Therapeutic Hypothermia Treatment Research Articles

Therapeutic Hypothermia Compared with Normothermia in Adults with Traumatic Brain Injury; Functional Outcome, Mortality, and Adverse Effects: A Systematic Review and Meta-Analysis.

The main focus of traumatic brain injury (TBI) management is prevention of secondary injury. Therapeutic hypothermia (TH), the induction of a targeted low core body temperature, has been explored as a potential neuroprotectant in TBI. The aim of this article is to synthesize the available clinical data comparing the use of TH with the use of normothermia in TBI. A systematic search was conducted through MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials for randomized clinical trials including one or more outcome of interest associated with TH use in TBI. Independent reviewers evaluated quality of the studies and extracted data on patients with TBI undergoing TH treatment compared with those undergoing normothermia treatment. Pooled estimates, confidence intervals (CIs), and risk ratios (RRs) or odds ratios were calculated for all outcomes. A total of 3,909 patients from 32 studies were eligible for analysis. Pooled analysis revealed a significant benefit of TH on mortality and functional outcome (RR 0.81, 95% CI 0.68-0.96, I2 = 41%; and RR 0.77; 95% CI 0.67-0.88, I2 = 68%, respectively). However, subgroup analysis based on risk of bias showed that only studies with a high risk of bias maintained this benefit. When divided by cooling method, reduced poor functional outcome was seen in the systemic surface cooling and cranial cooling groups (RR 0.68, 95% CI 0.59-0.79, I2 = 35%; and RR 0.44, 95% CI 0.29-0.67, I2 = 0%), and no difference was seen for the systemic intravenous or gastric cooling group. Reduced mortality was only seen in the systemic surface cooling group (RR 0.63, 95% CI 0.53-0.75, I2 = 0%,); however, this group had mostly high risk of bias studies. TH had an increased rate of pneumonia (RR 1.24, 95% CI 1.10-1.40, I2 = 32%), coagulation abnormalities (RR 1.63, 95% CI 1.09-2.44, I2 = 55%), and cardiac arrhythmias (RR 1.78, 95% CI 1.05-3.01, I2 = 21%). Once separated by low and high risk of bias, we saw no difference in these complications in the groups with low risk of bias. Overall quality of the evidence was moderate for mortality, functional outcome, and pneumonia and was low for coagulation abnormalities and cardiac arrhythmias. With the addition of several recent randomized clinical trials and a thorough quality assessment, we have provided an updated systematic review and meta-analysis that concludes that TH does not show any benefit over normothermia in terms of mortality and functional outcome.

Therapeutic hypothermia after perinatal asphyxia in Vietnam: medium-term outcomes at 18 months – a prospective cohort study

AimTo determine neurodevelopmental outcome at 18 months after therapeutic hypothermia for hypoxic-ischaemic encephalopathy (HIE) infants in Vietnam, a low-middle-income country.MethodProspective cohort study investigating outcomes at 18 months in severely asphyxiated...

Post Cardiac Arrest Care in the Cardiac Intensive Care Unit.

Cardiac arrests constitute a leading cause of mortality in the adult population and cardiologists are often tasked with the management of patients following cardiac arrest either as a consultant or primary provider in the cardiac intensive care unit. Familiarity with evidence-based practice for post-cardiac arrest care is a requisite for optimizing outcomes in this highly morbid group. This review will highlight important concepts necessary to managing these patients. Emerging evidence has further elucidated optimal care of post-arrest patients including timing for routine coronary angiography, utility of therapeutic hypothermia, permissive hypercapnia, and empiric aspiration pneumonia treatment. The complicated state of multi-organ failure following cardiac arrest needs to be carefully optimized by the clinician to prevent further neurologic injury and promote systemic recovery. Future studies should be aimed at understanding if these findings extend to specific patient populations, especially those at the highest risk for poor outcomes.

A narrative review of intravascular catheters in therapeutic hypothermia.

