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To evaluate the benefits of high-dose erythropoietin (EPO) combined with therapeutic hypothermia (TH) on brain magnetic resonance imaging (MRI) scores and neurodevelopmental outcomes in neonates with moderate to severe hypoxic-ischemic-ecephalopathy (HIE), especially in neonates who received TH between six to 12 hours of birth. This prospective, single-blind, randomized, placebo-controlled trial enrolled term newborns with moderate to severe HIE admitted to neonatal intensive care unit between April 2018 and April 2022. Hypothermia was started within 12 hours of birth. Infants were randomized to receive EPO 1000 U/kg or an equal volume of normal saline (placebo) on days 1, 2, 3, 5, and 7 of age in combination with hypothermia. Fifty-seven neonates with moderate to severe HIE were recruited; 10 were excluded. Forty-seven patients were included: 32 received TH within six hours (group I) and in 15 TH was started within six to 12 hours of birth (group II). The clinical characteristics of mothers and infants, maternal complications, and resuscitations performed during the perinatal period showed no statistical differences between EPO group and placebo groups I and II. The MRI scores and brain injury patterns did not differ between the EPO and placebo groups. There is no statistical significance in either group's seizure and severe electroencephalography background (initial and after rewarming) between EPO and placebo in each group. There were no differences in developmental outcomes (abnormal Denver II > 2 area, Gross Motor Function Classification Score >1); Bayley Scales of Infant and Toddler Development, third edition (BSID-III) score (cognitive, language, and motor); or disability (hearing impairment and impaired vision) between the EPO and placebo groups I and II at 12 and 18 months. Among term infants with moderate to severe HIE, TH with EPO administration, compared with TH alone, did not reduce brain injury on MRI or the risk of neurological sequelae both in patients who received TH within six hours and in those who received TH later (six to 12 hours). Further studies on the benefit of EPO injection alone or before TH in situations where TH cannot be performed are required. [ABSTRACT FROM AUTHOR]

Background: Quantitative EEG is frequently used to monitor children affected by acute encephalopathy (AE), with the expectation of providing comprehensive insights into continuous EEG monitoring. However, the potential of quantitative EEG for estimating outcomes in this context remains unclear. We sought reliable prognostic markers within the color density spectral array (CDSA) of the continuous EEG for AE-affected children undergoing therapeutic hypothermia (TH). Methods: This retrospective study analyzed CDSA data from eight scalp electrodes of 15 AE-affected children undergoing TH. Two CDSA features were investigated—high-frequency lines (HFLs) and periodic elevation in the low frequency band (PLFB)—along with the corresponding EEG characteristics. The inter-rater reliability for CDSA was assessed by four pediatric neurologists. Outcomes were grouped into either no/mild or severe decline in motor and cognitive functions, then compared with CDSA features. Results: The median EEG recording time was 114 (81–151) h per child. While at least 41 % of HFLs corresponded to typical sleep spindles, 94 % of PLFB aligned with cyclic changes in the amplitude of delta/theta waves on the raw EEG. Inter-rater reliability was higher for HFLs than for PLFB (kappa values: 0.69 vs. 0.46). HFLs were significantly more prevalent in children with no/mild decline than in children with severe decline (p = 0.017), whereas PLFB did not differ significantly (p = 0.33). Conclusions: This study provides preliminary evidence that reduced HFLs on CDSA predict unfavorable outcomes in AE-affected children undergoing TH. This suggests that maintaining high-frequency waves is critical for optimal brain function. [ABSTRACT FROM AUTHOR]

Serial neonatal encephalopathy (NE) examinations are difficult to perform in rural community hospitals as on-site experts are not readily available. We implemented a synchronous, acute care model of teleconsultation—the Maine Neonatal Encephalopathy Teleconsultation program (Maine NET)—to provide remote, joint assessment of NE by pediatric neurology and neonatology at nine community hospitals and one tertiary care center. We performed a qualitative study to interview clinicians about their experience of this program. From April 2018 to October 2022, we employed a semistructured interview format with 16 clinicians representing all participating hospitals. We utilized deductive analysis to assign a set of predefined codes to the transcribed interviews. Thematic analysis supported the anticipated benefits of Maine NET, demonstrating that clinicians felt resource utilization, collaborative decision making, communication, and continuity of care were improved. Clinicians overwhelmingly supported the program: "This program has truly saved babies' lives and future function. I have not met any parents through this journey, who aren't incredibly grateful for the care that is provided" and emphasized the benefit of collaboration between all care team members. Teleconsultation was felt to be "more than adequate to [assess] NE." Connectivity issues were cited as a limitation. Maine NET has positively impacted care delivery for newborns with clinical concerns for NE. Additionally, the program has improved resource allocation, collaborative decision making, communication, and equity of care. Addressing technological challenges will be vital to the success and sustainability of the planned Maine NET expansion. [ABSTRACT FROM AUTHOR]

• We use qEEG analysis to mimic a visual EEG analysis approach in neonatal hypoxic-ischemic encephalopathy. • Machine learning models were developed and validated on two independent EEG datasets. • The proposed model is effective in discriminating neonates requiring therapeutic hypothermia in the first 6 h of life. The study aimed to address the challenge of early assessment of neonatal hypoxic-ischemic encephalopathy (HIE) severity to identify candidates for therapeutic hypothermia (TH). The objective was to develop an automated classification model for neonatal EEGs, enabling accurate HIE severity assessment 24/7. EEGs recorded within 6 h of life after perinatal anoxia were visually graded into 3 severity groups (HIE French Classification) and quantified using 6 qEEG markers measuring amplitude, continuity and frequency content. Machine learning models were developed on a dataset of 90 EEGs and validated on an independent dataset of 60 EEGs. The selected model achieved an overall accuracy of 80.6% in the development phase and 80% in the validation phase. Notably, the model accurately identified 28 out of 30 children for whom TH was indicated after visual EEG analysis, with only 2 cases (moderate EEG abnormalities) not recommended for cooling. The combination of clinically relevant qEEG markers led to the development of an effective automated EEG classification model, particularly suited for the post-anoxic latency phase. This model successfully discriminated neonates requiring TH. The proposed model has potential as a bedside clinical decision support tool for TH. [ABSTRACT FROM AUTHOR]

To investigate the prevalence and associated outcomes of glucose abnormalities in infants with hypoxic ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH). Glucose values were reviewed in all HIE infants. Pearson's correlation was used to assess the association of hypo- and hyperglycemic episodes with neonatal brain MRI and neurodevelopmental outcomes (NDO) at 12 & 24 months. Of 153 infants included, 31, 56 and 43 had episodes of hypo-, hyperglycemia and combined, respectively. Hyperglycemia and combined hypo/hyper had higher mortality (p = 0.035), seizures (p = 0.009), and longer hospitalization (p = 0.023). Hypo- and hyperglycemia were associated with parenchymal hemorrhages (p = 0.028 & p = 0.027, respectively). Hypoglycemia was associated with restricted diffusion (p = 0.014), while hyperglycemia was associated with cortical injuries (p = 0.045). Each hour of hyper- or hypoglycemia was associated with 5.2–5.8 times unfavorable outcomes (p < 0.001). Blood glucose aberrations were detrimental in HIE infants treated with TH. Optimizing glucose management is crucial in this setting. [ABSTRACT FROM AUTHOR]

• Early measurement of GWR values using HCT could predict neurologic outcomes in OHCA survivors. • GWR values show variations in predicting neurologic outcomes based on HIBI severity. • GWR in the moderate group was associated with poor neurologic outcomes. • Early prediction of neurologic outcomes can guide treatment decisions. • GWR measurement is a noninvasive and cost-effective method to predict neurologic outcomes. Hypoxic-ischemic brain injury (HIBI) is a common complication of out-of-hospital cardiac arrest (OHCA). We investigated whether grey-to-white matter ratio (GWR) values, measured using early head computed tomography (HCT), were associated with neurologic outcomes based on the severity of HIBI in survivors of OHCA. This retrospective multicenter study included adult comatose OHCA survivors who underwent an HCT scan within 2 h after the return of spontaneous circulation. HIBI severity was assessed using the revised post-Cardiac Arrest Syndrome for Therapeutic hypothermia (rCAST) scale (low, moderate, and severe). Poor neurologic outcomes were defined as Cerebral Performance Categories 3 to 5 at 6 months after OHCA. Among 354 patients, 27% were women and 224 (63.3%) had poor neurologic outcomes. The distribution of severity was 19.5% low, 47.5% moderate, and 33.1% severe. The area under the receiver operating curves of the GWR values for predicting rCAST severity (low, moderate, and severe) were 0.52, 0.62, and 0.79, respectively. The severe group had significantly higher predictive performance than the moderate group (p = 0.02). Multivariate logistic regression analysis revealed a significant association between GWR values and poor neurologic outcomes in the moderate group (adjusted odds ratio = 0.012, 95% CI 0.0–0.54, p = 0.02). In this cohort study, GWR values measured using early HCT demonstrated variations in predicting neurologic outcomes based on HIBI severity. Furthermore, GWR in the moderate group was associated with poor neurologic outcomes. [ABSTRACT FROM AUTHOR]

