Effect Of Therapeutic Hypothermia Research Articles

The effects of therapeutic hypothermia on the expression of DKK3 and myocardial ischemia-reperfusion injury

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

Dried Blood Spot Metabolome Features of Ischemic-Hypoxic Encephalopathy: A Neonatal Rat Model.

Hypoxic-ischemic encephalopathy (HIE) is a severe neurological disorder caused by perinatal asphyxia with significant consequences. Early recognition and intervention are crucial, with therapeutic hypothermia (TH) being the primary treatment, but its efficacy depends on early initiation of treatment. Accurately assessing the HIE severity in neonatal care poses challenges, but omics approaches have made significant contribution to understanding its complex pathophysiology. Our study further explores the impact of HIE on the blood metabolome over time and investigated changes associated with hypothermia's therapeutic effects. Using a rat model of hypoxic-ischemic brain injury, we comprehensively analyzed dried blood spot samples for fat-soluble compounds using HPLC-MS. Our research shows significant changes in the blood metabolome after HIE, with a particularly rapid recovery of lipid metabolism observed. Significant changes in lipid metabolites were observed after 3 h of HIE, including increases in ceramides, carnitines, certain fatty acids, phosphocholines, and phosphoethanolamines, while sphingomyelins and N-acylethanolamines (NAEs) decreased (p < 0.05). Furthermore, NAEs were found to be significant features in the OPLS-DA model for HIE diagnosis, with an area under the curve of 0.812. TH showed a notable association with decreased concentrations of ceramides. Enrichment analysis further corroborated these observations, showing modulation in several key metabolic pathways, including arachidonic acid oxylipin metabolism, eicosanoid metabolism via lipooxygenases, and leukotriene C4 synthesis deficiency. Our study reveals dynamic changes in the blood metabolome after HIE and the therapeutic effects of hypothermia, which improves our understanding of the pathophysiology of HIE and could lead to the development of new rapid diagnostic approaches for neonatal HIE.

The Effect of Therapeutic Hypothermia on Ischemic Brain Injury in a Rat Model of Cardiac Arrest: An Assessment Using 18F-FDG PET.

Therapeutic hypothermia (TH) is widely acknowledged as one of the interventions for preventing hypoxic ischemic brain injury in comatose patients following cardiac arrest (CA). Despite its recognized efficacy, recent debates have questioned its effectiveness. This preclinical study evaluated the impact of TH on brain glucose metabolism, utilizing fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) in a rat model of CA. Asphyxia CA was induced in Sprague-Dawley rats using vecuronium. Brain PET images using 18F-FDG were obtained from 21 CA rats, who were randomized to receive either TH or no intervention. Of these, 9 rats in the TH group received hypothermia under general anesthesia and mechanical ventilation for eight hours, while the remaining 12 rats in the non-TH group were observed without intervention. We conducted regional and voxel-based analyses of standardized uptake values relative to the pons (SUVRpons) to compare the two groups. Survival rates were identical in both the TH and non-TH groups (67%). There was no discernible difference in the SUVRpons across the brain cortical regions between the groups. However, in a subgroup analysis of the rats that did not survive (n = 7), those in the TH group (n = 3) displayed significantly higher SUVRpons values across most cortical regions compared to those in the non-TH group (n = 4), with statistical significance after false-discovery rate correction (p < 0.05). The enhancement in SUVRpons due to TH intervention was only observed in the cortical regions of rats with severe encephalopathy that subsequently died. These findings suggest that the beneficial effects of TH on brain glucose metabolism in this asphyxia CA model may be confined to cases of severe ischemic encephalopathy.

Renal artery flow alterations in neonates with hypoxic ischemic encephalopathy.

