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Introduction: There are divergent views and limited data regarding therapeutic hypothermia (TH) for neonatal hypoxic ischaemic encephalopathy (HIE) in sub-Saharan Africa (SSA). Our aim was to map and synthesize the published literature describing the use of TH for HIE in SSA, and the associated outcomes. Method: We searched Pubmed, Scopus, Google Scholar, and Web of Science from 1 January 1996 to 31 December 2023 for research studies, protocols, feasibility studies and surveys on term and near-term babies with HIE (population) treated with TH (concept) in SSA (context). Results: Thirty records were included: Three surveys, one feasibility study and 26 publications describing 23 studies of 21 cohorts, cooling 1420 babies in South Africa, Uganda, and Ghana. There were five studies recruiting at follow-up, five pilot studies, one randomised controlled trial, one case series, and 10 birth cohorts. The methods and design of the studies were highly variable and often inadequate. Only three studies with adequately described and validated cooling methods, non-selective sequential recruitment, and neurological outcomes were identified. Two studies of babies from birth, both with intensive care facilities, reported survival with normal/mildly abnormal outcome in 71% at discharge in one study, and 71% at 12 months in another, with 16% cerebral palsy (CP) in survivors, and only 16% loss to follow-up. The third study, which only included clinic attenders after TH without intensive care, reported 7% CP in survivors, but 36% loss to follow-up. Conclusions: Data from the adequately described TH studies in SSA indicate outcomes at discharge and twelve months which are similar to global norms. However, these data are limited to South Africa. Interpretation of other studies was limited by loss to follow-up, variable methodology and exclusion of babies with severe HIE in some studies. There is a need for standardised definitions to facilitate interpretation in TH studies. [ABSTRACT FROM AUTHOR]

Background: Cardiac arrest (CA) is a leading cause of mortality and morbidity, with survivors often developing post-cardiac arrest syndrome (PCAS), characterized by systemic inflammation, ischemia–reperfusion injury (IRI), and multiorgan dysfunction. Acute kidney injury (AKI), a frequent complication, is associated with increased mortality and prolonged intensive care unit (ICU) stays. This study evaluates AKI incidence and progression in cardiac arrest patients managed with different temperature protocols and explores urinary biomarkers' predictive value for AKI risk. Methods: A prospective, single-center observational study was conducted, including patients with Return of Spontaneous Circulation (ROSC) post-cardiac arrest. Patients were stratified into three groups: therapeutic hypothermia (TH) at 33 °C, Targeted Temperature Management (TTM) at 35 °C, and no temperature management (No TTM). AKI was defined using KDIGO criteria, with serum creatinine and urinary biomarkers (TIMP-2 and IGFBP7) measured at regular intervals during ICU stay. Results: AKI incidence at 72 h was 31%, varying across protocols. It was higher in the No TTM group at 24 h and in the TH and TTM groups during rewarming. Persistent serum creatinine elevation and fluid imbalance were notable in the TH group. Biomarkers indicated moderate tubular stress in the TTM and No TTM groups. Conclusions: AKI is a frequent complication post-cardiac arrest, with the rewarming phase identified as critical for renal vulnerability. Tailored renal monitoring, biomarker-guided risk assessment, and precise temperature protocols are essential to improve outcomes. [ABSTRACT FROM AUTHOR]

Reperfusion therapy inevitably leads to brain–blood barrier (BBB) disruption and promotes damage despite its benefits for acute ischaemic stroke (AIS). An effective brain cytoprotective treatment is still needed as an adjunct to reperfusion therapy. Here, we explore the potential benefits of therapeutic hypothermia (HT) in attenuating early BBB leakage and improving neurological outcomes. Mild HT was induced during the early and peri-recanalization stages in a mouse model of transient middle cerebral artery occlusion and reperfusion (tMCAO/R). The results showed that mild HT attenuated early BBB leakage in AIS, decreased the infarction volume, and improved functional outcomes. RNA sequencing data of the microvessels indicated that HT decreased the transcription of the actin polymerization-related pathway. We further discovered that HT attenuated the ROCK1/MLC pathway, leading to a decrease in the polymerization of G-actin to F-actin. Arachidonic acid (AA), a known structural ROCK agonist, partially counteracted the protective effects of HT in the tMCAO/R model. Our study highlights the importance of early vascular protection during reperfusion and provides a new strategy for attenuating early BBB leakage by HT treatment for ischaemic stroke. [ABSTRACT FROM AUTHOR]

Background and Purpose: Therapeutic hypothermia (TH) has become the standard care to reduce morbidity and mortality in neonates affected by moderate‐to‐severe hypoxic–ischaemic encephalopathy (HIE). Despite the use of TH for HIE, the incidence of mortality and disabilities remains high. Experimental Approach: Nerve growth factor (NGF) is a potent neurotrophin, but clinical use is limited by its pain eliciting effects. CHF6467 is a recombinant modified form of human NGF devoid of algogenic activity (painless NGF). Key Results: In rodent hippocampal slices exposed to oxygen and glucose deprivation, CHF6467 protected neurons from death and reverted neurotransmission impairment when combined with hypothermia. In a model of rat neonatal HIE, intranasal CHF6467 (20 μg kg−1) significantly reduced brain infarct volume versus vehicle when delivered 10 min or 3 h after the insult. CHF6467 (20 and 40 μg kg−1, i.n.), significantly decreased brain infarct volume to a similar extent to TH and when combined, showed a synergistic neuroprotective effect. CHF6467 (20 μg kg−1, i.n.) per se and in combination with hypothermia reversed locomotor coordination impairment (Rotarod test) and memory deficits (Y‐maze and novel object recognition test) in the neonatal HIE rat model. Intranasal administration of CHF6467 resulted in meaningful concentrations in the brain, blunted HIE‐induced mRNA elevation of brain neuroinflammatory markers and, when combined to TH, significantly counteracted the increase in plasma levels of neurofilament light chain, a peripheral marker of neuroaxonal damage. Conclusion and Implications: CHF6467 administered intranasally is a promising therapy, in combination with TH, for the treatment of HIE. [ABSTRACT FROM AUTHOR]

