Transcript Perinatal-Asfiksi-Tedavisinde-final

Meltem Seli M.D.
Division of Perinatal Medicine
Yale University
TJOD 2015
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Perinatal Asphyxia or Neonatal encephalopathy is a
clinically defined syndrome of disturbed neurologic
function in the earliest days of life in an infant born
at or beyond 35 weeks of gestation, manifested by
a subnormal level of consciousness or seizures,
and often accompanied by difficulty with initiating
and maintaining respiration and depression of tone
and reflexes.
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A. Apgar Score of Less Than 5 at 5 Minutes and 10
Minutes
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B. Fetal Umbilical Artery Acidemia <7.0
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C. Neuroimaging Evidence of Acute Brain Injury
Seen on Brain Magnetic Resonance Imaging or
Magnetic Resonance Spectroscopy Consistent With
Hypoxia–Ischemia
D. Presence of Multisystem Organ Failure
Consistent With Hypoxic–Ischemic Encephalopathy
• Maternal:
• Fetal:
– Cardiac arrest
– Fetomaternal hemorrhage
– Asphyxiation
– Twin to twin transfusion
– Severe anaphylaxis
– Severe isoimmune hemolytic
disease
– Status epilepticus
– Cardiac arrhythmia
– Hypovolemic shock
• Uteroplacental:
– Placental abruption
– Cord prolapse
– Uterine rupture
– Hyperstimulation with
oxytocic agents
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Appearance of hypoxic-ischemic encephalopathy on axial diffusion-weighted
magnetic resonance imaging. A, A normal brain in a term newborn with no areas of
restricted diffusion. B, Severely restricted diffusion in the basal ganglia and thalami,
posterior limb of the internal capsule, and white matter. C, Focal restricted diffusion
in the putamen and optic radiations.
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A Category I or Category II fetal heart rate tracing
when associated with Apgar scores of 7 or higher
at 5 minutes, normal umbilical cord arterial blood
(± 1 standard deviation), or both is NOT consistent
with an acute hypoxic–ischemic event.
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A category II fetal heart rate pattern lasting 60
minutes or more that was identified on initial
presentation with persistently minimal or absent
variability and lacking accelerations, even in the
absence of decelerations, is suggestive of a
previously compromised or injured fetus.
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The patient who presents with a Category I fetal
heart rate pattern that converts to Category III as
defined by the Eunice Kennedy Shriver National
Institute of Child Health and Human Development
guidelines is suggestive of a hypoxic–ischemic
event.
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HIE contributes nearly ¼ of neonatal deaths and
major morbidity
10-15 % of babies with Hypoxic Ischemic
Encephalopathy will die
25–30% of HIE survivors will have long-term
neurodevelopmental disabilities that include
cerebral palsy, seizure disorder and mental
retardation.
Currently there are very few treatment options for
HIE and few clinical trials of new modalities are
underway.
Lancet 2005; 365:1147-1152
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Developmental Outcome is Spastic Quadriplegia or
Dyskinetic Cerebral Palsy
Other subtypes of cerebral palsy are less likely to
be associated with acute intrapartum hypoxic–
ischemic events.
Systemic Complications of HIE
• Acute renal failure in up to 20% of asphyxiated
term infants
• Myocardial dysfunction and hypotension in 28-50%
of term infants
• Elevated LFTs in 80-85% of term infants
• Coagulation impairment is relatively common in
severely asphyxiated infants
• Supportive care required!!
Hypoxia
Diving Reflex
Shunting of blood ->
Brain Adrenals & Heart
Away from lungs, kidney
gut & skin
Multi Organ
Injury
Slide Courtesy of Dr Orna Rosen
Phases of Cerebral Injury
• 2 phases to injury
• Initial insult at birth
• Secondary failure starts
within 6-24 hours of
birth
• Therapeutic window of 6
hours
Slide Courtesy of Dr Suhas Nafday, Director of Neonatal Cooling Program at CHAM
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Lowering the body temperature from standard 37
to 33.5-34 degrees using cooling wraps or cap
Core temperature measured via rectal or
esophageal probes
After 72 hours, core temperature is slowly
increased to 37 degrees over 24 hrs.