We aimed to develop a risk scoring system as a predictor of 24-month neurodevelopmental outcomes (cognitive, language, and motor) for neonates treated with therapeutic hypothermia for hypoxic-ischemic encephalopathy (HIE). This was a chart review of infants with HIE treated with therapeutic hypothermia who were admitted to the Neonatal Intensive Care Unit (NICU) at the University of Michigan between 2009 and 2019 and followed in the neonatal developmental clinic until 24 months of age. We examined bivariate associations between the neonatal characteristics and Bayley-III scores. We then performed stepwise logistic regression. To create the risk scores, a participant was given one point for each of the factors included in the final model. Fifty-five infants were included. The final model for Bayley cognitive abnormality included abnormal neonatal neurologic exam (p < 0.0001), white matter/watershed MRI abnormality (p = 0.01), 5-min Apgar score (p = 0.02), and EEG-confirmed seizures (p = 0.04). The model for language abnormality included abnormal neurologic exam (p = 0.0002), seizures (p = 0.007), clinical severity of HIE (p = 0.06), and basal ganglia/thalamus MRI abnormality (p = 0.17). The model for motor abnormality included seizures (p = 0.03), abnormal neurologic exam (p = 0.06) and basal ganglia/thalamus MRI abnormality (p = 0.02). The positive predictive values for the risk scores were 60 %, 85 % and 71 %, respectively, for the Bayley-III cognitive, language and motor domains. Our study identifies early clinical features that differentially predict domains of neurodevelopmental outcome and associated risk scores that may be of value to both clinicians and families. This novel scoring system should next be validated in a larger, prospective study. [ABSTRACT FROM AUTHOR]

Early repolarization syndrome (ERS) is an idiopathic ventricular fibrillation (VF) associated with inferolateral J waves. While electrical storm (ES) in ERS is not rare, their characteristics and risk factors are not fully understood. This study aimed to clarify the significance of ES in ERS. We evaluated 44 patients with ERS who experienced VF/sudden cardiac death or arrhythmic syncope. We assessed clinical characteristics to identify the risk factors for ES. In total, 13 patients (30%) experienced ES (ES group). Of these, 11 patients (85%) experienced ES during the acute phase of initial VF episodes and 2 patients (2%) experienced ES during follow-up. VF associated with ES occurred during therapeutic hypothermia in 6 of 13 patients (46%). The J-wave voltage during therapeutic hypothermia was higher in the ES group than that in the patients without ES. Isoproterenol was used in 5 patients (38%), which decreased J-wave voltage and relieved ES. Among the clinical markers, shorter QT and QTp intervals (the interval from QRS onset to the peak of T wave), pilsicainide-induced ST elevation, and high scores on the Shanghai Score System were associated with ES. Although pilsicainide induced ST elevation in 6 of 34 patients (18%), spontaneous Brugada electrocardiographic patterns did not appear to be associated with VF. Therapeutic hypothermia was also a risk factor for acute phase ES. Patients with ERS in the ES group frequently had short QT and QTp intervals, pilsicainide-induced ST elevations, and high Shanghai Score System scores. Therapeutic hypothermia was also associated with acute phase ES. [Display omitted] [ABSTRACT FROM AUTHOR]

To investigate the association between the presence and severity of seizures in asphyxiated newborns and their neurodevelopmental outcome at ages two and five years. Retrospective data analysis from a prospectively collected multicenter cohort of 186 term-born asphyxiated newborns undergoing therapeutic hypothermia (TH) in 11 centers in the Netherlands and Belgium. Seizures were diagnosed by amplitude-integrated electroencephalography (EEG) and raw EEG signal reading up to 48 hours after rewarming. Neurodevelopmental outcome was assessed by standardized testing at age two and five years. Primary outcome was death or long-term neurodevelopmental impairment (NDI) including cerebral palsy. Associations were calculated using univariate and multivariate logistic regression analyses adjusting for Thompson score and a validated brain magnetic resonance imaging (MRI) score. Seventy infants (38%) had seizures during TH or rewarming, and 44 (63%) of these needed two or more antiseizure medications (ASMs). Overall mortality was 21%. Follow-up data from 147 survivors were available for 137 infants (93%) at two and for 94 of 116 infants (81%) at five years. NDI was present in 26% at two and five years. Univariate analyses showed a significant association between seizures and death or NDI, but this was no longer significant after adjusting for Thompson and MRI score in the multivariate analysis; this was also true for severe seizures (need for two or more ASMs) or seizures starting during rewarming. The presence or severity of seizures in newborns undergoing TH for hypoxic-ischemic encephalopathy was not independently associated with death or NDI up to age five years after adjusting for several confounders. [ABSTRACT FROM AUTHOR]

Neonatal seizures caused by hypoxic-ischemic encephalopathy (HIE) have significant morbidity and mortality. There is variability in clinical practice regarding treatment duration with antiseizure medication (ASM) after resolution of provoked neonatal seizures. We examined epilepsy incidence and developmental outcomes in post-HIE neonates discharged or not on ASM. We conducted a retrospective chart review of all HIE-admitted neonates to the University of Iowa Hospitals & Clinics neonatal intensive care unit between January 2008 and February 2021 who presented with encephalopathy, underwent therapeutic hypothermia, and developed seizures. Neonates were divided into two groups depending on whether ASM was continued or discontinued on discharge. We evaluated the incidence of epilepsy and developmental outcomes on follow-up in these two cohorts up to 12 months. Sixty-nine neonates met the study criteria. ASM was continued on discharge in 41 neonates (59%) and discontinued before discharge in 28 (41%). At the 12-month follow-up, nine neonates (13%) had a diagnosis of epilepsy, out of which seven neonates had ASM continued on discharge (odds ratio [OR]: 2.84; 95% confidence interval [CI]: 0.48, 29.9)]. There was no statistical difference between the development of postneonatal epilepsy between the two groups (P value 0.29). There was no significant difference in developmental outcome between the two groups after adjusting for covariates like magnetic resonance imaging (MRI) brain abnormality and number of seizure days (OR: 0.68; 95% CI: 0.21, 2.22; P = 0.52). We found no significant risk of seizure recurrence by age 12 months in infants who had discontinued ASM before discharge compared with those who had continued ASM. There was no difference in developmental outcomes at the 12-month follow-up between groups after adjusting for brain MRI abnormality and the number of seizure days during admission. Our results support early discontinuation of ASM after resolution of acute provoked seizures in neonates with HIE. [ABSTRACT FROM AUTHOR]

Erythropoietin (EPO) is a proposed drug for the treatment of neonatal hypoxic-ischemic encephalopathy (HIE). Multiple studies have linked its use, either as a monotherapy or in conjunction with therapeutic hypothermia (TH), with improved neonatal outcomes including death and neurodisability. However, there is also evidence in the literature that raises concerns about its efficacy and safety for the treatment of neonatal encephalopathy (NE). We searched MEDLINE, Cochrane CENTRAL, and Embase for both observational studies and randomized controlled trials (RCTs) investigating the effectiveness of EPO in treating NE. Only studies in which at least 300 U/kg of EPO was used and reported any one of the following outcomes: death, death or neurodisability, and cerebral palsy, were included. Seven studies with 903 infants with the diagnosis of NE were included in our meta-analysis. EPO did not reduce the risk of death or neurodisability (risk ratio 0.68 [95% confidence interval [CI]: 0.43 to 1.09]) (P = 0.11). Similarly, the risk of cerebral palsy was not reduced by the administration of EPO (risk ratio 0.68 [95% CI: 0.33 to 1.40]) (P = 0.30). The risk of death was also not reduced at any dose of EPO regardless of the use of TH. The results of our meta-analysis do not support the use of EPO for the treatment of neonatal encephalopathy. However, future large-scale RCTs are needed to strengthen these findings. [ABSTRACT FROM AUTHOR]

