Trial of Edaravone for severe hypoxic ischemic encephalopathy in adults: a double-blind placebo-controlled study.

Neonatal hypoxic ischemic encephalopathy (HIE) is one of the most common causes of neonatal morbidity and mortality worldwide. It has an overall mortality rate ranging from 15% to 25%, with up to 50% of survivors developing long-term neurological disabilities. Therapeutic hypothermia (TH) has been the only effective treatment for moderate to severe HIE in neonates ≥35 weeks of gestation. Infants with mild HIE previously had been excluded from studies, but a recent study reported approximately 16% developed a disability at 18 to 22 months of age. Despite treatment, up to 29% of neonates with HIE still develop adverse outcomes. To decrease the prevalence of neonatal HIE, prevention is key and a better understanding of associated maternal, perinatal, and neonatal risk factors is needed. The aim of this study was to assess trends of HIE prevalence and use of TH, mortality, and clinical neonatal outcomes. This was a cross-sectional analysis using National Inpatient Sample data sets from 2010 to 2018. Included were newborn infants diagnosed with HIE or asphyxia, who were ≥35 weeks of gestation and had a birth weight ≥2500 g. Excluded were those with congenital heart disease, congenital central nervous system anomalies, congenital lung anomalies, congenital abdominal wall defects, gastroschisis or omphalocele, multiple congenital anomalies, common syndromes, and chromosomal disorders. Of the 32,180,617 infants included in the analysis, 31,249,100 were term infants (>35 weeks). The prevalence of all degrees of HIE for term infants was approximately 0.1%. There was a modest increase from 0.093% during the years 2010 and 2012 up to 0.097% during 2016 and 2018. Approximately 21% of cases were managed with TH. More infants with moderate HIE received TH than those with severe HIE (29.9% vs 19.9%; P < 0.01). Fewer infants with mild or unspecified HIE received TH than those with severe HIE (17.7% and 17.3%, respectively; P < 0.01). From 2010 to 2018, the use of TH increased overall and within each grade of HIE (P < 0.01). The mortality rate was higher in term infants with all degrees of asphyxia than the general population (10.8% vs 0.06%; P < 0.01). Over time, the mortality rate in term infants decreased from 12.3% in 2010 to 8.3% in 2018 (P < 0.01). The analysis included 931,517 were late preterm infants (35–36 weeks of gestation). The combined prevalence for all grades of HIE was 0.23% and did not change significantly over the years. Approximately 21% of late preterm infants were managed with TH. More infants with moderate HIE received TH than those with severe HIE (26.9% vs 20.1%). Fewer infants with mild HIE received TH (13.2%), and no significant difference was observed in infants with unspecified HIE compared with those with severe HIE (18.7% vs 20.1%). The use of TH increased has increased in late preterm infants over the years. The strongest factors associated with HIE were placental infarction or insufficiency, placental abruption, and cord prolapse. Female infant sex, maternal Hispanic ethnicity, and maternal Asian race were associated with lower risk of HIE. In conclusion, HIE prevalence remained essentially the same at 1 per 1000 live births. Use of TH increased, and mortality decreased over time. The strongest factors associated with HIE were placental factors.

