Download HIE - March of Dimes

2/5/2013
Hypothermia for Neonatal Brain Injury
A cool approach!
HIE: Acute Brain Injury
Hypoxia - Ischemia – Acidosis
Environment
1. Maternal
2. Utero-Placental
Meena Garg MD
Professor of Pediatrics
Fetus
3.Fetal
Bakersfield Perinatal Symposium
2013
ACOG
Hypoxic Ischemic Encephalopathy
Fetal Injury
Metabolic Acidosis
pH<7.0, BD>12
AAP
(HIE)
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Low Apgar Score 0-3 at 10 min
Metabolic acidosis pH < 7 or 7.1
Neurological manifestations (e.g. seizure,
hypotonia, coma)
Multisystem involvement (e.g. Kidney,
Lungs, liver, heart, intestines).
HIE: Acute Brain Injury
• HIE occurs in 2- 4 /1000 live births
• 15% to 20% HIE infants die in the
postnatal period
• 25%-30% sustain Neurological
disabilities
Neurological Examination HIE
Hypoxic Ischemic Encephalopathy
Mild
Moderate
Severe
Lethargic
coma
Normal
Hypotonia
Flaccid
↑
↑
↓/-
Absent
Present
Present
Consciousness Hyper alert
• Mild HIE: 100% normal outcome
Muscle Tone
DTR
• Moderate HIE: 10% Death, 30% Severe
motor and cognitive deficits
Seizures
Suck/Moro Overactive
Myoclonus
• Severe HIE: 50% Death, 95-100% Severe
motor and cognitive deficits
Present
↓ or absent
absent
Present
Absent
Pupils Dil/reactive Cons/reactive
HR / RR
EEG
Variable/fix
↑/N
Bradycardia/↓
Bradycardia/↓
Normal
Abnormal
Abnormal
Sarnat 1976
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Mod or Severe HIE: Abnormal signs in 3 out of 6 categories
Management - HIE
Supportive care
• Ventilator Support: O2 and CO2
• Ionotropic support: maintain CO and
BP for cerebral perfusion
• Maintain blood glucose level 75-100
• Control of seizures
• Avoid cerebral Edema: Prevent fluid
overload
Two Phases of Cerebral Injury
Motor and Cognitive Deficits in HIE
30% moderate HIE and 90% of severe HIE
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Latent >6-100
●Hypoxia
●Depolarizatio
n ● Cell death
●Excitotoxins
●Ca entry
Initial Insult
Improvements in intensive care do not
change these outcomes
CBF +
3
Adenosine
Zanthine
Secondary 3-10d
● Failing oxidative
metabolism
● Seizures
● Cytotoxic edema
● Excitotoxins
● Final Cell death
Brain Injury
2005
1
AMPA/ KA
Ca2+
Cell
Necrosis
Recovery
● Recovery of
oxidative metabolism
● Apoptotic cascade
● Inflammation
● Receptor
hyperactivity
ATP
Glutamate
NMDA
HYPOTHERMIA
Initial Insult
Reperfusion
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Learning Disability
Motor Dysfunction
Cerebral Palsy
Swallow /feeding dysfunction
Hearing Loss
Cortical blindness
Late death
2
2005
↑nNOS
Lactate
NO
↑ROS
Caspase
DNA damage
DNA fragmentation
4
2008
Apoptosis
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Therapeutic Hypothermia
Criteria for HIE Neonates
Gestation Age = or >36, Age < 6 hrs
1. Evidence of birth asphyxia
2. Presence of Clinical encephalopathy
or
Presence of encephalopathy by
aEEG or standard EEG.
2.
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Presence of Moderate or Severe by
Neurological exam:
Altered state of
consciousness (lethargy,
stupor or coma)