To compare kidney blood flow and kidney function tests in infants with hypoxic ischemic encephalopathy (HIE), and the effects of therapeutic hypothermia (TH) during the first 7days of life. Fifty-nine infants with HIE were prospectively evaluated. Infants with moderate-severe HIE who required TH were classified as group 1 (n = 36), infants with mild HIE were classified as group 2 (n = 23), and healthy infants were classified as group 3 (n = 60). Kidney function tests were evaluated on the sixth hour, third and seventh days of life in Group 1 and Group 2, and on the sixth hour and third day of life in group 3. Renal artery (RA) Doppler ultrasonography (dUS) was performed in all infants on the first, third, and seventh days of life. Systolic and end diastolic blood flow in RA tended to increase and RA resistive index (RI) tended to decrease with time in group 1 (p = 0.0001). While end diastolic blood flow rates in RA on the third day were similar in patients with severe HIE and mild HIE, it was lower in patients with mild-moderate-severe HIE than healthy newborns. On the seventh day, all three groups had similar values (p > 0.05). Serum blood urea nitrogen (BUN), creatinine, uric acid, and cystatin C levels gradually decreased and glomerular filtration rate (GFR) gradually increased during TH in group 1 (p = 0.0001). Serum creatinine levels gradually decreased while GFR gradually increased during the study period in group 2. Therapeutic hypothermia seems to help restore renal blood flow and kidney functions during the neonatal adaptive period with its neuroprotective properties.

Safety and efficacy of therapeutic hypothermia in neonates with mild hypoxic-ischemic encephalopathy

BackgroundThough there has been an increase in the number of neonates with hypoxic-ischemic encephalopathy (HIE) treated by therapeutic hypothermia (TH) in recent years, the effect of therapeutic hypothermia on mild HIE neonates is still uncertain.ObjectivesThis study aims to explore the safety and efficacy of therapeutic hypothermia in neonates with mild HIE.MethodsRetrospectively collected between January 2010 to December 2022 at Children’s Hospital of Fudan University, neonates with mild HIE were divided into TH and non-TH groups. Clinical data of the mild HIE neonates and their mothers’ general information during pregnancy were collected. SPSS 23.0 was used to compare the general condition, the incidence of adverse events, and efficacy in the two groups.ResultsA total of 71 neonates with mild HIE were included, including 31 in the TH group and 40 in the non-TH group. Compared with the non-TH group, the TH group had significantly lower 5-minute Apgar scores [6 (5–7) points vs. 7 (5–8) points, p = 0.033 ], but a higher rate of tracheal intubation at birth (68%, 21/31 vs. 40%, 16/40, p = 0.02), a higher rate of chest compressions > 30 s (39%, 12/31 vs. 15%, 6/40, p = 0.023), the later initiation enteral feeding [4 (3–4) days vs. 1 (1–2) days, p < 0.001], a higher usage rate of analgesic and sedative drugs (45%, 14/31 vs. 18%, 7/40, p = 0.011) and the longer hospital stay [12.5 (11–14) days vs. 9 (7-13.9) days, p = 0.003]. There was no death in 71 mild HIE neonates. TH group had lower incidence of brain injury (16%, 5/31 vs. 43%, 17/40, p = 0.017) and encephalopathy progression (10%, 3/31 vs. 45%, 18/40, p = 0.001) than the non-TH group. There was no statistical significance in the incidence of adverse events between the two groups.ConclusionTherapeutic hypothermia can reduce the incidence of brain injury in neonates with mild HIE.

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.

Therapeutic hypothermia in acute myocardial infarction

The review provides basic information on the effect of therapeutic hypothermia on myocardial ischemia, as well as analyzes experimental and clinical studies on therapeutic hypothermia in myocardial infarction. The results of comparison of general body hypothermia and local myocardial hypothermia are discussed. The ways of further studies of this technology in myocardial infarction are outlined.

Evaluation of heterogeneity in effect of therapeutic hypothermia by sex among infants with neonatal encephalopathy.

