
Neurocritical care – “brain focused care”
Neuroprotective Strategies
Cell death
Inflammation Oxidative Stress R
esp
on
se
Hours Days Weeks
Timing: Injury and Repair
Excitotoxicity
Ferriero DM, NEJM
Repair
Oxidative Stress
Free radical formation >>> antioxidants
Excess harmful free radicals (O2-, OH, H2O2)
Damages DNA, lipid membranes, proteins
• Neuroprotection strategy:
Anti-oxidants (melatonin, allopurinol, desferoxamine, N-acetylcysteine)
Slide courtesy of Fernando Gonalez
Excitotoxicity
Slide courtesy of Fernando Gonalez
Excess glutamate
Ca+ influx enzymes that damage cytoskeleton
and DNA
Worse with hypoglycemia & hypoxia
• Neuroprotection strategy:
Anti-glutamate (Xenon, canabinoids) and anti-
excitotoxic (topiramate,
levetiracetam, magnesium sulfate)
Apoptosis:
Programmed Cell Death
• Apoptosis plays critical role in both normal brain development and brain injury
• Neuroprotection strategy: – Caspase
inhibitors
Growth Factor
Response to Injury
Slide courtesy of Fernando Gonalez
Growth Factors
Endogenous upregulation in response to
hypoxia and brain injury
Play an important role in the response to
injury
• Neuroprotection strategy: Provide
exogenous growth factors (Epo)
Slide courtesy of Fernando Gonalez
Death or Disability = 52%
Hypothermia: Room for
Improvement
Optimizing Hypothermia
1. Preemie Hypothermia
– Neonates 330/7-356/7 weeks
2. Effect of Depth and Duration – 32.0°C vs 33.5°C
– 120 hours vs 72 hours
3. Delayed Cooling for HIE – Hypothermia initiated at 6-24 hours
4. Cooling for “mild” HIE
Closed
Recruiting
Closed
Planning
Optimizing Cooling
Eligibility
• Similar to initial cooling trials
• Moderate/severe encephalopathy or seizures
• Cooling initiated at <6hrs
4 Treatment groups • 120 hours vs 72 hours (“longer”) • 32.0°C vs 33.5°C (“deeper”) • 120hrs at 32.0°C (“longer and deeper”)
Shankaran S et al, JAMA 2014
Date of download: 1/17/2016 Copyright © 2016 American Medical
Association. All rights reserved.
Survival for the Hypothermia GroupsDotted lines represent day 3 (72 hours) and day 5 (120 hours).
Figure Legend:
Shankaran S et al, JAMA 2014
Decreased Survival
In “Longer” and “Deeper” Groups
Delayed Cooling Trial
• Eligibility
– Similar to initial cooling trials
– Moderate/severe encephalopathy or seizures identified at 6-24hrs
• Treatment groups – 33.5°C x 96 hrs vs 37°C
• Analysis
– Frequentist & Bayesian
Delayed Cooling Trial:
Frequentist
Cooled
(n=78)
Non-
cooled
(n=79) RR (95% CI) p-value
Death
moderate/severe
disability 19 (24%) 22 (28%) 0.9 (0.5-1.5) .6
Laptook et al, JAMA 2017
• Absolute risk difference: 3.5% (95% CI, −1% to 17%) • Estimated NNT = 29
• Frequentist statistics tell us that there is a 95% chance that
the true NNT lies between 1/100 with treatment causing
death disability to 1/6 spared death/disability
Delayed Cooling Trial:
Bayesian
Bayesian analysis
- 76% probability of any reduction in death/disability
- 64% probability of at least 2% reduction in death/disability
- INCORRECT INTERPRETATION: 76% CHANCE late
hypothermia reduces death/disability
- CORRECT INTERPRETATION: 64% chance that the NNT is 50 or
fewer
•“Results should not delay efforts to recognize HIE early and start hypothermia within 6 hours”
•“Hypothermia initiated at 6-24 hours may have benefit but
there is uncertainty in its effectiveness. Laptook et al, PAS, 2017
Laptook et al, JAMA 2017
Delayed Cooling Trial:
Risk of Harm?
