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Not every infant w encephalopathy is due to asphyxia (estimated to occur in about 1 in 4 infants)

36 weeksgestation and over with Seizures Altered state of consciousness (stupor, coma) 5 minute Apgar < 3 All infants treated with hypothermia Exclude infants with CNS anomalies

Lack of ATP/phosphokreatinine “energy break down” damage due to depolarization and excitation

Oxidative stress and excitotoxicity, through downstream intracellular signaling, produce both inflammation and repair. Cell death begins immediately and continues during a period of days to weeks. The cell-death phenotype changes from an early necrotic morphology to a pathology resembling apoptosis. This evolution is called the necrosis紡poptosis continuum

Of the variables that characterize a hypothermia regimen the one that is best studied in the perinatal period is the time of initiation of brain cooling. This is work from Alastair Gunn using brain ischemia in fetal sheep and then subjecting animals to cooling in-utero with time of initiation relative to ischemia either early (1.5hrs), delayed (5.5hrs) or after the onset of Sz (in this model at 8.5hrs) Plotted on the Y axis are the percent neuronal loss in different regions of the brain along the x axis Initiation of hypothermia early or delayed is effective and there appears to be decreasing efficacy with increasing duration of time following ischemia. Cooling starting at 8.5 hours following ischemia was not effective This work is the basis for the time of initiation at < 6hrs in the CoolCap and NRN Body cool trial

Reviewers’ conclusion: Therapeutic hypothermia is beneficial to term newborns with hypoxic ischemic encephalopathy

GMFCS on which scores can range from 1 to 5, with higher scores indicating greater inmpairment

To minimize potential confounding from cointerventions

Subgroup analysis: More infants with severely abnormal aEEG died or had a severe disability than did those with moderately abnormal results (56% vs. 38% RR 1.49, P=0.001

Gross Motor Classification System can range from 1 to 5, with higher score indicating greater impairment

Hypothermia Therapy for Full Term and Near Term Infants with Hypoxic-Ischemic Encephalopathy Elena Wachtel, MD Assistant Professor of Pediatrics Director of Hypothermia Program Medical Director of Neonatal Comprehensive Care Program

Objectives Hypothermia therapy for infants with Hypoxic-Ischemic Encephalopathy (HIE) - how it works - summary of prior trials Review results of TOBY trial New evidence on brain MRI after cooling What referral hospitals should know prior to transport to Cooling Center

Neonatal Encephalopathy due to Hypoxic-Ischemic Brain Injury Neonatal Encephalopathy (NE) is an important cause of death and disability in near term and full term infants, accounting for 15 to 28% of children with cerebral palsy Incidence of perinatal/birth asphyxia 1 to 8 per 1000 live term births Incidence of NE: 2-4 per 1000 live births in developed countries/year Up to 400 infants in NYC/ year Mortality: 15-60% >25 % of those who survive will be disabled

Acute Hypoxic-Ischemic Perinatal Event/Asphyxia Asphyxia: refers to impairment in the exchange of respiratory gases, oxygen and carbon dioxide Perinatal brain can be deprive of oxygen by two major pathogenic mechanisms: - Hypoxemia: diminished amount of oxygen the supply - Ischemia: diminished amount of blood perfusion the brain → oxygen and glucose deprivation - Hypercapnia: is a additional major feature, which exacerbate metabolic acidosis and leads to initial increase in cerebral blood flow

Vermont Oxford Neonatal Encephalopathy Registry – 2006 1775 infants enrolled, 495 HIE/cooled Majority presented with clinical seizures (62%) - Diagnostic method: 48% clinical only, EEG plus clinical 48%, EEG only 4% - EEG subtype: 85% conventional EEG, 37% aEEG Asphyxial risk factors only 14.4 % (maternal hemorrhage 10.3%, cord prolapse 2.9%) Inflammatory factors 21.1% (fever 17.9%, chorio 9.8%) Large variability in treatment and management Robert Pfister, MD Presented at the International Brain Monitoring Conference 2010