Therapeutic hypothermia (TH) has been regarded as a promising neuroprotective method for acute ischemic stroke (AIS) for decades. During the development of TH, most researchers focused on improving hypothermic benefits by optimizing treatment processes and conditions. Intravenous thrombolysis and endovascular thrombectomy, for instance, have been introduced into AIS treatment. However, the lack of specialized intervention consumables, especially intervention catheter, led to inaccurate and uncontrolled hypothermic temperature, limited the efficacy of TH. In this review, intervention catheters as well as accessory equipment utilized in TH treatment has been summarized. Hopefully, this review may inspire the future development of TH specialized intervention catheter, enhance the outcome of TH, and neuroprotective efficacy in AIS.

Volumetric changes in brain MRI of infants with hypoxic-ischemic encephalopathy and abnormal neurodevelopment who underwent therapeutic hypothermia

BackgroundHypoxic-ischemic encephalopathy (HIE) is a severe neonatal complication that can result in 40–60 % of long-term morbidity. Magnetic Resonance Imaging (MRI) is a noninvasive method which is usually performed before discharge to visually assess acquired cerebral lesions associated with HIE and severity of lesions possibly providing a guide for detecting adverse outcomes. This study aims to evaluate the impact of HIE on brain volume changes observed in MRI scans performed at a mean 10 days of life, which can serve as a prognostic indicator for abnormal neurodevelopmental (ND) outcomes at 18–24 months among HIE infants. MethodsWe retrospectively identified a cohort of HIE patients between June 2013 and March 2017. The inclusion criteria for therapeutic hypothermia (TH) were a gestational age ≥35 weeks, a birth weight ≥1800 g, and the presence of ≥ moderate HIE. Brain MRI was performed at a mean 10 days of life and brain volumes (total brain volume, cerebral volume, cerebellar volume, brain stem volume, and ventricle volume) were measured for quantitative assessment. At 18–24 months, the infants returned for follow-up evaluations, during which their cognitive, language, and motor skills were assessed using the Bayley Scales of Infant and Toddler Development III. ResultsThe study recruited a total of 240 infants between 2013 and 2017 for volumetric brain MRI evaluation. Among these, 83 were normal control infants, 107 were TH-treated HIE infants and 37 were HIE infants who did not receive TH due to contraindications. Clinical evaluation was further proceeded. We compared the brain volumes between the normal control infants (n = 83) with normal ND but TH-treated HIE infants (n = 76), abnormal ND TH-treated HIE infants (n = 31), and the severe HIE MRI group with no TH (n = 37). The abnormal ND TH-treated HIE infants demonstrated a significant decrease in brainstem volume and an increase in ventricle size (p < 0.001) (Table 4). Lastly, the severe brain MRI group who did not receive TH showed significantly smaller brain stem (p = 0.006), cerebellar (p = 0.006) and cerebrum volumes (p = 0.027), accompanied by larger ventricular size (p = 0.013) compared to the normal control group (Table 5). ConclusionIn addition to assessing the location of brain injuries in MRI scans, the reduction in brain stem volume coupled with an increase in ventricular volume in HIE infants may serve as a biomarker indicating severe HIE and adverse long-term ND outcomes among HIE infants who either received therapeutic hypothermia (TH) treatment or not.

Therapeutic Hypothermia Is Limited in Preventing Developmental Impairments after Neonatal Hypoxia-Ischemia

