No Disclosures or Conflicts of Interest. Objectives. Overview. Therapeutic Hypothermia and other Potential Neuroprotective Strategies for HIE

Transcription

1 Therapeutic Hypothermia and other Potential Neuroprotective Strategies for HIE Alexis Davis, M.D. Medical Director, Neonatal Intensive Care Unit Lucile Packard Children s Hospital Clinical Associate Professor of Pediatrics Stanford University School of Medicine No Disclosures or Conflicts of Interest LLU Newborn Brain Symposium September 14, 2017 Objectives Understand the biologic rationale for therapeutic hypothermia to treat hypoxic-ischemic encephalopathy Describe screening and eligibility criteria for therapeutic hypothermia List at least one potential adjuvant therapy to therapeutic hypothermia Overview Background Cooling trials Meta-analyses Unanswered questions about hypothermia Neuroprotective therapies on the horizon

2 Causes of neonatal mortality Congenital 7% Asphyxia 23% Other 7% Preterm 27% Sepsis/pneumonia 26% Tetanus 7% Diarrhea 3% Definition of Hypoxic Ischemic Encephalopathy (HIE) Synonyms: Post-asphyxial encephalopathy, birth asphyxia, and perinatal asphyxia Clinical syndrome consisting of abnormal neurologic findings in the first week of life in term infants believed to have experienced asphyxia during labor and delivery Hypoxia and ischemia due to systemic hypoxemia, reduced cerebral blood flow, or both are the primary underlying processes. Lawn JE, et al. Intl J Epidemiol (2006) Terminology Differential diagnosis of neonatal encephalopathy Perinatal asphyxia, birth asphyxia, HIE: use in medical documentation is unpopular Neonatal encephalopathy preferred term to describe CNS dysfunction in the newborn period Hypoxia-ischemia Inborn error of metabolism Genetic syndromes Congenital neuromuscular disease Brain malformations Neonatal stroke Sepsis

3 Epidemiology of HIE Incidence ranges from 1 to 8 per 1,000 births depending on definition used In the U.S. with 4 million births annually, HIE accounts for approximately 1,200 deaths and 1,800 disabled infants Risk factors for hypoxia-ischemia Preconceptual: IDDM, thyroid disease, fertility treatment, nulliparity, advanced maternal age Cord related events: compression, prolapse, abnormal insertion, single umbilical artery, entanglement, or true knot Placental events: abruption, previa, vasa-previa (with bleeding); thromboembolic/vasculitis phenomena; severe pre-eclampsia Perfusion abnormality: altered placental perfusion due to maternal hypertension or hypotension, tetanic uterine contractions, or uterine abnormality; uterine rupture Oxygenation abnormality: impaired maternal oxygenation due to cardiorespiratory instability, severe anemia; or impaired fetal oxygenation due to fetal anemia caused by hemolysis, bleeding or intrauterine sepsis Infant factors: IUGR; post-dates; breech presentation Timing of Insult in HIE Antepartum 20% Intrapartum 35% Intrapartum ± antepartum 35% Postpartum 10% Additional developmental vulnerabilities Developmental factor Immature vascular autoregulation Impaired vascular autoregulation Anatomic vascular factors Increased density of glutamate receptors (NMDA, AMPA) Infection/inflammation Developmental regulation of cell death mediators: Effect Deficient arteriolar muscular lining limits capacity for reactivity+decreased reactivity following insult = injury with even modest decreases in BP Penetrating vessels from meningeal arteries bend acutely near cortical-white matter junction (border zone within a border zone) Increased excitotoxic insult Increased microglia in WM; proinflammatory cytokines Increased cellular necrosis and apoptosis via: Volpe s Neurology of the Newborn, 4th Edition (2001) Fas death receptor, Fas ligand Caspases nnos glutathione peroxidase Unsaturated fatty acids Free Iron Increased apoptotic signaling Increased ROS formation/decreased antioxidant reserve