Inclusion Criteria for Brain Cooling
Infant > 35 weeks’ gestation with at least ONE of the following:
1. Apgar score of  5 at 10 minutes after birth
2. Continued need for assisted ventilation, including endotracheal
or bag/mask ventilation, at 10 minutes after birth
3. Acidosis defined as either umbilical cord pH or any arterial pH
within 60 minutes of birth <7.00
4. Base deficit  16 mmol/L on an umbilical cord blood gas sample
or any blood sample within 60 minutes of birth (arterial or
venous blood)
AND
moderate to severe encephalopathy with or without seizures OR the
presence of one or more signs in 3 of 6 categories on the chart
(Modified Sarnat Score)
Exclusion Criteria
• Infants expected to be > 6 hours of age at the time of cooling cap
placement. Major congenital abnormalities, such as diaphragmatic
hernia requiring ventilation, or congenital abnormalities suggestive
of chromosomal anomaly (Trisomy13, 18) or other syndromes that
include brain dysgenesis
• Imperforate anus (since this would prevent rectal temperature
recordings)
• Evidence of neurologically significant head trauma or skull fracture
causing major intracranial hemorrhage. Subgaleal bleeding is a
relative contraindication; the infant should be fully stabilized before
cooling is initiated
• Coagulopathy with active bleeding
• Severe PPHN/ possible need for ECMO
• Infants < 1,800g-birth weight
• Infants “in extremis” (those infants for whom no other additional
intensive management will be offered)
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Hippocrates
John Floyer in1679 used a
tub of ice to revive an infant
who was not crying at
delivery
James Miller and Bjorn Westin
in the 1950s developed a
scientific rationale for the use
of hypothermia in "asphyxia
neonatorum” in first case
series
Dropped out of favor after
Silverman paper in Pediatrics
1958-comments on heat loss
(Wyatt et al.Pediatrics 1997)
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Multiple studies of fetal Sheep, neonatal Rats,
newborn Piglets
Preservation of architecture in cortex of cooled fetal
sheep
Control
Cooled
Gunn et al J of Clin
Inv 1997
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Cooling needs to be started within ~ 6 h after birth
(and earlier is better)
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It needs to be continued for at least 24 h (72 h is
better)
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The brain needs to be cooled to 32 to 34ºC
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Prolonging the duration of hypothermia improves
neuroprotection
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 Metabolic rate of Brain
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Slows depolarization of brain cells
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Accumulation of excitatory amino acids
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Release of free radicals
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Keeps integrity of brain cells membranes
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Apoptosis (not necrosis)
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Population: Infants ≥ 35 weeks gestational
age with moderate to severe neonatal
encephalopathy
Intervention: Brain cooling vs. conventional
treatment
Outcome:
◦ Death
◦ Neurodevelopmental disability
◦ Combined outcome
RR 0.78, 95% CI 0.66 to 0.93, P=0.005
Relative risk 1.53, 95% CI 1.22 to 1.93, P<0.001
Edwards et al. BMJ 2010
Total RR 0.81, 95% CI 0.71 to 0.93, P=0.002
Edwards et al. BMJ 2010
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Cooling was safe and did not result in serious sideeffects, which included:
◦ slightly lower baseline heart rate (RR 5.96, 95% CI 2.15–
16.49; RD 0.07, 95% CI 0.04–0.11),
◦ a marginally significant increase in the need for blood
pressure support (RR 1.17, 95% CI 1.00–1.38; RD 0.08, 95%
CI 0.00–0.17),
◦ more babies with a platelet count below 150 X 109 /litre
(RR 1.55, 95% CI 1.14–2.11; RD 0.09, 95% CI 0.03–0.15).
WHO policy statement on Cooling for newborns with hypoxic ischaemic encephalopathy 2014
Standard of Care - 2014
Data from large randomized clinical trials indicate that
therapeutic hypothermia, using either selective head cooling or
systemic cooling, is an effective therapy for neonatal
encephalopathy. Infants selected for cooling must meet the
criteria outlined in published clinical trials. The implementation
of cooling needs to be performed at centers that have the
capability to manage medically complex infants.