Out-of-hospital cardiac arrest (OHCA) mortality remains alarmingly high in most countries. The majority of pharmacological attempts to improve outcomes have failed. Randomized trials have shown limited survival benefits with vasopressin, fibrinolysis, amiodarone, or lidocaine. Even the benefits of adrenaline remain a matter of debate. In this context, relying on technology may seem appealing. However, technological strategies have also yielded disappointing results. This is exemplified by automated external chest compression devices. When first introduced, theoretical models, animal studies, and early clinical trials suggested they could improve survival. Yet, randomized trials failed to confirm this benefit. Similarly, to date, extracorporeal membrane oxygenation (ECMO), therapeutic hypothermia, and primary angioplasty have demonstrated inconsistent survival advantage. Other technological innovations continue to be explored, such as artificial intelligence to improve the diagnosis of cardiac arrest during emergency calls, mobile applications to dispatch citizen responders to patients in cardiac arrest, geolocation of defibrillators, and even the delivery of defibrillators via drones. Nevertheless, it is clear that the focus and investment should prioritize the initial links in the chain of survival: early alerting, chest compressions, and defibrillation. Significant improvements in these critical steps can be achieved through the education of children. Modern technological tools must be leveraged to enhance this training by incorporating gamification and democratizing access to education. These strategies hold the potential to fundamentally improve the management of cardiac arrest. [ABSTRACT FROM AUTHOR]

Background/Objectives: Neonatal hypoxic-ischemic encephalopathy (HIE) due to perinatal complications remains an important pathology with a significant burden for neonates, families, and the healthcare system. Resuscitation and simulation team training are key elements in increasing patient safety. In this retrospective cohort study, we evaluated whether regular constant training of all personnel working in delivery rooms in South Tyrol improved the outcome of neonates with HIE. Methods: We retrospectively analyzed three groups of neonates with moderate to severe HIE who required therapeutic hypothermia. The first group included infants born before the systematic introduction of training and was compared to the second group, which included infants born after three years of regular training. A third group, which included infants born after the SARS-CoV-2 pandemic, was compared with the previous two to evaluate retention of skills and the long-term effect of our training program. Results: Over the three study periods, mortality decreased from 41.2% to 0% and 14.3%, respectively. There was also a significant reduction of patients with subclincal seizures detected only through EEG, from 47.1% in the first period to 43.7% and 14.3% in the second and third study periods, respectively. Clinical manifestations of seizures decreased significantly from 47.1% to 37.5% and 10.7%, respectively, as well as severe brain lesions in ultrasound (US) and MRI. Conclusions: In this study, constant and regular simulation training for all birth attendants significantly decreases mortality and improves the outcome in neonates with moderate to severe HIE. This positive effect seems to last even after a one-year period during which training sessions could not be performed due to the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Background: Therapeutic hypothermia (TH) represents a critical therapeutic intervention for patients with cardiac arrest, although treatment efficacy and prognostic factors may vary between individuals. Precise, personalized outcome predictions can empower better clinical decisions. Methods: In this multi-center retrospective cohort study involving nine medical centers in Taiwan, we developed machine learning algorithms to predict neurological outcomes in patients who experienced cardiac arrest with shockable rhythms and underwent TH. The study cohort comprised 209 patients treated between January 2014 and September 2019. The models were trained on patients' pre-treatment characteristics collected during this study period. The optimal artificial neural network (ANN) model was interpretable using the SHapley Additive exPlanations (SHAP) method. Results: Among the 209 enrolled patients, 79 (37.80%) demonstrated favorable neurological outcomes at discharge. The ANN model achieved an area under the curve value of 0.9089 (accuracy = 0.8330, precision = 0.7984, recall = 0.7492, specificity = 0.8846) for outcome prediction. SHAP analysis identified vital predictive features, including the dose of epinephrine during resuscitation, diabetes status, body temperature at return of spontaneous circulation (ROSC), whether the cardiac arrest was witnessed, and diastolic blood pressure at ROSC. Using real-life case examples, we demonstrated how the ANN model provides personalized prognostic predictions tailored to individuals' distinct profiles. Conclusion: Our machine learning approach delivers personalized forecasts of TH outcomes in cardiac arrest patients with shockable rhythms. By accounting for each patient's unique health history and cardiac arrest event details, the ANN model empowers more precise risk stratification, tailoring clinical decision-making regarding TH prognostication and optimizing personalized treatment planning. [ABSTRACT FROM AUTHOR]

Objective Neonates with moderate-to-severe perinatal asphyxia often develop acute kidney injury (AKI). Additionally, therapeutic hypothermia (TH) can affect renal blood flow. This study aimed to evaluate the association between renal regional oxygen saturation (rSrO 2) during TH and AKI in neonates with moderate and severe perinatal asphyxia. Study Design This retrospective longitudinal study included neonates with moderate-to-severe asphyxia who required TH. The primary outcome was the occurrence of AKI, classified as a rate of decrease in creatinine levels of <33% at 72 hours of TH. rSrO 2 was continuously monitored by near-infrared spectroscopy during the hypothermia and rewarming phases. Data analysis involved dividing the average rSrO 2 levels into 12-hour periods. We analyzed the association between AKI and rSrO 2 levels using univariate and multivariate logistic regression models. Furthermore, we assessed the predictive capacity of rSrO 2 for AKI by analyzing the area under the receiver operating characteristic curve. Results Ninety-one patients were included in the study. On average, patients with AKI exhibit lower rSrO 2 levels during TH. Specifically, rSrO 2 levels within the first 12 hours and between 25 and 72 hours of TH demonstrated the highest predictive capability for AKI. Multivariate logistic regression analysis revealed that rSrO 2 levels within the initial 12 hours (adjusted odds ratio [aOR] = 1.11, 95% confidence interval [CI]: 1.01–1.21) and between 61 and 72 hours (aOR = 0.85, 95% CI: 0.78–0.92) were significantly associated with AKI. Conclusion An increase in rSrO 2 during the first 12 hours of TH and lower rSrO 2 levels between 61 and 72 hours of treatment were associated with the development of AKI in asphyxiated neonates undergoing TH. Key Points Neonates with asphyxia often develop AKI. Renal saturations are affected by hypothermia and asphyxia Patients with AKI initially show higher rSrO 2 , then lower rSrO 2. Monitoring rSrO 2 identifies early AKI. [ABSTRACT FROM AUTHOR]