To determine long-term survival of patients after cardiac arrest undergoing emergent coronary angiography and therapeutic hypothermia. We analysed data from patients treated within the regional STEMI Network from January 2015 to December 2020. The primary endpoint was all-cause mortality at median follow-up. Secondary endpoints were periprocedural complications (arrhythmias, pulmonary edema, cardiogenic shock, mechanical complication, stent thrombosis, reinfarction, bleeding) and 6-month all-cause death. A landmark analysis was performed, studying two time periods; 0–6 months and beyond 6 months. From a total of 24,125 patients in the regional STEMI network, 494 patients who suffered from cardiac arrest were included and divided into two groups: treated with (n = 119) and without therapeutic hypothermia (n = 375). At median follow−up (16.0 [0.2–33.3] months), there was no difference in the adjusted mortality rate between groups (51.3 % with hypothermia vs 48.0 % without hypothermia; HR adj 1.08 95%CI [0.77–1.53]; p = 0.659). There was a higher frequency of bleeding in the hypothermia group (6.7 % vs 1.1 %; OR adj 7.99 95%CI [2.05–31.2]; p = 0.002), without difference for the rest of periprocedural complications. At 6-month follow−up, adjusted all-cause mortality rate was similar between groups (46.2 % with hypothermia vs 44.5 % without hypothermia; HR adj 1.02 95%CI [0.71–1.47]; p = 0.900). Also, no differences were observed in the adjusted mortality rate between 6 months and median follow−up (9.4 % with hypothermia vs 6.3 % without hypothermia; HR adj 2.02 95%CI [0.69–5.92]; p = 0.200). In a large cohort of patients with cardiac arrest within a regional STEMI network, those treated with therapeutic hypothermia did not improve long−term survival compared to those without hypothermia. • In patients withcardiac arrest with suspected STEMI, hypothermia did not improve long−term survival. • In a landmark analysis, hypothermia was not associated with better survival between 0 and 6 months or beyond. • There were no prespecified subgroups in whom hypothermia was associated with better long-term survival. • The maintained low survival rates after cardiac arrest should lead to a investigation of efficient therapeutic interventions. [ABSTRACT FROM AUTHOR]

To compare seizure burden between newborn infants treated with therapeutic hypothermia (TH) and those that were not and to compare the need for antiseizure medications (ASM) in a cohort of infants who were diagnosed with neonatal hypoxic-ischemic encephalopathy (HIE). This was a retrospective cohort study on infants born after 35 weeks' gestation, diagnosed with moderate to severe HIE, monitored with amplitude-integrated electroencephalography (aEEG) and eligible for TH. Infants born before the implementation of TH in 2008 were compared with infants born thereafter who received TH. Seizure burden was assessed from aEEG as total time in minutes of seizures activity per hour of recording. Other clinical and demographic data were retrieved from a prospective local database of infants with HIE. Overall, 149 of 207 infants were included in the study: 112 exposed to TH and 37 not exposed. Cooled infants had a lower seizure burden overall (0.4 vs 2.3 min/h, P < 0.001) and were also less likely to be treated with ASM (74% vs 100%, P < 0.001). In multivariable regression models, not exposed to TH, having a depressed aEEG background, and having higher Apgar scores were associated with higher seizure burden (incidence rate ratio: 4.78 for noncooled infants, P < 0.001); also, not exposed to TH was associated with a higher likelihood of multidrug ASM (odds ratio: 4.83, P < 0.001). TH in infants with moderate to severe HIE is associated with significant reduction of seizure burden and ASM therapy. [ABSTRACT FROM AUTHOR]

The majority of studies have investigated neurodevelopmental outcomes, whereas visual impairment is less explored in children with a history of neonatal (hypoxic-ischemic) encephalopathy. Our aim was to perform a detailed neurological and visual assessment and also to investigate the presence of cerebral visual impairment in infants and toddlers with neonatal encephalopathy. Thirty participants with a history of neonatal encephalopathy, who had been hospitalized for therapeutic hypothermia, underwent a detailed neurological examination at age five to 36 months. Age-matched, 30 healthy children were also enrolled as a control group. All children in the study and control groups received neurological and a comprehensive ophthalmologic examination, including visual field and visual acuity. Presence of cerebral visual impairment was also evaluated clinically. Rates of cerebral palsy, severe motor impairment, cognitive impairment, epilepsy, and cerebral visual impairment were found to be 20%, 10%, 15.3%, 10%, and 20%, respectively. When compared with healthy controls, oculomotor functions, pupillary light response, refractive parameters, anterior/posterior segment examinations, ocular visual impairment rates, and last, visual acuities were found similar. However, we found a statistically significant increase in visual field defects in our study group. It could be better to perform a comprehensive ophthalmologic examination including visual field, visual acuity, and oculomotor functions by a pediatric ophthalmologist to accurately diagnose neurovisual deficits in infants following therapeutic hypothermia. Early identification and rehabilitation of the visual deficits might improve the neurodevelopment in these children. [ABSTRACT FROM AUTHOR]

The neurologic prognosis of out-of-hospital cardiac arrest (OHCA) patients in whom return of spontaneous circulation (ROSC) is achieved remains poor. The aim of this study was to externally and prospectively validate two scoring systems developed by us: the CAST score, a scoring system to predict the neurological prognosis of OHCA patients undergoing targeted temperature management (TTM), and a simplified version of the same score developed for improved ease of use in clinical settings, the revised CAST (rCAST) score. This study was a prospective, multicenter, observational study conducted using the SOS KANTO 2017 registry, an OHCA registry involving hospitals in the Kanto region (including Tokyo) of Japan. The primary outcome was favorable neurological outcome (defined as Cerebral Performance Category score of 1 or 2) at 30 days and the secondary outcomes were favorable neurological outcome at 90 days and survival at 30 and 90 days. The predictive accuracies of the original CAST (oCAST) and rCAST scores were evaluated by using area under the receiver operating characteristic curve (AUC). Of 9909 OHCA patients, 565 showed ROSC and received TTM. Of these, we analyzed the data of 259 patients in this study. The areas under the receiver operating characteristic curve (AUCs) of the oCAST and rCAST scores for predicting a favorable neurological outcome at 30 days were 0.86 and 0.87, respectively, and those for predicting a favorable neurological outcome at 90 days were 0.87 and 0.88, respectively. The rCAST showed a higher predictive accuracy for the neurological outcome as compared with the NULL-PLEASE score. The patients with a favorable neurological outcome who had been classified into the high severity group based on the rCAST tended to have hypothermia at hospital arrival and to not show any signs of loss of gray-white matter differentiation on brain CT. Neurological function at 90 days was correlated with the rCAST (r = 0.63, p < 0.001). rCAST showed high predictive accuracy for the neurological prognosis of OHCA patients managed by TTM, comparable to that of the oCAST score. The scores on the rCAST were strongly correlated with the neurological functions at 90 days, implying that the rCAST is a useful scale for assessing the severity of brain injury after cardiac arrest. • oCAST and rCAST scores are useful to predict with a high accuracy, the neurological outcome of PCAS patients treated by TTM. • rCAST showed better predictive accuracy than the NULL-PLEASE score. • The predictive accuracies of rCAST and oCAST scores for the neurological outcome were comparable. • We observed a strong correlation between the score on rCAST and the neurological function at 90 days in PCAS patients. [ABSTRACT FROM AUTHOR]

Recent studies suggest that the incidence of perinatal hypoxic-ischemic encephalopathy (HIE) may be increasing in developed countries. However, this observed increase may be due to increased ascertainment and increased treatment with therapeutic hypothermia rather than an increase in disease burden. In a US population-based cross-sectional study, we determined the incidence of perinatal HIE over time. The study population included all 289,793 live-born infants ≥35 weeks gestational age born at 15 Kaiser Permanente Northern California hospitals between 2012 and 2019. Perinatal HIE was defined as the presence of both neonatal acidosis (i.e., cord blood pH < 7 or base deficit ≥10, or base deficit ≥10 on first infant gas) and neonatal encephalopathy confirmed by medical record review. Hospital discharge diagnoses of HIE were determined by extracting International Classification of Disease diagnostic codes for HIE assigned upon hospital discharge. The population incidence of perinatal HIE was 1.7 per 1000. Although the incidence of perinatal HIE did not change significantly, both hospital discharge diagnoses of HIE and treatment with therapeutic hypothermia increased significantly during the study period. The sensitivity and positive predictive value of a hospital discharge diagnosis of HIE for identifying perinatal HIE confirmed by chart review were 72% and 79%, respectively. During the study years, the incidence of perinatal HIE remained stable despite increases in hospital discharge diagnoses of HIE and in the use of therapeutic hypothermia. Our findings underscore the importance of applying stringent diagnostic criteria when diagnosing this complex condition. [ABSTRACT FROM AUTHOR]

Neonatal hypoxic-ischemic encephalopathy (HIE) is a common disease among newborns, which is a leading cause of neonatal death and permanent neurological sequelae. Therapeutic hypothermia (TH) is the only method for the treatment of HIE that has been recognized effective clinically at home and abroad, but the efficacy is limited. Recent research suggests that the cord blood-derived mononuclear cells (CB-MNCs), which the refer to blood cells containing one nucleus in the cord blood, exert anti-oxidative, anti-inflammatory, anti-apoptotic effects and play a neuroprotective role in HIE. This review focuses on safety and efficacy, the route of administration, dose, timing and combination treatment of CB-MNCs in HIE. [ABSTRACT FROM AUTHOR]