The only current treatment for neonatal hypoxia-ischemia (HI) is therapeutic hypothermia (TH), which still shows some limitations. Specific effects of TH in the several processes involved in brain injury progression remain unclear. In this study, the effects of TH treatment on developmental parameters, behavioral outcomes, and peripheral leukocytes were evaluated in neonatal male and female rats. In P7, animals were submitted to right common carotid artery occlusion followed by hypoxia (8% oxygen). TH was performed by reducing the animal scalp temperature to 32°C for 5 h. Behavioral parameters and developmental landmarks were evaluated. Animals were euthanized at P9 or P21, and cerebral hemispheres, spleen, and thymus were weighed. White blood cells (WBCs) were counted in blood smears. There was a reduction in the weight of the brain hemisphere ipsilateral to the carotid occlusion in HI and TH groups, as well as a reduction in body weight gain and a delay in the opening of the ipsilateral eye. Latency in negative geotaxis was increased by HI at P12. TH did not prevent brain weight loss, developmental impairments, or WBC number changes but prevented negative geotaxis impairment and spleen weight reduction. These data reinforce that a better understanding of the events that occur after HI and TH in both males and females is necessary and would allow the development of more adequate and sex-specific therapeutic approaches.

Experiences of parents whose school-aged children were treated with therapeutic hypothermia as newborns: A focus group study.

To describe parents' past and present experiences of their newborn infant's therapeutic hypothermia (TH) treatment after perinatal asphyxia 10-13 years after the event. Newborn infants are treated with TH following perinatal asphyxia to improve neurodevelopmental outcomes. A qualitative descriptive design using focus groups (FGs). Twenty one parents to 15 newborn infants treated with TH between 2007 and 2009 participated in five FGs. The FGs were transcribed verbatim and analysed using framework approach. The SRQR checklist was followed for study reporting. Two main categories were identified: hardships and reliefs during TH treatment and struggles of everyday life. Both categories include three subcategories, the first: (1) concern and gratitude for the unrecognized treatment, (2) insufficiency of information and proposed participation and (3) NICU nurses instilled security and hope. The second with subcategories: (1) unprocessed experiences of the TH treatment, (2) later challenges at school and (3) existential and psychological challenges in everyday life. TH of their newborns affected the parents psychologically not only during the treatment, but lasted months and years later. Information and communication with health care professionals and school management were inefficient and inadequate. The parents' concerns could be prevented by an improved identification and understanding of the problems and the needs of the infants and their families before discharge. Through more personalized and efficient preparation and communication by the nursing staff before discharge, many of the parents' worries and problems could be reduced. Check-up of parents' needs of psychosocial support before and after discharge and offering counselling should become routine. Also, nurses at Well-Baby Clinics and in school health care should receive knowledge about TH treatment and the challenges the children and the parents experience. Participation of parents was limited to the data provided through interviews.

Deep Learning to Optimize Magnetic Resonance Imaging Prediction of Motor Outcomes After Hypoxic-Ischemic Encephalopathy

BackgroundMagnetic resonance imaging (MRI) is the gold standard for outcome prediction after hypoxic-ischemic encephalopathy (HIE). Published scoring systems contain duplicative or conflicting elements. MethodsInfants ≥36 weeks gestational age (GA) with moderate to severe HIE, therapeutic hypothermia treatment, and T1/T2/diffusion-weighted imaging were identified. Adverse motor outcome was defined as Bayley-III motor score <85 or Alberta Infant Motor Scale <10th centile at 12 to 24 months. MRIs were scored using a published scoring system.Logistic regression (LR) and gradient-boosted deep learning (DL) models quantified the importance of clinical and imaging features. The cohort underwent 80/20 train/test split with fivefold cross validation. Feature selection eliminated low-value features. ResultsA total of 117 infants were identified with mean GA = 38.6 weeks, median cord pH = 7.01, and median 10-minute Apgar = 5. Adverse motor outcome was noted in 23 of 117 (20%).Putamen/globus pallidus injury on T1, GA, and cord pH were the most informative features. Feature selection improved model accuracy from 79% (48-feature MRI model) to 85% (three-feature model). The three-feature DL model had superior performance to the best LR model (area under the receiver-operator curve 0.69 versus 0.75). ConclusionsThe parsimonious DL model predicted adverse HIE motor outcomes with 85% accuracy using only three features (putamen/globus pallidus injury on T1, GA, and cord pH) and outperformed LR.

The Effect of Therapeutic Hypothermia on Prognosis in Patients Receiving Continuous Renal Replacement Therapy.