Background: Cerebrospinal fluid creatine kinase BB isoenzyme (CSF CK-BB) after cardiac arrest (CA) has been shown to have a high positive predictive value for poor neurological outcome, but it has not been evaluated in the setting of targeted temperature management (TTM) and modern CA care. We aimed to evaluate CSF CK-BB as a prognostic biomarker after CA. Methods: We performed a retrospective cohort study of patients with CA admitted between 2010 and 2020 to a three-hospital health system who remained comatose and had CSF CK-BB assayed between 36 and 84 h after CA. We examined the proportion of patients at hospital discharge who achieved favorable or intermediate neurological outcome, defined as Cerebral Performance Category score of 1–3, compared with those with poor outcome (Cerebral Performance Category score 4–5) for various CSF CK-BB thresholds. We also evaluated additive value of bilateral absence of somatosensory evoked potentials (SSEPs). Results: Among 214 eligible patients, the mean age was 54.7 ± 4.8 years, 72% of patients were male, 33% were nonwhite, 17% had shockable rhythm, 90% were out-of-hospital CA, and 83% received TTM. A total of 19 (9%) awakened. CSF CK-BB ≥ 230 U/L predicted a poor outcome at hospital discharge, with a specificity of 100% (95% confidence interval [CI] 82–100%) and sensitivity of 69% (95% CI 62–76%). When combined with bilaterally absent N20 response on SSEP, specificity remained 100% while sensitivity increased to 80% (95% CI 73–85%). Discordant CK-BB and SSEP findings were seen in 13 (9%) patients. Conclusions: Cerebrospinal fluid creatine kinase BB isoenzyme levels accurately predicted poor neurological outcome among CA survivors treated with TTM. The CSF CK-BB cutoff of 230 U/L optimizes sensitivity to 69% while maintaining a specificity of 100%. CSF CK-BB could be a useful addition to multimodal neurological prognostication after CA. [ABSTRACT FROM AUTHOR]

Hypoxic-ischemic encephalopathy (HIE) is a common cause of significant neonatal morbidity and mortality. The stronghold of the treatment for moderate-to-severe HIE is therapeutic hypothermia (TH) which provides a neuroprotective effect. However, it also is associated with pain and stress. Moreover, neonates with HIE are subjected to a significant number of painful procedures. Untreated pain during the early neonatal period may entail future challenges such as impaired brain growth and development as well as impaired pain sensitivity later in life. Hereby, the provision of adequate sedation and alleviation of pain and discomfort is essential. There are currently no universally accepted guidelines for sedation and pain management for this patient population. In this review, we highlight non-pharmacologic and pharmacologic methods currently in use to provide comfort and sedation to patients with HIE undergoing TH. [ABSTRACT FROM AUTHOR]

Background: Therapeutic hypothermia improves outcomes in experimental stroke models, especially after ischemia-reperfusion injury. In recent years, the safety and efficacy of hypothermia combining thrombolysis or mechanical thrombectomy have attracted widespread attention. The primary objective of the study was to evaluate the effectiveness and safety of hypothermia by combining reperfusion therapy in acute ischemic stroke patients. Methods: A systematic search was performed in PubMed, EMBASE, Cochrane Library, and the Clinical Trial Registries on articles published until May 2024. The full-text articles were thoroughly reviewed, and relevant information regarding study characteristics and outcomes was extracted. Mantel–Haenszel (M–H) random-effects model was used to calculate pooled risk ratios (RR) with 95% confidence intervals (CI). In addition, subgroup analyses were performed focusing on the different hypothermia modalities and duration. Results: After screening 2,265 articles, 10 studies were included in the present analysis with a total sample size of 785. Forest plots of clinical outcomes were as follows: modified Rankin Scale (mRS) ≤2 at 3 months (RR = 1.28, 95% CI 1.01–1.61, p = 0.04), mortality within 3 months (RR = 0.95, 95% CI 0.69–1.29, p = 0.73), total complications (RR = 1.02, 95% CI 0.89–1.16, p = 0.77) and pneumonia (RR = 1.35, 95% CI 0.76–2.40, p = 0.31). Subgroup analyses indicated a mild protective effect of selective cerebral hypothermia; however, the difference in mortality between the hypothermia and control groups was not statistically significant (RR = 0.88, 95% CI 0.57–1.35, p = 0.55). Patients undergoing hypothermia for 24–48 h experienced a higher rate of overall complications (RR = 1.37, 95% CI 1.01–1.86, p = 0.04) and pneumonia (RR = 2.84, 95% CI 1.05–7.66, p = 0.04). Conclusion: The preliminary evidence supports the safety and feasibility of hypothermia combined with reperfusion therapy, which should be further investigated in randomized controlled studies. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42024556625. [ABSTRACT FROM AUTHOR]

The electrophysiological mechanisms underlying melatonin's actions and the electrophysiological consequences of superimposed therapeutic hypothermia (TH) in preventing cardiac ischemia-reperfusion (IR) injury-induced arrhythmias remain largely unknown. This study aimed to unveil these issues using acute IR-injured hearts. Rabbits were divided into heart failure (HF), HF+melatonin, control, and control+melatonin groups. HF was induced by rapid right ventricular pacing. Melatonin was administered orally (10 mg/kg/day) for four weeks, and IR was created by 60-min coronary artery ligation and 30-min reperfusion. The hearts were then excised and Langendorff-perfused for optical mapping studies at normothermia, followed by TH. Melatonin significantly reduced ventricular fibrillation (VF) maintenance. In failing hearts, melatonin reduced the spatially discordant alternans (SDA) inducibility mainly by modulating intracellular Ca2+ dynamics via upregulation of sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) and calsequestrin 2 and attenuating the downregulation of phosphorylated phospholamban protein expression. In control hearts, melatonin improved conduction slowing and reduced dispersion of action potential duration (APDdispersion) by upregulating phosphorylated connexin 43, attenuating the downregulation of SERCA2a and phosphorylated phospholamban and attenuating the upregulation of phosphorylated Ca2+/calmodulin-dependent protein kinase II. TH significantly retarded intracellular Ca2+ decay slowed conduction, and increased APDdispersion, thereby facilitating SDA induction, which counteracted the beneficial effects of melatonin in reducing VF maintenance. [ABSTRACT FROM AUTHOR]

Background/Objectives: Hypoxic-ischemic encephalopathy (HIE) in late preterm and term neonates accounts for neonatal mortality and unfavorable neurodevelopmental outcomes in survivors despite therapeutic hypothermia (TH) for neuroprotection. The circumstances of death in neonates with HIE, including involvement of neonatal palliative care (NPC) specialists and neurodevelopmental follow-up at 18–24 months in survivors, warrant further evaluation. Methods: A retrospective multicenter cohort study including neonates ≥ 35 weeks gestational age with moderate to severe HIE receiving TH, registered in the Swiss National Asphyxia and Cooling Register between 2011 and 2021. Neurodevelopmental follow-up at 18–24 months in survivors was assessed. The groups of survivors and deaths were compared regarding perinatal demographic and HIE data. Prognostic factors leading to redirection of care (ROC) were depicted. Results: A total of 137 neonates were included, with 23 (16.8%) deaths and 114 (83.2%) survivors. All but one death (95.7%) occurred after ROC, with death on a median of 3.5 (2–6) days of life. Severe encephalopathy was indicated by a Sarnat score of 3 on admission, seizures were more frequent, and blood lactate values were higher on postnatal days 1 to 4 in neonates who died. Lactate in worst blood gas analysis (unit-adjusted odds ratio 1.25, 95% CI 1.02–1.54, p = 0.0352) was the only variable independently associated with ROC. NPC specialists were involved in one case. Of 114 survivors, 88 (77.2%) had neurodevelopmental assessments, and 21 (23.9%) of those had unfavorable outcomes (moderate to severe disability). Conclusions: Death in neonates with moderate to severe HIE receiving TH almost exclusively occurred after ROC. Parents thus had to make critical decisions and accompany their neonate at end-of-life within the first week of life. Involvement of NPC specialists is encouraged in ROC so that there is continuity of care for the families whether the neonate survives or not. [ABSTRACT FROM AUTHOR]