4 The perfect storm Mechanism of brain injury during HIE Hypoxia and acidosis lead to: Loss of autoregulation blood flow to the brain becomes passive and reflects systemic pressure Vasoconstriction of cerebral arterioles Hypoxia-Ischemia Primary Energy Failure Recovery Brain Injury Breach of the blood-brain barrier uncontrolled substance entry to the cerebral extracellular space Even modest hypoxia and ischemia can result in critically low cerebral O2 delivery Processes involved in HI Brain Injury 1 o energy failure Excitatory amino acids Loss of ionic balance Intracellular Ca ++ Lipases, proteases Free radicals CELL DEATH via NECROSIS Mechanism of brain injury during HIE Hypoxia-Ischemia Latent Period Primary Energy Failure Recovery Brain Injury Secondary Energy Failure Brain Injury

5 Processes involved in HI Brain Injury Timing of cellular events 1 o energy failure Excitatory amino acids Loss of ionic balance Intracellular Ca ++ Lipases, proteases Free radicals Necrosis Apoptosis 2 o energy failure Activated microglia Apoptosis Growth factors Protein synthesis Oxidative injury Excitatory amino acids CELL DEATH VIA APOPTOSIS Clinical findings in HIE Abnormal neurologic exam: Level of consciousness Tone Tendon reflexes Primitive reflexes Respiratory function Autonomic function Other findings include: Need for resuscitation Seizures EEG abnormalities Other organ injury (heart, lungs, liver, kidney, hematologic) Clinical variables that may potentiate brain damage Hypocarbia Cerebral vasoconstriction Hyperoxia Increased free radical production Hypotension/hypertension Loss of cerebral autoregulation Anemia Critical determinant of oxygen delivery Glucose homeostasis

6 Whole Body Hypothermia using a Cooling Blanket Treatment for HIE: Therapeutic Hypothermia Selective Head Cooling using the Olympic Cool Cap How does hypothermia work? Temperature is a critical aspect of cellular metabolism Glutamate/excitatory amino acids= Ca++ Nitric oxide synthase Activation of microglia= inflammation Free radical production= oxidative damage Apoptosis Cerebral metabolic rate blood brain barrier damage and edema, hemorrhage and neutrophil infiltration Prevents or attenuates secondary energy failure

7 Therapeutic window- why 6 hours? Gunn AJ, NeoReviewsI 2002 Cooling trials Trial (Publication date) N GA (wks) Mode Transport Cooling Eicher (2005) Whole body Yes CoolCap (2005) Selective head No NICHD (2005) Whole body No TOBY (2009) Whole body Yes Neo.nEURO (2010) Whole body No Zhou (2010) Selective head No ICE (2011) Whole body Yes Temp goal & site 33 ± 0.5 rectal C rectal 33.5 C esophageal 33.5 C rectal C rectal 34 ± 0.2 nasopharyngeal C rectal Meta-analysis: Primary outcome of death or major disability Outcome Weight (%) Risk ratio Azzopardi (0.68, 1.07) Gluckman (0.66, 1.02) Gunn (0.46, 3.44) Jacobs (0.60, 0.94) Shankaran (0.54, 0.93) Simbruner (0.46, 0.82) Zhou (0.46, 0.82) Total (95% CI) (0.69, 0.84) Relative risk Hypothermia Normothermia Conclusion: Hypothermia improves survival and neurodevelopmental outcome in newborns with moderate to severe HIE. Whole body cooling and selective head cooling are effective. Tagin MA, et al. Arch Pediatr Adolesc Med 2012 Meta-analysis: Efficacy Outcomes Outcome No. of studies/ No. of participants Risk ratio Mortality 12/ (0.65, 0.92) ND disability in survivors 6/ (0.54, 0.84) Severe cerebral palsy 3/ (0.48, 0.88) MDI <70 4/ (0.54, 0.90) PDI <70 4/ (0.54, 0.90) Severe visual deficit 4/ (0.35, 0.98) Severe hearing deficit 4/ (0.36, 1.55) Epilepsy 5/ (0.48, 1.31) Life support withdrawn 6/ (0.73, 1.18) Shah P, Semin Fetal Neonatal Med (2010) Relative risk Hypothermia Normothermia