Our objective was to examine heterogeneity in the effect of therapeutic hypothermia by sex in infants with moderate or severe neonatal encephalopathy. We conducted a post hoc analysis of the Induced Hypothermia trial, which included infants born at gestational ages ≥36 weeks, admitted at ≤6 postnatal hours with evidence of severe acidosis or perinatal complications and moderate or severe neonatal encephalopathy. Multivariate modified Poisson regression models were used to compare the treatment effect of whole-body hypothermia versus control, with an evaluation of interaction by sex, on the primary outcome of death or moderate or severe disability at 18-22 months of corrected age. A total of 101 infants (51 male, 50 female) were randomly assigned to hypothermia treatment and 104 infants (64 male, 40 female) to control. The primary outcome occurred in 45% of the hypothermia group and 63% of the control group (RR 0.73; 95% CI 0.56, 0.94). There was no significant difference (interaction P = 0.50) in the treatment effect of hypothermia on the primary outcome between females (RR 0.79; 95% CI 0.54, 1.17) compared to males (RR 0.63; 95% CI 0.44, 0.91). We found no evidence that sex influences the treatment effect of hypothermia in infants with moderate or severe neonatal encephalopathy. Preclinical evidence suggests a differential effect in response to cooling treatment of hypoxic-ischemic injury between males and females. We found no evidence of heterogeneity in the treatment effect of whole-body hypothermia by sex in this post hoc subgroup analysis of infants with moderate or severe neonatal encephalopathy from the National Institute of Child Health and Human Development Neonatal Research NetworkInduced Hypothermia trial.

WITHDRAWN: Effect of Therapeutic Hypothermia on Cognitive Impairment in a Mouse Model of Ischemia-Reperfusion Injury.

Ahead of Print article withdrawn by publisher.

Short-term effects of therapeutic hypothermia following hypoxia-ischemia in neonatal male and female rats.

Nowadays, the only treatment for human babies suffering from hypoxia-ischemia (HI) is therapeutic hypothermia (TH). However, a better understanding of the specific effects of TH in males and females is important to improve its clinical application. The present study evaluated the short-term effects of TH on the brain injury and behavioral outcomes in male and female neonatal rats submitted to neonatal HI. Seven-day-old Wistar rats underwent a surgery for unilateral occlusion of the right common carotid artery and were exposed to a hypoxic atmosphere (8% oxygen) for 75 min. Then, the animals in the TH group were submitted to TH (scalp temperature of 32°C) for 5 h. In the behavioral tests, no remarkable differences triggered by HI or TH were observed relative to SHAM animals. Only females of the HI group presented lower latency to complete the righting reflex test. TH reduced the volume of brain injury in males, but not in females. The animals of the HI group showed a reduction in the number of neurons in the CA1 and dentate gyrus (DG) regions of the hippocampus and TH partially prevented neuronal death. In the CA1 region of the hippocampus, animals from the HI group showed more degenerating cells relative to the SHAM, which was reversed by TH. In the DG, animals from the HI group showed an increase in the number of degenerating neurons, which was partially reversed by TH only in males. Our data show that HI leads to a brain injury, which was attenuated by TH in a sex-dependent way and clarify the importance of the assessment of males and females in order to outline specific strategies for the treatment of each sex in newborns suffering from HI.

Target temperature management in traumatic brain injury with a focus on adverse events, recognition, and prevention.

Traumatic brain injury (TBI) is a critical cause of disability and death worldwide. Many studies have been conducted aimed at achieving favorable neurologic outcomes by reducing secondary brain injury in TBI patients. However, ground-breaking outcomes are still insufficient so far. Because mild-to-moderate hypothermia (32°C-35°C) has been confirmed to help neurological recovery for recovered patients after circulatory arrest, it has been recognized as a major neuroprotective treatment plan for TBI patients. Thereafter, many clinical studies about the effect of therapeutic hypothermia (TH) on severe TBI have been conducted. However, efficacy and safety have not been demonstrated in many large-scale randomized controlled studies. Rather, some studies have demonstrated an increase in mortality rate due to complications such as pneumonia, so it is not highly recommended for severe TBI patients. Recently, some studies have shown results suggesting TH may help reperfusion/ischemic injury prevention after surgery in the case of mass lesions, such as acute subdural hematoma, and it has also been shown to be effective in intracranial pressure control. In conclusion, TH is still at the center of neuroprotective therapeutic studies regarding TBI. If proper measures can be taken to mitigate the many adverse events that may occur during the course of treatment, more positive efficacy can be confirmed. In this review, we look into adverse events that may occur during the process of the induction, maintenance, and rewarming of targeted temperature management and consider ways to prevent and address them.

Comparing the effect of different loading doses of phenobarbitone on serum phenobarbitone levels in babies with neonatal seizures and effect of therapeutic hypothermia on phenobarbitone levels.

