Lamia Soghier MD Assistant Professor of Pediatrics Attending Neonatologist AECOM - CHAM.

Lamia Soghier MDAssistant Professor of Pediatrics

Attending Neonatologist AECOM - CHAM

No Financial Disclosure

Objectives:Pathophysiology of HIE and current

interventionsHistorical Origins of Neonatal hypothermiaEvidence based Questions?Bench to Bedside

Animal Studies Clinical Trials Meta-analysis

Unanswered Questions

Brought to the NICU

What are the consequences of HIE?

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.

Vannucci et al. Pediatrics 1997

Multi Organ Injury

PathophysiologyHypoxia

Diving Reflex

Shunting of blood -> Brain Adrenals & Heart

Away from lungs, kidney gut & skin

Slide Courtesy of Dr Orna Rosen

Insult(~ 30 min)

Reperfusion

Hypoxic depolarization

Cell lysis

Excitotoxins

Calcium Entry

Latent(6-15h)

Recovery of oxidative metabolism

Apoptotic cascade

2° inflammation

Calcium Entry

Secondary

(3-10d)

Failing oxidative metabolism

seizures

Cytotoxic edema

Excitotoxins

Final cell death

Intervention needed

NEURO TOXIC CASCADE IN HIE – Ferriero, 2008 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

Hypoxia-ischemia

Anaerobic Glycoglysis

Adenosine

ATP

Glutamate

HypoxanthineIntracellular Ca++

XanthineOxidase

Activates Lipases ActivatesNos

XanthineFree Fatty Acids

O2

Lactate

Free Radicals Free Radicals

Nmda Receptor

Nitric Oxide

O2

Il-Tnf-

Il-Tnf-Interferon

Secondary Secondary Energy FailureEnergy Failure

Slide Courtesy of Dr Orna Rosen Papadoupoulous et al Neoreviews 2010

“Main Players”

Excitatory Amino Acids

Intracellular Calcium

Free Radicals

Inflammatory Mediators

Nitric Oxide Synthase

Xanthine Oxidase

cerebral metabolic rate

(Hypothermia*)

Excitatory Amino Acid

Antagonists

Oxygen Free Radical

Inhibitors / Scavengers*

Prevention of Nitric Oxide

Formation

Growth Factors (apoptosis

inhibition)

Neuroprotective Strategies


Papadoupoulous et al Neoreviews 2010

How Hypothermia Prevent HIE damage?

Metabolic rate of Brain

Slows depolarization of brain cells

Accumulation of excitatory amino acids

Release of free radicals

Keeps integrity of brain cells membranes

Apoptosis (not necrosis)


Historical Origins of Cooling Babies!!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

(Wyatt et al.Pediatrics 1997)

EB QuestionPopulation: Infants ≥ 36 weeks gestational

age with moderate to severe neonatal encephalopathy

Intervention: Brain cooling vs. conventional treatment

Outcome: DeathNeurodevelopmental disabilityCombined outcome

Animal StudiesMultiple studies of fetal Sheep, neonatal Rats,

newborn PigletsPreservation of architecture in cortex of cooled

fetal sheep Control Cooled

Gunn et al J of ClinInv 1997

Animal DataCooling needs to be started within ~ 6 h after

birth (and earlier is better)

It needs to be continued for at least 24 h (72 h is better)

The brain needs to be cooled to 32 to 34ºC

Prolonging the duration of hypothermia improves neuroprotection

Inclusion Criteria for Brain Cooling

Infant > 36 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)

MODIFIED SARNAT’S STAGING

Shankaran et al. NICHD trial NEJM 2005

CEREBRAL FUNCTION MONITORING Normal and Abnormal aEEG Tracings

MODERATELY ABNORMAL (Upper margin >10 mV &

lower margin <5 mV)

NORMAL aEEG TRACING

Lower margin of band of aEEG activity above 7.5 mV

SEVERELY ABNORMAL(Upper margin <10 mV &

lower margin <5 mV)

SEIZURES(sudden increase in voltage,narrow band aEEG & period

of suppression) Slide Courtesy of Dr Orna Rosen

Positive Predictive Value of aEEG with clinical picture

Abnormal aEEG in asphyxiated infant has >70% PPV of death or severe CP (Hellstrom-Westas Arch.Dis.Child1995,Toet Arch Dis Child 1999)

Correlation between severe aEEG changes and poor outcome (CoolCap trial 2005)

Exclusion Criteria Infants expected to be > 6 hours of age at the time of cooling cap

placementMajor 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)

What is the difference between Whole body cooling and Selective head cooling? WBC provides homogenous cooling to all

structures of brain (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


Cool Cap Trial

● 234 infants studied75% 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%) infants8 cooled and 8 control infants lost to follow

up

The Cool Cap Trial

Gluckman P et al Lancet 365: 663, 2005Slide Courtesy of Dr Suhas Nafday, Director of Neonatal Cooling Program at CHAM