Primary Subject area Neonatal-Perinatal Medicine Background Therapeutic hypothermia (TH) is the standard treatment for neonatal hypoxic ischemic encephalopathy (HIE) to improve mortality and long-term impairment. Accurate costing algorithms are essential to evaluate cost-effective interventions and identify cost drivers. Objectives We aimed to validate the Canadian Neonatal Network (CNN) costing algorithm for HIE infants treated with TH against costs obtained from hospital-based finance software (CPSS) and compare the costs of TH for infants with mild/moderate to those with severe HIE. We aimed to validate the Canadian Neonatal Network (CNN) costing algorithm for HIE infants treated with TH against costs obtained from hospital-based finance software (CPSS) and compare the costs of TH for infants with mild/moderate to those with severe HIE. Design/Methods Retrospective cohort study including 98 infants admitted with HIE and receiving TH in a tertiary NICU between 2016 and 2018. Clinical characteristics and CNN costing data were collected from the local CNN database and actual cost were obtained from CPSS. The primary outcome was the difference in total hospital stay cost between CNN algorithm and CPSS. The differences between both algorithms were also identified in 8 different cost centres such as nursing, respiratory, imaging, etc. Costs per patients using both algorithms were compared using Pearson correlation coefficient (r) and paired t-test. Characteristics and costs per infant were compared between infants with mild/moderate HIE and those with severe HIE. Results Among the 98 patients with HIE that received TH, 2 (2%) had mild HIE, 75 (77%) had moderate HIE and 21 (21%) had severe HIE on admission. Mortality rate was 10% (10/98) and median length of stay was 12 days [IQR 10-16]. Total mean cost per infant using the CNN algorithm was $32,727 (SD $23,751 and correlated highly to the CPSS mean $28.373(SD $28.989) (r=0.93, p<0.01). There was no significant difference in mean total costs estimated between the algorithms ($1051, 95% CI $-1073, $3174). There was a strong correlation between cost estimates using the CNN algorithm and CPSS in nursing, physician, transfusion and indirect costs (r range 0.94-0.99) (Figure 1). Mean daily costs per infant with mild/moderate HIE ($1579, SD 808) were lower compared to infants with severe HIE ($2069, SD 1518). In both groups, daily costs were higher in the first days of hospitalization and slightly decreased over time (Figure 2). Conclusion The CNN algorithm accurately predicts hospital stay costs for infants diagnosed with HIE and received TH in our centre. Severity of encephalopathy and severity of illness are associated with higher hospital costs.

Hypoxic-ischaemic encephalopathy (HIE) affects 2-4/1000 live term births. Treatment with therapeutic hypothermia (TH) improves the long-term neurodevelopmental outcome of neonates with moderate to severe HIE. However, early prediction of outcome still remains challenging, and no reliable and easily obtainable biomarker has been identified to date. Neonates with HIE display impaired thermoregulation, resulting in spontaneous hypothermia. The degree of cooling required to achieve TH may therefore act as a biomarker of injury severity. The present study demonstrates a correlation between servo-controlled mattress temperature during TH and short-term outcome. Neonates with an unfavourable outcome require less cooling to maintain a core temperature between 33 and 34°C during TH compared to neonates with a favourable outcome. The degree of impaired temperature regulation was strongly associated with a high magnetic resonance imaging injury score and death. Cooling device output temperature is a potential and easily obtainable early physiological biomarker of outcome in infants with HIE undergoing TH. Neonatal hypoxic-ischaemic encephalopathy (HIE) is a leading cause of death and disability in children. Therapeutic hypothermia (TH) at 33.5°C for 72h is the only therapy to date shown to improve outcome in moderate to severe HIE; however, assessment of severity and prediction of outcome remains challenging. Infants with HIE display significant physiological perturbations, including spontaneous hypothermia. We hypothesized that neonates with more severe brain injury on magnetic resonance imaging (MRI) would exhibit a greater degree of spontaneous hypothermia, and thus require less active cooling to attain TH. Twenty-eight neonates with moderate or severe HIE treated with TH were included in the present study. MRI images obtained on day of life 4-7 were scored according to standardized injury criteria. Unfavourable outcome was defined as death or significant grey matter injury on MRI according to a previously validated scoring system. A significantly higher cooling device output temperature was seen in infants with an unfavourable outcome. All neonates who required the mattress to provide a temperature≥32°C to maintain their core body temperature at 33.5°C had a high likelihood of unfavourable outcome (likelihood ratio=14.4).By contrast, infants who never required a device output temperature ≥32°C had a low likelihood of an unfavourable outcome (likelihood ratio=0.07, P<0.001). Infants with significant grey matter injury on MRI require less active cooling to maintain target temperature during TH. The cooling device output temperature has the potential to be an easily accessible physiological biomarker and predictor of injury and mortality in neonates with moderate or severe HIE.