Aim: Few studies have investigated the differential effects of targeted temperature management (TTM) according to the severity of the condition in pediatric patients with post-cardiac arrest syndrome (PCAS). This study was aimed at evaluating the differential effects of TTM in pediatric patients with PCAS according to a risk classification tool developed by us, the rCAST. Methods: We used data from a nationwide prospective registry for out-of-hospital cardiac arrest (OHCA) patients in Japan. We classified eligible pediatric PCAS patients (aged ≤ 18 years) into quintiles based on their rCAST scores and evaluated the effect of TTM on the neurological outcomes in each severity group. Then, focusing on the severity group that appeared to benefit from TTM, we also evaluated the effect of TTM by propensity score analysis. Good neurological outcome was defined as a score on the Cerebral Performance Category or Pediatric Cerebral Performance Category scale of ≤2 at 30 days. Results: Among 1526 OHCA pediatric patients enrolled in the registry, the data of 307 PCAS patients were analyzed. None of the patients in the fifth quintile (rCAST ≥ 18.5) showed a good neurological outcome, regardless of whether they received TTM or not (0% [0/20] vs. 0% [0/73]). The propensity score analysis showed that TTM was significantly associated with a good neurological outcome in patients with rCAST scores in the first to fourth quintile (odds ratio: 1.21 [1.04–1.40], p = 0.014). Conclusions: TTM was significantly associated with good neurological outcomes in pediatric PCAS patients with rCAST scores of ≤18.0. [ABSTRACT FROM AUTHOR]

Purpose: Perinatal hypoxic-ischemic encephalopathy (HIE) is a significant cause of neonatal brain injury. Therapeutic hypothermia (TH) is the standard treatment for term neonates, but its safety and efficacy in neonates < 36 weeks gestational age (GA) remains unclear. This case series aimed to evaluate the outcomes of preterm infants with HIE treated with TH. Methods: Retrospective analysis of preterm infants (< 36w GA) treated with TH (01/2019–06/2024). Data on demographics, clinical complications, coagulation profiles, brain magnetic resonance imaging (MRI), and neurodevelopment outcomes were analyzed. Results: Seventeen patients were included (range 32.5–35.5w, median 34.4; birthweight range 1556-2493 g, median 2300 g), 58.8% were male. Placental abruption was identified in 7 cases (41.2%), and 8 (47.1%) required advanced resuscitation. Thirteen patients (76.5%) presented anemia, 12 (70.6%) coagulopathy, 9 (52.9%) thrombocytopenia, and 9 (52.9%) acute liver failure. Hypofibrinogenemia (< 1 g/L) was significantly associated with severe intracranial hemorrhage (ICH), defined as extracerebral, intraventricular or parenchymal hemorrhage causing mass effect. MRI findings were classified based on the predominant lesion: I- hypoxic-ischemic injury, II- severe ICH, or III- normal/mild findings. Severe ICH was the predominant lesion in 4 cases (23.5%). White matter injury was seen in 12 (76%). Death occurred in 8 cases (47.1%). Of the 9 surviving patients, at 2 years, 6 (66.7%) had normal neurodevelopment, while 1 (11.1%) had severe disability. Conclusion: Coagulation abnormalities, particularly hypofibrinogenemia, significantly increase the risk of severe ICH in < 36w infants treated with TH. The safety and efficacy of TH in this population require further investigation. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to review the pharmacokinetic profile of gentamicin among neonates with hypoxic ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH) treatment. Methods: This was a retrospective study of neonates with HIE undergoing TH in the neonatal intensive care unit who received gentamicin between 2009 and 2014. Demographic information, diagnoses, laboratory test results, and medication administration and monitoring information were collected, and data were analyzed using SciPy. Results: A total of 57 neonates were analyzed. The median birth weight was 3.25 kg (interquartile range [IQR] 2.8–3.68), and median gestational age was 39 weeks (IQR 38–40). An elevated gentamicin trough level (defined as > 2 mg/L) was observed in 61% (35/57) of neonates. Half of the neonates (49%) had multiple gentamicin trough levels obtained, and 4% of the neonates were switched to an alternate agent. There was a significant difference in the number of dosing interval changes in neonates with elevated gentamicin trough levels compared with those with therapeutic gentamicin trough levels (P < 0.001). Of the neonates with elevated gentamicin trough levels, 14% (5/35) failed their hearing screen (P = 0.389). Conclusions: Neonates with HIE undergoing TH may have an altered pharmacokinetic profile, requiring multiple blood draws so medication levels can be monitored and doses adjusted. Traditional gentamicin dosing regimens may not be ideal for this patient population, and further guidance is required for alternative treatment regimens. [ABSTRACT FROM AUTHOR]

Neonatal hypoxic-ischemic encephalopathy (HIE) is a critical condition resulting from impaired oxygen and blood flow to the brain during birth, leading to neuroinflammation, neuronal apoptosis, and long-term neurological deficits. Despite the use of therapeutic hypothermia, current treatments remain inadequate in fully preventing brain damage. Recent advances in mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) offer a novel, cell-free therapeutic approach, as these EVs can cross the blood-brain barrier (BBB) and deliver functional microRNAs (miRNAs) to modulate key pathways involved in inflammation and neuroprotection. This review examines how specific miRNAs encapsulated in MSC-EVs—including miR-21, miR-124, miR-146, and the miR-17-92 cluster—target the complex inflammatory responses that drive HIE pathology. By modulating pathways such as NF-κB, STAT3, and PI3K/Akt, these miRNAs influence neuroinflammatory processes, reduce neuronal apoptosis, and promote tissue repair. The aim is to assess the therapeutic potential of miRNA-loaded MSC-EVs in mitigating inflammation and neuronal damage, thus addressing the limitations of current therapies like therapeutic hypothermia. [ABSTRACT FROM AUTHOR]

