1. Tailoring TTM for Challenging Patients - TTM in Neonatology Masaki Shimizu, MD PhD Division of Neonatology Saitama Children’s Medical Center Delivering a baby with asphyxia or hypoxic ischemic encephalopathy (HIE) is extremely distressing for the family. Neonatal asphyxia and HIE are clinical situations that physicians in perinatal and neonatal care should avoid as much as possible. So, strategies are needed to improve the prognosis of infants with HIE and avoid a high incidence of severe sequelae. Against this background, therapeutic hypothermia was introduced into clinical practice over fifteen years ago to treat newborns with severe HIE.

2. Definition of moderate or severe HIE – Metabolic acidosis cord pH < 7.0 or Base deficit ≥ 12 mmol/L – Early onset encephalopathy – Multisystem organ dysfunction – Other causes such as coagulation, metabolic and genetic disorders or maternal trauma excluded We initially confirmed the diagnostic criteria for HIE. Infants with the moderate or severe HIE are candidates for therapeutic hypothermia. Various maternal and fetal/neonatal factors are associated with HIE. Hypoxia and ischemia in the perinatal environment results in metabolic acidosis, which is the first criterion for a diagnosis of HIE. A cord pH below 7.0 induces more severe HIE. The second is the encephalopathy diagnosed based on neurological findings. The third criterion is multiple organ failure as a complication of exposure to hypoxia and ischemia. Thus, encephalopathy due to perinatal hypoxia and ischemia is diagnosed as HIE based on these criteria.

3. Definition of moderate or severe HIE Cerebral circulation Systematic circulation Failure of Cardiac function Redistribution of circulation Fall into metabolic acidosis Brain hypovolemia Glucose supply reduction Oxygen supply reduction Failure of autoregulation Fetal bradycardia Placental abruption Prolapse of umbilical cord This slide shows systematic circulatory collapse in HIE, which causes regulation of the cerebral circulation to fail, resulting in decreased cerebral circulation. Finally, the circulation of cerebral neural cells decreases, which reduces the supply of glucose and oxygen, resulting in various disorders.

4. Hypoxic-Ischemic injury Necrosis APOPTOSIS Delayed brain cell death Anaerobic glycolysis ATP depletion NOS↑ NO activation NO↑ GABA NMDA AMPA Ca 2+ Pre synapse Glutamate Mg 2+ hypoxanthine xanthineuric acid transferrin ferritin free Fe Free radicals ATP Free radicals Microglia IL-1β IL-6 TNFα Citrulline PAF NSE CPK Arg Ca 2+ Inflammatory cytokines Glutamate release Post synapse Destruction Depolarization Na-K ATPase Ca 2+ Ca pomp HIE Pathophysiology Various investigations have revealed information about the mechanisms that cause neuronal damage in HIE. Neuronal cells initially become necrotic due to hypoxic-ischemic injury, which is irreversible. Furthermore, various metabolic pathways become activated over time, and they induce secondary neuronal cell death and further damage over a wide area of the brain. Firstly, the excitatory amino acid, glutamate, is released into the synaptic cleft. Secondly, calcium channels on the postsynaptic membrane open, allowing a large inflow of calcium ions that activate various metabolic pathways. Thirdly, large numbers of generated free radicals cause neuronal cell damage and destruction, resulting in the apoptosis of neuronal and glial cells as well as secondary neuronal cell death.

5. Therapeutic strategy for HIE StrategyIntervention Decrease cerebral metabolic rateHypothermia Block NMDA receptor channelMagnesium Decrease glutamate releaseAdenosine Adenosine agonists Adenosine uptake inhibitors Inhibit voltage-sensitive Ca++ channels Calcium channel blockers Decrease free radical reactionsFree radical scavengers Allopurinol Vitamins C and E Super oxide dismutase (SOD) Prevent free radical formationIndomethacin Iron chelators Allopurinol NOS inhibitors Decrease inflammatory responseAllopurinol Inflammatory antagonists (blocking IL-1 and TNF-α, steroids) Attenuate apoptosis pathwayCaspase inhibitors Neuronal cell damage arises via various metabolic pathways. Consequently, a wide range of treatment strategies have been developed, investigated and clinically applied.

6. Therapeutic strategy for HIE StrategyIntervention Decrease cerebral metabolic rate Hypothermia Block NMDA receptor channelMagnesium Decrease glutamate releaseAdenosine Adenosine agonists Adenosine uptake inhibitors Inhibit voltage-sensitive Ca 2+ channelsCalcium channel blockers Decrease free radical reactionsFree radical scavengers Allopurinol Vitamins C and E Super oxide dismutase (SOD) Prevent free radical formationIndomethacin Iron chelators Allopurinol NOS inhibitors Decrease inflammatory responseAllopurinol Inflammatory antagonists (blocking IL-1 and TNF-α, steroids) Attenuate apoptosis pathwayCaspase inhibitors One such strategy is hypothermia.

