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Hypoxic ischemic encephalopathy (HIE) and
Therapeutic Hypothermia: the evidence
Krisa Van Meurs, M.D.
Rosemarie Hess Professor of Neonatal and Developmental Medicine
Stanford University School of Medicine
Medical Director, NeuroNICU
Lucile Packard Children’s Hospital Stanford
Palo Alto, California
NEOBRAIN Brasil 2019
1st International PBSF Congress on Neonatal Neuroprotection and Neuromonitoring
São Paulo, Brasil
November 7-9, 2019
Causes of neonatal mortality
Sepsis/pneumonia26%
Tetanus7%
Diarrhea3%
Preterm27%
Asphyxia23%
Congenital7%
Other7%
Lawn JE, et al. Intl J Epidemiol (2006)
Incidence and outcome of HIE
▪ Incidence ranges from 1 to 6 per 1,000 births
▪ Moderate encephalopathy is associated with 10% risk of death
and 30% risk of disability
▪ Severe encephalopathy is associated with 60% risk of death
and most survivors will be disabled
Kurinczuk JJ et al., Early Human Dev (2010)
Pin TW et al., Eur J Paediatr Neurol (2009)
Clinical findings in HIE
▪ Abnormal neurologic exam:
Level of consciousness
Tone
Tendon reflexes
Primitive reflexes
Respiratory function
Autonomic function
▪ Other clinical findings:
Need for resuscitation
Seizures
EEG abnormalities
Other organ injury
Differential diagnosis of neonatal encephalopathy
▪ Inborn error of metabolism
▪ Genetic syndromes
▪ Congenital neuromuscular disease
▪ Brain malformations
▪ Neonatal stroke
▪ Sepsis
Mechanism of brain injury during HIE
The therapeutic window is ~6 hours,
the duration of the latent phase between
primary and secondary energy failure.
x
1 hr 6-24º days
Recovery
Brain Injury
Brain Injury
Secondary Energy
Failure
Hypoxia-Ischemia
Primary Energy
Failure
Latent Period
Processes involved in HI Brain Injury
1o energy failure
↑ Excitatory amino acids
Loss of ionic balance
↑ Intracellular Ca++
↑ Lipases, proteases
↑ Free radicals
2o energy failure
▪ Activated microglia
▪ Apoptosis
▪ ↓ Growth factors
▪ ↓ Protein synthesis
▪ Oxidative injury
▪ ↑ Excitatory amino acids
Effects of brain temperature reductions on hypoxic ischemic injury
Cooling prevents or attenuates secondary energy failure by:
Glutamate
Nitric oxide synthase
Activation of microglia
Free radical production
Apoptosis
Methods of delivering therapeutic hypothermia
Whole body cooling: Rectal or
esophageal temperature 33oC x 72
hrs, then slow rewarming
Selective head cooling: Body
temperature 34-35oC x 72 hrs,
then slow rewarming
Cooling trials
Trial (Publication date) NGA
(wks)Mode
Transport
Cooling
Temp goal
& site
Eicher (2005) 65 ≥35 Whole body Yes 33° ± 0.5 rectal
CoolCap (2005) 234 ≥36 Selective head No 34-35°C rectal
NICHD (2005) 208 ≥36 Whole body No 33.5°C esophageal
TOBY (2009) 325 ≥36 Whole body Yes 33.5°C rectal
Neo.nEURO (2010) 125 ≥36 Whole body No 33-34°C rectal
Zhou (2010) 194 ≥37 Selective head No 34° ± 0.2 nasopharyngeal
ICE (2011) 221 ≥35 Whole body Yes 33-34°C rectal
Meta-analysis of hypothermia RCTs
Tagin MA et al., Arch Pediatr Adolesc Med (2012)
Conclusion: Hypothermia improves survival and neurodevelopment in
newborns with moderate to severe HIE. Risk ratio is 0.76 with
confidence interval 0.69-0.84. Number need to treat =7.