Continuous renal replacement therapy (CRRT) is a commonly used therapeutic modality in the pediatric intensive care unit (PICU) for the treatment of severe acute kidney injury, as well as for addressing metabolic abnormalities, fluid-electrolyte imbalances, and acid-base disorders. According to reports, therapeutic hypothermia treatment has demonstrated the ability to decrease cellular metabolism, oxygen consumption, formation of free radicals, cell death, and inflammatory signals. The study encompassed all individuals who underwent CRRT at both Manisa City Hospital and Manisa Celal Bayar University Hospital throughout the period from February 2021 to November 2022. A total of 14 patients who received CRRT were subjected to a warming procedure utilizing an external blanket and an external heater attached to the CRRT venous return line, resulting in the attainment of a body temperature exceeding 36°C. Therapeutic hypothermia was implemented on 12 patients to maintain their body temperature within the range of 32-35°C. The study population exhibited a median age of 24.5 months, with males comprising 61.5% of the sample. A therapeutic hypothermia treatment was administered to a cohort of 12 patients. The patients who had therapeutic hypothermia exhibited a significantly reduced vasoactive-inotropic score (p = 0.038). Patients who did not receive therapeutic hypothermia exhibited a prolonged need for mechanical ventilation (p = 0.020). The duration of stay in the PICU for patients who underwent therapeutic hypothermia was shown to be considerably shorter compared to those who did not receive therapeutic hypothermia (p = 0.047). The potential efficacy of moderate therapeutic hypothermia appears promising, particularly in the context of patients who are receiving CRRT for severe sepsis and acute respiratory distress syndrome. This is attributed to the anti-inflammatory properties and hypometabolic effects associated with this intervention. To the best of our current understanding, this study represents the initial investigation showcasing the effectiveness of combining therapeutic hypothermia with CRRT in the pediatric population.

Epicardial electrical heterogeneity after amiodarone treatment increases vulnerability to ventricular arrhythmias under therapeutic hypothermia.

Amiodarone is commonly used during therapeutic hypothermia (TH) following cardiac arrest due to ventricular arrhythmias. However, electrophysiological changes and proarrhythmic risk after amiodarone treatment have not yet been explored in TH. Epicardial high-density bi-ventricular mapping was performed in pigs under baseline temperature (BT), TH (32-34°C), and amiodarone treatment during TH. The total activation time (TAT), conduction velocity (CV), local electrogram (LE) duration, and wavefront propagation from pre-specified segments were analyzed during sinus rhythm (SR) or right ventricular (RV) pacing (RVP), along with tissue expression of connexin 43. The vulnerability to ventricular arrhythmias was assessed. Compared to BT, TH increased the global TAT, decreased the CV, and generated heterogeneous electrical substrate during SR and RVP. During TH, the CV reduction and LE duration prolongation were greater in the anterior mid RV than in the other areas, which changed the wavefront propagation in all animals. Compared to TH alone, amiodarone treatment during TH further increased the TAT and LE duration and decreased the CV. Heterogeneous conduction was partially attenuated after amiodarone treatment. After TH and amiodarone treatment, the connexin 43 expression in the anterior mid RV was lower than that in the other areas, compatible with the heterogeneous CV reduction. The animals under TH and amiodarone treatment had a higher incidence of inducible ventricular arrhythmias than those under BT or TH without amiodarone. Electrical heterogeneity during amiodarone treatment and TH was associated with vulnerability to ventricular arrhythmias.

Exposure to Maternal Diabetes during Pregnancy Is Associated with Aggravated Short-Term Neonatal and Neurological Outcomes following Perinatal Hypoxic-Ischemic Encephalopathy.