Background: Therapeutic hypothermia (TH) is the standard treatment for moderate to severe hypoxic–ischemic encephalopathy (HIE) in developed countries, but data on its safety and efficacy in low-middle-income countries are limited and often conflicting. The impact of enteral feeding during TH remains inadequately explored. We aimed to examine TH's effects on mortality and brain injury and evaluate the safety and effectiveness of minimal enteral feeding during TH. Here, we report our single-center experience with TH over a 10-year period". Methods: A total of 187 neonates with moderate to severe HIE who underwent cooling were included in this retrospective study. Post-rewarming MRI scans were scored using a validated MRI scoring system. The primary outcomes were mortality and composite outcomes of mortality and brain injury. Results: The mortality rate was 3% in moderate and 25% in severe cases (p < 0.001). Overall, 85% (160/187) of neonates received minimal enteral nutrition. Multivariate regression analysis revealed that the severity of HIE at admission (OR 3.4 (1.03–11.6); p < 0.04) and gestational age (OR: 0.624 (0.442–0.882); p < 0.008) were independent predictors of composite outcomes of death and brain injuries. MRI score was a strong predictor of mortality (AUC: 0.89; p < 0.001) and of ability to orally feed at discharge (AUC: 0.73; p < 0.001). Conclusions: Mortality rates associated with TH in infants with moderate–severe HIE align with those in high-income countries, and minimal enteral feeding during TH is safe. The severity of HIE, MRI scores, and feeding status are important predictors of outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Status epilepticus represents a significant neurological emergency, with high morbidity and mortality rates. In addition to standard care, the identification of adjuvant strategies is essential to improve the outcome. Areas covered: The authors conducted a narrative review to provide an update on the value of hypothermia as an antiseizure and neuroprotective treatment in status epilepticus. Expert opinion: The use of targeted temperature management in the treatment of hypothermia in patients with status epilepticus represents a potentially promising adjuvant strategy, supported by a substantial body of experimental evidence. However, further clinical data demonstrating its efficacy are necessary before it can be recommended for routine use in targeted patient populations, such as those with refractory or super-refractory status epilepticus. [ABSTRACT FROM AUTHOR]

Prevention of brain injury during carotid endarterectomy (CEA) remains a significant challenge. Moderate controlled systemic hypothermia may serve as a potential neuroprotective measure during these procedures.Aim of the study. To investigate the neuroprotective effects of moderate systemic hypothermia during CEA.Materials and methods. Fifty-nine patients undergoing CEA under combined anesthesia were included. Patients were divided into two groups: the hypothermia group (N=33) and the normothermia control group (N=26). Both groups received standard measures to prevent cerebral ischemia. The hypothermia group received additional moderate systemic hypothermia aimed at a temperature range of 34–35°C. Cognitive function was assessed preoperatively and at 2, 5, and 30 days postoperatively using neurocognitive tests. Statistical analysis was performed with IBM SPSS Statistics.Results. The incidence of cognitive impairment was 21.1% in the hypothermia group and 26.9% in the normothermia group. Postoperative cognitive impairment was more common in the normothermia group: 15.38% on day 5 and 11.5% on day 30 postoperatively compared to 12.1% and 6.1% in the hypothermia group (P

BackgroundTherapeutic hypothermia improves outcomes in experimental stroke models, especially after ischemia-reperfusion injury. In recent years, the safety and efficacy of hypothermia combining thrombolysis or mechanical thrombectomy have attracted widespread attention. The primary objective of the study was to evaluate the effectiveness and safety of hypothermia by combining reperfusion therapy in acute ischemic stroke patients.MethodsA systematic search was performed in PubMed, EMBASE, Cochrane Library, and the Clinical Trial Registries on articles published until May 2024. The full-text articles were thoroughly reviewed, and relevant information regarding study characteristics and outcomes was extracted. Mantel–Haenszel (M–H) random-effects model was used to calculate pooled risk ratios (RR) with 95% confidence intervals (CI). In addition, subgroup analyses were performed focusing on the different hypothermia modalities and duration.ResultsAfter screening 2,265 articles, 10 studies were included in the present analysis with a total sample size of 785. Forest plots of clinical outcomes were as follows: modified Rankin Scale (mRS) ≤2 at 3 months (RR = 1.28, 95% CI 1.01–1.61, p = 0.04), mortality within 3 months (RR = 0.95, 95% CI 0.69–1.29, p = 0.73), total complications (RR = 1.02, 95% CI 0.89–1.16, p = 0.77) and pneumonia (RR = 1.35, 95% CI 0.76–2.40, p = 0.31). Subgroup analyses indicated a mild protective effect of selective cerebral hypothermia; however, the difference in mortality between the hypothermia and control groups was not statistically significant (RR = 0.88, 95% CI 0.57–1.35, p = 0.55). Patients undergoing hypothermia for 24–48 h experienced a higher rate of overall complications (RR = 1.37, 95% CI 1.01–1.86, p = 0.04) and pneumonia (RR = 2.84, 95% CI 1.05–7.66, p = 0.04).ConclusionThe preliminary evidence supports the safety and feasibility of hypothermia combined with reperfusion therapy, which should be further investigated in randomized controlled studies.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42024556625.

Hypoxic-ischemic encephalopathy (HIE) is a common cause of significant neonatal morbidity and mortality. The stronghold of the treatment for moderate-to-severe HIE is therapeutic hypothermia (TH) which provides a neuroprotective effect. However, it also is associated with pain and stress. Moreover, neonates with HIE are subjected to a significant number of painful procedures. Untreated pain during the early neonatal period may entail future challenges such as impaired brain growth and development as well as impaired pain sensitivity later in life. Hereby, the provision of adequate sedation and alleviation of pain and discomfort is essential. There are currently no universally accepted guidelines for sedation and pain management for this patient population. In this review, we highlight non-pharmacologic and pharmacologic methods currently in use to provide comfort and sedation to patients with HIE undergoing TH.