Pathophysiology Primary phase of cell injury: - oxidative energy failure/ hypoxic depolarization of cells - cytotoxic edema - accumulation of excitatory amino acids Latent phase: - transient resolution of hypoxia induced cytotoxic edema - at least partial recovery of cerebral oxidative metabolism Secondary phase: - secondary cytotoxic edema - accumulation of exitotoxins - failure of oxidative energy metabolism and mitochondrial activity - apoptotic neuronal cell death

Pathophysiology, cont. Ferriero, D.M., 2004. Neonatal brain injury. N. Engl. J. Med. 351, 1995

Timing of Pathological Events after Hypoxia-Ischemia

Hypothermia Therapy: How it Works It derives most of its protective effects from a graded reduction in cerebral metabolism that slows cell depolarization and development of edema Reduces accumulation of excitotoxic neurotransmitters (e.g. glutamate) Attenuates secondary energy failure Suppresses : - oxygen free radical release - lipid peroxidation of cell membranes - apoptotic processes (e.g. caspase activity)

Timing of Initiation of Hypothermia A.Gunn

Methods of Hypothermia Two methods are being evaluated in newborn infants with HIE: Whole body cooling Selective head cooling with mild systemic hypothermia Cool Cap is an FDA approved device specifically for hypothermia treatment for infants with moderate/severe encephalopathy (Nov 2007) Therapeutic hypothermia aims to: - lower the temperature of the deep brain structures to 33 to 34 C°with WBC and 34 to 35 C°with Cool Cap

Criteria for Referral/Evaluation for Hypothermia Criteria A. Infants >36 weeks gestation admitted to the NICU with ONE of the following: - Apgar score of less than 5 at 10 minutes after birth - Continued need for resuscitation, including endotracheal or mask ventilation, at 10 minutes after birth - Acidosis defined as either umbilical cord pH or any arterial pH within 60 minutes of birth < 7.00 - Base Deficit >16 mmol/L in umbilical cord blood sample or any blood sample within 60 minutes of birth (arterial or venous blood)

Criteria for Referral/Evaluation for Hypothermia, cont. Criteria B. Moderate to severe encephalopathy (Sarnat 2 or 3) consisting of an altered state of consciousness (as shown by lethargy, stupor, or coma) and at least one or more of the following: - Hypotonia - Abnormal reflexes, including oculomotor and pupillary abnormalities - Absent or weak suck - Clinical seizures

Who Would Qualify for Cooling/Inclusion Criteria Blood Gas pH <7.0 OR BD >16 No Blood Gas Acute Event AND 5 minute Apgar < 5 or Need for Ventilation at Birth AND Presents of seizures or moderate/sever HIE NICHD

Summary of Hypothermia Trials Methods: - Cool Cap: head cooling + mild body cool to rectal T: 34.5+0.5ºC, - NICHD: whole body cooling to esophageal T : 33.5+ 0.5ºC - TOBY: whole body cooling rectal T 33.5+ 0.5ºC - ICE: whole body cooling rectal T 33.5+ 0.5ºC Timing: - started within 6 hours of birth & continued for 72 hours Selection criteria: - evidence of acute perinatal event (pH: <7.0, BD > 16, need for respiratory support by 10min, Apgars < 5 at 10 min) - moderate to severe clinical encephalopathy (Sarnat criteria) - Cool Cap, TOBY: aEEG amplitude abnormalities and/or seizures Primary outcome: - moderate or severe disability at 18 months (Cool Cap and TOBY: severe )

Cochrane Database Review Efficacy of hypothermia for neonatal HIE Eight randomized controlled trials were included in this review, comprising 638 term infants with moderate/ severe encephalopathy and evidence of intrapartum asphyxia (Gunn 1998; Shankaran 2002; ICE 2002; Akisu 2003; Eicher 2005; Gluckman 2005; Shankaran 2005; Lin 2006) Revised on 08/2007, Jacobs S, et al

Jacobs S, et al 2007; The Cochrane Collaboration

Results of Meta-analysis Reduction in the combined outcome of mortality or major NND to 18 months of age RR 0.76 (0.65-0.89), NNT= 7 Subgroup analysis for severe encephalopathy RR 0.8 (0.68-0.94), NNT= 6 Statistically significant reductions in mortality RR 0.74 (0.58-0.94), NNT 11 and In neurodevelopmental disability in survivors RR 0.68 (0.51-0.92), NNT= 8

