Caroline O. Chua, MDChief, Neonatal FellowRegional NICUMaria Fareri Children’s Hospital atWestchester Medical Center

Lance A. Parton, MDAssociate DirectorRegional NICUMaria Fareri Children’s Hospital atWestchester Medical Center

Hypoxic Ischemic EncephalopathyHypoxic Ischemic Encephalopathy

One of the leading causes of severe long-term One of the leading causes of severe long-term neurologic deficits in infants and children (cerebral palsy)neurologic deficits in infants and children (cerebral palsy)

Incidence of 2-3 per 1,000 term live births Incidence of 2-3 per 1,000 term live births

Etiologies: abruptio (25%), uterine rupture, prepartum Etiologies: abruptio (25%), uterine rupture, prepartum hemorrhage, dystocia, prolapsed cord, placental hemorrhage, dystocia, prolapsed cord, placental insufficiency, twins, extramural deliveriesinsufficiency, twins, extramural deliveries

Mortality is 15-20%Mortality is 15-20%>25% of survivors have permanent disabilities>25% of survivors have permanent disabilities

HYPOXIA - ISCHEMIA

Anaerobic Glycolysis

ATP

Glutamate

NMDA Receptor

Intracellular Ca+

Activates Lipases

Free Fatty Acids

Free RadicalsO2

Adenosine

Hypoxanthine

Xanthine

Free Radicals

O2

Lactate

Activates NOS

NO

Free Radicals

NEURONAL CELL DEATH

Superoxide radicals

Xanthine oxidase inhibitors

NMDA receptor blocker

Ca+ channel blocker

Hypothermia

Free radical scavengers

Cyclooxygenaseinhibitors

Activates proteasesActivates nuclease

Disruption of cytoskeleton

Damage to DNA

Foundation FactFoundation Fact The ability to identify infants at highest risk for The ability to identify infants at highest risk for

progressing to HIE is critical progressing to HIE is critical

PrimaryEnergy Failure

Injury

Resolve

Resolve

HypoxiaIschemia

SecondaryEnergy Failure

Injury

No Injury

Latent phase

Potential Therapeutic Window

Hypothermic Treatment of HIEHypothermic Treatment of HIE 2 phases to injury2 phases to injury Initial insult at birthInitial insult at birth Secondary failure Secondary failure

starts within 6-24 starts within 6-24 hours of birthhours of birth

Therapeutic window Therapeutic window of 6 hoursof 6 hours

Head Cooling: How It WorksHead Cooling: How It Works Reduces cellular metabolic demands, delaying Reduces cellular metabolic demands, delaying

depolarizationdepolarization

Reduces release of excitatory amino acids (e.g. Reduces release of excitatory amino acids (e.g. glutamate) and free radicalsglutamate) and free radicals

Reduces intracellular reactions of excitatory amino acidsReduces intracellular reactions of excitatory amino acids

Reduces release of pro-inflammatory cytokines, Reduces release of pro-inflammatory cytokines, microglial activation, and neutrophil recruitment.microglial activation, and neutrophil recruitment.

Suppression of apoptotic biochemical pathways (e.g. Suppression of apoptotic biochemical pathways (e.g. caspase activity).caspase activity).

Selective Head CoolingSelective Head Cooling TechniqueTechnique

Head is fitted with cooling Head is fitted with cooling capcap

Body is warmed with radiant Body is warmed with radiant warmerwarmer

AdvantagesAdvantages Brain is cooler than the rest Brain is cooler than the rest

of the bodyof the body Fewer side effectsFewer side effects

Cool-Cap TrialCool-Cap Trial Randomized, controlled, masked, multi-center Randomized, controlled, masked, multi-center

(25), international trial (n=234)(25), international trial (n=234) Protocol:Protocol:

Standard of care or rectal temp of 34 to 35Standard of care or rectal temp of 34 to 35C for 72 C for 72 hours using cool caphours using cool cap