Hypoxic ischaemic encephalopathy (HIE) is a common cause of neonatal death and severe neurological deficit in children, contributing to medico-legal litigation. To describe the neurodevelopmental outcomes of infants with moderate and severe HIE at Chris Hani Baragwanath Academic Hospital and the proportions with neurodevelopmental impairment (NDI) and complications. To explore the effect of HIE severity and therapeutic hypothermia (TH) on neurodevelopmental outcome. A retrospective, descriptive study at the Neonatal Neurodevelopmental Clinic included 239 infants with moderate and severe HIE, between 2015 and 2020. Neurodevelopmental outcomes were assessed by using the Griffiths Mental Developmental Scales at 1 year. General Quotient (GQ) scores defined NDI. Clinical and investigation criteria determined those with neurological complications. Of the 239 infants, 211 (88.3%) and 28 (11.7%) had moderate HIE and severe HIE, respectively. Cerebral palsy (CP) was diagnosed in 9.2% and NDI in 17.1%. Severe HIE infants had significantly higher rates of NDI and CP, 50% (14) and 21.4% (6) respectively, as compared to those of moderate HIE infants, who had 12.7% (27) NDI and 7.6% (16) CP; 152(72%) moderate and 14 (50%) severe HIE infants received TH. Those who received TH were less likely to have NDI (p = 0.005), CP (p = 0.002), epilepsy and visual impairment. Developmental scores at 1 year of age were in the average range for the cohort, with equivalent profiles across domains. Those with severe HIE had the worst outcomes. Therapeutic hypothermia was associated with decreased CP and NDI in both groups. This report supports the use of TH as a neuroprotective strategy in stage 2 and 3 HIE, highlighting the need for neurodevelopmental assessments at 2 years and beyond to determine longer-term outcomes and subtle deficits.

Therapeutic Hypothermia in Neonatal Hypoxic Ischemic Encephalopathy: Electrographic Seizures and Magnetic Resonance Imaging Evidence of Injury

Background The outcome of perinatal hypoxic-ischaemic encephalopathy (HIE) in middle-to-low-income countries varies between regions. Objectives To determine the mortality and morbidity, and factors influencing the deaths of infants with perinatal HIE. Methods A retrospective study was conducted at Chiang Mai University Hospital, Thailand. Perinatal HIE infants of >35 weeks gestation, birthweight ≥2000 g and admitted during 2005-2019 were reviewed. Baseline Characteristics, clinical course and outcome at discharge were compared between the period before and after initiation of therapeutic hypothermia (TH). Risk of death in HIE infants who underwent TH was identified Results A total of 162 HIE infants were included. Compared to the period before TH initiation, the mortality rate was significantly decreased in the TH period. (27% vs. 12.8%, p=0.04) Among 100 HIE infants who underwent TH, the mortality rates was 14%(14/100), of whom 2.5% (2/76) and 50% (12/24) were in the moderate and severe HIE groups. Apgar score at 5 mins ≤1, severe HIE, seizures, hypoglycaemia, organ involvement ≥ five sites, ammonia ≥100 umol/L, lactate ≥14 mmol/L, and requirement for two or more inotropic drugs were risks of death. Multivariate analysis demonstrated that severe HIE (aOR 732.8, 95% CI 4.7–114643, p=0.01) and a need for two or more inotropic drugs (aOR 45.7, 95% CI 1.5–1040, p=0.029) were significant factors for mortality. Conclusion In the period of TH, perinatal HIE infants had decreased mortality. Severe HIE and a need for two or more inotropic drugs were associated with death in the infant with HIE who underwent TH. Abbreviations: AED: anti-epileptic drug; BW, birthweight; CI: confidence interval; CMU: Chiang Mai University; EEG: electro-encephalogram; GA: gestational age; HIE: hypoxic-ischaemic encephalopathy; IQR: interquartile range; NICU: neonatal intensive care unit; SD: standard deviation; TH: therapeutic hypothermia.