To describe longitudinal motor development in children treated with therapeutic- hypothermia (TH) due to neonatal hypoxic-ischaemic encephalopathy (HIE) and to explore motor functioning in early adolescence. Children treated with TH due to HIE during 2007–2009, in Stockholm, participated in a prospective follow-up study. Motor development was assessed on four occasions, reported as percentiles and at mean ages. Alberta Infant Motor Scale was used at 0.35 years of age, Bayley Scales of Infant and Toddler Development-III at 2.1 years and Movement Assessment Battery for Children (MABC-2) at 7.3 and 11.1 years of age. MABC-2 Checklist was completed by parents at 7.3 and 11.1 years of age. General cognition was assessed using Wechsler Intelligence Scales for Children Fifth Edition (WISC-V). Thirty-one percent (14/45) of the children had a motor score ≤ 15th percentile, indicating risk of motor difficulties at 11.1 years of age, and simultaneously the scores from parents of 52% (23/44), indicating risk of motor difficulties in the everyday context. These children had significantly lower motor percentile at 2.1 years of age, but within the normal range. Longitudinal motor development displayed a weak association with WISC-V Full Scale IQ (r s 0.38, p = 0.013). Among survivors of hypothermia-treated HIE free of moderate/severe cerebral palsy, a third had MABC-2 scores indicating risk of motor difficulties at 11.1 years of age. As motor difficulties became more apparent over time, we suggest that children treated with TH due to neonatal HIE should be followed into at least middle school age. • In survivors treated with TH after HIE without moderate/severe CP , 31% are at risk of motor difficulties in early adolescence. • Motor difficulties become more obvious when the children enter early adolescence. • Children scoring at risk of motor difficulties in early adolescence had lower scores in earlier motor assessment. • The association between FSIQ and longitudinal motor outcomes over time was weak. • Children treated with TH due to HIE should be followed into at least middle school age. [ABSTRACT FROM AUTHOR]

The recommended target temperature in the treatment of comatous patients after cardiac arrest has recently changed. We analyzed the impact on the neurological outcome of a change in the target temperature from July 2021. This was a retrospective analysis comparing the discharge status of 78 patients with a target temperature of 33 °C (group 1) with that of 24 patients with a target temperature of 36.5 °C (group 2). Pearson chi-square and Mann-Whitney U tests were used. The initial rhythm was defibrillable in 65% of group 1 and 71% of group 2, and cardiac arrest was witnessed in 93% of group 1 and 96% of group 2. There was an adverse outcome (death or vegetative state) in 37 patients in group 1 (47%) compared to 18 in group 2 (74%) (Pearson chi-square 5.612, p = 0.018). In our series of patients, the temperature control target temperature change from 33 °C to 36.5 °C was associated with worse neurological outcome. Further studies are needed to evaluate the outcome of a generalized modification of temperature control targets in comatose patients after cardiac arrest in our postpandemic era. [ABSTRACT FROM AUTHOR]

Out-hospital cardiac arrest (OHCA) is a major cause of mortality and morbidity worldwide. The magnitude of the post-resuscitation inflammatory response is closely related to the severity of the circulatory dysfunction. Currently, targeted temperature management (TTM) has become an essential part of the post-resuscitation care for unconscious OHCA survivors. Some novel prognostic inflammatory markers may help predict outcomes of OHCA patients after TTM. A retrospective observational cohort study of 65 OHCA patients treated with TTM was conducted in a tertiary hospital in Taiwan. The primary outcome measure was in-hospital mortality. Baseline and post-TTM neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte (PLR), and the systemic immune inflammation index (SII) were identified as potential predictors. These patients had a mean age of 62.2 ± 17.0 years. Among the total sample, 53.8% had an initial shockable rhythm and 61.5% had a presumed cardiac etiology. The median resuscitation duration was 20 min (IQR 13.5–28.5) and 60% received subsequent percutaneous coronary intervention. The mean baseline NLR, PLR and SII were 7.5 ± 16.7, 118 ± 207, 1395 ± 3004, and the mean post-TTM NLR, PLR and SII were 15.0 ± 11.6, 206 ± 124, 2369 ± 2569, respectively. Using multiple logistic regression analysis, post-TTM NLR was one of the independent factors which predicted in-hospital mortality (adjusted odds ratio (aOR): 1.249, 95% confidence interval (CI): 1.040–1.501, p = 0.017). Post-TTM NLR is a predictor of in-hospital mortality in OHCA patients who underwent TTM. [ABSTRACT FROM AUTHOR]

[Display omitted] Over decades, nearly all attempts to translate the benefits of therapeutic hypothermia in stroke models of lower-order species to stroke patients have failed. Potentially overlooked reasons may be biological gaps between different species and the mismatched initiation of therapeutic hypothermia in translational studies. Here, we introduce a novel strategy of selective therapeutic hypothermia in a non-human primate ischemia-reperfusion model, in which autologous blood was cooled ex vivo and the cool blood transfusion was administered at the middle cerebral artery just after the onset of reperfusion. Cold autologous blood cooled the targeted brain rapidly to below 34 °C while the rectal temperature remained around 36 °C with the assistance of a heat blanket during a 2-h hypothermic process. Therapeutic hypothermia or extracorporeal-circulation related complications were not observed. Cold autologous blood treatment reduced infarct sizes, preserved white matter integrity, and improved functional outcomes. Together, our results suggest that therapeutic hypothermia, induced by cold autologous blood transfusion, was achieved in a feasible, swift, and safe way in a non-human primate model of stroke. More importantly, this novel hypothermic approach conferred neuroprotection in a clinically relevant model of ischemic stroke due to reduced brain damage and improved neurofunction. This study reveals an underappreciated potential for this novel hypothermic modality for acute ischemic stroke in the era of effective reperfusion. [ABSTRACT FROM AUTHOR]

Perinatal asphyxia represents the first cause of severe neurological disabilities and the second cause of neonatal death in term-born babies. Currently, no treatment can prevent immediate cell death from necrosis, but some therapeutic interventions, such as therapeutic hypothermia (TH), can reduce delayed cell death from apoptosis. TH significantly improves the combined outcome of mortality or major neurodevelopmental disability, but the number of patients to be treated is 7 to get 1 child with no adverse neurological outcome. The aim of this educational review is to analyze the other care strategies to be implemented to improve the neurological outcome of children with hypoxic ischemic encephalopathy (HIE). Hypocapnia, hypoglycemia, pain control, and functional brain monitoring are recognized as appropriate approaches to improve outcome in critically ill infants with HIE. Pharmacologic neuroprotective adjuncts are currently under investigation. New drugs such as allopurinol and melatonin seem to provide positive effects although more randomized controlled trials are required to establish the effective therapeutic scheme. In the meantime, sustaining the respiratory, metabolic, and cardiovascular system during TH can be a valuable aid in managing and treating the patient with HIE in an optimal way. [ABSTRACT FROM AUTHOR]

Systemic inflammatory conditions are often associated with hypothermia or hyperthermia. Therapeutic hypothermia is used in post-cardiac arrest and some other acute diseases. There is a need for more knowledge concerning the effect of various temperatures on the acute inflammatory response. The complement system plays a crucial role in initiating the inflammatory response. We hypothesized that temperatures above and below the physiologic 37 °C affect complement activation and cytokine production ex vivo. Lepirudin-anticoagulated human whole blood from 10 healthy donors was incubated in the presence or absence of Escherichia coli at different temperatures (4 °C, 12 °C, 20 °C, 33 °C, 37 °C, 39 °C, and 41 °C). Complement activation was assessed by the terminal C5b-9 complement complex (TCC) and the alternative convertase C3bBbP using ELISA. Cytokines were measured using a 27-plex assay. Granulocyte and monocyte activation was evaluated by CD11b surface expression using flow cytometry. A consistent increase in complement activation was observed with rising temperature, reaching a maximum at 41 °C, both in the absence (C3bBbP p < 0.05) and presence (C3bBbP p < 0.05 and TCC p < 0.05) of E. coli. Tem p erature alone did not affect cytokine production, whereas incubation with E. coli significantly increased cytokine levels of IL-1β, IL-2, IL-6, IL-8, IFN-γ, and TNF at temperatures > 20 °C. Maximum increase occurred at 39 °C. However, a consistent decrease was observed at 41 °C, significant for IL-1β (p = 0.003). Granulocyte CD11b displayed the same temperature-dependent pattern as cytokines, with a corresponding increase in endothelial cell apoptosis and necrosis. Thus, blood temperature differentially determines the degree of complement activation and cytokine release. • Blood temperature determined the complement activation and cytokine release. • Temperature per se increased complement activation. • Temperature affected cytokine production, when incubated with E. coli. • IL-1β increased maximum at 39 °C and decreased at 41 °C. [ABSTRACT FROM AUTHOR]