With current recommendation for phenobarbitone dosing, we have noted that babies are extremely sedated with elevated serum phenobarbitone levels. We postulate that asphyxiated neonates with hypoxic liver injury have impaired drug metabolism and renal injury affects drug elimination, thus elevating serum drug levels. Therapeutic hypothermia (TH) could further affect the drug levels. To determine the serum levels of the phenobarbitone in babies receiving different loading doses of phenobarbitone for neonatal seizures and to study the effect of asphyxia and TH on drug levels. Prospective observational cohort study. Term neonates with seizures of any cause were given phenobarbitone up to a maximum loading of 40 mg/kg followed by maintenance dose of 5 mg/kg/day. Serum phenobarbitone levels were assessed after 4 h of the initial loading dose and subsequently at 24, 48 and 72 h from the time after maximum loading dose. Babies were divided into three groups Group 1 (HIE + TH-hypoxic ischemic encephalopathy undergoing TH), Group 2 (HIE - TH-hypoxic ischemic encephalopathy without TH) and Group 3 (non-HIE group). A total of 47 babies completed the study. Twenty-three (49%) received 20 mg/kg, 14 (30%) received 30 mg/kg and 10 (21%) received 40 mg per kg of phenobarbitone as loading dose. HIE was the major cause of seizures 28 (59%) followed by hypoglycemia 7 (14%), cerebral malformations 4 (8%), inborn errors of metabolism 2 (4%) and hypocalcemia 1 (2%) while the cause of seizures was not known in 6 (13%). Median (IQR) Phenobarbitone levels at 72 h in babies who received 20 mg/kg loading dose of phenobarbitone was 46.72 (44.02-50.49) mcg/ml in HIE + TH group, 40.53 (28.66-65.09) mcg/ml in HIE - TH group and 49 (37-65) mcg/ml in non-HIE group. After a loading dose of 30 mg/kg, phenobarbitone level was 63.76 (59.5-65.94) mcg/ml in HIE + TH group, 42.5 (34.75-48.75) mcg/ml in HIE - TH group and 42.07 (40-49.05) mcg/ml in non-HIE group. After 40 mg/kg loading dose, it was 62.3 (60.2-64.9) mcg/ml in HIE + TH group, 57.0 (49.8-60.2) mcg/ml in HIE - TH group and 48.15 (40.8-50.97) mcg/ml in non-HIE group. In babies who received &gt;20 mg/kg loading dose, 100% of HIE + TH, 80% of HIE - TH and 60% of non-HIE had supratherapeutic levels of phenobarbitone. At higher loading doses of 30 and 40 mg/kg, steady state concentration of serum phenobarbitone is higher in babies with hypoxic ischemic encephalopathy who underwent TH than in babies with non-HIE causes of seizures. Loading dose beyond 20 mg/kg should be used with close monitoring of serum drug level.

Effects of therapeutic hypothermia on the safety of children with severe traumatic brain injury: a systematic review and meta-analysis.

BackgroundTherapeutic hypothermia (TH) is effective to treat adult traumatic brain injury (TBI), but there is still controversy about its safety to treat the children with severe TBI.MethodsClinical studies on TH in children with severe TBI from January 2000 to September 2020 were screened in PubMed, Web of Science, Embase, Cochrane Library, Nature, NCKI, and Wanfang online databases. Data were meta-analyzed by Rev Man 5.3. Differences in mortality, adverse outcomes, duration of Pediatric Intensive Care Unit (PICU), incidence of infection, and incidence of arrhythmia were compared between experimental group and control group. The heterogeneity of the results was evaluated by chi-square test and I2 test in Rev Man 5.3, and publication bias was evaluated by funnel plot.ResultsFive articles were included, including 421 children. Cochrane evaluation was B grade or above, and Jadad scale score was over three points. The overall mortality between two groups showed great difference [odds ratio (OR) =1.72, 95% CI: 0.98–3.02, Z=1.87, P=0.04]. The incidence of adverse outcomes (OR =1.39, 95% CI: 0.86–2.25, Z=1.34, P=0.18), the duration of PICU [mean difference (MD) =0.51, 95% CI: −0.33 to 1.35, Z=1.19, P=0.24], the incidence of infection (OR =0.79, 95% CI: 0.51–1.23, Z=1.03, P=0.30), and the incidence of arrhythmia (OR =3.10, 95% CI: 0.77–12.50, Z=1.59, P=0.11) were not considerably different.DiscussionTH significantly reduced overall mortality in children with severe TBI, but did not significantly improve the incidence of adverse outcomes, PICU duration, infection rate, or arrhythmia. These results provided a reference for selecting proper clinical treatment methods for children with severe TBI.