Infants of diabetic mothers (IDM) are at higher risk of perinatal morbidities and glycemic instability, but the impact of maternal diabetes on neonatal and neurological short-term outcomes of neonates with hypoxic-ischemic encephalopathy (HIE) remains poorly described. Our objective was to determine the impact of maternal diabetes on neonatal and neurological short-term outcomes following neonatal HIE. This was a retrospective single-center study including 102 term neonates with HIE who received therapeutic hypothermia (TH) treatment between 2013 and 2020. Multiple regression analysis was used to assess the relationship between the presence of maternal diabetes and short-term outcomes. Neonates with HIE and maternal diabetes exposure had a significantly lower gestational age at birth (38.6 vs. 39.7 weeks of gestation, p = 0.005) and a significantly higher mean birth weight (3,588 ± 752 vs. 3,214 ± 514 g, p = 0.012). IDM with HIE were ventilated for longer duration (8 vs. 4 days, p = 0.0047) and had a longer neonatal intensive care unit (NICU) stay (18 vs. 11 days, p = 0.0483) as well as took longer time to reach full oral feed (15 vs. 7 days, p = 0.0432) compared with neonates of nondiabetic mother. Maternal diabetes was also associated with an increased risk of death or abnormal neurological examination at discharge in neonates with HIE (odds ratio: 6.41 [1.54-26.32]). In neonates with HIE, maternal diabetes is associated with an increased risk of death or short-term neonatal morbidities, such as longer duration of ventilation, prolonged neonatal stay, greater need for tube feeding, and being discharged with an abnormal neurological examination. Strategies to prevent, reduce, or better control maternal diabetes during pregnancy should be prioritized to minimize complications after perinatal asphyxia. · Maternal DB is associated with unfavorable outcomes.. · IDM have longer ventilatory support and tube feeding.. · IDM have higher risk of abnormal neurological examination..

Neutrophil Extracellular Traps Release following Hypoxic-Ischemic Brain Injury in Newborn Rats Treated with Therapeutic Hypothermia.

The peripheral immune system plays a critical role in neuroinflammation of the central nervous system after an insult. Hypoxic-ischemic encephalopathy (HIE) induces a strong neuroinflammatory response in neonates, which is often associated with exacerbated outcomes. In adult models of ischemic stroke, neutrophils infiltrate injured brain tissue immediately after an ischemic insult and aggravate inflammation via various mechanisms, including neutrophil extracellular trap (NETs) formation. In this study, we used a neonatal model of experimental hypoxic-ischemic (HI) brain injury and demonstrated that circulating neutrophils were rapidly activated in neonatal blood. We observed an increased infiltration of neutrophils in the brain after exposure to HI. After treatment with either normothermia (NT) or therapeutic hypothermia (TH), we observed a significantly enhanced expression level of the NETosis marker Citrullinated H3 (Cit-H3), which was significantly more pronounced in animals treated with TH than in those treated with NT. NETs and NLR family pyrin domain containing 3 (NLRP-3) inflammasome assembly are closely linked in adult models of ischemic brain injury. In this study, we observed an increase in the activation of the NLRP-3 inflammasome at the time points analyzed, particularly immediately after TH, when we observed a significant increase in NETs structures in the brain. Together, these results suggest the important pathological functions of early arriving neutrophils and NETosis following neonatal HI, particularly after TH treatment, which is a promising starting point for the development of potential new therapeutic targets for neonatal HIE.

Therapeutic Hypothermia Treatment for an Infant with Hypoxic-Ischemic Encephalopathy and Gastroschisis: A Case Report

Gastroschisis is a congenital, typically isolated, full-thickness abdominal wall defect in which the abdominal contents, usually only the small intestine, remain outside the abdominal cavity. It is commonly detected on fetal ultrasonography, and has generally excellent survival and outcomes, though these can be decreased in cases of complicated gastroschisis. We present the case of a female infant with a prenatal diagnosis of gastroschisis who required a prolonged and complex resuscitation after delivery. In addition to her gastroschisis, she presented with a history and physical examination consistent with severe hypoxic-ischemic encephalopathy and was treated with therapeutic hypothermia (TH) without further compromise to her bowel. In addition, careful consideration of neuroprotection, fluid status, bowel viability, and hemodynamics were undertaken in her care. She was discharged home on full enteral feeds, with only mild language and gross motor delays at 6 months of age. To our knowledge, there are no reports in the literature of the use of TH in the setting of unrepaired simple gastroschisis.