8 Meta-analysis: Safety Outcomes Recommendations for use of Hypothermia Outcome No. of studies/ No. of participants Risk ratio Arrhythmia 5/ (1.55, 10.74) Hypotension 8/ (0.93, 1.13) Coagulopathy 7/ (0.80, 1.15) Thrombocytopenia 4/ (1.07, 1.52) Seizure after enrollment 8/ (0.86, 1.06) Renal failure 5/ (0.53, 1.70) Hepatic side effects 5/ (0.69, 1.04) Infection 7/ (0.40, 1.88) Pulmonary hypertension 5/ (0.95, 1.96) Relative risk Hypothermia Normothermia Hypothermia at <6 hours decreases mortality and severe disability with minimal side effects and without increasing disability Severe HIE less likely benefit No difference in outcome between head and body cooling Peliowski A, et al. Paediatr Child Health (2012) Therapeutic hypothermia is an effective therapy, treated infants should meet trial entry criteria, and education of referring hospitals regarding identification of hypothermia candidates is critical. AAP Committee on Fetus and Newborn. Pediatrics (2014) Newborns with moderate to severe HIE should be offered hypothermia Treatment should be consistent with trial protocols. Perlman JM, et al. Circulation (2010) ILCOR statement Shah P, Semin Fetal Neonatal Med (2010) CPQCC Tool Kit Screening Criteria Birth& 36$weeks$ 6$hours$ Screening and selection of appropriate candidates for cooling 0&(&10&mins& 10&(&60&mins& Apgar$ 6$ at$10$min$ History$of$acute$ perinatal$event$ Con?nued$PPV$ at$10$min$or$cpr$! Request$cord$blood$gas$! Obtain$blood$gas$at$ 1$hour$of$age$! Perform$targeted$neurologic$exam$using$chart$below$! Observe$for$seizures$ Cord$blood$gas$ ph$ 7.15$or$BE$ J10$ 60&(&120&mins& Call$LPCH$APending$Neonatologist$ $at$(650)$723j7342$to$discuss$the$need$ for$transfer$and$cooling$ download

9 NICHD Trial: Inclusion Criteria Step A: Clinical/Biochemical A1: If blood gas is available A2: If blood gas is not available, or ph between 7.01 and 7.15, or Base deficit 10 to 15.9mEq/L Infant should have: Cord or first postnatal blood gas within 1 hour with ph 7.0 or Base deficit on cord gas or first postnatal blood gas within 1 hour at 16 meq/l Shankaran S et al., N Engl J Med (2005) Infant should have: Acute perinatal event and either An Apgar score 5 at 10 minutes or Continued need for ventilation initiated at birth and continued for at least 10 minutes NICHD Trial: Exclusion criteria Congenital or chromosomal anomaly Birth weight < 1800 grams Chronologic age > 6 hours Refusal of consent by parent or physician Decision to not provide full intensive care Shankaran S et al., N Engl J Med (2005) Neurological Examination Stage of encephalopathy based on a modified Sarnat exam is needed for study eligibility and enrolled babies are stratified by level of encephalopathy The Sarnat stage correlates well with childhood outcomes Sarnat HB and Sarnat, Arch Neurol (1976) Shankaran S et al, Early Human Devel (1991) Robertson CM. Fetal and Neonatal Brain Injury(2003) Badawi et al. Dev Med Child Neurol (2005) Ambalavanan et al. Pediatrics (2006) Shankaran S et al. J Pediatr (2012) NICHD Inclusion Criteria step B: the modified Sarnat exam Six categories (level of consciousness, spontaneous activity, posture, tone, primitive reflexes, and autonomic system) Two categories have subcategories Each of the 6 categories contributes 1 point To be eligible for cooling: 3 of 6 categories have to be coded as either moderate or severe encephalopathy