To investigate the clinical, laboratory, electrophysiological, and imaging features associated with death or neurological impairment at 1 year of age in term neonates with hypoxic–ischemic encephalopathy (HIE) treated by therapeutic hypothermia (TH). This was a single-center retrospective and descriptive study conducted over a period of 2 years. We included consecutive term newborns with moderate or severe HIE who were treated by TH initiated within the sixth hour after birth and continued for 72 h,. For all patients, brain magnetic resonance imaging (MRI) was performed before the eighth day and a score was established; furthermore, at least two electroencephalograms were recorded. Among the 33 patients included, 20 neonates had a favorable outcome and 13 had an unfavorable outcome. Early clinical seizures (15% vs. 53.8%, p = 0.047), the persistence of a poor prognosis according to the electroencephalogram pattern after TH (0% vs. 69.2%, p = 0.0001), and an elevated score on the early brain MRI (2 vs. 11, p < 0.001) combined with a high lactate/ N -acetyl-aspartate ratio (0.52 vs. 1.33, p = 0.008) on spectroscopy were associated with death and a poor outcome. A combination of tools can help the medical team to establish the most reliable prognosis for these full-term neonates, to guide care, and to inform parents most appropriately and sincerely. [ABSTRACT FROM AUTHOR]

Limited training in targeted neurological examination makes it challenging for frontline providers to identify newborns with perinatal asphyxia eligible for therapeutic hypothermia. This training is important in the era of telemedicine, where the experts can remotely guide further care of these newborns. This randomized controlled pilot study was conducted in a South Indian tertiary hospital. Neonatal nurses, who had no previous hands-on experience in MSEE, were trained in modified Sarnat staging by a didactic teaching session using online teaching module. The nurses were then randomized into two groups for hands-on demonstration by the same trainer (low-fidelity mannequin versus a healthy term newly born infant). After the training period, MSEEs of a normal newborn were performed independently by nurses and were video recorded and assessed by three blinded neonatologists with expertise in neonatal neurology. A follow-up examination was performed by the same nurses after three months to assess skill retention. The 10 global ratings of the components of the MSEE were comparable among both groups in both initial and follow-up assessments. The overall diagnostic value was comparable between the simulation and traditional groups (93.75%, 94.11%, respectively). Follow-up examination after three months showed better skill retention in the simulation group (84%) compared with the traditional group (66.7%). Online-based and low-fidelity mannequin training was equally effective as the traditional method of teaching MSEE in term neonates. [ABSTRACT FROM AUTHOR]

In the setting of acute ST-elevation myocardial infarction (STEMI), several randomized control trials (RCTs) suggested a potential benefit with the use of therapeutic hypothermia (TH). However, results from previous studies are contradictory. We performed a comprehensive literature search for studies that evaluated the efficacy and safety of adjunctive TH compared to the standard percutaneous coronary intervention (PCI) in awake patients with STEMI. The primary outcomes were the infarct size (IS) and microvascular obstruction (MVO) assessed by cardiac imaging at the end of follow-up. The secondary outcomes were major adverse cardiovascular events (MACE), procedure-related complications, and door-to-balloon time. Relative risk (RR) or the mean difference (MD) and corresponding 95 % confidence intervals (CIs) were calculated using the random-effects model. A total of 10 RCTs, including 706 patients were included. As compared to standard PCI, TH was not associated with a statistically significant improvement in the IS (MD: -0.87 %, 95%CI: −2.97, 1.23; P = 0.42) or in the MVO (MD: 0.11 %, 95%CI: −0.06, 0.27; P = 0.21). MACE and its components were comparable between the two groups. However, the TH approach was associated with an increased risk of infection and prolonged door-to-balloon time. Furthermore, there was a trend in the TH group toward an increased incidence of stent thrombosis and paroxysmal atrial fibrillation. According to our meta-analysis of published RCTs, TH is not beneficial in awake patients with STEMI and has a marginal safety profile with potential for care delays. Larger-scale RCTs are needed to further clarify our results. • Therapeutic hypothermia (TH) is proposed as an adjunctive strategy to reduce myocardial reperfusion injury in STEMI patients. • Our meta-analysis showed no benefit of TH in STEMI patients, with a marginal safety profile and potential for care delays. • Unless selective intracoronary hypothermia finds evidence of benefit, the clinical utility of this approach may be futile. • More RCTs are needed to validate our results. [ABSTRACT FROM AUTHOR]

Therapeutic hypothermia was recommended as the only neuroprotective treatment in comatose patients after return of spontaneous circulation (ROSC). With new evidence suggesting a similar neuroprotective effect of 36 °C and 33 °C, the term "therapeutic hypothermia" was substituted by "targeted temperature management" in 2011, which in turn was replaced by the term "temperature control" in 2022 because of new evidence of the similar effects of target normothermia and 33 °C. However, there is no clear consensus on the efficacy of therapeutic hypothermia. In this article, we provide an overview of the recent evidence from basic and clinical research related to therapeutic hypothermia and re-evaluate its application as a post-ROSC neuroprotective intervention in clinical settings. [ABSTRACT FROM AUTHOR]

General movements (GMs) have been recognized as the most accurate clinical tools for predicting cerebral palsy (CP). This study aimed to compare the type and prognostic value of abnormal GMs in infants with hypoxic ischemic encephalopathy treated or not with therapeutic hypothermia (TH). This was a single-center retrospective study. We compared GMs of 55 cooled term infants versus 30 non-cooled term infants with hypoxic ischemic encephalopathy (HIE) and their motor outcome at 24 months of age. We also included data regarding early brain MRI scans. Rates of cerebral palsy was 5.4% and 46.7% in cooled and non-cooled infants respectively (p < 0.001). None of cooled infants showed cramped-synchronized GMs, whereas among non-cooled infants the cramped-synchronized pattern was present in 17.2% and 20% of infants at 1 and 3 months of age respectively. Hypokinesis was never seen in cooled infants and it was present in 23.3% of non-cooled ones. Absent fidgety correlated with CP in 14% and 73% of cooled and non-cooled infants respectively. At brain MRI cooled infants had fewer and less severe cerebral lesions compared to non-cooled infants (p = 0.003). Abnormal GMs are reduced in infants treated with TH. Hypokinesis and cramped-synchronized GMs are not observed in cooled infants and the associations between absent fidgety movements and CP it is largely abolished. TH is associated with changes in prognostic value of GMs. • Therapeutic hypothermia reduces brain lesions and abnormal GMs. • In this sample, absent fidgety is a weak predictor of cerebral palsy in cooled infants. • Hypokinesis and cramped synchronized GMs are no longer seen in cooled infants. [ABSTRACT FROM AUTHOR]

• TH reduce myocardial infarction size, myocardial injury, inflammatory response. • TH inhibite DKK3/Wnt/β-catenin pathway. • TH alleviate myocardial I/R injury. The impact and mechanisms of therapeutic hypothermia (TH) on myocardial ischemia–reperfusion (I/R) injury are still unknown. Sprague-Dawley (SD) rat model and primary cardiomyocytes were applied in our study. TTC staining evaluated myocardial infarction, while H&E staining assessed myocardial injury. ELISA quantified lactate dehydrogenase (LDH), IL-1β, IL-6, and TNF-α. Blood serum concentrations of CK, CK-MB, and cTnT were detected using a biochemical assay. TUNEL assay, flow cytometry and western blot were used to detect cell apoptosis. EdU assay was applied to examine cell proliferation. The expression of DKK3 and β-catenin protein was analyzed using Realtime PCR and Western blot. TH alleviated myocardial infarction size and injury in rat models of I/R, and reduced serum levels of myocardial injury markers and inflammatory factors in animal and cell models. In addition, TH inhibited the increased apoptosis and β-catenin expression as well as decreased DKK3 expression caused by I/R in I/R cell models, while si-DKK3 reversed the changes brought by TH, and XAV939 inhibited the effects of si-DKK3. TH may reduce myocardial infarction size, myocardial injury, inflammatory response and apoptosis through DKK3/Wnt/β-catenin pathway, thereby alleviating myocardial I/R injury. [ABSTRACT FROM AUTHOR]