Adverse events
• 19% cooled vs 8% not cooled
• RR 2.2 (95% CI 0.9 – 5.6, p=0.07)
- High glucose
- Bleeding
- Subcutaneous fat necrosis
Laptook et al, PAS, 2017
Laptook et al, JAMA 2017
UCSF has not adopted late cooling
Reminder: Time is
Brain
From Gunn & Thoresen, NeuroRx 2006
Better Outcome with
Early Cooling
• TOBY trial
– 105 infants cooled by <4 hours
• Lower death/disability
• RR 0.77 (95% CI, 0.44 to 1.04)
– 220 infants cooled at 4-6 hours
• No effect
• RR 0.95 (95% CI, 0.72 to 1.25)
Azzopardi et al, NEJM 2010
Don’t Delay! Cooling on transport
Safe
Better temperature
regulation
Faster time to
target temp
More stable at
target temp
Akula VP et al, J Pediatr 2015
Cell death
Inflammation
Repair
Oxidative Stress R
esp
on
se
Hours Days Weeks
Add On & Alternate Agents
Excitotoxicity
Ferriero DM, NEJM
Caspase inhibitors
Anti-inflammatories
(minocycline)
Growth factors
(Epo, stem cells)
Antioxidants
(melatonin,
allopurinol, 2-
Iminobiotin, N-
acetylcysteine) NMDA-2nd messenger
modulation (Xenon)
Anti-excitotoxic (topiramate,
levetiracetam, magnesium
sulfate, cannabinoids)
Improved tissue
oxygenation
Erythropoietin
Erythropoietic Vasculogenic
Anti-apoptotic
Neurotrophic
Anti-inflammatory
↑Iron utilization,
↑Tissue oxygenation
Neurogenesis
Improved cell
survival
Acute Effects
Long Term
Effects
↓ Glutamate toxicity
Juul SE, Clinics in Perinatology 2004
Epo – Animal Studies
EPO
Traudt CM et al. Dev Neurosci 2013
Gonzalez F et al. Stroke 2013 Gonzalez F et al. Dev Neurosci 2007& 2009
No EPO
Epo – Human Studies
• Target populations
– HIE, stroke, preterm
• Epo 500-3000 U/kg safe in preterm and
term
• Phase III RTC – No difference in death or
disability at 2 years (preterm birth)
Juul SE & Pet GC, Clin Perinatol 2015
Juul et al, NEJM, 2020
HEAL Trial
• High dose Epo for Asphyxia and encephaLopathy
• N= 500
– Epo + HT vs. placebo + HT
– Five doses, 1000 U/kg
• Multicenter: >20 hospitals in the U.S.
• 2 Year primary outcome = death or mod/severe neurodevelopmental impairment
– Standardized neurologic exam, cerebral palsy severity, Bayley III
NINDS U01: 2016 – 2022; ClinicalTrials.gov NCT# 02811263; FDA IND 102,138
Stem Cells Create a Favorable
Micro-Environment
Slide courtesy of Fernando Gonalez
van Velthoven, Peds Res 2012
Neural Stem Cell Therapy –
Animal Studies • Mesenchymal or neural stem
cells
– Migrate to the site of inflammation
– Demonstrate graft survival,
dispersion, and differentiation
– Therapeutic potential
• Restore cellular energy
• Blunt inflammatory response
• Promote neurogenesis
• Enhance angiogenesis
Daadi, et al Stroke 2010
Archambault J, et al PLOS 2017
Stem Cells & Functional Neurologic
Assessments – Animal Studies
Archambault J, et al PLOS 2017
Cylinder Test
Water Maze Test
Rotatrod Test
Object
Recognition Test
Stem Cell Clinical Trial
• 4 doses of autologous cord blood
– Birth, 24, 48, and 72 hrs
Cotton M et al. Pediatrics 2014
Cells
n=18
Cooled
only
N=46 p
Survived to 15mo 16 (89%) 35 (76%) 0.25
Survived and Bayley >85 13 (74%) 19 (41%) 0.05
In the Pipeline… Cannabinoids Neurosteroids N-Acetyl Cysteine
Melatonin
How Does Neurocritical Care
Improve Outcomes?