Olympic Cool CapR System

Cerebral function monitor

Final Count

234

Lost to Follow-up

18-MonthPrimary Outcome

Cooled108

Control110

Favourable49 )45%(

Unfavourable59 )55%(

Favourable37 )34%(


16

218

The Cool Cap Trial : Primary Outcomes

Gluckman P et al Lancet 365: 663, 2005Slide Courtesy of Dr Suhas Nafday, Director of Neonatal Cooling Program

A priori defined group excluding infants with severely abnormal aEEG w/seizure

n=172

Cooled84

Control88

Favourable44 )52%(

Favourable30 )34%(


Fisher’s exact p=0.02: logistic regression, OR: 0.42 )0.22, 0.80(, p=0.009


The Cool Cap Trial: If you exclude severely abnormal aEEG

Gluckman P et al Lancet 365: 663, 2005Slide Courtesy of Dr Suhas Nafday,

Intermediate aEEG group – cooled vs control odds ratio 0·47 95% CI 0·26–0·87, p=0·021

● 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

The Cool CAP trial : Adverse Effects

Gluckman P et al Lancet 365: 663, 2005Slide Courtesy of Dr Suhas Nafday

TOBY Trial – NEJM 2009

NICHD trial

What do the combined results show? Trial RR of Death or

Severe disability at 18 months

Confidence Interval

Cool Cap

(n=218)

0.82 0.66 -1.02

TOBY

(n=325)

0.86 0.68 -1.07

NICHD

(n=239)

0.72 0.54 - 0.95

Hypothermia during transport? Infant cooling evaluation or ICE trial (Jacobs et

al – Hot topics 2008)

Whole Body Cooling x 72 hrs started 2002Differs from other trials

Simple eligibility CriteriaIncluded infants outborn (70%)Included infants 35 weeks or moreBoth passive and active cooling on transport

Decrease in mortality in cooled groupAwaiting neurodevelopmental outcomes

European neo.nEURO.network trial (Simbruner 08)

Multicenter trial (n=129) terminated prior to completion in 2006

Whole body cooling x 72 hoursDiffers 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

European neo.nEURO.network trial (Simbruner 08)

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 lossSame held true for infants for both severe and

moderate encephalopathy group

Eicher Trial 2005 • Clinical signs

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

• Neurological signs

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

Infants required one clinical sign and two neurologic findings of HIE

Eicher Trial 05

Eicher D et al Pediatr Neurol 32: 11-34, 2005

● 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

Meta-analysis of all Trials

Edwards et al. BMJ 2010

Death or Severe Disability at 18 months


Total RR 0.81, 95% CI 0.71 to 0.93, P=0.002

Survival with normal neurological function at 18 months


Relative risk 1.53, 95% CI 1.22 to 1.93, P<0.001

Meta-analysis of 3 major trials

Less Mortality in Hypothermia group

RR 0.78, 95% CI 0.66 to 0.93, P=0.005

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

Hypothermia for Perinatal HIEfor Perinatal HIEWhere should it be done and by whom?

Executive Summary of the NICHD Workshop on Hypothermia and Perinatal Asphyxia J Pediatr 2006;148


Guidelines• Providers must be highly experienced in evaluating treatment candidates, knowledgeable in the techniques to administer hypothermia, and have a comprehensive follow-up 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

Hypothermia for Perinatal HIEfor Perinatal HIEWhere should it be done and by whom?

Executive Summary of the NICHD Workshop on Hypothermia and Perinatal Asphyxia J Pediatr 2006;148

The Neonatal Brain Cooling Program at The Children’s Hospital at Montefiore

Regional Cooling Centers Consortium

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

Montefiore North (Previously OLM)

Jacobi Medical Center North Central Bronx Hospital Lincoln Hospital and Mental

Health Center St. Barnabas Hospital Flushing Hospital Medical Center


Management in the Delivery Room 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


Neonatal Hypothermia Program at CHAMThe 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]


Practical Tips for NICU’s:Transferring Newborns for Cooling

Educate staff, especially ‘off-hours’ personnel to recognize eligibility for cooling

Besides providing cardiorespiratory stability:IV glucose, ASAPAvoid Hyperoxia and HyperthermiaUse double lumen UV lines, low line OK for D10WInitiate transport call ASAP, don’t wait for

lines/images/labsDiscuss cooling but make no promise re: use and

outcome


REQUESTS PRIOR TO TRANSPORT TEAM ARRIVAL

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.


Special ConsiderationsPatients 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


Unanswered QuestionsWhat is the optimal

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?

What new combination treatments are under investigation?Phenobarbitol – China- Lin J Perinat 2006

CT scan Neonatal NBS

What new combination treatments are under investigation?Morphine- nEURO trialTopiramate + delayed hypothermia > 6 hours in

neonatal rats – Liu 2004

Anti-inflammatory agents? Xanthine oxidase inhibitors? Stem cells?

Hypoxia + PBS

Hypoxia + Topiramate

Rats were sacrificed at 35days of age

Alistar Gunn – Hot Topics 2008“ 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

Lamia Soghier MD Assistant Professor of Pediatrics Attending Neonatologist AECOM - CHAM.

Documents

Transcript of Lamia Soghier MD Assistant Professor of Pediatrics Attending Neonatologist AECOM - CHAM.