• Hypoxic-ischemic encephalopathy is the leading cause of neonatal encephalopathy. • Therapeutic hypothermia offers limited improvement in neurodevelopmental outcomes. • Transcranial ultrasound stimulation (TUS) can modulate specific brain regions. • TUS has drawn attention for its potential to modulate brain activity in adults. • TUS may induce neuroplasticity, potentially transforming HIE treatment in newborns. Perinatal hypoxic-ischemic encephalopathy (HIE) is the most common cause of neonatal encephalopathy, accounting for over half of all cases and the consequences of HIE can be devastating, making it one of the most severe perinatal complications. Therapeutic hypothermia has been shown to offer neuroprotection by reducing metabolic demand and slowing the cascade of injury processes. However, despite its benefits, therapeutic hypothermia has only modestly improved neurodevelopmental outcomes, indicating a major need for additional therapeutic approaches. Low-intensity transcranial ultrasound stimulation (TUS) is an emerging non-invasive brain stimulation technique for focally modulating specific brain regions that has recently drawn attention for its potential to modulate brain activity and promote neuroplasticity. The capacity of TUS to induce neuroplasticity through specific sonication parameters has been demonstrated in adult patients. Leveraging TUS to enhance functional connectivity and inhibit GABAergic systems within the injured thalami holds promise for inducing neuroplasticity in neonates with HIE. We hypothesize that enhancing thalamocortical functional connectivity and reducing local GABA levels through the use of TUS could potentially improve neurodevelopmental outcomes in neonates with HIE who have sustained thalamic injury and aim to test this hypothesis. Testing of the hypothesis will be conducted with a comprehensive assessment of safety and feasibility in neonates through a Phase I study, followed by further clinical studies to evaluate efficacy. [ABSTRACT FROM AUTHOR]

Secondary brain injury has devastating effects on morbidity, mortality and good functional outcomes. Neuroprotection is multimodal, with decades of preclinical and small clinical studies showing the benefits of therapeutic hypothermia. The basic scientific principles have merit, yet large randomized controlled trials fail to show a clear benefit. This article will review the basic science – the practical aspects of delivering targeted temperature management and evaluate the evidence behind its use for acute brain injuries. With a lack of high-quality evidence for hypothermia, recent consensus statements are shifting the paradigm away from hypothermia to the maintenance of normothermia and prevention of pyrexia. [ABSTRACT FROM AUTHOR]

Background: Hypoxic-ischemic encephalopathy (HIE) occurs in 1-4:1000 live births. Although neonates with moderate-severe HIE have been studied over several decades, newborns with mild HIE remain understudied, including seizure occurrence, electroencephalography (EEG) characteristics, and outcome.Methods: We conducted a retrospective cohort study of neonates ≥35 weeks of gestation with mild HIE who underwent therapeutic hypothermia to correlate the early EEG background pattern with clinical course and outcomes.Results: Of the included 29 neonates, 10 infants had a moderately to severely abnormal EEG background and 19 had either a normal or a mildly abnormal background. Those with moderately to severely abnormal background also had more multiorgan dysfunction (90% vs 42%, P = 0.02) and a higher incidence of subdural and intraventricular hemorrhages (80% vs 26%, P = 0.02). The overall seizure incidence was 20.7% and was significantly higher in newborns with more severely abnormal background compared to neonates with less abnormal background (50% vs 5%; P = 0.01; relative risk, 9.5; 95% confidence interval, 1.28-70.6). Seizure onset was between 11 and 63 hours of life. Regardless of the EEG background pattern, seizures were brief with an overall low seizure burden. None of the newborns with normal or mildly abnormal background had a new onset of seizures after 24 hours of recording or developed epilepsy during infancy.Conclusions: In neonates with mild HIE, early moderately to severely abnormal EEG background is common and strongly associated with an increased risk for seizures. [ABSTRACT FROM AUTHOR]

Therapeutic hypothermia (TH) without sedation may lead to discomfort, which may be associated with adverse consequences in neonates with hypoxic-ischemic encephalopathy (HIE). The aim of this study was to assess the association between level of exposure to opioids and temperature, with electroencephalography (EEG) background activity post-TH and magnetic resonance imaging (MRI) brain injury in neonates with HIE. Thirty-one neonates with mild-to-moderate HIE who underwent TH were identified. MRIs were reviewed for presence of brain injury. Quantitative EEG background features including EEG discontinuity index and spectral power densities were calculated during rewarming and post-rewarming periods. Dose of opioids administered during TH and temperatures were collected from the medical charts. Multivariable linear and logistic regression analyses were conducted to assess the associations between cumulative dose of opioids and temperature with EEG background and MRI while adjusting for markers of HIE severity. Higher opioid doses (β = −0.21, p = 0.02) and reduced skin temperature (β = 0.14, p < 0.01) were associated with lower EEG discontinuity index recorded post-TH. Higher opioid doses (β = 0.75, p = 0.01) and reduced skin temperature (β = −0.39, p = 0.02) were also associated with higher EEG Delta power post-TH. MRI brain injury was observed in 14 patients (45%). In adjusted regression analyses, higher opioid doses (OR = 0.00; 95%CI: 0–0.19; p = 0.01), reduced skin temperature (OR = 41.19; 95%CI: 2.27–747.86; p = 0.01) and reduced cooling device output temperature (OR = 1.91; 95%CI: 1.05–3.48; p = 0.04) showed an association with lower odds of brain injury. Higher level of exposure to opioids and reduced skin temperature during TH in mild-to-moderate HIE were associated with improved EEG background activity post-TH. Moreover, higher exposure to opioids, reduced skin temperature and reduced device output temperature were associated with lower odds of brain injury on MRI. • Opioid analgesia may affect temperature regulation processes in neonates with HIE during therapeutic hypothermia. • Exposure to opioids and reduced skin temperature were associated with EEG background recovery and lower odds of MRI injury. • Reduced cooling device output temperature was associated with lower odds of MRI injury. • Findings highlight the importance of further investigating the impact of sedation in milder forms of HIE. [ABSTRACT FROM AUTHOR]

Early diagnosis of impaired myocardial function and timely therapeutic hypothermia is vital among patients with Neonatal Encephalopathy (NE). Traditional markers of myocardial function (Left Ventricular Ejection Fraction (LV EF) & LV Fractional Shortening (LV FS) can be variably reduced. Speckle tracking echocardiography (STE) is a more sensitive marker for impairment but remains inadequately studied in this patient population. A retrospective study of neonates who underwent therapeutic hypothermia (TH) for NE from 2009 to2020 were matched 1:1 with normal neonates with normal echocardiograms performed for indications other than NE. Matching was based on gestational age, birth weight, days of age, and sex. Left ventricular 4 Chamber (4Ch) strain, right ventricular 4 Chamber (RV 4Ch), and RV free wall strain (RV FWS) were measured offline using vendor independent strain software (TomTec, GMBH, Munich, Germany). Ninety pairs of NE patients and controls were studied. Compared to controls, RV 4Ch strain (−17.3 % vs. -19.6 %), RV FWS (−18.8 % vs. -21.9 %), and RV fractional area change (FAC) (35 % vs. 37 %) were lower in NE cases (all p < 0.001), while differences in LV 4Ch strain, LV EF, and LV FS did not reach statistical significance. Moderate/severe NE (72 %) was associated with lower LV 4Ch strain compared to mild NE (−22.2 %/−19.3 % vs. -25.4 %, p = 0.004). RV 4Ch strain (−14.9 % vs. -18.8 %, p = 0.020) and RV FAC (27 % vs. 36 %, p = 0.006) were lower in severe NE compared to mild NE. Lower LV 4Ch was associated with need for chest compressions (−18.5 % vs. -23.3 %), epinephrine at delivery (−19.3 % vs. -23.4 %), and decreased survival to discharge (−15.9 % vs. -22.7 %). RV and LV strain mechanics are impaired in NE patients. Lower RV Strain and LV 4Ch strain were associated with need for increased medical support and decreased survival to discharge. • Largest study describing left and right ventricular myocardial mechanics among neonates with NE compared with a group of matched controls. • Evaluates RV and LV 4Ch strain among patients undergoing therapeutic hypothermia with mild, moderate, and severe NE • Lower RV and LV GLS are associated with decreased survival to discharge [ABSTRACT FROM AUTHOR]

• NICU-staff are well-willing to support parental presence during TH. • Parent-infant closeness during TH is possible. • Standardized routines can promote parent-infant closeness. • The NICU environment seem to either promote or curb parent-infant closeness. The aim of this study was to investigate care practices among Neonatal Intensive Care Units (NICU) providing Therapeutic hypothermia (TH), and more specific to investigate staff's experiences of parental participation, presence, and possibilities of being close with their infant during TH. A descriptive, qualitative, and quantitative study. All Swedish NICUs providing TH (n = 10) participated. Data were collected during January–April 2021 via a questionnaire followed by a semi-structured interview with the registered nurse and the neonatologist responsible for TH at each unit. Descriptive statistics were calculated, and a qualitative content analysis was performed. All NICUs allowed parents unlimited stay with their infants and were keen to support parental presence, which was a prerequisite for promoting parent-infant closeness. Standardized routines regarding the infants' care space and course of action were described as time-efficient and staff-saving, which freed up time to focus on the families. Standardized routines regarding the care space setup and the medical and caring approach, as well as the NICU environment and practices around the families, can promote or curb the possibilities of parent-infant closeness. Well-established care practices and good environmental conditions with flexibility regarding the family's needs are therefore required. [ABSTRACT FROM AUTHOR]