Woodbridge, CT winter 2015
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Multicenter trial (n=129) terminated prior to
completion in 2006
Whole body cooling x 72 hours
Differs from other trials
◦ Uses Griffiths General Quotient for
neurodevelopmental assessment and Palisano
score
◦ Included infants with moderate or severe aEEG or
EEG changes
◦ Used Morphine for both control and hypothermia
groups
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Clinical signs
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 Cord pH ≤ 7.0 or BE ≥ 13
 Initial postnatal pH < 7.1
 Apgar score < 5 at 10 min
 Need for resuscitation after 5
min
 Fetal bradycardia (< 80 bpm x
15 min)
 A postnatal hypoxic-ischemic
event
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Hypothermic infants were
cooled with plastic bags
filled with ice and then
placed on a cooling blanket
servo-controlled at 33.5 ±
0.5° C
Normothermic infants were
kept at 37 ± 5° C
Neurological signs
Pediatric Neurology 2005 ; 32: 1 11-17
Potential pathways for brain injury after hypoxiaischemia.
Perlman J M Pediatrics 2006;117:S28-S33
©2006 by American Academy of Pediatrics
The Cool Cap Trial
● 234 infants studied
◦ 75% U.S. sites
◦ 25% UK, Canada, New Zealand
● Safety reviews at 25, 50 and 75%
enrolment revealed no major
concerns
● Follow up available on 218 (93%)
infants
◦ 8 cooled and 8 control infants lost to follow up
Slide Courtesy of Dr Suhas
Nafday, Director of Neonatal
Cooling Program at CHAM
Gluckman P et al Lancet 365: 663, 2005
The Cool Cap Trial :
Primary Outcomes
Final
Count
234
Lost to
Follow-up
16
18-Month
Primary Outcome
218
Cooled
108
Favourable
49 (45%)
Unfavourable
59 (55%)
Slide Courtesy of Dr Suhas Nafday,
Director of Neonatal Cooling Program
Control
110
Favourable
37 (34%)
Unfavourable
73 (66%)
Gluckman P et al Lancet 365: 663, 2005
The Cool Cap Trial: If you
exclude severely abnormal aEEG
A priori defined group excluding infants with
severely abnormal aEEG w/seizure
n=172
Cooled
84
Favourable
44 (52%)
Unfavourable
40 (48%)
Control
88
Favourable
30 (34%)
Unfavourable
58 (66%)
Fisher’s exact p=0.02: logistic regression, OR: 0.42 (0.22, 0.80), p=0.009
Slide Courtesy of Dr Suhas Nafday,
Gluckman P et al Lancet 365: 663, 2005
Intermediate aEEG group – cooled vs control odds ratio 0·47
95% CI 0·26–0·87, p=0·021
The Cool CAP trial : Adverse
Effects
No increase in severe hypotension despite
full volume and inotrope support: 3 cooled
vs. 3 non-cooled infants (p=1.00)
● Scalp edema common (32 cooled and 1
control infant, p<0.0001), but transient
● One case of scalp damage under the cap in
an infant dying of severe hypotension and
coagulopathy
● Sinus bradycardia, without hypotension, was
very common during cooling and reversed
on rewarming
●
Slide Courtesy of Dr Suhas Nafday
Gluckman P et al Lancet 365: 663, 2005
What is the difference between Whole body
cooling and Selective head cooling?