Meta-analysis: Efficacy outcomes
Mortality 12/1390 0.78 (0.65, 0.92)
ND disability in survivors 6/687 0.67 (0.54, 0.84)
Severe cerebral palsy 3/518 0.65 (0.48, 0.88)
MDI <70 4/522 0.70 (0.54, 0.90)
PDI <70 4/512 0.70 (0.54, 0.90)
Severe visual deficit 4/535 0.59 (0.35, 0.98)
Severe hearing deficit 4/510 0.75 (0.36, 1.55)
Epilepsy 5/413 0.80 (0.48, 1.31)
Life support withdrawn 6/746 0.93 (0.73, 1.18)
Relative riskOutcomeNo. of studies/
No. of participants
0.5Hypothermia
1.5Normothermia
Relative risk
Shah P, Semin Fetal Neonatal Med (2010)
Meta-analysis: Safety outcomes
Arrhythmia 5/806 4.08 (1.55, 10.74)
Hypotension 8/1108 1.03 (0.93, 1.13)
Coagulopathy 7/1114 0.96 (0.80, 1.15)
Thrombocytopenia 4/638 1.28 (1.07, 1.52)
Seizure after enrollment 8/1102 0.96 (0.86, 1.06)
Renal failure 5/310 0.95 (0.53, 1.70)
Hepatic side effects 5/678 0.85 (0.69, 1.04)
Infection 7/544 0.86 (0.40, 1.88)
Pulmonary hypertension 5/636 1.36 (0.95, 1.96)
Relative riskOutcomeNo. of studies/
No. of participantsRelative risk
0.5Normothermia
1.5Hypothermia
Shah P, Semin Fetal Neonatal Med (2010)
Recommendations for use of therapeutic hypothermia
▪ Hypothermia at <6 hours decreases mortality and severe disability
with minimal side effects and without increasing disability
Severe HIE less likely benefit
No difference in outcome between head and body cooling
Peliowski A, et al. Paediatr Child Health (2012)
▪ Therapeutic hypothermia is an effective therapy, treated infants
should meet trial entry criteria, and education of referring
hospitals regarding identification of hypothermia candidates is
critical.AAP Committee on Fetus and Newborn. Pediatrics (2014)
▪ Newborns with moderate to severe HIE should be offered
hypothermia. Treatment should be consistent with trial protocols.Perlman JM, et al. Circulation (2010) ILCOR statement
NICHD Neonatal NetworkEligibility criteria for therapeutic hypothermia
If blood gas is available If blood gas is not available,or pH 7.01 - 7.15
or Base deficit 10 -15.9mEq/L
Infant should have:
▪ Cord or first postnatal blood gas
within 1 hour with pH ≤ 7.0
or
▪ Base deficit on cord gas or first
postnatal blood gas within 1 hour
at ≥ 16 mEq/L
Infant should have history of acute
perinatal event and
▪ Apgar score ≤ 5 at 10 minutes
or
▪ Continued need for ventilation at
10 minutes
Two step process for infants ≥36 weeks and ≤6 hours of age
Shankaran S, et al. NEJM (2005)
Clinical staging of HIE: Modified Sarnat exam
Categories Moderate encephalopathy Severe encephalopathy
Level of consciousness Lethargic Stupor or coma
Tone Hypotonia Flaccid
Posture Distal flexion,
Complete extension
Decerebrate
Spontaneous Activity Decreased No activity
Primitive reflexes
Suck
Moro
Weak
Incomplete
Absent
Absent
Autonomic function
Pupils
Heart rate
Respiration
Constricted
Bradycardia
Periodic
Deviated, dilated
or non-reactive
Variable
Apnea
Modified from Sarnat and Sarnat, Arch Neurol (1976)
0
10
20
30
40
50
60
70
80
90
100
Pe
rce
nt
NICHD Trial: Primary Outcome
Death or Disability
44%
Hypothermia
n = 102
RR: O.72
95% CI 0.54-.95
P value= 0.0162%
Control Group
n = 106
Shankaran S et al., N Engl J Med (2005)
Disability defined as:
Bayley MDI <70
GMFCS ≥ level 2
Hearing impairment
Seizure disorder
Blindness
NICHD Trial: Subgroup Analysis in Moderate Encephalopathy Group
0
10
20
30
40
50
60
70
80
90
100
Pe
rcen
t
Hypothermia
Control
Death or
mod-severe CP
Death or
blindness
Death or
deafness
Death or
MDI < 70
Death or
multiple
disabilities
p = 0.13
p = 0.10p = 0.09
p = 0.14
p = 0.25
0
10
20
30
40
50
60
70
80
90
100
Pe
rcen
t
Death or
mod-severe CP
Death or
blindness
Death or
deafness
Death or
MDI < 70
Death or
multiple
disabilities
Hypothermia
Control
NICHD Trial: Subgroup Analysis in Severe Encephalopathy Group
p = 0.26
p = 0.22p = 0.48
p = 0.08
p = 0.31
Shankaran S et al., N Engl J Med (2005)
Questions regarding hypothermia therapy
▪ What is the most effective technique for cooling, selective head or whole body cooling?