The article in Critical Care Medicine discusses the potential benefits of combining hydrogen inhalation and targeted temperature management for improving neurologic outcomes in patients resuscitated from out-of-hospital cardiac arrest. The study highlights the importance of individualized treatment timing and duration, as well as the need for more comprehensive neuropsychological assessments to evaluate patient outcomes accurately. Future research should focus on long-term neurologic recovery, safety in specific populations, and integrating this treatment into emergency care protocols to maximize its clinical value. [Extracted from the article]

Placental lesions are associated with worse neonatal outcomes, but their association with neonatal hypoxic-ischemic encephalopathy (HIE), including the full range of severity from mild to severe HIE, has not been well described. To determine the association of acute and chronic placental lesions with mild versus moderate to severe HIE; secondarily, to assess the impact of multiple placental lesions on severity of HIE. This retrospective study of prospectively collected data included neonates born at ≥36 weeks, with a birth weight of >1800 g, diagnosed with HIE between January 2012 and November 2022. The cohort was divided into those with mild versus moderate to severe HIE, based on the modified Sarnat staging. Placental histologic diagnoses were made according to the Amsterdam Placental Workshop Group Consensus Statement. Placental pathologic lesions were classified into acute inflammation with attention to stages and grades of maternal and fetal inflammatory responses (MIR and FIR, respectively), maternal vascular malperfusion, fetal vascular malperfusion, villitis of unknown etiology, and other lesions. Chi-square and Fisher's exact test were used to compare rates of placental pathologies between mild and moderate to severe HIE groups. Of 394 neonates ≥36 weeks' gestation diagnosed with HIE, 172 had mild HIE and received supportive care, while 180 had moderate to severe HIE and underwent therapeutic hypothermia. 42 patients were excluded due to lack of placental pathology reports. FIR was significantly associated with moderate to severe HIE vs. mild HIE (53 % vs. 38 %, P < 0.01). Higher grade and stage of FIR was also associated with worse severity of HIE (moderate to severe HIE showed FIR stage ≥2 in 81 % and grade 2 in 15 % vs. 34 % and 3 % in those with mild HIE, respectively). MIR was diagnosed in more placentas from the moderate to severe HIE group (58 % vs. 47 %, P = 0.04) with higher stage and grade MIR in patients with moderate to severe HIE (86 % with MIR stage ≥2 and 19 % with MIR grade 2). High-grade (patchy/diffuse) chronic villitis was more prevalent in the moderate to severe HIE group vs. mild HIE group (18 % vs. 8 %, P < 0.01). There is a higher prevalence of placental inflammatory lesions in neonates with moderate to severe HIE compared to those with mild HIE. • High prevalence of placental inflammatory lesions in neonates with HIE. • MIR emerged as the predominant placental pathologic lesion correlated with the severity of neonatal encephalopathy. • FIR is more frequently linked to adverse fetal outcomes. [ABSTRACT FROM AUTHOR]

To maintain core body temperature in mammals, CNS thermoregulatory networks respond to cold exposure by increasing brown adipose tissue and shivering thermogenesis. However, in hibernation or torpor, this canonical thermoregulatory response is replaced by a new, emerging paradigm, thermoregulatory inversion (TI), an alternative homeostatic state in which cold exposure inhibits thermogenesis and warm exposure stimulates thermogenesis. Here, we demonstrate that in the non-torpid rat, either exclusion of the canonical thermoregulatory integrator in the preoptic hypothalamus or inhibition of neurons in the ventromedial periventricular area (VMPeA) induces the TI state through an alternative thermoregulatory pathway. Within this pathway, we have identified a dynorphinergic input to the dorsomedial hypothalamus from the dorsolateral parabrachial nucleus that plays a critical role in mediating the cold-evoked inhibition of thermogenesis during TI. Our results reveal a novel thermosensory reflex circuit within the mammalian CNS thermoregulatory pathways and support the potential for pharmacologically inducing the TI state to elicit therapeutic hypothermia in non-hibernating species, including humans. [Display omitted] • Ventromedial periventricular area controls thermoregulatory inversion (TI) • Dynorphinergic pathways are required for TI inhibition of thermogenesis • The neural circuitry mediating TI may mediate torpor hypothermia • TI could be a novel approach to managing therapeutic hypothermia Morrison et al. show that the inhibition of ventromedial periventricular area (VMPeA) induces a state of thermoregulatory inversion (TI) in which thermogenic responses to cold ambient exposure are actively inhibited by an alternative thermoregulatory pathway via a dynorphinergic system. VMPeA is a switch for this novel thermoregulatory paradigm. [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]

The effectiveness of target temperature management (TTM) in poor-grade aneurysmal subarachnoid hemorrhage (aSAH) remains a topic of debate. In order to assess the clinical efficacy of TTM in patients with poor-grade aSAH, we conducted a systematic review and meta-analysis. This research was registered in PROSPERO (CRD42023445582) and included all relevant publications up until October 2023. We compared the TTM groups with the control groups in terms of unfavorable outcomes (modified Rankin scale [mRS] score > 3), mortality, delayed cerebral ischemia (DCI), cerebral vasospasm (CVS), and specific complications. Subgroup analyses were performed based on country, study type, follow-up time, TTM method, cooling maintenance period, and rewarming rate. Effect sizes were calculated as relative risk (RR) using random-effect or fixed-effect models. The quality of the articles was assessed using the methodological index for non-randomized studies scale. Our analysis included a total of 5 clinical studies (including 1 randomized controlled trial) and 219 patients (85 in the TTM group and 134 in the control group). Most of the studies were of moderate quality. TTM was found to be associated with a statistically significant improvement in mortality (mRS score 6) rates compared with the control group (RR = 0.61, 95% confidence interval [CI]: 0.40-0.94, p = 0.026). However, there was no statistically significant difference in unfavorable outcomes (mRS 4-6) between the TTM and control groups (RR = 0.94, 95% CI: 0.71-1.26, p = 0.702). The incidence of adverse events, including DCI, CVS, pneumonia, cardiac complications, and electrolyte imbalance, did not significantly differ between the two groups. In conclusion, our overall results suggest that TTM does not significantly reduce unfavorable outcomes in poor-grade aSAH patients. However, TTM may decrease mortality rates. Preoperative TTM may cause patients to miss the opportunity for surgery, although it temporarily protects the brain. Furthermore, the incidence of adverse events was similar between the TTM and control groups.