Umbilical artery gas results help obstetricians assess fetal well-being during labor and guide screening decisions on eligibility for therapeutic hypothermia (ie, whole-body or head cooling). The accuracy of results, especially for the base deficit on arterial cord gas analysis, in predicting brain injury is questioned. A novel biomarker specifically calculated for fetal acid-base physiology and response to asphyxia—neonatal eucapnic pH as a marker of neonatal metabolic acidosis—has the potential to be an accurate predictor of hypoxic-ischemic encephalopathy. We aimed to compare false-negative rates of hypoxic-ischemic encephalopathy for umbilical artery pH, base deficit, and neonatal eucapnic pH in assessing fetal acid-base balance as a marker of fetal well-being and predicting acute brain injury. This is a retrospective single-center cohort study of newborns ≥ 35 weeks of gestation diagnosed with hypoxic-ischemic encephalopathy. We compared false-negative rates for any grade of hypoxic-ischemic encephalopathy using unilateral paired chi-square statistical analysis based on cutoff values for umbilical artery pH ≤7.00, base deficit ≥16 mmol/L, base deficit ≥12 mmol/L and neonatal eucapnic pH ≤7.14. We performed an analysis of variance between umbilical artery pH, base deficit, and neonatal eucapnic pH for each hypoxic-ischemic encephalopathy grade. We included 113 newborns. False-negative rate for hypoxic-ischemic encephalopathy was significantly higher for base deficit <16 mmol/L (n=78/113; 69.0%) than <12 mmol/L (n=46/113; 40.7%), pH >7.00 (n=41/113; 36.3%), or neonatal eucpanic pH >7.14 (n=35/113; 31.0%) (P <.0001). All true-positive cases were identified using only umbilical artery pH and neonatal eucapnic pH. Base deficit ≥16 or ≥12 mmol/L did not add any value in identifying newborns with hypoxic-ischemic encephalopathy when using umbilical artery pH and neonatal eucapnic pH. No association emerged between any marker and hypoxic-ischemic encephalopathy severity grading. Our findings support the accuracy of neonatal eucapnic pH to assess fetal well-being during labor and to improve predictive performance for acute brain injury. Neonatal eucpanic pH, in addition to umbilical artery pH, may be a viable alternative in identifying newborns at risk for hypoxic-ischemic encephalopathy. [Display omitted] [ABSTRACT FROM AUTHOR]

Swedish guidelines for therapeutic hypothermia (TH) after perinatal asphyxia were established in 2007, following several randomised studies that demonstrated improved outcomes. We assessed the implementation of hypothermia treatment in a mid-Swedish region with a sizeable proportion of outborn infants. A population-based TH cohort from 2007 to 2015 was scrutinised for adherence to national guidelines, interhospital transport, including the use of a cooling mattress made of phase change material for thermal management, and outcomes. Of 136 admitted infants, 99 (73 %) were born outside the hospital. Ninety-eight percent fulfilled the criteria for postnatal depression/acidosis, and all patients had moderate-to-severe encephalopathy. Treatment was initiated within 6 h in 85 % of patients; amplitude-integrated electroencephalography/electroencephalography was recorded in 98 %, cranial ultrasound in 78 %, brain magnetic resonance imaging in 79 %, hearing tests in all, and follow-up was performed in 93 %. Although target body temperature was attained later (p < 0.01) in outborn than in inborn infants, at a mean (standard deviations) age of 6.2 (3.2) h vs 4.4 (2.6) h, 40 % of those transported using the cooling mattress were already within the therapeutic temperature range on arrival, and few were excessively cooled. The mortality rate was 23 %, and 38 % of the survivors had neurodevelopmental impairment at a median of 2.5 years. The regionalisation of TH, including interhospital transport, was feasible and resulted in outcomes comparable to those of randomised controlled studies. • Therapeutic hypothermia (TH) improves outcomes in asphyxiated term neonates with moderate-to-severe encephalopathy. • Population-based data on TH implementation are scarce. • Centralisation of TH was feasible, and performed well also in a sparsely populated region requiring swift long-distance transport. [ABSTRACT FROM AUTHOR]

Organophosphorus nerve agents, such as soman (GD), produce excitotoxic effects resulting in sustained status epilepticus (SSE) and brain damage. Previous work shows that neuronal inhibitory effects of A 1 adenosine receptor (A 1 AR) agonists, such as N6- Bicyclo (2.2.1)-hept-2-yl-5′-chloro-5′-deoxyadenosine (Cl-ENBA), suppresses GD-induced SSE and improves neuropathology. Some other physiologic effects of these agonists are hypothermia, hypotension, and sedation. Hypothermia may also shield the brain from injury by slowing down chemical insults, lessening inflammation, and contributing to improved neurological outcomes. Therefore, we attempted to isolate the hypothermic effect from ENBA by assessing the neuroprotective efficacy of direct surface body cooling in a rat GD-induced SSE model, and comparing the effects on seizure termination, neuropathology, and survival. Male rats implanted with a body temperature (T b) transponder and electroencephalographic (EEG) electrodes were primed with asoxime (HI-6), exposed to GD 30 min later, and then treated with Cl-ENBA or had T b lowered directly via body cooling at 30 min after the onset of seizure activity. Afterwards, they were either allowed to develop hypothermia as expected, or received thermal support to maintain normothermic T b for a period of 6-h. Neuropathology was assessed at 24 h. Regardless of Cl-ENBA or surface cooling, all hypothermic GD-exposed groups had significantly improved 24-h survival compared to rats with normothermic T b (81% vs. 39%, p < 0.001). Cl-ENBA offered neuroprotection independently of hypothermic T b. While hypothermia enhanced the overall efficacy of Cl-ENBA by improving survival outcomes, body cooling didn't reduce seizure activity or neuropathology following GD-induced SSE. • A 1 adenosine receptor agonist ENBA induced hypothermia & improved neuropathology. • Therapeutic hypothermia induced by ENBA or body cooling was evaluated after soman. • Body cooling alone didn't prevent seizure and neuropathology after soman exposure. • Anticonvulsant & neuroprotection induced by ENBA were independent of hypothermia. • Hypothermia enhanced the overall efficacy of ENBA by improving survival outcomes. [ABSTRACT FROM AUTHOR]

Objective: Fibroblast Growth Factor 21 (FGF21) and Growth Differentiation Factor-15 (GDF-15) are putative neuroprotective cold stress hormones (CSHs) provoked by cold exposure that may be age-dependent. We sought to characterize serum FGF21 and GDF-15 levels in pediatric cardiac arrest (CA) patients and their association with use of therapeutic hypothermia (TH).Methods: Secondary analysis of serum samples from clinical trials. We measured FGF21 and GDF-15 levels in pediatric patients post-CA and compared levels to both pediatric intensive care (PICU) and healthy controls. Post-CA, we compared normothermia (NT) vs TH (33 °C for 72 h) treated cohorts at < 24 h, 24 h, 48 h, 72 h, and examined the change in CSHs over 72 h. We also assessed association between hospital mortality and initial levels.Results: We assessed 144 samples from 68 patients (27 CA [14 TH, 13 NT], 9 PICU and 32 healthy controls). Median initial FGF21 levels were higher post-CA vs. healthy controls (392 vs. 40 pg/mL, respectively, P < 0.001). Median GDF-15 levels were higher post-CA vs. healthy controls (7,089 vs. 396 pg/mL, respectively, P < 0.001). In the CA group, the median change in FGF21 from PICU day 1-3 (after 72 h of temperature control), was higher in TH vs. NT (231 vs. -20 pg/mL, respectively, P < 0.05), with no difference in GDF-15 over time. Serum GDF-15 levels were higher in CA patients that died vs. survived (19,450 vs. 5,337 pg/mL, respectively, P < 0.05), whereas serum FGF21 levels were not associated with mortality.Conclusion: Serum levels of FGF21 and GDF-15 increased after pediatric CA, and FGF21 appears to be augmented by TH. [ABSTRACT FROM AUTHOR]

Aim: To determine the safety and feasibility of an early (12 h) waking and extubation protocol for out-of-hospital cardiac arrest (OHCA) patients receiving targeted temperature management (TTM).Methods: This was a single-centre, prospective, non-randomised, observational, safety and feasibility pilot study which included successfully resuscitated OHCA patients, of presumed cardiac cause. Inclusion criteria were: OHCA patients aged over 18 years with a return of spontaneous circulation, who were going to receive TTM33 (TTM at 33 °C for 24 h and prevention of hyperthermia for 72 h) as part of their post cardiac arrest care. Clinical stability was measured against physiological and neurological parameters as well as clinical assessment.Results: 50 consecutive patients were included (median age 65.5 years, 82% male) in the study. Four (8%) patients died within the first twelve hours and were excluded from the final cohort (n = 46). Twenty-three patients (46%) were considered clinically stable and suitable for early waking based on the intention to treat analysis; 12 patients were extubated early based on a variety of clinical factors (21.4 ± 8.6 h) whilst continuing to receive TTM33 with a mean core temperature of 34.2 °C when extubated. Of these, five patients were discharged from the intensive care unit (ICU) <48 h after admission with a mean ICU length of stay 1.8 ± 0.4 days. Twenty-eight patients (56%) were discharged from the ICU with a modified Rankin Score of 0-2. The overall intra-hospital mortality was 50% (n = 25).Conclusions: It is safe and feasible to wake selected comatose OHCA patients at 12 h, allowing for earlier positive neuro-prognostication and reduced ICU stay. [ABSTRACT FROM AUTHOR]