7. Microdialysis hippocampus CA1 in HIE model rats I would like to introduce two reports. The first report addresses cooling temperature. The horizontal axis in this graph shows elapsed time after ischemia and the vertical axis shows glutamate levels. Based on the results shown here, 34 degrees Celsius was defined as the target temperature for treating HIE. Brain hypothermia Target temperature ⇒ 34  C Brain hypothermia Target temperature ⇒ 34  C

8. Microdialysis hippocampus CA1 in HIE model rats 100 75 50 25 0 Parasagittal cortex Lateral cortex Striatum DG CA1/2 Neuronal loss (%) control late hypothermia (5.5 h – 34  C) early hypothermia (90 min – 34  C) Gunn TR Pediatr Res. 1997;41:898A Neuronal loss scores in selected cerebral regions Brain hypothermia Therapeutic window ⇒ 6 h after birth Brain hypothermia Therapeutic window ⇒ 6 h after birth The second addresses the therapeutic time window. The lower graph shows neuronal loss in various brain regions cooled at 34 degrees Celsius for 5.5 and 1.5 hours after ischemic insult compared with controls. The loss of neuronal cells is obvious at 1.5 hours compared with controls, but the loss of neuronal cells is significantly inhibited even when cooling is applied at 5.5 h after ischemic insult. These findings suggest that some neuronal cells can be saved in a baby with asphyxia if hypothermia is started within 5.5 hours of birth. Therefore, the window for therapeutic HIE was determined as 6 hours from birth. Brain hypothermia Target temperature ⇒ 34  C Brain hypothermia Target temperature ⇒ 34  C

9. CoSTR2010 guidelines TREATMENT RECOMMENDATIONS Newborn term infants with evolving moderate/severe hypoxic ischemic encephalopathy should be offered therapeutic hypothermia Whole body cooling and selective head cooling are both appropriate strategies. Treatment should be consistent with protocols used in RCTs: Commence within 6 h of birth Continue cooling for 72 h Rewarm for at least 4 h Carefully monitor adverse effects of cooling – thrombocytopenia and hypotension International Liaison Committee On Resuscitation (ILCOR) Newborns in Japan are resuscitated in accordance with the CoSTR2010 guidelines proposed by ILCOR, which recommend that, Newborn term infants with evolving moderate/severe hypoxic ischemic encephalopathy should be offered therapeutic hypothermia. Treatment should be consistent with the protocols used in the RCTs and start within 6 h of birth. It should continue for 72 h and rewarming should take at least 4 hours. The infant should be carefully monitored for adverse effects of cooling, namely thrombocytopenia and hypotension.

10. TH (n = 63) HIE without TH (n = 25) Normal Disabled Dead Mortality and Neurological Prognosis Walks alone Many intelligible words / Carries out simple commands Requests by pointing EEG MRI This slide shows treatment outcomes at our NICU. When aged between 1.5 and 2 years, the following are assessed in patients: the ability to walk alone, utter many intelligible words/carry out simple commands and request by pointing. Abnormal EEG and MRI findings are also searched. The ratio of all findings as normal was higher in a group of infants treated with TH compared with a group that had HIE without TH. Rates of good outcomes and combined rates of disability and death were better in the TH group. However, follow-up of the neurological outcomes of these infants until starting school revealed impaired mental development, although motor development seemed normal in some children. Thus, we surveyed neurological outcomes at the age of starting school. normalabnormaldeath BHT Group35 (55.6 ％ ) 24 (38.1 ％ ) 4 (6.3 ％ ) Non BHT Group5 (20.0 ％ ) 12 (48.0 ％ ) 8 (32.0 ％ ) P=0.010 Over 18 months old

11. From: Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy: An Updated Systematic Review and Meta- analysis Arch Pediatr Adolesc Med. 2012;166(6):558-566. doi:10.1001/archpediatrics.2011.1772 Figure 2. Forest plot of composite primary outcomes death or major disability in survivors. Diamond indicates overall summary estimate for analysis (width of the diamond represents the 95% CI). M-H, Mantel-Haenzel test. Figure Legend: This is a systematic review of TH for neonatal HIE reported in the JAMA Network in 2011. The composite primary outcome of death or major disability in survivors was more favorable in a group treated with hypothermia than normothermia.

12. From: Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy: An Updated Systematic Review and Meta- analysis Arch Pediatr Adolesc Med. 2012;166(6):558-566. doi:10.1001/archpediatrics.2011.1772 Figure 6. Forest plot for the primary outcome of death or major disability by method of cooling in newborns with moderate to severe encephalopathy. Diamond indicates overall summary estimate for the analysis (width of the diamond represents the 95% CI). M-H indicates Mantel-Haenzel test. Figure Legend: This is a systematic review of cooling methods that were also reported in the JAMA Network. The upper and lower rows show the results of the total body cooling and the selectively head cooling, respectively. Both methods seem equally favorable.

