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Aim: We evaluated the predictive ability of prolonged requirements for mechanical ventilation or tube feeding support for 18-month composite outcomes in infants with hypoxic-ischaemic encephalopathy treated with hypothermia., Methods: This retrospective, nationwide, observational study focused on newborn infants registered in Japan's Baby Cooling Registry between 1 January 2012 and 31 December 2016. The adverse outcomes were defined as death or survival with cerebral palsy, visual or auditory impairment or the requirement for mechanical ventilation or tube feeding at 18 months of age., Results: Adverse outcomes occurred in 165 (28%) of the 591 children in the final cohort. These were predicted by prolonged dependence on mechanical ventilation or tube feeding for more than seven and more than 14 days. The respective values were positive predictive value 0.34 (95% CI 0.33-0.34) and 0.60 (95% CI 0.56-0.62), negative predictive value 0.97 (95% CI 0.91-0.99) and 0.93 (95% CI 0.90-0.95) and area under the curve 0.59 (95% CI 0.54-0.64) and 0.81 (95% CI 0.77-0.85)., Conclusion: Prolonged dependence on mechanical ventilation or tube feeding for more than 14 days may be useful in predicting 18-month outcomes in newborn infants who have received therapeutic hypothermia., (© 2023 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: To explore the predictive value of the Thompson score during the first 4 days of life for estimating short-term adverse outcomes in neonatal encephalopathy., Methods: This observational study evaluated infants with neonatal encephalopathy (≥36 weeks of gestation) registered in a multicenter cohort of cooled infants in Japan. The Thompson score was evaluated at 0-24, 24-48, 48-72, and 72-90 h of age. Adverse outcomes included death, survival with respiratory impairment (requiring tracheostomy), or survival with feeding impairment (requiring gavage feeding) at discharge., Results: Of the 632 infants, 21 (3.3%) died, 59 (9.3%) survived with respiratory impairment, and 113 (17.9%) survived with feeding impairment. The Thompson score throughout the first 4 days accurately predicted death, respiratory impairment, or feeding impairment. The 72-90 h score showed the highest accuracy. A cutoff of ≥15 had a sensitivity of 0.85 and specificity of 0.92 for death or respiratory impairment, while a cutoff of ≥14 had a sensitivity of 0.71 and a specificity of 0.92 for death, respiratory or feeding impairment., Conclusion: A high Thompson score during the first 4 days of life, especially at 72-90 h could thus be useful for estimating the need for prolonged life support., Impact: The Thompson score on days 1-4 of age was useful in predicting death and respiratory or feeding impairments. The 72-90 h Thompson score showed the highest predictive capability. Owing to the rarity of withdrawal of life-sustaining treatment in Japan, 43% of infants with persistent severe encephalopathy with a Thompson score of ≥15 at 72-90 h of age could regain spontaneous breathing, be extubated, and survive without tracheostomy. Meanwhile, approximately 50% of infants who survived without tracheostomy required gavage feeding. Our results could provide useful information for clinical decision making regarding infants with persistent severe encephalopathy., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

This study investigated the 3-year clinical outcomes in relation to the severity of encephalopathy in high-survival infants who underwent therapeutic hypothermia. This retrospective observational study was conducted in level II/III neonatal intensive care units in Japan. The nationwide cohort included 474 infants registered in the Baby Cooling Registry of Japan between January 2012 and December 2016. Clinical characteristics, mortality rate and severe neurological impairment at age 3 years were evaluated. Of the infants, 48 (10.4%), 291 (63.1%) and 122 (26.5%) had mild, moderate and severe encephalopathy, respectively, upon admission. By age 3, 53 (11.2%) infants died, whereas 110 (26.1%) developed major disabilities. The mild group survived up to age 3. In the moderate group, 13 (4.5%) died and 44 (15.8%) developed major disabilities. In the severe group, 39 (32.0%) died by age 3. Adverse outcomes were observed in 100 (82.0%) infants. Mortality was relatively low in all subgroups, but the incidence of major disabilities was relatively high in the severe group. The relatively low mortality and high morbidity may be due to Japanese social and ethical norms, which rarely encourage the withdrawal of intensive life support. Cultural and ethical backgrounds may need to be considered when assessing the effect of therapeutic interventions., (© 2022. The Author(s).)