Hypotonia
Abnormal reflexes including
oculomotor or pupillary
abnormalities Absent or
weak suck
Clinical seizures
1. Presence of Asphyxia at Birth?
GA >/=36, Age < 6 hrs + one of the following:
a. Acute hypoxic ischemic insult, 10 minute
AS < 5
b. Resuscitation + Ventilation support 10
minutes after birth
c. pH <7.00 or BE > - 16 at less than 1hr of age
Presence of Moderate or Severe
Encephalopathy by 20 minutes of aEEG
or EEG
(Abnormal EEG background or Seizures)
a. Low voltage
b. Discontinuous background
c. Moderate to severe burst suppression
d. Electrographic seizures
e. Seizures + abnormal background
Mild HIE patients are not cooled
3) 20 minutes of EEG or aEEG
o Low voltage EEG or aEEG
Exclusion Criteria For Hypothermia in
HIE Neonates
o Discontinuous background
o Burst suppression
o Seizures
Normal Tracing
Severe HIE- upper margin <10 μv
Mod HIE lower margin <5μv
1) BW < 1800g and GA <36 wks
2) >6 hrs of age
3) Evidence of head trauma, skull
fracture causing major intracranial
hemorrhage
4) Major lethal congenital anomalies
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Management Prior to Transport
Management During Transport
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No active cooling by placing cooling packs
during transport
Monitor temperature and keep temp 36.5 to
37.3
Do not turn off the warmer routinely
Overcooling may worsen side effects of
cooling
Whole Body
Cooling
Selective
Head Cooling
Three phases of Therapeutic Hypothermia
• Monitor temperature
• Avoid T >37.5ºC and overcooling to
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<34ºC
No active cooling measures
No Passive cooling measures for
lack of standards
T< 34°C can worsen bleeding, DIC,
thrombocytopenia, PPHN etc.
Can we Cool infants on Transport?
• Currently there are no clinical guidelines or
recommendations for cooling in transport
• Difficult to maintain temperature in range
• 34% of 35 infants cooled on transported had at
least 1 rectal <32°C and 14% <30°C. (Fairchild et al)
• Overcooled infants reported to have higher
mortality
• Cooling affects aEEG and Neurological exam
findings
Hypothermia Patient Preparation
• If patient meets criteria for cooling expedite
transport for arrival before 6 hrs of age
• Notify Attending on call for neurological exam
• Notify vEEG lab for stat EEG –neurologist
reading required
• aEEG started before or at the same time as
regular EEG is started
• Establish lines as much as possible
• Set up: Pre-cool the cooling system to be used –
cool cap or blanket
• Labs: CBC+ Manual Diff, blood c/s, ABG, DIC
panel (PT,PTT, Fib, FDP), LFTs
• Baseline EKG
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HIE General Management
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Adequate ventilation: O2 and CO2
Wean to extubate if stable.
Adequate perfusion and BP
Control of brain swelling: avoid fluid overload
(SIADH)- restrict fluids to 2/3rd maintenance
Ionotropes may be needed to support BP
Maintain blood glucose level 75-100
Recognition and Control of seizures
Monitoring renal function and adjust medication
doses for renal insufficiency as needed
Hypothermia RCT Control Group with Poor
Outcomes
• Control group had worse neurodevelopmental
outcomes at 18-22 month FU
• Control group had worse neurodevelopmental
outcomes at 5 year FU
• Hyperthermia or Core T >38ºC in control HIE
infants resulted in worse outcomes
Hypothermia for 72 hrs- Management
• Monitor skin, rectal or esophageal, and ambient or
water temp
• Rectal temperature 34 to 35ºC by adjusting cap
temperature
• Esophageal temp 33.5 servo controlled
• Continuous vEEG monitoring till off hypothermia and
seizure free for 24-48 hrs.
• Seizures may be suppressed by cooling
• NPO during cooling
• Monitor and correct ABG, acidosis, glucose,
coagulation and DIC
• 12 hourly scalp check for edema or skin breakdown
Hypothermia Decreases Death and Disability
Therapeutic Hypothermia is safe when strict
guidelines are used from the clinical trials
72 hours of Cooling at a core temperature of 33.534.5°C decreased death or disability in
– Moderate HIE by 12-18%
– Severe HIE - 13-20%
Cooled HIE infants continue to perform better
than controls at school age (5 year follow up)
There is no increase in severe disability or
cerebral palsy in survivors
Hypothermia RCT Control Group Results
• 22.5% of control infants in the first
hypothermia trials had T >37.5ºC
• T >38ºC in control HIE infants resulted in
worse outcomes
– T >38ºC resulted in Normal outcome in 9 %
of HIE infants compared to Normal
outcome of 30% if core T was <38ºC
Physiological effect : Hypothermia
• ↓VO2
• ↓Insulin sensitivity and secretion, ↑Fat
metabolism
• T<30ºC: V. Tach. or V. Fib.