▪ What is the long term outcome at school age and beyond?
▪ What is the most effective temperature and duration of cooling?
▪ What is the optimal age to initiate hypothermia and when is it too late?
▪ Do newborns <36 weeks gestation benefit?
▪ Should we cool babies with mild HIE?
▪ Is cooling on transport appropriate and safe?
Higgins RD et al. J Pediatr (2011)
Selective head versus whole body cooling
Cochrane Review Update
Neonatology 2013;104:260–262DOI: 10.1159/000353681
262
Study or subgroup Hypothermia Standard care Weight,
%
Risk ratio
M-H, fixed (95% CI)
Risk ratio
M-H, fixed, 95% CI even ts total events total
1.1.1 Selective head cooling with mild systemic hypothermia Gunn, 1998 7 18 4 13 1.1 1.26 (0.46, 3.44) Cool Cap Study, 2005 59 108 73 110 17.6 0.82 (0.66, 1.02) Zhou, 2010 31 100 46 94 11.5 0.63 (0.44, 0.91) Subtotal (95% CI) 226 217 30.3 0.77 (0.64, 0.92) Total events 97 123 Heterogeneity: 2 = 2.46, d.f. = 2 (p = 0.29), I 2 = 19% Test for overall effect: Z = 2.78 (p = 0.005)
1.1.2 Whole body cooling Eicher, 2005 14 27 21 25 5.3 0.62 (0.41, 0.92) NICHD Study, 2005 45 102 64 103 15.5 0.71 (0.54, 0.93) TOBY Study, 2009 74 163 86 162 21.0 0.86 (0.68, 1.07) neo.nEURO Study, 2010 27 53 48 58 11.2 0.62 (0.46, 0.82) ICE Study, 2011 55 107 67 101 16.8 0.77 (0.62, 0.98) Subtotal (95% CI) 452 449 69.7 0.75 (0.66, 0.84) Total events 215 286 Heterogeneity: 2 = 4.25, d.f. = 4 (p = 0.37), I 2 = 6% Test for overall effect: Z = 4.80 (p < 0.00001)
Total (95% CI) 678 666 100.0 0.75 (0.68, 0.83) Total events 312 409 Heterogeneity: 2 = 6.89, d.f. = 7 (p = 0.44), I 2 = 0% Test for overall effect: Z = 5.53 (p < 0.00001) Test for subgroup differences: 2 = 0.06, d.f. = 1 (p = 0.81), I 2 = 0%
0.2 0.5 1 2
Favorshypothermia
Favorsstandard care
5
Fig. 1. Therapeutic hypothermia versus standard care. Effect on death or disability in survivors assessed (by method of cooling).
Study or subgroup Hypothermia Standard care Weight,
%
Risk ratio
M-H, fixed (95% CI)
Risk ratio
M-H, fixed, 95% CI events total events to tal
1.2.1 Selective head cooling with mild systemic hypothermia Gunn, 1998 3 18 3 13 1.4 0.72 (0.17, 3.03) Akisu, 2003 0 11 2 10 1.0 0.18 (0.01, 3.41) Cool Cap Study, 2005 36 108 42 110 16.7 0.87 (0.61, 1.25) Lin, 2006 2 32 2 30 0.8 0.94 (0.14, 6.24) Zhou, 2010 20 100 27 94 11.2 0.70 (0.42, 1.15) Subtotal (95% CI) 269 257 31.1 0.78 (0.59, 1.04) Total events 61 76 Heterogeneity: 2 = 1.56, d.f. = 4 (p = 0.82), I 2 = 0% Test for overall effect: Z = 1.72 (p = 0.09)
1.2.2 Whole body cooling Shankaran, 2002 2 9 3 10 1.1 0.74 (0.16, 3.48) Eicher, 2005 10 32 14 33 5.5 0.74 (0.38, 1.41) NICHD Study, 2005 24 102 38 103 15.2 0.64 (0.41, 0.98) TOBY Study, 2009 42 163 44 162 17.7 0.95 (0.66, 1.36) neo.nEURO Study, 2010 20 53 33 58 12.6 0.66 (0.44, 1.00) ICE Study, 2011 27 108 42 109 16.8 0.65 (0.43, 0.97) Subtotal (95% CI) 467 475 68.9 0.73 (0.61, 0.89) Total events 125 174 Heterogeneity: 2 = 2.92, d.f. = 5 (p = 0.71), I 2 = 0% Test for overall effect: Z = 3.18 (p = 0.001)
Total (95% CI) 736 732 100.0 0.75 (0.64, 0.88) Total events 186 250 Heterogeneity: 2 = 4.72, d.f. = 10 (p = 0.91), I 2 = 0% Test for overall effect: Z = 3.59 (p = 0.0003) Test for subgroup differences: 2 = 0.13, d.f. = 1 (p = 0.72), I 2 = 0%
0.01 0.1 1 10
Favorshypothermia
Favorsstandard care
100
Fig. 2. Therapeutic hypothermia versus standard care. Effect on death (by method of cooling).