Background: Therapeutic hypothermia is a standard of care for neonatal encephalopathy; however, approximately one in two newborn infants fails to respond to this treatment. Recent studies have suggested potential relationships between body temperature, heart rate and the outcome of cooled infants., Methods: The clinical data of 756 infants registered to the Baby Cooling Registry of Japan between January 2012 and December 2016 were analysed to assess the relationship between body temperature, heart rate and adverse outcomes (death or severe impairment at 18 months corrected age)., Results: A lower body temperature at admission was associated with adverse outcomes in the univariate analysis (P < 0.001), the significance of which was lost when adjusted for the severity of encephalopathy and other covariates. A higher body temperature during cooling and higher heart rate before and during cooling were associated with adverse outcomes in both univariate (all P < 0.001) and multivariate (P = 0.012, P < 0.001 and P < 0.001, respectively) analyses., Conclusions: Severe hypoxia-ischaemia might be a common causative of faster heart rates before and during cooling and low body temperature before cooling, whereas causal relationships between slightly higher temperatures during cooling and adverse outcomes need to be elucidated in future studies., Impact: In a large cohort of encephalopathic newborn infants, dual roles of body temperature to the outcome were shown; adverse outcomes were associated with a lower body temperature at admission and higher body temperature during cooling. A higher heart rate before and during cooling were associated with adverse outcomes. Severe hypoxia-ischaemia might be a common causative of faster heart rates before and during cooling and low body temperature before cooling. The exact mechanism underlying the relationship between slightly higher body temperature during cooling and adverse outcomes remains unknown, which needs to be elucidated in future studies., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Therapeutic hypothermia following neonatal encephalopathy is neuroprotective. However, approximately one in two cooled infants still die or develop permanent neurological impairments. Further understanding of variables associated with the effectiveness of cooling is important to improve the therapeutic regimen. To identify clinical factors associated with short-term outcomes of cooled infants, clinical data of 509 cooled infants registered to the Baby Cooling Registry of Japan between 2012 and 2014 were evaluated. Independent variables of death during the initial hospitalization and survival discharge from the cooling hospital at ≤28 days of life were assessed. Death was associated with higher Thompson scores at admission (p < 0.001); higher heart rates after 3-72 hours of cooling (p < 0.001); and higher body temperature after 24 hours of cooling (p = 0.002). Survival discharge was associated with higher 10 minutes Apgar scores (p < 0.001); higher blood pH and base excess (both p < 0.001); lower Thompson scores (at admission and after 24 hours of cooling; both p < 0.001); lower heart rates at initiating cooling (p = 0.003) and after 24 hours of cooling (p < 0.001) and lower average values after 3-72 hours of cooling (p < 0.001); higher body temperature at admission (p < 0.001); and lower body temperature after 24 hours and lower mean values after 3-72 hours of cooling (both p < 0.001). Survival discharge was best explained by higher blood pH (p < 0.05), higher body temperature at admission (p < 0.01), and lower body temperature and heart rate after 24 hours of cooling (p < 0.01 and <0.001, respectively). Lower heart rate, higher body temperature at admission, and lower body temperature during cooling were associated with favorable short-term outcomes.

Therapeutic hypothermia is recommended for moderate and severe neonatal encephalopathy, but is being applied to a wider range of neonates than originally envisaged. To examine the clinical use of therapeutic hypothermia, data collected during the first 3 years (2012-2014) of the Baby Cooling Registry of Japan were analysed. Of 485 cooled neonates, 96.5% were ≥36 weeks gestation and 99.4% weighed ≥1,800 g. Severe acidosis (pH < 7 or base deficit ≥16 mmol/L) was present in 68.9%, and 96.7% required resuscitation for >10 min. Stage II/III encephalopathy was evident in 88.3%; hypotonia, seizures and abnormal amplitude-integrated electroencephalogram were observed in the majority of the remainder. In-hospital mortality was 2.7%; 90.7% were discharged home. Apgar scores and severity of acidosis/encephalopathy did not change over time. The time to reach the target temperature was shorter in 2014 than in 2012. The proportion undergoing whole-body cooling rose from 45.4% to 81.6%, while selective head cooling fell over time. Mortality, duration of mechanical ventilation and requirement for tube feeding at discharge remained unchanged. Adherence to standard cooling protocols was high throughout, with a consistent trend towards cooling being achieved more promptly. The mortality rate of cooled neonates was considerably lower than that reported in previous studies.