Evaluation and Neurodevelopmental Outcomes of Infants with Hypoxic Ischemic Encephalopathy Treated with Therapeutic Hypothermia: A Single Center Experience

Hypoxic ischemic encephalopathy (HIE) is an important cause of mortality and morbidity in newborns. Our study aimed to determine the neurodevelopmental outcomes, risk factors, and the relationship between risk factors and prognosis of cases followed up with HIE diagnosis and who were treated with hypothermia treatment. Medical records of 23 patients who were followed up with HIE diagnosis in the pediatric neurology outpatient clinic between January 1, 2018, and December 31, 2021, and treated with therapeutic hypothermia in the newborn period were retrospectively reviewed. Denver Developmental Screening Test II was used in the developmental evaluation. Neurodevelopment was normal in 12 (52.2%) of 23 cases and retarded for age in 11 (47.8%) cases. Variables such as Sarnat encephalopathy score in the neonatal period, need for prolonged ventilation, presence of severe acidosis at birth, Apgar scores at the 1st and 5th minutes, and abnormal cranial magnetic resonance (Mrg) findings were determined to be major factors in determining neurodevelopmental prognosis in asphyxic cases. The male gender was found to be riskier in terms of prognosis. Of the patients with HIE, retardation was determined for fine motor skills in 52.2%, speaking in 39.1%, gross motor skills in 26.1%, and personal development in 21.7%. Epilepsy, cerebral palsy, and speech disorders were the most common chronic period problems in patients with HIE. Despite therapeutic hypothermia treatment, neurodevelopmental problems are still observed in newborns with HIE. We found that male gender, low Apgar score, severe acidosis, and abnormal cranial Mrg findings in the neonatal period are risk factors in determining the neurodevelopmental prognosis of newborns with HIE. Monitoring and supporting the development of HIE cases with risk factors from the first months of life and intervening in developmental problems promptly are crucial in order to improve long-term outcomes.

Therapeutic Hypothermia Combined with Hydrogen Sulfide Treatment Attenuated Early Blood–Brain Barrier Disruption and Brain Edema Induced by Cardiac Arrest and Resuscitation in Rat Model

Brain injury remains a major problem in patients suffering cardiac arrest (CA). Disruption of the blood–brain barrier (BBB) is an important factor leading to brain injury. Therapeutic hypothermia is widely accepted to limit neurological impairment. However, the efficacy is incomplete. Hydrogen sulfide (H2S), a signaling gas molecule, has protective effects after cerebral ischemia reperfusion injury. This study showed that combination of hypothermia and H2S after resuscitation was more beneficial for attenuated BBB disruption and brain edema than that of hypothermia or H2S treatment alone. CA was induced by ventricular fibrillation for 4 min. Hypothermia was performed by applying alcohol and ice bags to the body surface under anesthesia. We used sodium hydrosulphide (NaHS) as the H2S donor. We found that global brain ischemia induced by CA and cardiopulmonary resuscitation (CPR) resulted in brain edema and BBB disruption; Hypothermia or H2S treatment diminished brain edema, decreased the permeability and preserved the structure of BBB during the early period of CA and resuscitation, and more importantly, improved the neurologic function, increased the 7-day survival rate after resuscitation; the combination of hypothermia and H2S treatment was more beneficial than that of hypothermia or H2S treatment alone. The beneficial effects were associated with the inhibition of matrix metalloproteinase-9 expression, attenuated the degradation of the tight junction protein occludin, and subsequently protected the structure of BBB. These findings suggest that combined use of therapeutic hypothermia and hydrogen sulfide treatment during resuscitation of CA patients could be a potential strategy to improve clinical outcomes and survival rate.