Dow
nlo
ad
ed b
y:
98
.207.1
57.6
4 -
10
/29/2
01
3 3
:38:3
8 P
M
Jacobs SE, et al. Cochrane Database Sys Rev (2013)
Conclusions:
• Both head and body cooling decrease the outcome of death or major disability
• However, body cooling significantly decreases mortality, neuromotor disability,
and developmental delay but head cooling does not. May be due to small
sample size.
• It is not possible to determine if one method is preferable
Effect of hypothermia on childhood outcomes
Eligibility: Children aged 6-7 enrolled in TOBY trial
Primary outcome: Survival with IQ≥ 85
Results:
Azzopardi D, et al. NEJM (2014)
Conclusion: Moderate hypothermia after perinatal asphyxia resulted
in improved neurocognitive outcomes at age 6-7 years.
HT group
N=163
Control group
N=162
P value
Survival with IQ ≥ 85 (testable) 52% 39% 0.04
Death 29% 30% 0.81
Survival with IQ ≥ 85 (all survivors) 77% 63% 0.05
Cerebral palsy 21% 36% 0.03
Effect of hypothermia on childhood outcomes
Eligibility: Children age 6-7 enrolled in NICHD cooling trial
1o outcome: Death or IQ less than 70
Results: HT group Control P value
n=97 n=93
Death or IQ <70 (%) 47% 62% .06
Death 28% 44% .04
IQ <70 27% 33% .51
Conclusion: The outcome of death or IQ<70 was lower in the hypothermia
group but not significantly. Hypothermia resulted in fewer deaths and did not
increase the rate of severe disability.
Shankaran S, et al. NEJM (2011)
Optimizing (longer, deeper) cooling
Study design: Multi-center, randomized, non-masked with factorial
design
Eligibility: Same NICHD criteria
Intervention: 33.5º C x 72 hours
33.5º C x 120 hours
32º C x 72 hours
32º C x 120 hours
1º outcome: Death or moderate/severe disability at 18-22
months of age
Sample size: 726 (stopped after enrollment of 364 patients)
Shankaran S, et al. JAMA (2015)
Survival curves for the 4 hypothermia groups
Shankaran S, et al. JAMA 2015
Optimizing cooling for neonatal HIE: Results
Results: In-hospital mortality rates and disability rates for survivors in the four treatment groups were:
Mortality Disability Death/disability
33.5°C for 72 h 7% 23% 32%
32.0°C for 72 h 14% 20% 32%
33.5°C for 120 h 16% 19% 32%
32.0°C for 120 h 17% 11% 32%
An interaction between longer and deeper cooling was found.
Conclusion: Longer or deeper cooling or both compared with cooling at 33.5º C for 72 hours did not reduce the primary outcome of death or disability.
Shankaran S, et al. JAMA (2015)
Shankaran S, et al, JAMA (2017)
Should a baby be cooled after 6 hours?
How this happens:
▪ Arrival at a cooling center after 6 hrs of age
▪ Progress from stage I to II/III encephalopathy after 6 hrs of age
▪ Are not recognized to qualify until after 6hrs of age
▪ Cooling cannot be initiated within 6 hours of age (equipment or
personnel not available)
NICHD trial: “Late” hypothermia for HIE
Study design: Multi-center, randomized, non-masked,
Bayesian analysis
Eligibility: 6-24 hours of age with evidence of moderate or
severe encephalopathy
Intervention: Whole body cooling to esophageal temperature
33.5º C x 96 hours or control
1º outcome: Death or moderate/severe disability at 18-22
months of age
Sample size: 168
Laptook A, et al. JAMA 2017
Probability of treatment benefit
Conclusion: 76% of newborns cooled between 6-24 hours
will have some benefit.