Interventions for the management of Pain and Sedation in Newborns undergoing Therapeutic hypothermia for hypoxic-ischemic encephalopathy (IPSNUT): protocol of a systematic review

BackgroundClinical research has shown that therapeutic hypothermia after neonatal hypoxic-ischemic injury improves survival without disability. There is no consensus regarding pain relief or sedation during therapeutic hypothermia in newborns; however, therapeutic hypothermia seems to be associated with pain and stress, and adequate analgesia and sedation are central to maximize the effect of therapeutic hypothermia. Pain needs to be adequately managed in all patients, especially the newborn infant due to the potential short- and long-term negative effects of inadequately treated pain in this population.MethodsWe will perform a systematic review of pharmacological and non-pharmacological interventions for the management of pain and sedation in newborn infants undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy. We will include randomized, quasi-randomized controlled trials and observational studies. The use of pharmacological or non-pharmacological interventions will be compared to other pharmacological and or non-pharmacological interventions or no intervention/placebo. The primary outcomes for this review will be analgesia and sedation assessed with validated pain scales, circulatory instability, mortality to discharge, and moderate-to-severe neurodevelopmental disability. We will search the following databases: CINAHL, ClinicalTrials.gov, Cochrane Library, Embase, PubMed, Scopus, and Web of Science. Two independent researchers will screen the records for inclusion, extract data using a data extraction form, and assess the risk of bias in the included trials.DiscussionThe result of this review will summarize the knowledge regarding the management of pain and sedation in infants treated with therapeutic hypothermia and potentially provide clinicians with guidance on the effective and safe methods.Systematic review registrationPROSPERO CRD42020205755

Hypothermia cannot ameliorate renal fibrosis after asphyxia in the newborn piglet.

The effects of therapeutic hypothermia (TH) on renal function are not widely reported, especially in longer term animal models. The hypothesis of this study was that TH of the kidneys of hypoxic-ischemic newborn piglets would reduce pathological renal fibrosis. Twenty-five newborn piglets obtained within 24 h of birth were classified into a control group (n = 5), an hypoxic insult with normothermia (HI-NT) group (n = 12), and an hypoxic insult with TH (HI-TH) group (33.5 °C ± 0.5 °C for 24 h; n = 8). Five days after the insult, all piglets were sacrificed under deep anesthesia by isoflurane inhalation. The kidneys were perfused with phosphate-buffered paraformaldehyde and immersed in formalin buffer. Territory fibrosis was studied and scored in the renal medulla using Azan staining. Fibrosis area scores (means ± standard deviations) based on Azan staining were 1.00 ± 0.46 in the control group, 2.85 ± 0.93 in the HI-NT group, and 3.58 ± 1.14 in the HI-TH group. The fibrosis area of the HI-NT and HI-TH groups was larger than that of the control. The HI-NT and HI-TH groups were not statistically different. Renal fibrosis is affected by perinatal asphyxia and cannot be prevented by TH, based on histopathological findings.