Aim: CoolCuddle, enabling parents to cuddle their babies with neonatal encephalopathy (NE) during therapeutic hypothermia and intensive care (TH), was developed in research settings. To determine the impact of implementing CoolCuddle in usual care in six diverse neonatal intensive care units on the cooling process and intensive care., Methods: This vital sign cohort study embedded within the CoolCuddle implementation study enrolled 36 infants receiving TH for NE. Nurses received training on CoolCuddle and a standard operating procedure using an instruction video. After consenting, parents experienced up to 2 h of CoolCuddle with 30 min of pre- and post-cuddle observation. We used multilevel, clustered linear modelling to assess the physiological stability in temperature, cardio-respiratory and neurophysiology across the CoolCuddle., Results: In 60 CoolCuddles over 93.12 h, respiratory parameters, heart rate or neurological function did not vary between the epochs (p > 0.05). During cuddle, sleep-wake cycling on amplitude-integrated EEG increased (p = 0.008) and there was weak evidence of lower pain scores (p = 0.08). No adverse effects were observed., Conclusion: Implementing CoolCuddle with support in usual practice maintained physiological stability and did not significantly affect the cooling process or intensive care, and may improve infant comfort. Ongoing monitoring of adverse effects when implementing CoolCuddle is recommended., (© 2024 The Author(s). Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Aim: To examine the efficacy of current non-servo-based cooling methods used by NETS NSW in treating hypoxic ischaemic encephalopathy (HIE) with therapeutic hypothermia (TH) in neonatal retrieval., Methods: A retrospective observational study of infants treated with TH for HIE retrieved by NETS NSW from January 2017 to June 2020 inclusive. Primary outcomes were the proportion of neonates achieving TH within 6 h of life and maintaining temperature in a therapeutic range., Results: 82 patients were included in analysis. Mean gestational age (GA) was 39 weeks (IQR 38-40) and mean birthweight (BW) 3297 g (SD 607 g). 68 infants (82.9%) were passively cooled while 14 (17.1%) were cooled with gel packs. 20 infants (21.4%) had rectal temperature monitoring before retrieval. 45 infants (55.6%) reached TH within 6 h of birth. Only 56 infants (68.3%) reached TH during retrieval. Of these infants, 45 (80.4%) had subsequent temperatures outside the therapeutic range., Conclusions: Infants receiving TH through non-servo-controlled methods are commonly exposed to temperature instability and overcooling. Introduction of servo-controlled cooling devices is required to improve care and management of perinatal HIE in retrieval., (© 2024 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Postcardiac arrest (PCA) syndrome is associated with high cardiovascular morbidity and mortality. Prolongation of the QT interval can lead to life-threatening ventricular arrhythmias and sudden cardiac death. Therapeutic hypothermia (TH) is widely used to improve neurological outcomes in PCA patients, but its effects on the QT interval remain a subject of investigation. This study aimed to evaluate the impact of TH on corrected QT (QTc) intervals in PCA patients. A total of 48 patients (mean age 63.2 ± 11.3 years) who survived cardiac arrest and underwent TH were included. Standard 12-lead electrocardiograms (ECGs) and serum electrolyte levels were assessed before and after TH. The QT and QTc intervals were measured using Bazett's formula, and QT dispersion (QTd) was calculated as the difference between the maximum and minimum QT intervals. Following TH, a significant increase in RR intervals was observed (480.75 ± 91.75 ms vs. 660.43 ± 97.35 ms, p < 0.05). QTc intervals increased significantly from 397.13 ± 12.45 ms to 449.25 ± 21.40 ms ( p < 0.05). Similarly, QTd increased from 55.48 ± 12.45 ms to 67.41 ± 13.42 ms ( p < 0.05). The prolongation of the QT interval was associated with a significant decrease in serum potassium and calcium levels. In conclusion, TH leads to a significant prolongation of the QT and QTc intervals and an increase in QTd. These findings suggest that close ECG monitoring is essential in PCA patients undergoing TH, particularly in those with predisposing factors for arrhythmias.

Background: The effects of endovascular therapeutic hypothermia (ETH) in ST-elevation myocardial infarction (STEMI) regional contractility are unknown, and its impact on segmental contractility has still not been evaluated. We sought to evaluate segmental myocardial strain after ETH adjuvant to percutaneous coronary intervention (PCI) in STEMI., Methods: We included patients who underwent 1.5 T cardiac magnetic resonance exams 5 and 30 days after acute anterior or inferior STEMI in a previous randomized trial. Left ventricle (LV) strain was evaluated on infarcted, adjacent, and remote myocardium. Segmental circumferential (CS) and radial strains (RS) were measured using feature-tracking imaging. Repeated-measures of ANOVA was used for comparisons within time and treatment., Results: Forty patients were divided into hypothermia (ETH, n=29) and control (n=11) groups, with 5210 LV segments. In ETH infarcted areas, RS (11.2±16 vs. 14.8±15.2, p=0.001) and CS (-5.4±11.1 vs. -8±11.1, p=0.001) showed recovery from 5 to 30 days compared to controls (11.4±14 vs. 13.1±16.8, p=0.09; -6.5±10.6 vs. -6.4±12.5, p=0.94). In control remote areas, RS (28±18 vs. 31.7±18.5, p=0.001) and CS (-15.5±10.7 vs. -17.1±9, p=0.001) improved from 5 to 30 days compared to ETH (28.6±18.6 vs. 29±20, p=0.44; -15.2±10.4 vs. -15.3±10.6, p=0.82). Transmural infarcted areas in ETH improved RS (11.8±13.2 vs. 8.17±14.7, p=0.001) and CS (-6.1±10.9 vs. -3.1±11.3, p=0.001) compared to controls, with better contractility at 30 days., Conclusions: In anterior or inferior STEMI patients, ETH adjuvant to PCI is associated with significant improvement in RS and CS of infarcted areas, including transmural segments, but not in the remote area. This might further increase our pathophysiological knowledge on early LV remodeling and ultimately suggest potential clinical value., Availability of Data and Materials: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Lucas de Mello Queiroz reports financial support was provided by National Council for Scientific and Technological Development. Jose Carlos Nicolau reports financial support was provided by National Council for Scientific and Technological Development. Jose Carlos Nicolau reports a relationship with Amgen Inc that includes: funding grants. Jose Carlos Nicolau reports a relationship with AstraZeneca that includes: funding grants. Jose Carlos Nicolau reports a relationship with Bayer Corporation that includes: funding grants. Jose Carlos Nicolau reports a relationship with CSL Behring that includes: funding grants. Jose Carlos Nicolau reports a relationship with Daiichi Sankyo Inc that includes: funding grants. Jose Carlos Nicolau reports a relationship with DalCor Pharmaceuticals Canada Inc that includes: funding grants. Jose Carlos Nicolau reports a relationship with Esperion Therapeutics Inc that includes: funding grants. Jose Carlos Nicolau reports a relationship with Janssen Pharmaceuticals Inc that includes: funding grants. Jose Carlos Nicolau reports a relationship with Novartis that includes: funding grants. Jose Carlos Nicolau reports a relationship with Novo Nordisk that includes: funding grants. Jose Carlos Nicolau reports a relationship with Sanofi that includes: funding grants. Jose Carlos Nicolau reports a relationship with Vifor Pharma Switzerland SA that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Competing interests Sponsors or founders had no role in the design and conduct of the study, in the collection, analysis, and interpretation of the data, or in the preparation or review of the manuscript. JCN reports research grants from Amgen, AstraZeneca, Bayer, CSL Behring, Daiichi Sankyo, Dalcor, Esperion, Janssen, Novartis, Novo Nordisk, Sanofi and Vifor. No potential conflict of interest related to the present manuscript., (Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aim: To explore the relationship between motor activities and executive functions (EF) in children (aged 10-12 years) with a history of neonatal hypothermia-treated hypoxic-ischemic encephalopathy (HIE)., Material and Methods: Forty-five children (mean age 11 years) with a history of neonatal hypothermia-treated HIE in Stockholm (2007-2009) were included in this cross-sectional study. The children were assessed with Movement Assessment Battery for Children-2 (MABC-2) and Wechsler Intelligence Scale for Children-V (WISC-V). Their parents completed Behavior Rating Inventory of Executive Function-2 (BRIEF-2), Five to Fifteen-R, and MABC-2 Checklist., Results: Associations between motor capacity and EF, specifically Processing Speed, Working Memory, Flexibility, and Inhibition, were detected. Children scoring below the 15 th percentile on MABC-2 had weaker EF, evident in Cognitive Proficiency Index from WISC-V (t43 = 2.515, p  = 0.016) and a higher mean Global Executive Composition Score from BRIEF-2 (t43 = -2.890, p  = 0.006). Children with stronger EF exhibited better motor capacity. Parental questionnaires indicated everyday difficulties in 52% of the children., Conclusions: Weaker EF were associated with difficulties in motor activities in early adolescence following hypothermia-treated HIE. These results highlight the importance of evaluating both motor activities and EF to understand children's everyday challenges.