Background: Therapeutic hypothermia is now recommended as a standard of care for neonatal encephalopathy. Although adherence to standard cooling protocols used in the phase-III trials is essential, empiric approaches have prevailed in Japan., Aim: To elucidate the gap between the standard cooling methods and the current practice in Japan., Method: In July 2010, a questionnaire regarding the practice of neonatal encephalopathy was mailed to clinical leads of registered neonatal intensive care units., Result: 56.2% of the units were incapable of offering therapeutic hypothermia because of the reasons such as the shortage of human/medical resources (85.1%) and limited number of cases (21.1%). Eighty-nine centres provided therapeutic hypothermia using either selective-head cooling (88.8%) or whole-body cooling (11.2%). Various target temperatures and cooling durations were used; 20.2% of the units cooled infants without using purpose-built equipments, whereas 14.6% did not continuously monitor the body temperature., Discussion: Only 43.8% of the units provided therapeutic hypothermia. Even in centres where hypothermia was offered, adherence to the standard protocols was extremely poor. To secure the safety and efficacy, further promotion of the standard cooling protocols is required; an efficient cooling centre network has to be established by optimizing the work forth distribution and transportation system., (© 2011 The Author(s)/Acta Paediatrica © 2011 Foundation Acta Paediatrica.)

Neuroprotection following brain injury has been a top priority in neuroscience since the Hippocratic era. However, of hundreds of "experimentally-neuroprotective treatments", currently only hypothermia is clinically available. Interpretation of bench-work may have to account for the variation in developmental stages and types of injury. For example GABAergic stimulators have been used to reduce cerebral energy consumption; recent studies suggested the paradoxical excitation of premature neurons following GABAergic stimuli because of the high intracellular chloride concentration during the perinatal period. Even for hypothermia, many questions remain unanswered:selective-head cooling following perinatal hypoxia-ischemia appeared rather deleterious for infants with the most severe encephalopathy or low birth-weight. In a piglet model, different cooling levels provided differential regional brain protection:35 degrees C was optimal for deep-grey-matter whereas the cortical-grey-matter was better protected at 33 degrees C, suggesting that a single cooling level may not be equally optimal for the entire brain. Another experimental study used magnetic-resonance spectroscopy to demonstrate that the more severe the acute event was, the shorter the therapeutic time window was, explaining the lower effectiveness of neuroprotection following the most severe hypoxia-ischemia. Another suggestion from our translational research was the dependence of cerebral temperatures on body weight under selective-head cooling:the smaller the body weight, the lower the brain temperature, presumably because of the larger surface area to brain volume ratio in small subjects. Thus translational research is essential to achieve "tailored" treatments, that address for individual and regional cerebral conditions. Although therapeutic options have become available in the tertiary centre settings, neuroprotection should not remain an expensive treatment only available in rich countries. We have recently developed a cooling system that can maintain stable hypothermia over 24 hours without an electric supply. Experimental studies to optimise high-tech cooling need to run in parallel with studies to increase the distribution of these treatments worldwide.

Objective: We sought to compare the prognostic utilities of early MRI spin-spin relaxometry and proton magnetic resonance spectroscopy in neonatal encephalopathy., Methods: Twenty-one term infants with neonatal encephalopathy were studied at a mean age of 3.1 days (range: 1-5). Basal ganglia, thalamic and frontal, parietal, and occipital white matter spin-spin relaxation times were determined from images with echo times of 25 and 200 milliseconds. Metabolite ratios were determined from an 8-mL thalamic-region magnetic resonance spectroscopy voxel (1H point-resolved spectroscopy; echo time 270 milliseconds). Outcomes were assigned at age 1 year as follows: (1) normal, (2) moderate (neuromotor signs or Griffiths developmental quotient of 75-84), (3) severe (functional neuromotor deficit or developmental quotient <75 or died). Predictive efficacies for differentiation between normal and adverse (combined moderate and severe) outcomes were compared by receiver operating characteristic curve analysis and logistic regression., Results: Thalamic and basal ganglia spin-spin relaxation times correlated positively with outcome and predicted adversity. Although thalamic and basal ganglia spin-spin relaxation times were prognostic of adversity, magnetic resonance spectroscopy metabolite ratios were better predictors, and, of these, lactate/N-acetylaspartate was most accurate., Conclusions: Deep gray matter spin-spin relaxation time was increased in the first few days after birth in infants with an adverse outcome. Proton magnetic resonance spectroscopy was more prognostic than spin-spin relaxation time, with lactate/N-acetylaspartate the best measure. Nevertheless, both techniques were useful for early prognosis, and the potential superior spatial resolution of spin-spin relaxometry may define better the precise anatomic pattern of injury in the early days after birth.