Objective To investigate the challenges faced when redirecting care in severe HIE and how this impacts on survival with severe disability. Methods Retrospective observational study of 10 patients with severe neonatal HIE who had redirection of care considered from 2012 to 2015. Data were collected from Badger net and medical notes. Results 9 out of 10 had therapeutic hypothermia. 1 patient never had therapeutic hypothermia due to brain stem death. 6 did not complete the therapeutic hypothermia (4 died and 1 had severe persistent pulmonary hypertension). 5 patients died (50%) and 5 survived. In those who survived, 2 parents refused redirection of care. 3 had MRI brain prior to the decision for redirection of care. The mean age at redirection of care for the babies who died was 2.1 days (range 1–4) compared to 3 days (range 2–4) in those that survived. The mean Thompson score in those who died was 12 (range 10–16) and those who survived 8 (range 6–13). Cerebral function monitoring in 8 patients showed severe abnormalities (low voltage/burst suppression/status epilepticus). In 2 patients the CFM had significant artifact and was difficult to interpret. Full montage EEG in the survived patients showed features of HIE insult in 4 cases and featureless in one case. MRI brain was done in the 5 patients that survived and all had severe changes (MRI scores 2A, 2B, 2A/2B and 3- Scores based on Neonatal Institute of Child health and Human development Neonatal Research Network). Conclusion Our findings suggest that redirection of care is difficult for both parents and clinicians and awaiting more information can delay redirection of care with the likelihood of survival with risks of severe neurodevelopmental delay. Clinicians are often not confident in making this call based on CFM and clinical examination alone. A full montage EEG at 48 hours may aid prognostication and can be done at the bedside. Parental awareness of window of opportunity is appropriate in these settings.

Recently, we have demonstrated that concurrent hypothermia and mesenchymal stem cells (MSCs) transplantation synergistically improved severe neonatal hypoxic ischemic encephalopathy (HIE). The current study was designed to determine whether hypothermia could extend the therapeutic time window of MSC transplantation for severe neonatal HIE. To induce HIE, newborn rat pups were exposed to 8% oxygen for 2 h following unilateral carotid artery ligation on postnatal day (P) 7. After approving severe HIE involving >50% of the ipsilateral hemisphere volume, hypothermia (32 °C) for 2 days was started. MSCs were transplanted 2 days after HIE modeling. Follow-up brain MRI, sensorimotor function tests, assessment of inflammatory cytokines in the cerebrospinal fluid (CSF), and histological evaluation of peri-infarction area were performed. HIE induced progressively increasing brain infarction area over time, increased cell death, reactive gliosis and brain inflammation, and impaired sensorimotor function. All these damages observed in severe HIE showed better, robust improvement with a combination treatment of hypothermia and delayed MSC transplantation than with either stand-alone therapy. Hypothermia itself did not significantly reduce brain injury, but broadened the therapeutic time window of MSC transplantation for severe newborn HIE.

Background- The prevalence of severe Hypoxic Ischemic Encephalopathy (HIE) is increasing and their prognosis for meaningful recovery is poor. Adjunctive Hyperbaric Oxygen therapy (HBOT) has been used in patients with severe disorder of consciousness but studies to evaluate benefits are scarce. Objective- Evaluate the changes in level of consciousness, neurological status and functional status in patients with severe hypoxic ischemic encephalopathy (HIE) who underwent HBOT. Methods- This is a retrospective study involving 54 patients with severe HIE. Validated outcome scales (Coma Recovery Scale-Revised for level of consciousness, Glasgow Coma Scale for neurological status, and Glasgow Outcome Scale for functional status) prior to starting HBOT and at discharge were evaluated. Clinical Data, Duration of injury, Number of HBOT sessions and medical complications attributed to HBOT were analysed. Wilcoxon sign ranked test was used for statistical analysis. Results- Fifty two percent patients had change in level of consciousness with 13% achieving consciousness. Fifty percent patients had improvement in neurologic Status. 35% of patients showed functional improvement with 13% patients achieving independence for ADLs at discharge. Higher initial GOS score significantly increased the odds of having higher GCS and level of consciousness at discharge. Younger age, female gender, HBOT session started within a month of injury and higher GOS score significantly increased the odds of functional recovery at discharge. No major complications were attributed to HBOT. Conclusions- There is scope for improvement in consciousness, neurological status, and functional status after severe HIE. HBOT is safe and well tolerated by persons with severe HIE.