Passively rewarmed for 4 h (at ~0.5Passively rewarmed for 4 h (at ~0.5C/h)C/h) Primary end point: death or severe Primary end point: death or severe

neurodevelopmental disability at 18 monthsneurodevelopmental disability at 18 months Confirmed Cool-Cap System is Confirmed Cool-Cap System is Effective & SafeEffective & Safe

Gluckman et al. Lancet. 2005; 365:663-670

Cool-Cap Trial Findings – EfficacyCool-Cap Trial Findings – Efficacy

Statistically significant treatment effect for Statistically significant treatment effect for moderately abnormal aEEG (moderately abnormal aEEG (p p = 0.04)= 0.04)

Moderate encephalopathy: 1 out of 6 is shifted Moderate encephalopathy: 1 out of 6 is shifted from unfavorable to favorable outcomefrom unfavorable to favorable outcome

Severe encephalopathy: no effect on death and Severe encephalopathy: no effect on death and severe disabilitysevere disability

Gluckman et al. Lancet. 2005; 365:663-670

Cool-Cap Trial Findings – SafetyCool-Cap Trial Findings – Safety No statistical difference in mortality @ 18 mos No statistical difference in mortality @ 18 mos

33% (36/108) cooled vs. 38% (42/110) control33% (36/108) cooled vs. 38% (42/110) control

No difference in rates of any No difference in rates of any Serious Adverse Serious Adverse EventsEvents

Scalp edema in some – Scalp edema in some – resolved quicklyresolved quickly

Conclusion – Cooling is safe when the Cool-Cap Conclusion – Cooling is safe when the Cool-Cap clinical trial protocol is followedclinical trial protocol is followed

Gluckman et al. Lancet. 2005; 365:663-670

Predictive Calculations of Efficacy for Hypothermia Predictive Calculations of Efficacy for Hypothermia to treat Neonatal HIEto treat Neonatal HIE

Perlman and Shah, 2008Perlman and Shah, 2008

15-18 babies are born daily in the U.S. with 15-18 babies are born daily in the U.S. with moderate to severe HIEmoderate to severe HIE

10-12, of the above, die or develop moderate to 10-12, of the above, die or develop moderate to severe disabilitysevere disability

Hypothermia to all 15-18 babies would prevent 3 Hypothermia to all 15-18 babies would prevent 3 from death or moderate to severe disability from death or moderate to severe disability without any significant adverse effectswithout any significant adverse effects

Selecting Infants for Treatment Selecting Infants for Treatment Indications For UseIndications For Use

The Olympic Cool-CapThe Olympic Cool-Cap System System is indicated for use in is indicated for use in full-term infants with clinical evidence of with clinical evidence of moderate to severe hypoxic-ischemic encephalopathy (HIE) as defined by criteria A, B as defined by criteria A, B andand C C

The Cool-Cap System provides selective head cooling The Cool-Cap System provides selective head cooling with mild systemic hypothermia to prevent or reduce the with mild systemic hypothermia to prevent or reduce the severity of neurological injury associated with HIEseverity of neurological injury associated with HIE

* Cool as early as possible and within 6 hours of birth

Criteria ACriteria AInfant at Infant at ≥ 36w gestational age and ≥ 36w gestational age and at least oneat least one of of

the followingthe following

Apgar score ≤ 5 at 10 minApgar score ≤ 5 at 10 min

Continued need for resuscitation, including Continued need for resuscitation, including endotracheal or mask ventilation, at 10 min after birthendotracheal or mask ventilation, at 10 min after birth

Acidosis defined as either umbilical cord pH or any Acidosis defined as either umbilical cord pH or any arterial pH <7.00 within 60 min of birtharterial pH <7.00 within 60 min of birth

Base deficit ≥ 16 mmol/L in umbilical cord blood Base deficit ≥ 16 mmol/L in umbilical cord blood sample sample oror any blood sample within 60 min of birth any blood sample within 60 min of birth (arterial or venous blood)(arterial or venous blood)

Criteria BCriteria B Infant with moderate to severe encephalopathy Infant with moderate to severe encephalopathy

consisting of altered state of consciousness (as shown consisting of altered state of consciousness (as shown by lethargy, stupor, or coma) and by lethargy, stupor, or coma) and at least oneat least one of the followingof the following