10 Modified Sarnat Exam Stage 1 (Mild) Stage 2 (Moderate) Stage 3 (Severe) Level of consciousness Hyperalert Lethargic Stuporous Tone Normal Hypotonia Flaccid Posture Mild distal flexion Strong distal flexion Decerebrate Activity Normal Decreased None Primitive reflexes Suck Moro Autonomic function Pupils Heart rate Respiration Weak Strong Dilated Tachycardia Normal Weak or absent Incomplete Constricted Bradycardia Periodic Absent Absent Variable Variable Apnea Exam pearls Examine in 2 phases: Observation and active manipulation Score the awake state. Start with observation (activity, posture, HR, respiration) Active portion: Do the least noxious part of exam first (tone) and the most noxious last (examining pupils) While seizures make an infant eligible for cooling the Sarnat exam should still be documented Modified from Sarnat and Sarnat, Arch Neurol (1976) Other clinical factors that confound the exam Transient effects of delivery, anesthesia, analgesia Examination findings may improve or get worse Severity and timing of hypoxia-ischemia Compensatory hemodynamic changes Endogenous CNS protective mechanisms Associated conditions: Respiratory distress Simultaneous mix of neurological findings Components of none/mild, moderate or severe encephalopathy Other considerations If following the DR resuscitation, the Sarnat exam shows evidence of moderate or severe encephalopathy (abnormalities in 3 categories), the newborn should be cooled as long as there are no exclusions and the other laboratory/historical criteria are met. Improvement or changes in the Sarnat exam over time are the norm and should not be interpreted as negating the overall risk of HIE and adverse neurodevelopmental outcome. Newborns with laboratory or historical data making them potentially eligible with a normal initial Sarnat exam should be examined hourly for changes in the Sarnat exam.

11 Summary Has standard cooling solved the HIE problem? Hypothermia has been shown to reduce the rate of death or disability for infants with HIE Good safety profile of intervention, few adverse events Now standard of care when applied within trial criteria (Committee On Fetus and Newborn, Pediatrics 2014) There may be select circumstances outside trial criteria where cooling may be considered Austin T et al Arch Dis Child 2012 Postnatal collapse Encephalopathy of uncertain etiology Underscores the role of registries (VON, TOBY)

12 Rates of death/disability in cooling trials Trial Cooled Control OR (05% CI) P value Cool Cap ( ) 0.1 NICHD ( ) TOBY ( ) 0.17 The search to improve outcomes continues Does longer and/or deeper cooling improve outcomes? How critical is the 6h therapeutic window? Are there adjunct therapies that might improve outcomes? ICE Neo.Neuro ( ) Rate of disability still high % - despite therapeutic hypothermia Optimizing cooling strategies at <6 hrs of age for neonatal HIE (NICHD) Study Intervention: 2x2 factorial design of cooling to 32 C and/or 120 hours: Optimizing Cooling: Results Increased risk of death in all intervention groups compared to standard of care Temperature 33.5 v 32 Time 72 v C for 72 hrs (std) 32C for 72hr 33.5 for 120 hrs 32C for 120 hrs 3 5 Shankaran et al JAMA 2014; 312: Shankaran et al JAMA 2014; 312:

13 Should a baby be cooled after 6 hours? How this happens: Arrive at a referral center after 6 hrs of age Progress from stage I to II/III encephalopathy or seizures after 6 hrs of age Are not recognized to qualify until after 6 hrs of age Cooling cannot be initiated within 6 hrs of age (equipment/personnel availability) Practice creep in the absence of evidence Late (6-24 hrs) hypothermia for HIE in term infants PI: A Laptook (Brown) for the NICHD Neonatal Network Enrolled 168 infants ( ) Primary outcome: death or disability at months Bayesian analysis: probability that the hypothesis is true based on the observed data Recommended for trials with a limited sample size Primary analyses adjusted for level of encephalopathy and age at randomization PRELIMINARY RESULTS PRESENTED AT HOT TOPICS 2016 Study cohort- highlights Groups similar in baseline demographics High rate of fetal deceleration (72% cooled, 71% control) Largely outborn population (86% cooled, 88% control) Majority of infants classified as moderate encephalopathy (88% cooled, 92% control) Adjusted Risk Ratios (arr)* for Primary and Secondary Outcomes: Bayesian analysis Cooled (n=78) Non-cooled (n=79) arr (Neutral prior) Primary n % n % 95% credible intervals Death or mod/sev disability Secondary ( ) Death ( ) Severe disability ( ) P-TB (Neutral prior) arr<1.0 arr< Moderate disability Mild disability ( ) *Adjusted for level of encephalopathy and age at randomization Posterior treatment benefit.25.13