Brain Temperature in Neonates with Hypoxic-Ischemic Encephalopathy during Therapeutic Hypothermia

ObjectiveTo examine the influence of timing of initiation of therapeutic hypothermia (TH) on brain injury on MRI and on neurodevelopmental outcomes at 18 months.DesignRetrospective cohort study.SettingTertiary neonatal intensive care unit...

Therapeutic hypothermia is the standard-of-care treatment for infants diagnosed with moderate-to-severe hypoxic-ischemic encephalopathy (HIE). MRI for assessing brain injury is usually performed after hypothermia because of logistical challenges in bringing acutely sick infants receiving hypothermia from the neonatal intensive care unit (NICU) to the MRI suite. Perhaps examining and comparing early cerebral oxygen metabolism disturbances to those after rewarming will lead to a better understanding of the mechanisms of brain injury in HIE and the effects of therapeutic hypothermia. The objectives were to assess the feasibility of performing a novel T2-relaxation under spin tagging (TRUST) MRI technique to measure venous oxygen saturation very early in the time course of treatment, 18-24h after the initiation of therapeutic hypothermia, to provide a framework to measure neonatal cerebral oxygen metabolism noninvasively, and to compare parameters between early and post-hypothermia MRIs. Early (18-24h after initiating hypothermia) MRIs were performed during hypothermia treatment in nine infants with HIE (six with moderate and three with severe HIE). Six infants subsequently had an MRI after hypothermia. Mean values of cerebral blood flow, oxygen extraction fraction, and cerebral metabolic rate of oxygen from MRIs during hypothermia were compared between infants with moderate and severe HIE; and in those with moderate HIE, we compared cerebral oxygen metabolism parameters between MRIs performed during and after hypothermia. During the initial hypothermia MRI at 23.5±5.2h after birth, infants with severe HIE had lower oxygen extraction fraction (P=0.04) and cerebral metabolic rate of oxygen (P=0.03) and a trend toward lower cerebral blood flow (P=0.33) compared to infants with moderate HIE. In infants with moderate HIE, cerebral blood flow decreased and oxygen extraction fraction increased between MRIs during and after hypothermia (although not significantly); cerebral metabolic rate of oxygen (P=0.93) was not different. Early MRIs were technically feasible while maintaining hypothermic goal temperatures in infants with HIE. Cerebral oxygen metabolism early during hypothermia is more disturbed in severe HIE. In infants with moderate HIE, cerebral blood flow decreased and oxygen extraction fraction increased between early and post-hypothermia scans. A comparison of cerebral oxygen metabolism parameters between early and post-hypothermia MRIs might improve our understanding of the evolution of HIE and the benefits of hypothermia. This approach could guide the use of adjunctive neuroprotective strategies in affected infants.

N-acetylcysteine (NAC) and vitamin D provide effective neuroprotection in animal models of severe or inflammation-sensitized hypoxic ischemic encephalopathy (HIE). To translate these FDA-approved drugs to HIE neonates, we conducted an early phase, open-label trial of 10 days of NAC (25, 40 mg/kg q12h) + 1,25(OH)2D (calcitriol 0.05 mg/kg q12h, 0.03 mg/kg q24h), (NVD), for pharmacokinetic (PK) estimates during therapeutic hypothermia and normothermia. We paired PK samples with pharmacodynamic (PD) targets of plasma isoprostanoids, CNS glutathione (GSH) and total creatine (tCr) by serial MRS in basal ganglia (BG) before and after NVD infusion at five days. Infants had moderate (n = 14) or severe HIE (n = 16), funisitis (32%), and vitamin D deficiency (75%). NVD resulted in rapid, dose-responsive increases in CNS GSH and tCr that correlated positively with plasma [NAC], inversely with plasma isofurans, and was greater in infants with lower baseline [GSH] and [tCr], suggesting increases in these PD markers were titrated by neural demand. Hypothermia and normothermia altered NAC PK estimates. NVD was well tolerated. Excluding genetic syndromes (2), prolonged ECMO (2), lost-to-follow-up (1) and SIDS death (1), 24 NVD treated HIE infants have no evidence of cerebral palsy, autism or cognitive delay at 24–48 months. These data confirm that low, safe doses of NVD in HIE neonates decreased oxidative stress in plasma and CNS, improved CNS energetics, and are associated with favorable developmental outcomes at two to four years.