• WBC provides homogenous cooling to all structures
of nervous system (peripheral and central) Laptook
et al Pediatrics 2001
• SHC combined with some body cooling provides
cooling to the peripheral structures but minimizes
temperature gradients across the brain (Thorensen
et al. Ped Res 2001)
• SHC may have less adverse side effects than WBC
cooling
Intervention needed
Insult
(~ 30 min)
Hypoxic
depolarization
Cell lysis
Excitotoxins
Latent
Secondary
(6-15h)
(3-10d)
Recovery of
oxidative
metabolism
Failing
oxidative
metabolism
Apoptotic
cascade
seizures
2°
inflammation
Calcium Entry
Calcium Entry
Reperfusion
Cytotoxic
edema
Excitotoxins
Final cell
death
NEURO TOXIC CASCADE IN HIE – Ferriero, 2008
“Main Players”
• Excitatory Amino
Acids
• Intracellular Calcium
• Free Radicals
• Inflammatory
Mediators
• Nitric Oxide Synthase
• Xanthine Oxidase
Papadoupoulous et al Neoreviews 2010
Neuroprotective Strategies
•  cerebral metabolic
rate (Hypothermia*)
• Excitatory Amino Acid
Antagonists
• Oxygen Free Radical
Inhibitors / Scavengers*
• Prevention of Nitric
Oxide Formation
• Growth Factors
(apoptosis inhibition)
Edwards et al. BMJ 2010
Trial
Cool Cap
(n=218)
TOBY
(n=325)
NICHD
RR of Death
or Severe
disability at
18 months
0.82
Confidence
Interval
0.86
0.68 -1.07
0.72
0.54 - 0.95
0.66 -1.02
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Infant cooling evaluation or ICE trial (Jacobs et
al – Hot topics 2008)
Whole Body Cooling x 72 hrs started 2002
Differs from other trials
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Simple eligibility Criteria
Included infants outborn (70%)
Included infants 35 weeks or more
Both passive and active cooling on transport
Decrease in mortality in cooled group
Awaiting neurodevelopmental outcomes
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Results: Hypothermia group :
◦ More Survival free of severe disability
Relative Risk 2.86 with CI (1.58-5.19)
◦ Severe Disability was less
Relative Risk 0.34 with CI (0.2-0.57)
◦ Reduction in Cerebral Palsy
◦ Trend to reduction of cortical blindness, hearing
loss
◦ Same held true for infants for both severe and
moderate encephalopathy group
Eicher Trial 05
● Enrolled 65 infants
● 33 hypothermia
● 32 control
● Outcome: incidence of abnormal neurodevelopmental
scores by Bayley II (follow-up done on only 28 infants) at 12
months of age
● Death or severe neuromotor disability was 52% in the
hypothermia group and 84% in the normothermia group
(p=0.019) -- Mortality: 31% cooled & 42% controls
Eicher D et al Pediatr Neurol 32: 11-34, 2005
Hypothermia for Perinatal HIE
Where should it be done and by whom?
Guidelines
 To
implement brain cooling, HIE should be defined by
the rigorous criteria and published protocols (Body Cooling
or CoolCap) and should be strictly adhered to
 Appropriate personnel need to be available day and night
to implement the protocol
 Collection of appropriate data and assurance of follow-up
after discharge to ascertain outcome
Executive Summary of the NICHD Workshop on Hypothermia and Perinatal Asphyxia
J Pediatr 2006;148
Slide Courtesy of Dr Suhas Nafday, Director of Neonatal Cooling Program at CHAM
Hypothermia for Perinatal HIE
Where should it be done and by whom?
Guidelines
• Providers
must be highly experienced in evaluating
treatment candidates, knowledgeable in the techniques to
administer hypothermia, and have a comprehensive followup program to determine neurodevelopmental outcome
• Large regional referral centers will be critical for providing
this intervention, given that more than 40% of the patients
in the Body Cool trial were out-born
• Need for longer follow-up of infants receiving
hypothermia
Executive Summary of the NICHD Workshop on Hypothermia and Perinatal Asphyxia
J Pediatr 2006;148
Regional Cooling Centers
Consortium
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Children’s Hospital at
Montefiore
Presbyterian Hospital-Weill
Cornell Medical College
North Shore - Long Island
Jewish Health System
NYU Medical Center
Mt. Sinai Medical Center
Westchester Medical Center
Morgan Stanley Hospital
(Columbia University
Medical Center)
Winthrop-University Hospital
Referring Institutions
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Montefiore North (Previously
OLM)
Jacobi Medical Center
North Central Bronx Hospital
Lincoln Hospital and Mental
Health Center
St. Barnabas Hospital
Flushing Hospital Medical
Center
Slide Courtesy of Dr Suhas Nafday, Director of Neonatal Cooling Program at CHAM
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Resuscitation of asphyxiated infants should
be done according to NRP guidelines using
100% O2.
The radiant warmer should be turned off as
soon as adequate ventilation and heart rate
are obtained
Maintain rectal temperature at 35 + 0.5 Cº
range; if necessary use radiant warmer to
prevent overcooling of the infant
Slide Courtesy of Dr Suhas Nafday, Director of Neonatal Cooling Program at CHAM
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The time frame for neonatal therapeutic hypothermia is
critical-Treatment must be administered within six
hours of birth.