Correction: Effect of Therapeutic Hypothermia Treatment on Acute Phase Reactants.

Correction to: Effect of Therapeutic Hypothermia Treatment on Acute Phase ReactantsZ Geburtshilfe Neonatol 2022; 226(05): 319-324DOI: 10.1055/a-1846-1545

Effect of Therapeutic Hypothermia Treatment on Acute Phase Reactants.

In our study, we aimed to examine the effect of therapeutic hypothermia treatment on C-reactive protein (CRP) and interleukin-6 (IL-6) in infants with hypoxic ischemic encephalopathy (HIE). The data of the patients with the diagnosis of HIE we followed up in our unit between 2017 and 2018 were analyzed retrospectively. Patients who died during follow-up and patients with proven septicemia at the time of examination were excluded from the study. The routine CRP and IL-6 values ​​of the patients included in the study were compared before and after hypothermia treatment. Therapeutic hypothermia treatment applied for 72 hours was found to cause a statistically significant increase in CRP after treatment when compared with the values ​​measured before treatment (0.6 (0.2-1.9) before and median (P25-75), and after treatment 7.5 (4-18) and median (P25-75) mg/L, p=0.00). While IL-6 was found to be high in the early period due to the effect of hypoxia, it was found to be low after hypothermia treatment (80.5 (40-200) median (P25-75) - 32 (18-50) median (P25-75) pg/ml, p=0.131). While the white blood cell count was high before hypothermia treatment due to hypoxia, it was found to be low after treatment (24600 (19600-30100) median (P25-75) -11300 (8800-14200) median (P25-75)/µL, p=0.001). White blood cells and IL-6 can be found to be high due to hypoxia without infection, and CRP can be found to be high after therapeutic hypothermia treatment without infection. The effect of hypoxia and hypothermia should be considered when evaluating acute phase reactants.

Early predictors of abnormal MRI patterns in asphyxiated infants: S100B protein urine levels.

The early detection and stratification of asphyxiated infants at higher risk for impaired neurodevelopment is challenging. S100B protein is a well-established biomarker of brain damage, but lacks conclusive validation according to the "gold standard" methodology for hypoxic-ischemic encephalopathy (HIE) prognostication, i.e. brain MRI. The aim of the present study was to investigate the predictive role of urinary S100B concentrations, assessed in a cohort of HIE infants receiving therapeutic hypothermia (TH), compared to brain MRI. Assessment of urine S100B concentrations was performed by immunoluminometric assay at first void and at 4, 8, 12, 16, 20, 24, 48, 72, 96, 108 and 120-h after birth. Neurologic evaluation, routine laboratory parameters, amplitude-integrated electroencephalography, and cerebral ultrasound were performed according to standard protocols. Brain MRI was performed at 7-10days of life. Overall, 74 HIE neonates receiving TH were included in the study. S100B correlated, already at first void, with the MRI patterns with higher concentrations in infants with the most severe MRI lesions. High S100B urine levels soon after birth constitute trustable predictors of brain injury as confirmed by MRI. Results support the reliability of S100B in clinical daily practice and open the way to its inclusion in the panel of parameters used for the selection of cases suitable for TH treatment.

Urinary metabotypes of newborns with perinatal asphyxia undergoing therapeutic hypothermia.