Moderate Hypothermia to Treat Perinatal Asphyxial Encephalopathy Study Design: International RCT Study population and methods: Newborn infants with GA > 36 wks, < 6 hours of age and perinatal asphyxia, randomized to intensive care and whole body cooling or intensive care along Inclusion criteria: same as prior trials, plus aEEG with CFM Primary Outcome: death of severe disability at 18 months of age Secondary Outcome: survival without severe disability and specific neurologic outcomes NEJM, D. Azzopardi, et al., 361:1349-58, October 1, 2009

Measurement of Outcomes Composite outcome of death or severe NDD assessed at 18 months of age Severe NDD was defined as a score < 70 on the Mental Developmental Index (Bayley Scales of Infant Development II) or A score 3-5 on the Gross Motor Function Classification System (GMFCS) or Bilateral cortical visual impairment

Intensive Care/Clinical Management Protocol: provided on ventilatory, circulatory care, management of seizures and fluid requirements Sedation: morphine or chloral hydrate Treatment group: hypothermia was achieved by tecotherm cooling mattress to a rectal T 33.5 C° + 0.5 C° and maintained for 72 hours Rewarming: by 0.5 C° per hour to max 37 + 0.2 C° for at least 4 hours Infants who received intensive care alone maintained T at 37 + 0.2 C°

Whole Body Cooling with Tecotherm Mattress

Mean Rectal Temperatures During the Study

Results: Main Neurodevelopmental Outcomesat 18 months P=.05 P=.003

Conclusion Induction of moderate hypothermia for 72 hours in infants who had perinatal asphyxia did no significantly reduce the combined rate of death or severe disability but resulted in improved neurologic outcomes in survivors

Discussion The primary outcome of TOBY, as in the Cool Cap and NICHD trials, chosen because of concerns that cooling might increase survival with disability Results of all three trials are supporting the benefit from hypothermia: The RR associated with cooling (vs. no cooling) was 0.82 (95% CI, 0.66-1.02) in the Cool Cap trial, 0.72 (95% CI, 0.71-0.93 ) in the NICHD trial and 0.86 (95% CI, 0.68-1.07) in the TOBY trial

Discussion, cont. Only TOBY trial found a significant increase in the rate of survival without neurologic abnormality with cooling ( RR 1.57; 95% CI, 1.16-2.12) Only the NICHD trial detected a significant effect of hypothermia on the primary outcome, and only TOBY detected significant improvements in specific neurologic outcomes Both TOBY and Cool Cap trial showed that the increase risk of death or severe disability in infants with the most abnormal grade on aEEG

Assessment of Brain Tissue Injury after Moderate Hypothermia in Neonates with HIE A nested sub-study of a RCT/TOBY Hypothesis: Whole body cooling would be associated with a reduction in cerebral lesions seen on MRI that are characteristic of HIE, including lesions that predict later neurodevelopmental impairments 151 of 325 infants had MRI imaging, 131 scans suitable for analysis Timing of imaging: 1-3 weeks - T1 and T2 weighted sequences in transverse and sagittal planes Mary Rutherford, et al., The Lancet Neurology, November 6th, 2009

MRI and Prediction of Neurodevelopmental Outcome When MRI is normal or mildly abnormal the outcome almost invariably normal Extensive cortical or white matter involvement is associated with significant motor and cognitive deficit Moderate BGT injury is associated with athetoid CP, with relatively good cognition and social and visual interaction and a low incidence of seizures Severe bilateral BGT lesions are always associated with spastic quadriplegia, microcephaly and frequent seizures Abnormal signal intensity within the PLIC predicts abnormal motor outcome

Grades of Cerebral Lesions seen on MRI in infants with HIE Sites of lesions in HIE: - Posterior limb of the internal capsule (PLIV) - Basal Ganglia and thalami (BGT) - Cortex - Subcortical white matter - Brainstem Severity of BGT lesions : - (1) Mild: focal abnormal signal intensity (SI) with normal PLIC - (2) Moderate: multifocal abnormal SI with abnormal or equivocal PLIC - (3) Severe: widespread abnormal SI with abnormal PLIC