Background: Hypoxic-ischemic encephalopathy (HIE) is one of the main causes of neurodevelopmental disorders. We developed a model that has diagnostic and prognostic value in predicting the neurodevelopmental outcomes in newborns with HIE. HIE staging allows us to start therapeutic interventions early in newborns with suspected encephalopathy.&#x0D; Methods: This was a retrospective study in a cohort of 58 full-term neonates with clinical suspicion of HIE. We assessed electroclinical variables at birth [etiology of hypoxia, neonatal seizures, HIE stages based on Sarnat criteria, use of therapeutic hypothermia, neuroimaging tests and electroencephalography (EEG) findings] and two years of follow up (EEG findings, development of epilepsy, the presence of cognitive deficits, behavioral issues, language problems, visual or hearing disturbances, and cerebral palsy).&#x0D; Results: There was a high electro-clinical correlation to severe HIE (88.8%) and moderate HIE (50%). There was a considerable proportion of patients affected by mild HIE, based on clinical examination, who presented with an abnormal EEG (32.3%). There is a relationship between the onset of neonatal seizures, epilepsy, and severe HIE diagnosed with EEG (88.9%). A higher percentage of patients with moderate and severe HIE, based on EEG findings, present abnormal results in cranial ultrasound and cerebral magnetic resonance imaging (62.5%). At two years of age, functional neurodevelopment disturbances were observed most frequently in patients affected with severe and moderate HIE based on EEG.&#x0D; Conclusions: This study shows a model with diagnostic and prognostic value in predicting newborns' neurodevelopmental outcomes with suspected HIE. This knowledge allows us to assess the role of performing serial EEG in patients with suspected HIE and the relevance of EEG findings in the prognosis of neurodevelopmental disorders.

Hypoxic ischemic encephalopathy (HIE) is a serious neurological complication that may develop in asphyxiated infants. Severity of encephalopathy may vary, and concurrent multiorgan dysfunctions are commonly observed. Analyzing the incidence of such complications according to severity of HIE, and how they correlate with each other, may shape clinical judgment and allow for early intervention. The study included a total of 57 HIE infants, in which 27/57 (47.37%) met Sarnat inclusion criteria for moderate stage II HIE (Group A) and 30/57 (52.63%) for severe stage III HIE (Group B). Both groups were assessed and compared for incidence of kidney dysfunction, liver dysfunction, coagulopathy, qualitative cardiac abnormalities, respiratory-related dysfunction, and bone marrow insufficiency/thrombocytopenia. All assessments were performed before initiation of therapeutic hypothermia. The complications were further assessed for the presence of correlations. Group B experienced significantly higher incidence of kidney dysfunction (A: 2/27 [7.4%] vs. B: 21/30 [70%], p < 0.001), liver dysfunction (A: 14/27 [51.8%] vs. B: 28/30 [93.3%], p < 0.001), and thrombocytopenia (A: 8/27 [29.6%] vs. B 21/30 [70%], p = 0.002) in our study group. Kidney dysfunction and bone marrow insufficiency showed the highest affiliation with other organ systems in both groups, correlating positively with each other as well as HIE severity, cardiac abnormalities, liver dysfunction, and infant death. A total of 8/57 (14%) infant deaths were observed, all originating from grade III severe HIE group (p = 0.003). Multiorgan dysfunction showed a significant difference between HIE severity (A: 12/27 [44.4%] vs. B: 28/30 [93.3%], p < 0.001). A positive correlation was obtained between multiorgan dysfunction, HIE severity, and infant death. Stage III HIE infants are more likely to experience abnormalities in the kidneys, liver, bone marrow as compared with stage II HIE infants. Correlations between organ complications are present, and should be taken into account during clinical assessment of HIE infants. The probability of mortality is higher in stage III HIE infants with observed multiorgan dysfunctions.