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).

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98

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57.6

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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.