T1 – Weighted MRI images Mary Rutherford Normal Term Severe Basal Ganglia Lesions Basal Ganglia and White Matter Lesions

More MRI Appearances Moderate BG and thalamic lesions with abnormal increased SI Cortical Lesions Around the central Cilcus and interhemispheric fissure

More MRI Appearances

TOBY: MRI results % P=0.02 P=0.01 P=0.02

Results Therapeutic hypothermia was associated with reduction in lesions in the basal ganglia or thalamus (OR: 0.36, 95% CI 0.15-0.84); white matter (OR : 0.30, 95% CI 0.12-0.77); abnormal posterior limb of the internal capsule (OR: 0.38, 95% CI 0.17-0.85) The accuracy of prediction by MRI of death or disability to 18 months of age was 0.84 (0.74-0.94 in the cooled group and 0.81 (0.71-0.91) in the non-cooled group

Results, cont There was no increase in hemorrhagic lesions or sinus thrombosis associated with cooling - 25 cooled v.s. 22 non-cooled (p = 0.46) - 1 cooled v.s. 2 non-cooled The AEEG grade correlated with abnormalities in the BGT (p= .001), white matter (p < .0001), and posterior limb of the internal capsule (p,.0001); and normal scans (p=.0010

Conclusion Therapeutic hypothermia decreases brain tissue injury in infants with hypoxic-ischemic encephalopathy The predictive value of MRI for subsequent neurological impairment is not affected by therapeutic hypothermia

Predictive Ability of Major MRI Abnormalities Cooled Non-cooled Sensitivity 0.88 (0.79-0.97) 0.94 (0.88-1.0) Specificity 0.82 (0.72-0.92) 0.68 90.56-0.80) PPV 0.76 (0.65-0.87) 0.74 (0.63-0.85) NPV 0.91 (0.83-0.99) 0.92 (0.85-0.99)

Referral Hospitals Know the eligibility and exclusion criteria (flyer for referral hospitals is available) - Have criteria readily available in the NICU and DR Know your referral institution/cooling center Consult as early as possible Some patients might not qualify for the treatment and come back to the referral Hospital 1-877-ICENICU

Who should not be Cooled? Patients who do not meet criteria for any of the published RCT protocols Patients < 35 weeks gestation: safety and efficacy unknown Infants with traumatic, hemorrhagic brain and/or spinal cord injury Infants in “extremis,” I.e. a reasonable neonatologist would not continue resuscitation and/or intensive care Infants with evidence of serious congenital CNS problems (trisomy 13, 18, syndrome with known poor prognosis)

Management in the Delivery Room If infant depressed at birth with a need for resuscitation (10 min or more), the overhead heater should be turn off as soon as adequate ventilation and heart rate obtained Resuscitation of asphyxiated infants should be done according to NRP guidelines Resuscitation with 100% FIO2 is preferred Administration of D10W and NaHCO3 Active heating is also turned in the transport incubator Temperature of the warmer on admission to the NICU should be set at 35C servo

Changes in Temperature Clinics in Perinatology 2009

Preparation for Transport to Cooling Center Important information for Cooling Center: detailed history, blood gas, birth weigh, head circumference General Care for stabilization - UA/double lumen UV important but should not delay the transport Start Dextrose infusion with Ca Gluconate at TF: 60cc/kg/d Continue passive hypothermia

Preparation for Transport to Cooling Center, cont. Establish adequate oxygenation and ventilation - High O2 levels and low CO2 deleterious , correlate with damage to brain cells Restore or maintain good cardiac output and blood pressure for optimal brain and organ tissue perfusion Correct acidosis

Talking to the Parents Flyer for the parents is available at the cooling center Key Points: - Olympic Cool Cap System is FDA approved therapy for HIE - Initial insult may have caused some cell death - cannot be reversed - Cooling only affects secondary phase brain injury that occurs after 6 hours - Non-invasive therapy with low side-effect rate - Keep expectations moderate, monitoring development over time is important

Thank you!

Ingmar Rosen, MD