1. Protocol-driven approach
– Higher rates of favorable outcomes
2. Specialized teams in dedicated units
– Reduces morbidity & mortality
– Improves resource utilization
3. Attention to basic physiology to
reduce brain injury
– Temperature, glucose, blood pressure,
CO2, O2
Kramer & Zygun, Current Op Critical Care, 2014
Neuro-
Critical Care Team
Ne
on
ato
log
y
Nu
rsin
g
Ne
uro
log
y
Leadership
Brain Focused Care:
Preventing Secondary Injury • Maintain normal temperature
• Maintain normal glucose
• Avoid hypocapnea (permissive
hypercapnea)
• Avoid hyperoxia and hypoxia
• Maintain normal blood pressure
Don’t Forget Life After the NICU
• Environmental
enrichment
– Motor
– Cognitive
– Social
– Sensory
Neuroplasticity
Training-Based Interventions
• Harnessing experience-dependent
plasticity
• Principles:
– Child generated
– Task specific
– Repetitive & intense
• 90-hours of child-active training within 6-weeks
– Salient and motivating to the child
“The ultimate goal of rehabilitation is to induce early
neuroplasticity that restores the full potential of the
injured brain” – Iona Novak
• Animal model of
hemiplegic CP
– Non-use post-injury no
functional recovery
– Early training-based
interventions +
environmental enrichment
functional recovery &
restored corticospinal
connectivity
– Late implementation no
effect
Martin et al., Dev Med & Child Neurol 2011
Don’t Just “Wait & See”
Summary
Many ways to achieve “neuroprotection” • Prenatal Care
• Brain focused neurocritical care
Newer agents may be synergistic with hypothermia
Strategies that target multiple mechanisms will be more likely to succeed
Effects of neurocritical care - sedatives, anti-seizure agents, pressors, etc - needs further study to optimize clinical care
Early rehabilitation can harness experience-dependent plasticity to restore function Slide courtesy of Fernando
Gonalez
Target
modifiable
risk factors
Acknowledgements Neurology
Donna M. Ferriero, UCSF
Dawn Gano, UCSF
Sharon Wietstock, UCSF
Yvonne Wu, UCSF
Steven Miller, Hospital for Sick Children
Vann Chau, Hospital for Sick Children
Emily Tam, Hospital for Sick Children
Taeun Chang, DC National Children’s Hospital Janet Soul, Boston Children’s Hospital Faye Silverstein, U Michigan
Kevin Staley, Mass General Hospital
Monica Lemmon, Duke
Cameron Thomas, Cincinnati Children’s
Neonatology/Pediatrics
Sonia Bonifacio, UCSF/Stanford
Elizabeth Rogers, UCSF
Michael Kuzniewicz, Kaiser Permanente
Patrick McQuillen, UCSF
Neuroradiology
A. James Barkovich, UCSF
Duan Xu, UCSF
Olga Tymofiyeva, UCSF
Yi Li, UCSF
Neurophysiology Joseph E. Sullivan, UCSF Maria Roberta Cilio, UCSF Adam Numis, UCSF Renee A. Shellhaas, U Michigan
Nicholas Abend, CHOP Courtney Wusthoff, Stanford Tammy Tsuchida, DC National Children’s Hosp Catherine Chu, Mass General Hospital Shavonne Massey, CHOP
Biostatistics and Epidemiology Charles McCullough, UCSF David Glidden, UCSF Nursing Linda Franck, BSN, PhD Susan Peloquin, Elizabeth Papp, Jeannie Chan NICN Nurses, UCSF
Psychology Shannon Lundy, UCSF Bridget Johnson, UCSF Research Assistants Laurel Haeusslein
Manogna Manne Jessica Kan Vedder Isheeta Madeka Bria Bailey Rebecka Craig Olivia Girvan
Children
&
Families