Abstract 11243: Novel Peptide for Cardiopulmonary Resuscitation

Introduction: While effective for out-of-hospital cardiac arrest, therapeutic hypothermia can be difficult to timely implement clinically. No drugs exist for improving neurologically intact survival. We have developed a novel peptide (TAT-PHLPP) that inhibits PH domain and Leucine rich repeat Protein Phosphatases (PHLPP), leading to Akt activation and mimicking of the protective effects of therapeutic hypothermia without the need of physical cooling. Hypothesis: We hypothesize that when administered intravenously during CPR, TAT-PHLPP improves neurologically intact survival. Methods: We conducted parallel studies in mouse and swine models. In C57BL6 mice (n = 72), we induced a 8 or 12-min asystolic cardiac arrest with KCl, followed by initiation of CPR and blinded randomized administration of TAT-PHLPP (7.5 mg/kg) or saline placebo. The primary outcomes were 4-h and 5-day survival, mean arterial blood pressure (MAP) and cerebral blood flow (CBF). We assessed PHLPP-NHERF1 binding and glucose utilization (via pyruvate dehydrogenase (PDH) phosphorylation and ATP generation). In 16 swine, we induced 5 min of VF followed by ACLS with vest CPR and administered two doses of TAT-PHLPP or saline. Survival (24 h) and neurological function were assessed. Plasma biomarkers taurine and glutamate levels in mice were measured and validated in CA patients (n=68) with a shockable rhythm at the time of hospital arrival, 6, 24, 48, and 72 h post-hospital arrival. Results: In mice, compared to saline, TAT-PHLPP significantly improved 4-h and 5-day survival, increased post-ROSC MAP and CBF, inhibited PHLPP-NHERF1 binding, increased p-Akt, decreased p-PDH (increased activity) at 15 min post-ROSC, enhanced ATP generation in both heart and brain, and reduced plasma taurine and glutamate levels. In swine, TAT-PHLPP improved 24 h neurologically intact survival (1/9 in control vs. 6/7 with peptide, p &lt; 0.01). In patients, taurine levels were higher in non-survivors (n=44) than survivors (n=24) at 6 h of post-hospital arrival (65.9 ± 34.8 vs. 45.6 ±23.7, p&lt; 0.001). Conclusions: TAT-PHLPP has high translational potential as a first-of-class biologic treatment to reproduce critical outcomes of therapeutic hypothermia and improve cardiac arrest survival.

The Effect of Therapeutic Hypothermia after Cardiac Arrest on the Neurological Outcome and Survival-A Systematic Review of RCTs Published between 2016 and 2020.

Therapeutic hypothermia is a treatment used for patients who have suffered cardiorespiratory arrest and remain conscious after the recovery of spontaneous circulation. However, its effectiveness is controversial. The objective of this systematic review is to summarize the scientific evidence available about the effect of therapeutic hypothermia on neurological status and survival in this type of patients. Methodology: A primary search in CINAHL, CUIDEN, Pubmed, Web of Science, and Scopus databases was carried out. Randomized clinical trials (RCT) published from 2016 to 2020 were selected. Results: 17 studies were selected for inclusion and most relevant data were extracted. Methodological quality was assessed by the RoB tool. Conclusions: Although therapeutic hypothermia is a safe technique with few adverse and manageable effects, it has not shown to improve survival rate and neurological status of adult nor pediatric patients. It is possible that its positive effect on neuroprotection could be achieved only by preventing hyperthermia although further investigation is needed.

The Effect of Therapeutic Hypothermia on Plasma Levels of Thyroid Hormones During Hemorrhagic Shock in Adult Male Wistar Rats

Background and Aim: Hemorrhagic shock (HS) is one of the most important causes of death. In this study, we investigated the benefits of therapeutic hypothermia (32°C) during HS on blood pressure (BP) and the role of thyroid hormones during HS. Materials and Methods: Twenty-four male Wistar rats were divided into two normothermic hemorrhagic (NH) and hypothermic hemorrhagic (HH) groups (32°C during shock); the animals were then anesthetized, a microcatheter was inserted into the femoral artery, and one into the femoral vein. The arterial samples were centrifuged, and plasma was isolated to measure thyroid hormones later. The microcatheter was fixed to a physiograph to record BP. Animals were exposed to HS for 90 minutes by withdrawing blood from the femoral vein and BP was assessed during HS. Results: The BP of HH animals was significantly higher in most times of HS and at 40 minutes (56.8±4.2 mmHg) in comparison to NH rats (45.4±3.8 mmHg) (P&lt;0.05). In addition, the amount of BP in HH animals at the end of the shock period at 90 minutes (63.8±5.5 mmHg) was significantly (P&lt;0.001) higher in comparison with the NH groups (39±3.2 mmHg). Levels of thyroid hormones T4 and T3 at the end of shock were lower in the HH group compared to the NH group (P&lt;0.001). Conclusion: Therapeutic hypothermia indirectly reduces the level of thyroid hormones and directly reduces the metabolism of non-vital tissues, preserves blood in the central arteries, and increases BP.