Laptook A, et al. JAMA (2017)
Therapeutic hypothermia for HIE in premature infants 33-35 weeks gestation
Purpose: To determine if cooling benefits infants 33-35 weeks
gestation with moderate to severe HIE
Methods: Randomized controlled trial whole body hypothermia
with esophageal temperature 33.5o C for 72 hours
1º outcome: Death or moderate to severe neurodevelopmental
impairment at 18-22 months
Sample size: 168, 145 enrolled as of November 1, 2019
PIs: Roger Faix, MD and Abbot Laptook, MD
NICHD Neonatal Research Network
Clinical Trials.gov NCT 01793129
Need for cooling plus therapies
Controls Cooled
Death or moderate to severe disability 62-83% 44-55%
Death 27-57% 24-38%
Cerebral palsy 30-48% 19-33%
Conclusion: Additional neuroprotective strategies are needed to
further reduce mortality and morbidity.
Shankaran S, NEJM (2005) Simbruner G, et al. Pediatrics (2010)
Gluckman P, et al. Lancet (2005) Jacobs S, et al. Arch Pediatr Adolesc Med (2011)
Azzopardi D, et al NEJM (2009)
Potential therapies to augment neuroprotection
▪ Anticonvulsant or antiexcitatory
Phenobarbital, topiramate, levetiracetam, xenon, magnesium sulfate, bumetanide
▪ Anti-inflammatory or antioxidant
Sodium cromoglicate, minocycline, indomethacin, melatonin, N-acetylcysteine,
allopurinol, pomegranate polyphenols, 7-nitroindazole, 2-iminobiotin, necrostatin 1
▪ Multiple mechanisms
Erythropoietin
▪ Growth factors and cell-based therapies
Nerve growth factor, insulin-like growth factor 1, brain derived neurotrophic factor,
autologous cord-blood transplantation
Modified from Johnston MV et al. Lancet Neurology 2011
Erythropoietin (Epo)
Generally used for erythropoiesis, may also provide neuroprotection
Mechanisms:
Figure from Juul SE & Pet GC , Clinics Perinatol (2015)
High dose Epo and hypothermia for HIE NEATO trial: Phase II
▪ Purpose: To determine if Epo plus hypothermia improve MRI
brain injury and short term outcomes in newborns with HIE
▪ Methods: Double masked trial of 50 newborns randomized to
receive 1,000 units/kg IV x 5 doses or placebo
Primary outcomes: MRI brain injury score, Alberta Motor score
(AIMS), and Warner initial developmental evaluation (WIDEA).
▪ Results: Epo treated infants had a lower brain injury score
(p=.002), higher motor score (p=.03), and higher WIDEA (p=.05).
▪ Conclusions: High dose Epo with hypothermia resulted in less
brain injury and better 1-year motor outcomes.
Wu Y, et al. Pediatrics (2016)
High Dose Epo for Asphyxia and Encephalopathy HEAL trial – Phase III
Purpose: Determine if Epo provides benefit in infants ≥ 36 weeks with moderate to severe HIE treated with hypothermia
Methods: Double masked RCT Epo 1,000 units/kg IV x 5 doses or placebo initiated at <24 hours of age.
Primary outcome: Death or moderate to severe neurodevelopmental impairment at 18-24 months of age.
Secondary outcomes: Safety, brain injury by MRI at 7 days of age, and serial biomarkers of brain injury.
Sample size: 500 infants, completed in 2019, follow-up ongoing
PIs: Yvonne Wu, MD MPH and Sandra Juul, MD PhD
Clinical Trials.gov NCT 02811263
Juul S, et al. Neonatology (2018)
Conclusions
▪ Therapeutic hypothermia as used in clinical trials reduces death and major disability and improves long term outcomes
▪ Adverse effects of cooling are uncommon
▪ Trials of cooling in premature infants 33-35 weeks are in progress.
▪ Other neuroprotective therapies are being tested in randomized trials and may hopefully provide additional improvements in outcome
▪ At this time, erythropoietin looks the most promising and results will be available in 2 years.