Perinatal asphyxia (PA) still occurs in about three to five per 1,000 deliveries in developed countries; 20% of these infants show hypoxic-ischemic encephalopathy (HIE) on brain magnetic resonance imaging (MRI). The aim of our study was to apply metabolomic analysis to newborns undergoing therapeutic hypothermia (TH) after PA to identify a distinct metabotype associated with the development of HIE on brain MRI. We enrolled 53 infants born at >35 weeks of gestation with PA: 21 of them showed HIE on brain MRI (the "HIE" group), and 32 did not (the "no HIE" group). Urine samples were collected at 24, 48 and 72 hours of TH. Metabolomic data were acquired using high-resolution mass spectrometry and analyzed with univariate and multivariate methods. Considering the first urines collected during TH, untargeted analysis found 111 relevant predictors capable of discriminating between the two groups. Of 35 metabolites showing independent discriminatory power, four have been well characterized: L-alanine, Creatine, L-3-methylhistidine, and L-lysine. The first three relate to cellular energy metabolism; their involvement suggests a multimodal derangement of cellular energy metabolism during PA/HIE. In addition, seven other metabolites with a lower annotation level (proline betaine, L-prolyl-L-phenylalanine, 2-methyl-dodecanedioic acid, S-(2-methylpropionyl)-dihydrolipoamide-E, 2,6 dimethylheptanoyl carnitine, Octanoylglucuronide, 19-hydroxyandrost-4-ene-3,17-dione) showed biological consistency with the clinical picture of PA. Moreover, 4 annotated metabolites (L-lysine, L-3-methylhistidine, 2-methyl-dodecanedioic acid, S-(2-methylpropionyl)-dihydrolipoamide-E) retained a significant difference between the "HIE" and "no HIE" groups during all the TH treatment. Our analysis identified a distinct urinary metabotype associated with pathological findings on MRI, and discovered 2 putative markers (L-lysine, L-3-methylhistidine) which may be useful for identifying neonates at risk of developing HIE after PA.

Impact of Hypoxia-Ischemia on Neurogenesis and Structural and Functional Outcomes in a Mild-Moderate Neonatal Hypoxia-Ischemia Brain Injury Model.

Hypoxic-ischemic encephalopathy (HIE) is a common type of brain injury caused by a lack of oxygen and blood flow to the brain during the perinatal period. The incidence of HIE is approximately 2–3 cases per 1000 live births in high-income settings; while in low- and middle-income countries, the incidence is 3–10-fold higher. Therapeutic hypothermia (TH) is the current standard treatment for neonates affected by moderate–severe HIE. However, more than 50% of all infants with suspected HIE have mild encephalopathy, and these infants are not treated with TH because of their lower risk of adverse outcomes. Despite this, several analyses of pooled data provide increasing evidence that infants who initially have mild encephalopathy may present signs of more significant brain injury later in life. The purpose of this study was to expand our knowledge about the effect of mild–moderate hypoxia-ischemia (HI) at the cellular, structural, and functional levels. An established rat model of mild–moderate HI was used, where postnatal day (P) 7 rats were exposed to unilateral permanent occlusion of the left carotid artery and 90 min of 8% hypoxia, followed by TH or normothermia (NT) treatment. The extent of injury was assessed using histology (P14 and P42) and MRI (P11 and P32), as well as with short-term and long-term behavioral tests. Neurogenesis was assessed by BrdU staining. We showed that mild–moderate HI leads to a progressive loss of brain tissue, pathological changes in MRI scans, as well as an impairment of long-term motor function. At P14, the median area loss assessed by histology for HI animals was 20% (p < 0.05), corresponding to mild–moderate brain injury, increasing to 55% (p < 0.05) at P42. The data assessed by MRI corroborated our results. HI led to a decrease in neurogenesis, especially in the hippocampus and the lateral ventricle at early time points, with a delayed partial recovery. TH was not neuroprotective at early time points following mild–moderate HI, but prevented the increase in brain damage over time. Additionally, rats treated with TH showed better long-term motor function. Altogether, our results bring more light to the understanding of pathophysiology following mild-moderate HI. We showed that, in the context of mild-moderate HI, TH failed to be significantly neuroprotective. However, animals treated with TH showed a significant improvement in motor, but not cognitive long-term function. These results are in line with what is observed in some cases where neonates with mild HIE are at risk of neurodevelopmental deficits in infancy or childhood. Whether TH should be used as a preventive treatment to reduce adverse outcomes in mild-HIE remains of active interest, and more research has to be carried out in order to address this question.