Hypoxic-ischemic encephalopathy (HIE) resulting from perinatal asphyxia presents a substantial risk of mortality and long-term sequelae in neonates. Therapeutic hypothermia (TH) improves both short- and long-term outcomes in near-term/term neonates with moderate to severe HIE. While neonates with perinatal asphyxia and TH often require polypharmacy, the impact of both covariates on pharmacokinetics and pharmacodynamics is only partially described and quantified. In this pooled, multicenter retrospective study, longitudinal trends of human serum albumin (HSA, the major drug binding protein) and total protein (TP) concentrations in near-term/term neonates were described using linear mixed models and compared between cohorts (TH vs control neonates, and moderate vs severe HIE TH cases). A mathematical function for HSA concentrations in neonates with HIE undergoing TH was derived (AlbuCool function). The pooled dataset to estimate these functions contained 330 TH neonates and 425 controls with 1725 and 1415 HSA observations, respectively. The median (interquartile range) HSA concentration was 27.0 (23.0-31.0) g/L for the TH cohort, and 32.1 (28.4-35.7) g/L for the control cohort. Estimated mean HSA concentrations were significantly lower (P < .001) in TH compared to control cases, as well as in severe compared to moderate HIE cases (P < .001) over the first 7 postnatal days. The HSA function for neonates with HIE undergoing TH was: HSA (g/L) = 32.28 - 2.94 * PNA + 0.33 * PNA 2 (PNA is postnatal age). The integration of this function in pharmacokinetic models holds the promise to improve the predictive performance of these models, and consequently, the pharmacotherapy of HSA-bound drugs in this vulnerable population., (© 2025 The Author(s). The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

We aimed to evaluate the efficacy of peritoneal dialysis (PD) in hypoxic-ischemic acute kidney injury (AKI) in newborns with hypoxic-ischemic encephalopathy (HIE) who underwent therapeutic hypothermia (TH). This was a retrospective study including the newborns with HIE/TH who developed hypoxic-ischemic AKI and underwent PD between January 2022 and June 2024. The blood test results obtained before starting PD were compared with the blood test results obtained just before the decision to terminate PD or, in case of death, with the final blood test results obtained before death. Twenty-one newborns were included in the study. Four (19%) of these newborns were diagnosed with moderate HIE, and 17 (81%) were diagnosed with severe HIE. The median gestational age of the patients was 38 (36-39) weeks, and the mean birth weight was 3083 ± 494 g. The median postnatal day when PD started was 3 (2-4) days and its duration was 7 (4-10) days. All patients had fluid overload as an indication for PD dialysis, and fluid overload was accompanied by hyperkalemia in 8 (38.1%) patients. After PD, blood pH, bicarbonate, and sodium values increased significantly ( p ≤ 0.001, 0.009, <0.001, respectively), and potassium, phosphorus, and creatinine values decreased significantly ( p ≤ 0.001, <0.001, 0.031, respectively) compared with the predialysis values. PD corrects acidosis and electrolyte imbalance and may be considered as a successful renal replacement therapy for hypoxic-ischemic AKI in neonates with HIE/TH, especially in units with limited resources.

Objective: To assess variability among data elements collected among existing neonatal hypoxic-ischemic encephalopathy (HIE) data registries worldwide and to determine the need for future harmonization of standard common data elements., Study Design: This was a cross-sectional study of data elements collected from current or recently employed HIE registry data forms. Registries were identified by literature search and email inquiries to investigators worldwide. Data elements were categorized by group consensus., Results: A total of 1281 data elements were abstracted from 22 registries based in 14 countries, including 3 middle-income countries. Registries had a median of 106.5 distinct data elements per registry (range 59-458). The most commonly collected data were related to pregnancy, therapeutic hypothermia, and short-term hospital outcomes. The least consistently collected data were laboratory values other than acid/base status values. Only 4 variables were consistently collected in every registry. Five registries included neurodevelopmental follow-up fields and 5 others linked their data to a separate follow-up registry., Conclusion: Many HIE registries are collecting patient data around the world, but there is considerable variability in the number, type, and format of data collected. Future attempts to develop standard common data elements to harmonize data collection globally will be crucial to facilitate worldwide collaboration and to optimize management and outcome of neonatal HIE., Competing Interests: Declaration of Competing Interest There was no source of funding directly associated with this study. The authors have no conflicts of interest to declare., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Subcutaneous fat necrosis (SCFN) in newborns is an uncommon and self-limiting non-infectious panniculitis. It can occur in the first weeks of life in full-term newborns with hypoxic-ischemic encephalopathy who underwent therapeutic hypothermia. Hypercalcemia may develop and has been implicated as the cause of several complications as nephrocalcinosis. Hypercalcemia has been previously reported to appear only after resolution of skin lesions. Herein, we report how hypercalcemia can be evident already at diagnosis of subcutaneous fat necrosis after therapeutic hypothermia and can be associated with an early onset developing nephrocalcinosis. We compare two cases of these uncommon findings and review the recent literature., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2025 De Rose, Maddaloni, Salvatori, Campi, Gatto, Martini, Savarese, Bersani, Ubertini, Serrao, Costa, Braguglia, Gallini, Vento and Dotta.)