13. Cochrane Database Syst Rev. 2013 Jan 31;1:CD003311 Cooling for newborns with hypoxic ischemic encephalopathy. Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Source: Neonatal Services, Royal Women’s Hospital, Parkville, Melbourne, Australia. AUTHORS' CONCLUSIONS: 11 randomized controlled trials (n = 1,505 infants) Therapeutic hypothermia is beneficial for term and late preterm newborns with hypoxic ischemic encephalopathy. Cooling reduces mortality without increasing major disability in survivors Hypothermia should be applied to term and late preterm infants with moderate-to-severe hypoxic ischemic encephalopathy if identified within 6 h of delivery Further trials to determine appropriate techniques of cooling, including refinement of patient selection, duration of cooling, and method of providing therapeutic hypothermia, will refine understanding of this intervention. This slides shows the outcome of a study entitled, “Cooling for newborns with hypoxic ischemic encephalopathy” that was published in the Cochrane database during January 2013. This study reviewed 1,505 patients in 11 RCTs, and the authors concluded that therapeutic hypothermia is beneficial for term and late preterm newborns with hypoxic ischemic encephalopathy. However, they also stated that further study is needed to determine the appropriate techniques for cooling, including refinement of patient selection, duration of cooling and method of providing therapeutic hypothermia.

14. Neonatal head cooling pad Selective head cooling Temperature control Nasopharyngeal Rectal Blanket Neonatal body pad Whole body cooling Temperature control Rectal temperature Cooling System This slide shows details of the cooling methods. The head is selectively cooled or the whole body is generally cooled to treat HIE.

15. Neonatal head cooling pad Selective head cooling Temperature control Nasopharyngeal Rectal Blanket Neonatal body pad Whole body cooling Temperature control Rectal temperature Cooling System The right figure shows cooling pads attached to the head for selective head cooling. Temperature is controlled by monitoring the nasopharyngeal or rectal temperature.

16. Neonatal head cooling pad Selective head cooling Temperature controlNasopharyngeal Rectal Blanket Neonatal body pad Whole body cooling Temperature control Rectal Cooling System The left figure shows cooling pads placed under, or brought into close contact with the body for efficient whole body cooling. Temperature is controlled during whole body cooling by monitoring the rectal temperature.

17. Neonatal Hypothermia Therapy These photographs show actual hypothermia therapy applied to an infant with severe HIE. The whole body is cooled at our institution by attaching cooling pads to both the head and the trunk. The cooling temperature is set at 34 degrees Celsius, and the duration is 72 hours according to the ILCOR CoSTR2010 guidelines.

18. Neonatal Hypothermia Therapy Mild hypothermia; target temperature < 34ºC Many devices required for:  Cooling  Management of circulation  Respiration, metabolism, others ArcticSun5000 Amplitude EEG NIRS The cardiorespiratory system, infection, blood glucose level, electrolytes and brain metabolism are monitored and continuous EEG is applied when the target cooling temperature is 34 degrees Celsius. Here is the main equipment used in neonatal hypothermia therapy. General intensive care in addition to temperature control is necessary to maintain the body at this temperature and circulation management is particularly important. The systemic circulation must be preserved using blood transfusion and a vasopressor to maintain cerebral circulation.

19. More rapid and efficient cooling Selective head cooling and Whole body cooling Large body mass Large water volume More efficient Rapid cooling Sometimes excessive A recent study has shown that earlier cooling improves the prognosis. We tried a new method of applying more rapid and efficient temperature reduction by simultaneously cooling the head and the trunk using this device. Because the cooling area is quite large, the likelihood of heat exchange is high, and the area is rapidly cooled. Cooling can occasionally be excessive, which warrants immediate attention. However, temperature control is excellent and this device can be used safely. ArcticSun5000

20. Ｓｕｍｍａｒｙ Therapeutic hypothermia appears neuroprotective when started within 6 h of birth in newborns with moderate to severe HIE. Cooling is standard of care for infants with HIE, although more study is required to determine optimal selection criteria and treatment protocol. Temperature management at 34ºC needs strict whole body control and much medical equipment. Efficient cooling and adequate pads are required for neonatal TH. Future therapy will involve more rapid and efficient cooling, and further treatment strategies. (neuroprotective drugs, regenerative therapy) Therapeutic hypothermia appears to be neuroprotective when started within 6 hours of birth in newborns with moderate to severe HIE. Cooling has become the standard of care for infants with HIE, although more study is required to determine the optimal selection criteria and treatment protocol. To maintain the temperature at 34 degrees Celsius requires strict whole-body control, which requires several types of medical equipment. An efficient cooling method and adequate pads are required for neonatal TH. Future therapy will involve more rapid and effective cooling, and other types of strategies such as neuroprotective drugs and regenerative therapy.

21. Acknowledgement 4th Annual Targeted Temperature Management teaching CHAIR Dr. Mauro Oddo HOSTING CHAIR Pr. Dr. V CERNÝ C.R. Bard Medivance