HypotoniaHypotonia

Abnormal reflexes, including oculomotor or pupillary Abnormal reflexes, including oculomotor or pupillary abnormalitiesabnormalities

Absent or weak suckAbsent or weak suck

Clinical seizuresClinical seizures

Criteria CCriteria C

Infant has an amplitude-integrated Infant has an amplitude-integrated encephalogram / cerebral function monitor encephalogram / cerebral function monitor (aEEG/CFM) recording of at least 20 minutes (aEEG/CFM) recording of at least 20 minutes duration that shows either duration that shows either moderately/severely abnormal aEEG moderately/severely abnormal aEEG background activity or background activity or seizuresseizures

* Use Olympic CFM 6000

ContraindicationsContraindications

Imperforate anusImperforate anus

Evidence of head trauma or skull fracture Evidence of head trauma or skull fracture causing major intracranial hemorrhagecausing major intracranial hemorrhage

Birth weight < 1,800gBirth weight < 1,800g

Practical Tips for NBN/NICUsPractical Tips for NBN/NICUsTransferring Newborns for CoolingTransferring Newborns for Cooling

Educate staff, especially “off-hours” personnel to Educate staff, especially “off-hours” personnel to recognize eligibility for coolingrecognize eligibility for cooling

Provide cardiorespiratory stabilityProvide cardiorespiratory stability

Avoid hyperthermiaAvoid hyperthermia Turn off radiant warmerTurn off radiant warmer Maintain Rectal Temperature: 34 - 35Maintain Rectal Temperature: 34 - 35 C C

IV Glucose, ASAPIV Glucose, ASAP

Practical Tips for NBN/NICUsPractical Tips for NBN/NICUsTransferring Newborns for CoolingTransferring Newborns for Cooling

Cord Gas/ ABG/ VBG; birth weight and head Cord Gas/ ABG/ VBG; birth weight and head circumferencecircumference

Use double lumen UV lines (preferably)Use double lumen UV lines (preferably)

Initiate transportInitiate transport Call WMC-Transport team ASAP Call WMC-Transport team ASAP 866 - WMC PEDS or 866 – 468 - 6962866 - WMC PEDS or 866 – 468 - 6962 Don’t wait for lines, images, labsDon’t wait for lines, images, labs

Discuss cooling but make no promises regarding: use of Discuss cooling but make no promises regarding: use of cooling and outcomecooling and outcome

Call (24/7):(866) WMC-PEDS

MFCH is the only NICU in the Hudson ValleyEmploying the Head-Cooling Cool Cap®

for patients who may have Perinatal Asphyxia

Cool Cap ® in PlaceCool Cap® Monitor

E C M OExtra Corporeal Membrane Oxygenation

Maria Fareri Children’s Hospital

Call (24/7):(866) WMC-PEDS

or(866) 468-6962

NewbornInfantChildYoung Adult

Extra Corporeal Membrane OxygenationHeart-Lung Bypass

Cardiovascular SurgeryCardiovascular SurgeryPediatric IntensivistsPediatric Intensivists

Neonatal IntensivistsNeonatal Intensivists

Pediatric SurgeryPediatric Surgery

Pediatric CardiologyPediatric Cardiology

Perfusion TeamPerfusion TeamECMO NursesECMO Nurses

Maternal-Fetal MedicineMaternal-Fetal MedicinePediatric Pediatric PulmonaryPulmonary

Congenital Diaphragmatic HerniaMeconium Aspiration Syndrome

Persistent Pulmonary HypertensionRespiratory Distress Syndrome

PneumoniaSepsis

Congenital Heart DiseaseSepsis

Pneumonia/Respiratory FailureTrauma

Smoke InhalationNear Drowning

Consider for the Following Conditions:Consider for the Following Conditions:Neonatal Pediatric

ECMOECMOTeamTeam

Call (24/7):(866) WMC-PEDS

or (866) 468-6962

A.S.A.P. Cool within 6 hours of birth