Neonatal patient 36 weeks or greater, and has suffered
possible brain injury during birth, please call us
immediately at (718) 904-4032
Upon arrival at the Weiler NICU, an aEEG and
neurological assessment will determine if the therapeutic
intervention is appropriate for the infant
Questions about Weiler’s Neonatal Therapeutic
Hypothermia Program can be referred to Suhas Nafday,
MD, at 718-904-4105, [email protected]
Slide Courtesy of Dr Suhas Nafday, Director of Neonatal Cooling Program at CHAM
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Educate staff, especially ‘off-hours’
personnel to recognize eligibility for
cooling
Besides providing cardiorespiratory
stability:
IV glucose, ASAP
Avoid Hyperoxia and Hyperthermia
Use double lumen UV lines, low line OK for D10W
Initiate transport call ASAP, don’t wait for
lines/images/labs
◦ Discuss cooling but make no promise re: use and
outcome
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Slide Courtesy of Dr Suhas Nafday, Director of Neonatal Cooling Program at CHAM
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Transport consent should be obtained from
parents. We would FAX the consent form. Please
return the signed form ASAP @ 718-904-2649.
Clean the head and get a head circumference
prior to arrival of the transport team to facilitate
placement of the leads and the correct size of
Cool Cap
Secure vascular access-placement of
double/single lumen umbilical vein catheter and
umbilical artery catheter prior to departure, if
there is time
Ventilatory support is necessary during
hypothermia treatment
Maintain skin temperature at greater than 36°C
and less than 37 °C
Don’t treat with phenobarbital (prophylactic
treatment) unless there is evidence of clinical
seizures.
Slide Courtesy of Dr Suhas Nafday, Director of Neonatal Cooling Program at CHAM
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Patients who clearly exhibit signs of severe HIE
on early neurologic evaluation (Sarnat 3), but
normal tracings on aEEG should be offered
hypothermia treatment
Patients who have moderate HIE on neurologic
exam with normal aEEG can be monitored with
continuous aEEG recording up to 6 hours of life
and treated with hypothermia if aEEG becomes
abnormal
If these inclusion/exclusion criteria are met and
infants are found eligible for cooling, the
hypothermia treatment can be initiated
No informed consent is necessary (FDA
approved devise), however parents would be
given written information about the treatment
Slide Courtesy of Dr Suhas Nafday, Director of Neonatal Cooling Program at CHAM
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What is the optimal
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Depth of hypothermia?
Duration of hypothermia?
Mode of delivery- Whole body vs.Selective?
Impact of time of initiation? Starting at
resuscitation? After 6hours?
Use of aEEG to target treatment to babies that
are more likely to benefit?
Long term follow up more than 18-22
months?
Benefit of using combined treatment?
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Phenobarbitol – China- Lin J Perinat 2006
CT scan
Neonatal NBS
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Morphine- nEURO trial
Topiramate + delayed hypothermia > 6
hours in neonatal rats – Liu 2004
Hypoxia
+ PBS
Hypoxia
+ Topiramate
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Anti-inflammatory agents? Xanthine oxidase
were cells?
sacrificed at 35days of age
inhibitors? Rats
Stem
“ Cooling is An Evolving
Therapy”
There are too many unanswered questions for
hypothermia to be a true “standard of care”
But…………..
We don’t need to wait for another 100 years to
start cooling babies!!!!
Randomization to normothermia is no longer
reasonable
Pathophysiology
• The immature brain is in some ways
more resistant to hypoxic-ischemic
events compared to older children &
adults
– This may be due to:
• Lower cerebral metabolic rate
• Immaturity in the development of the balance
of neurotransmitters
• Plasticity of the immature CNS
Pathophysiology
• Gestational age plays an important role
in the susceptibility of CNS structures
–< 20 weeks: Insult leads to
neuronal heterotopia or
polymicrogyria
–26-36 weeks: Insult affects
white matter, leading to
periventricular leukomalacia
Management - Hypothermia
• Has become standard of care
• Whole-body and head-cooling available
–Unclear if one regimen is
superior to the other currently either one is
utilized, based on availability
• Aim to get core (rectal) temperature to
33-35º C for 72 hours