Destructive hypoxic-ischemic brain injury in full-term infants with normothermia and hypothermia

Background. Despite the achievements of neonatology, severe asphyxia at birth and hypoxic-ischemic encephalopathy in full-term infants are still associated with high lethality, long-term neurological morbidity and disability. In the algorithm for the ma­nagement of children with hypoxic-ischemic encephalopathy, it is important to use methods of additional examinations, including ultrasound examination of the brain (neurosonography), its potential for the early evaluation of the severity of the brain tissue injury using therapeutic hypothermia. Thus, the aim of the research was to determine the effect of therapeutic hypothermia on the severity of neurosonographic signs of destructive hypoxic-ischemic brain injury in full-term newborns. Materials and methods. Data were analyzed for 50 full-term neonates with severe asphyxiation and signs of destructive hypoxic-ischemic brain injury. The first group (hypothermia group 1) included 12 newborn infants who were treated with hypothermia in 2014–2016. The second group (hypothermia group 2) — 14 children with severe asphyxiation who were treated with hypothermia in 2011–2013. The third group (group of normothermia) consisted of 24 full-term babies born in 2009–2010, with no therapeutic hypothermia. Results. The share of the most severe destructive brain injuries (diffuse ischemic lesions) was 33.3 % in the first group, 35.7 % in the second group and 45.8 % in the third group. Significant differences between groups in terms of the frequency of diffuse ischemic brain injures were not found. In general, in the structure of destructive hypoxic-ischemic brain injuries in newborns after hypothermia, diffuse ischemic lesions were detected in 34.6 % of cases (non-significant differences with the group of normothermia, p = 0.385 according to Fisher’s criterion calculations). When studying the indicators of cerebral blood flow, reliable differences were found for the index of resistance of the anterior cerebral artery on the third day of life (0.53 ± 0.05 for normothermia group and 0.65 ± 0.04 for hypothermia group). Conclusions. Despite the reduction in the proportion of the most severe diffuse ischemic brain injuries among the total number of diagnosed destructive hypoxic-ischemic lesions during the introduction of hypothermia, the statistical analysis did not reveal any significant differences between the groups. After all, the development of diffuse ischemic brain injuries, first of all, is due to primary asphyxia lesions that lead to global deaths of neurons, or by these injuries, the phase of the therapeutic window in which ended up at the time of birth. But significant differences in the parameters of cerebral hemodynamics prove the fact that the potential of therapeutic hypothermia for the prevention of secondary reperfusion injury remains in these cases.

Impact of neonatal anoxia and hypothermic treatment on development and memory of rats

Therapeutic hypothermia (TH) is well established as a standard treatment for term and near-term infants. However, therapeutic effects of hypothermia following neonatal anoxia in very premature babies remains inconclusive. The present rodent model of preterm neonatal anoxia has been shown to alter developmental milestones and hippocampal neurogenesis, and to disrupt spatial learning and memory in adulthood. These effects seem to be reduced by post-insult hypothermia. Epigenetic-related mechanisms have been postulated as valuable tools for developing new therapies. Dentate gyrus neurogenesis is regulated by epigenetic factors. This study evaluated whether TH effects in a rodent model of preterm oxygen deprivation are based on epigenetic alterations. The effects of TH on both developmental features (somatic growth, maturation of physical characteristics and early neurological reflexes) and performance of behavioral tasks at adulthood (spatial reference and working memory, and fear conditioning) were investigated in association with the possible involvement of the epigenetic operator Enhancer of zeste homolog 2 (Ezh2), possibly related to long-lasting effects on hippocampal neurogenesis. Results showed that TH reduced both anoxia-induced hippocampal neurodegeneration and anoxia-induced impairments on risk assessment behavior, acquisition of spatial memory, and extinction of auditory and contextual fear conditioning. In contrast, TH did not prevent developmental alterations caused by neonatal anoxia and did not restore hippocampal neurogenesis or cause changes in EZH2 levels. In conclusion, despite the beneficial effects of TH in hippocampal neurodegeneration and in reversing disruption of performance of behavioral tasks following oxygen deprivation in prematurity, these effects seem not related to developmental alterations and hippocampal neurogenesis and, apparently, is not caused by Ezh2-mediated epigenetic alteration.