14 Probability of treatment benefit Conclusions Relatively low rates of death or disability in this study cohort (24% cooled vs. 28% non-cooled) Reflects outcomes of study cohort that is mostly moderate encephalopathy Bayesian analysis suggests possible treatment benefit 77% likelihood of reduced death or disability But also potential for treatment harm underscores importance of informed consent The results should not delay efforts to recognize HIE early and initiate hypothermia within 6 h of birth The frontrunners What s next? Adjuvant therapies to hypothermia Xenon Erythropoietin/Darbepoietin

15 Xenon (Xe) gas Xenon delivery system Rare, expensive, anesthetic gas minimal cardiovascular side effects Inhibits NMDA receptor, other glutamate receptors, and reduces apoptosis Due to high cost, Xenon therapy requires special ventilators to scavenge exhaled gas Dose is limited by FiO2 requirement, infants with severe respiratory failure may not be suitable candidates Global neuropathy score with HT and Xenon Xenon: Human Feasibility study 25% (n=1) or 50% Xenon for up to 18 hours No adverse respiratory or cardiovascular effects Suppressed seizures and EEG activity Results: 3 deaths, 7 of 11 survivors with MDI/PDI scores > 70 at 18-month follow-up Conclusion: 18 hours of Xe50% and 24 hours of HT offer reductions of 28% and 48%. in global neuropathy, respectively. The combination of Xe and HT is additive yielding 75% reduction. Chakkarapani E, et al. Ann Neurol 2010 Dingley J et al Pediatrics 2014

16 TOBY-Xe Study Azzopardi D et al, Lancet Neurology 2016 Total Body Hypothermia plus Xenon Trial Cooling + 30% Xenon compared to cooling alone Cooling initiated <6h Xenon initiated <12h, continued for 24h Target sample size 138; 92 infants enrolled ( ) Primary outcome: MRI at 15 days of life Results: Use of Xenon is feasible and safe No differences in MRI outcomes (FA in PLIC, Lactate:aspartate in thalamus) Similar rate of death in treatment and control groups Developmental outcomes not yet published Xenon Trials: Bristol, UK NCT patients enrolled Intervention: 50% Xenon for 18 hours PLUS cooling x 72h Outcomes: 1) time to aeeg background pattern recovery 2) Brain MRI outcomes at <2 weeks Status: completed, results anticipated October 2015? NCT Anticipated enrollment: 52 patients Intervention: 50% Xenon for 18 hours PLUS cooling x 72h Outcomes: Bayley III scores at months Estimated study completion date: December 2018 Erythropoietin (Epo) Generally used for erythropoiesis, may also provide neuroprotection Mechanisms include: decreased apoptosis, enhanced neurogenesis, decreased inflammation, and decreased susceptibility to glutamate toxicity Preterm infants treated with Epo for anemia have demonstrated improved neurodevelopmental outcomes Term infants treated with Epo have decreased seizures, improved EEG, and better neurologic outcome NEATO Trial Wu Y et al, Pediatrics 2016 Neonatal Erythropoietin and Therapeutic Hypothermia Outcomes Phase II, blinded RCT of infants with moderate-severe encephalopathy undergoing cooling Intervention: Epo 1000 U/kg IV on days 1, 2, 3, 5, and 7 Outcomes assessed: brain MRI in newborn period, developmental assessment at 12 months Results: Lower global MRI injury score in Epo-treated infants Improved motor and overall developmental scores in Epo-treated infants Neubauer AP, et al. Stroke 2007 Zhu C, et al. Pediatrics 2009 Elmahdy H, et al. Pediatrics 2010