• T<34ºC: ↑PR, QRS and QT, sinus
bradycardia, T<35ºC: ↓ CO
• T <35ºC: ↓Platelet function, ↑ Clotting time
• T<35ºC: ↑UOP, ↑Loss of urinary electrolytes,
↓creatinine clearance
• T 34-36ºC: Shivering in adults
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Rewarming after completing 72 hrs of cooling
Common Side Effects of Hypothermia
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Sinus Bradycardia, Prolongation QT
Transient hyperglycemia
Anticoagulant effects- DIC
Prolonged the half-lives of medications
Inhibition of antimicrobial activity
Scalp edema
• Rewarming slowly to avoid seizures and
worsening of PPHN
• Increase core temp by 0.5°C per hour
• When core temp is 37 for 2-3 hrs then
increase the overhead warmer temp to
increase skin temp by 0.5 per hr
• Maintain skin temp 36.5°C to 37.3°C
After Completing 72 hrs Hypothermia
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MRI/MRS studies early at 3-7 days of age and
follow up as needed
Follow up EEGs for adequate control of
seizures and adjusting AEDs
Evaluation for need for inpatient and
outpatient OT-PT
HRIF: Neurodevelopmental follow up
Neurology Follow up for patients on AEDs
MRI and MR-Spectroscopy Evaluation
after HIE
Non-contrast MRI (T1 and T2
images), DWI and MRS
MRI
MRI findings in HIE
2d old FT with HIE
24-48 hour post cooling
1) Acute Near Total Asphyxia:
Basal Ganglia and Thalamus (BGT) and
perirolandic cortex
2) Prolonged Partial Asphyxia:
White matter and overlying cortex in
the vascular watershed zones
3) Global: Combination of 1) and 2)
1) Abnormal BGT signal
2) Loss of PLC Myelination
3) Loss of grey white matter diff.
MRS
Brain
BGT
lactate peak
↑Pi and ↓PCr
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CBF +
ATP
Glutamate
NMDA
Ca2+
Other Targets for Neuroprotection
Cell
Necrosis
Adenosine
Zanthine
3
1
AMPA/ KA
2
↑nNOS
Lactate
NO
↑ROS
Caspase
DNA damage
DNA fragmentation
4
Apoptosis
Targets for Neuroprotection
1
2
3
4
• Glutamate receptor blockade: Mg, AMPA/Kainate
receptor blockade by topiramate, NMDA blockade
• Glutamate release- Adenosine, Adenosine agonists,
adenosine uptake inhibitors
• Calcium Channel blockers
• Free radical scavengers: allopurinol, vitamin C and E,
SOD
• Prevent free radical formation: Indomethacin, iron
chelators, Allopurinol, NOS inhibitors, polyphenols
(Pomegranate juice, Resveratrol Anti-inflammatory:
Allopurinol, blocking IL1, TNF alpha,
• Decrease apoptosis: Caspase inhibitors
Hypothermia for adult Stroke
Not Recommended
• Mild Hypothermia 33°C for 24-72 hrs
• Delays in cooling due to need for imaging
• Cooling ↓ ICP with trend of rebound ↑ ICP
during re-warming
• Trend towards ↑ sepsis in cooled
• No improvement in neurological outcomes
Tokutomi et al, Neurosurgery 2003
Hypothermia for Adult Cardiac Arrest
• Comatose adults with spontaneous
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circulation after out-of-hospital cardiac arrest
from ventricular fibrillation
ILCOR recommends hypothermia
(endovascular and external) to 32-34ºC for
12 – 24 hours
ILCOR 2006; Hypothermia After Cardiac Arrest
(HACA) Study Group (RCT)
Hypothermia after TBI- Adults
Not Recommended
• National Acute Brain Injury Multicenter
Study
• 392 patients age 16 to 65 years
• Mild hypothermia at 33°C for 48 hrs
• Hypothermia started at 8.4 ± 3 hrs
• Study stopped - no differences in outcomes
Clifton et al, NEJM 2001
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Hypothermia after TBI- Children
Not Recommended
Therapeutic Hypothermia after
Pediatric Cardiac Arrest (THAPCA)
(Ongoing Clinical trial)
• 225 Pediatric patients with TBI were assigned
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to 24 hrs of hypothermia (32.5ºC) or
normothermia
6 month FU : unfavorable outcome (death
and disability) in 31% cooled versus 21% of
not-cooled subjects
WORK IN
PROGRESS
• Multicenter RCT of Pediatric patients with in
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hospital (IH-THAPCA) and out of hospital
cardiac arrest (OH-THAPCA)
Age > 48 hrs and <18 years
Whole body cooling to 33.5ºC for 48 hrs
(Hutchison, 2008)
Can we Improve Hypothermia
treatment in HIE ?
1. Continue hypothermia for > 72 hrs?
2. Hypothermia may be more effective at T <
33.5ºC?
3. Late cooling- does it work if infant presents
at > 6 hrs of age?
4. Can we cool HIE infants <36 wk GA?
Neonatal Research Network -19 Centers USA
CA
NM
TEXAS
Thank You
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