Background: Target temperature management (TTM) is a recommended therapy for patients after cardiac arrest (PCA). The TaIwan Network of Targeted Temperature ManagEment for CARDiac Arrest (TIMECARD) registry was established for PCA who receive TTM therapy in Taiwan. We aim to determine the variables that may affect neurologic outcomes in PCA who undergo TTM.Methods: We retrieved demographic variables, resuscitation variables, and cerebral performance category (CPC) scale score at hospital discharge from the TIMECARD registry. The primary outcome was a favorable neurologic outcome, defined as a CPC scale of 1 or 2 at discharge. A total of 540 PCA treated between January 2014 and September 2019 were identified from the registry. Univariate and multivariate analyses were performed to identify significant variables.Results: The mortality rate was 58.1% (314/540). Favorable neurologic outcomes were noted in 117 patients (21.7%). The factors significantly influencing the neurologic outcome (p < 0.05) were the presence of an initial shockable rhythm or pulseless electric activity, a witnessed cardiac-arrest event, bystander cardiopulmonary resuscitation, a smaller total dose of epinephrine, the diastolic blood pressure value at return of spontaneous circulation, a pre-arrest CPC score of 1, coronary angiography, new-onset seizure, and new-onset serious infection. Older patients and those with premorbid diabetes mellitus, chronic kidney disease, malignancy, obstructive lung disease, or cerebrovascular accident were more likely to have an unfavorable neurologic outcome.Conclusion: In the TIMECARD registry, some PCA baseline characteristics, cardiac arrest events, cardiopulmonary resuscitation characteristics, and post-arrest management characteristics were significantly associated with neurologic outcomes. [ABSTRACT FROM AUTHOR]

• Therapeutic hypothermia is the only effective treatment for Hypoxic ischemic encephalopathy (HIE). • Sovateltide, ETB receptor agonist, promotes repair and regeneration in the brain. • Sovateltide attenuates oxidative stress, neural damage with enhancing VEGF and NGF. • Our results show the potential of sovateltide as a new therapeutic agent for HIE. Therapeutic hypothermia with modest results is the only treatment currently available for neonatal hypoxic ischemic encephalopathy (HIE). Endothelin B (ETB) receptors in the brain are shown to have neural restorative capacity. ETB receptors agonist sovateltide alone or as an adjuvant therapy may enhance neurovascular remodeling in HIE. Sprague-Dawley rat pups were grouped based on treatments into (1) Control; (2) HIE + Vehicle; (3) HIE + Hypothermia; (4) HIE + sovateltide; and (5) HIE + sovateltide + hypothermia. HIE was induced on postnatal day (PND) 7, followed by sovateltide (5 µg/kg) intracerebroventricular injection and/or hypothermia. On PND 10, brains were analyzed for the expression of vascular endothelial growth factor (VEGF), nerve growth factor (NGF), ETB receptors, oxidative stress and cellular damage markers. Vehicle-treated animals had high oxidative stress level as indicated by an increase in lipid peroxidation factor, malondialdehyde, and decreased antioxidants, reduced glutathione and superoxide dismutase, compared to control. These effects were reversed in sovateltide alone (p < 0.001) or in combination with the therapeutic hypothermia (p < 0.001), indicating that ETB receptor activation reduces oxidative stress injury following HIE. Animals receiving sovateltide demonstrated a significant (p < 0.0001) upregulation of ETB receptor, VEGF, and NGF expression in the brain compared to vehicle-treated animals. Additionally, sovateltide alone or in combination with therapeutic hypothermia significantly (p < 0.001) reduced cell death when compared to vehicle or therapeutic hypothermia alone, demonstrating that sovateltide is neuroprotective and attenuates neural damage following HIE. These findings are important and merit additional studies for development of new interventions for improving neurodevelopmental outcomes after HIE. [ABSTRACT FROM AUTHOR]

Our objective was to evaluate the potential additional value of electroencephalogram (EEG) and evoked potentials in neonates with hypoxic-ischemic encephalopathy to predict their disability at 1 and 2 years old. 30 full-term infants after perinatal asphyxia who underwent therapeutic hypothermia were evaluated at 1 year and 2 years for disability using International Classification of Functioning, Disability and Health classification. Scores for EEG, sensory evoked potentials and brainstem auditory evoked potentials were evaluated after withdrawal of therapeutic hypothermia that lasted 72 h. A regression approach was investigated to build models allowing to distinguish neonates according to their disability at 1 and 2 years. Two models were built, the first by considering the clinical data and EEG before and after therapeutic hypothermia and the second by incorporating evoked potentials recording. Adding EEG and evoked potentials data after rewarming improved dramatically the accuracy of the model considering outcome at 1 and 2 years. We propose to record systematically EEG and evoked potentials following rewarming to predict the outcome of neonates with hypoxic ischemic encephalopathy. Combination of altered evoked potentials with no improvement of EEG after rewarming appeared to be a robust criterion for a poor outcome. • Outcome of neonates with HIE remains uncertain. • Adding EEG and EP data after rewarming to clinical data improved the accuracy of a prediction model. • EEG and EP should be performed after withdrawal of TH to predict the outcome of neonates with HIE. [ABSTRACT FROM AUTHOR]

Background: Women experience worse neurological outcomes following out-of-hospital cardiac arrest (OHCA). It is unknown whether sex disparities exist in the use of targeted temperature management (TTM), a standard of care treatment to improve neurological outcomes.Methods: We performed a retrospective study of prospectively collected patients who survived to hospital admission following OHCA from the Cardiac Arrest Registry to Enhance Survival from 2013 through 2019. We compared receipt of TTM by sex in a mixed-effects model adjusted for patient, arrest, neighborhood, and hospital factors, with the admitting hospital modeled as a random intercept.Results: Among 123,419 patients, women had lower rates of shockable rhythms (24.4 % vs. 39.2%, P < .001) and lower rates of presumed cardiac aetiologies for arrest (74.3% vs. 81.1%, P < .001). Despite receiving a similar rate of TTM in the field (12.1% vs. 12.6%, P = .02), women received less TTM than men upon admission to the hospital (41.6% vs. 46.4%, P < .001). In an adjusted mixed-effects model, women were less likely than men to receive TTM (Odds Ratio 0.91, 95% Confidence Interval 0.89 to 0.94). Among the 27,729 patients with data indicating the reason for not using TTM, a higher percentage of women did not receive TTM due to Do-Not-Resuscitate orders/family requests (15.1% vs. 11.4%, p < .001) and non-shockable rhythms (11.1% vs. 8.4%, p < .001).Conclusions: We found that women received less TTM than men, likely due to early care limitations and a preponderance of non-shockable rhythms. [ABSTRACT FROM AUTHOR]

Background: Whether the electrocardiography (ECG) serial changes predict outcomes in cardiac arrest survivors undergoing therapeutic hypothermia remains unclear.Methods and Results: This retrospective observational study enrolled 366 adult nontraumatic cardiac arrest survivors who underwent therapeutic hypothermia in a tertiary transfer center during 2006-2018. The ECG at return of spontaneous circulation (ROSC), during hypothermia and after rewarming were analyzed. 295 cardiac arrest survivors were included. Compared with the survivors, the non-survivors had longer QRS durations at the ROSC (118.33 ± 32.47 ms vs 106.88 ± 29.78 ms, p < 0.001) and after rewarming (99.26 ± 25.07 ms vs 93.03 ± 19.09 ms, p = 0.008). The enrolled patients were classified into 4 groups based on QRS duration at the ROSC and after rewarming, namely (1) narrow-narrow (narrow QRS at ROSC and narrow QRS after rewarming, n = 156), (2) narrow-wide (n = 29), (3) wide-narrow (n = 87), and (4) wide-wide (n = 23) group. The wide-wide group had the worst survival rates [odds ratio (OR) = 0.141, p = 0.001], followed by the narrow-wide group (OR 0.223, p = 0.003) and the wide-narrow group (OR 0.389, p = 0.003).Conclusions: In cardiac arrest survivors given therapeutic hypothermia, QRS durations at the ROSC, after rewarming and their changes may predict survival to hospital discharge. [ABSTRACT FROM AUTHOR]