17 HEAL Study High-dose Erythropoietin for Asphyxia and Encephalopathy NCT Multicenter, Phase III RCT Intervention: Epo 1000 U/kg on days 1, 2, 3, 4, and 7 Currently enrolling DANCE trial Darbe Administration in Newborns Undergoing Cooling for Encephalopathy NCT PI: Mariana Baserga, Univ of Utah Phase I/II study of darbepoietin (2 or 10mcg/kg x 2 doses) v placebo Results: no adverse events with either darbe dose, plasma concentrations sufficient for weekly dosing Baserga M et al Ped Res 2015; 78(3): Epo vs darbe? Darbe has longer half life, dosing frequency may be reduced NICHD Neonatal Research Network is developing a trial that will test both and compare efficacy Remaining controversies Therapeutic drift or should we cool infants with mild encephalopathy? What about late cooling? What about premature infants?

18 Relation of severity of encephalopathy to outcome of HIE Mortality (%) Disability (%) Normal (%) Mild Moderate Severe All Re-thinking mild encephalopathy DuPont et al, J Pediatr 2013 Retrospective study of 46,887 babies ( ) 144 with perinatal acidemia 60 of 144 infants had mild encephalopathy 12/60 (20%) with abnormal short-term outcomes Abnormal feeding (8) Abnormal brain MRI (6) Seizures (5) Abnormal neuro exam at discharge (7) G-tube (1) Death (1) Robertson C et al., Dev Med Child Neurol (1985) Thornberg E et al., Acta Pediatrica (1995) Re-thinking mild encephalopathy (2) Gagne-Loranger M et al, Am J Perinatol newborns referred for possible cooling ( ): 60% cooled Among the 66 infants with mild encephalopathy who were not cooled: Average ph death 11 (17%) with seizures Among the 50 with brain MRI: 20 (40%) with abnormal findings 31% of cooled babies with mild encephalopathy had abnormal brain MRI Re-thinking mild encephalopathy (3) Murray D et al, Pediatrics year outcomes compared between 47 infants with HIE and 30 controls Pre-cooling era: Sarnat exam and EEG used to classify infants as mild, moderate, severe Statistically significant differences seen in all domains of WPPSI-III

19 Re-thinking mild encephalopathy (4) Walsh BH et al, J Pediatr infants undergoing therapeutic hypothermia for neonatal encephalopathy (48 mild, 35 moderate, 6 severe) No difference in rate of MRI abnormalities across grades of HIE (54% mild, 54% moderate, 50% severe) More basal ganglia injury with severe HIE Similar rate of watershed injury across grades of HIE PRIME study results DWI Prospective Research in Mild Encephalopathy Multicenter Study, PI: G. Sant Anna (McGill) Preliminary results: 39% of infants had abnormal EEG (<9h), abnormal brain MRI finding, or abnormal neurologic exam at discharge T2

20 MEND Trial Mild Encephalopathy in Newborns treated with Darbepoietin Phase II: single dose of Darbe 10mcg/kg <24h of age month developmental outcomes Enrollment begins November 2017 Whole body HT for moderate to severe HIE in premature infants weeks A Bayesian study NCT Study PI: Roger Faix, M.D. Univ of Utah, Salt Lake City To assess whether whole body cooling initiated at <6 hour and continued for 72 hours at a temperature of 33.5 C will reduce death and disability at months in infants weeks gestation with moderate to severe HIE Design: Randomized, unblinded, Bayesian design Recruitment estimated at 3-5 years, N=168 Currently enrolling Other neuroprotective strategies N-acetyl cysteine Allopurinol AEDs: phenobarbital, topiramate, leviteracetam Stem cell therapy Melatonin, cannabinoids Conclusions Therapeutic hypothermia for newborns weeks gestation and <6 hours of age who meet eligibility criteria used in clinical trials will reduce death and major disability Potential role for cooling 6-24 hours of life Adverse effects of cooling are uncommon Additional research is needed to continue to determine if if HT benefits preterm infants and those with mild encephalopathy Other neuroprotective therapies are being tested and hopefully will provide additional benefits for this population

21 Future Directions: challenges Ability to see a significant improvement with additive therapy will require: Big effect size (unlikely) Bigger trials to detect a smaller but significant effect size (cost, feasibility issues) Importance of patient selection in trials