Selective Head Cooling for Acute Hypoxic Ischemic Encephalopathy Caroline O. Chua, MD Chief, Neonatal Fellow Regional NICU Maria Fareri Children’s Hospital at Westchester Medical Center Lance A. Parton, MD Associate Director Regional NICU Maria Fareri Children’s Hospital at Westchester Medical Center 1

Hypoxic Ischemic Encephalopathy One of the leading causes of severe long-term neurologic deficits in infants and children (cerebral palsy) Incidence of 2-3 per 1,000 term live births Etiologies: abruptio (25%), uterine rupture, prepartum hemorrhage, dystocia, prolapsed cord, placental insufficiency, twins, extramural deliveries Mortality is 15-20% >25% of survivors have permanent disabilities

HYPOXIA - ISCHEMIA Anaerobic Glycolysis ATP Adenosine Lactate Glutamate Hypothermia NMDA Receptor NMDA receptor blocker Hypoxanthine Intracellular Ca+ Ca+ channel blocker Xanthine oxidase inhibitors Activates NOS Activates Lipases Activates proteases Activates nuclease Cyclooxygenase inhibitors Xanthine NO O2 Free Fatty Acids Disruption of cytoskeleton Damage to DNA Superoxide radicals O2 Free Radicals Free radical scavengers Free Radicals Free Radicals NEURONAL CELL DEATH

Potential Therapeutic Window Foundation Fact The ability to identify infants at highest risk for progressing to HIE is critical Hypoxia Ischemia Injury No Injury Primary Energy Failure Resolve Secondary Energy Failure Resolve Injury Latent phase Potential Therapeutic Window

Hypothermic Treatment of HIE 2 phases to injury Initial insult at birth Secondary failure starts within 6-24 hours of birth Therapeutic window of 6 hours

Head Cooling: How It Works Reduces cellular metabolic demands, delaying depolarization Reduces release of excitatory amino acids (e.g. glutamate) and free radicals Reduces intracellular reactions of excitatory amino acids Reduces release of pro-inflammatory cytokines, microglial activation, and neutrophil recruitment. Suppression of apoptotic biochemical pathways (e.g. caspase activity).

Selective Head Cooling Technique Head is fitted with cooling cap Body is warmed with radiant warmer Advantages Brain is cooler than the rest of the body Fewer side effects

Cool-Cap Trial Randomized, controlled, masked, multi-center (25), international trial (n=234) Protocol: Standard of care or rectal temp of 34 to 35C for 72 hours using cool cap Passively rewarmed for 4 h (at ~0.5C/h) Primary end point: death or severe neurodevelopmental disability at 18 months Confirmed Cool-Cap System is Effective & Safe Gluckman et al. Lancet. 2005; 365:663-670

Cool-Cap Trial Findings – Efficacy Statistically significant treatment effect for moderately abnormal aEEG (p = 0.04) Moderate encephalopathy: 1 out of 6 is shifted from unfavorable to favorable outcome Severe encephalopathy: no effect on death and severe disability Gluckman et al. Lancet. 2005; 365:663-670

Cool-Cap Trial Findings – Safety No statistical difference in mortality @ 18 mos 33% (36/108) cooled vs. 38% (42/110) control No difference in rates of any Serious Adverse Events Scalp edema in some – resolved quickly Conclusion – Cooling is safe when the Cool-Cap clinical trial protocol is followed Gluckman et al. Lancet. 2005; 365:663-670

Predictive Calculations of Efficacy for Hypothermia to treat Neonatal HIE Perlman and Shah, 2008 15-18 babies are born daily in the U.S. with moderate to severe HIE 10-12, of the above, die or develop moderate to severe disability Hypothermia to all 15-18 babies would prevent 3 from death or moderate to severe disability without any significant adverse effects

Selecting Infants for Treatment Indications For Use The Olympic Cool-Cap System is indicated for use in full-term infants with clinical evidence of moderate to severe hypoxic-ischemic encephalopathy (HIE) as defined by criteria A, B and C The Cool-Cap System provides selective head cooling with mild systemic hypothermia to prevent or reduce the severity of neurological injury associated with HIE * Cool as early as possible and within 6 hours of birth

Criteria A Infant at ≥ 36w gestational age and at least one of the following Apgar score ≤ 5 at 10 min Continued need for resuscitation, including endotracheal or mask ventilation, at 10 min after birth Acidosis defined as either umbilical cord pH or any arterial pH <7.00 within 60 min of birth Base deficit ≥ 16 mmol/L in umbilical cord blood sample or any blood sample within 60 min of birth (arterial or venous blood)

Criteria B Infant with moderate to severe encephalopathy consisting of altered state of consciousness (as shown by lethargy, stupor, or coma) and at least one of the following Hypotonia Abnormal reflexes, including oculomotor or pupillary abnormalities Absent or weak suck Clinical seizures

Criteria C Infant has an amplitude-integrated encephalogram / cerebral function monitor (aEEG/CFM) recording of at least 20 minutes duration that shows either moderately/severely abnormal aEEG background activity or seizures * Use Olympic CFM 6000

Contraindications Imperforate anus Evidence of head trauma or skull fracture causing major intracranial hemorrhage Birth weight < 1,800g

Practical Tips for NBN/NICUs Transferring Newborns for Cooling Educate staff, especially “off-hours” personnel to recognize eligibility for cooling Provide cardiorespiratory stability Avoid hyperthermia Turn off radiant warmer Maintain Rectal Temperature: 34 - 35 C IV Glucose, ASAP

Practical Tips for NBN/NICUs Transferring Newborns for Cooling Cord Gas/ ABG/ VBG; birth weight and head circumference Use double lumen UV lines (preferably) Initiate transport Call WMC-Transport team ASAP 866 - WMC PEDS or 866 – 468 - 6962 Don’t wait for lines, images, labs Discuss cooling but make no promises regarding: use of cooling and outcome

Possible Brain Insult At Birth? Call (24/7): (866) WMC-PEDS MFCH is the only NICU in the Hudson Valley Employing the Head-Cooling Cool Cap® for patients who may have Perinatal Asphyxia Cool Cap ® in Place Cool Cap® Monitor 19

Maria Fareri Children’s Hospital E C M O Extra Corporeal Membrane Oxygenation Call (24/7): (866) WMC-PEDS or (866) 468-6962 Newborn Infant Child Young Adult 20

Extra Corporeal Membrane Oxygenation Heart-Lung Bypass Consider for the Following Conditions: Neonatal Pediatric Congenital Diaphragmatic Hernia Meconium Aspiration Syndrome Persistent Pulmonary Hypertension Respiratory Distress Syndrome Pneumonia Sepsis Congenital Heart Disease Sepsis Pneumonia/Respiratory Failure Trauma Smoke Inhalation Near Drowning ECMO Team Pediatric Surgery Cardiovascular Surgery Pediatric Intensivists Neonatal Intensivists Pediatric Cardiology Maternal-Fetal Medicine Pediatric Pulmonary ECMO Nurses Perfusion Team 21

Possible Brain Insult At Birth? Call (24/7): (866) WMC-PEDS or (866) 468-6962 A.S.A.P. Cool within 6 hours of birth 22