Effect Of Mild Therapeutic Hypothermia Research Articles

Effect of Mild Therapeutic Hypothermia Combined with Stereotactic Aspiration on Patients with Severe Cerebral Hemorrhage.

This study aimed to investigate the effects of mild therapeutic hypothermia combined with stereotactic aspiration of spontaneous intracerebral hematoma on neurological function, inflammatory markers, cerebral hematoma, and cerebral edema in patients with severe cerebral hemorrhage. The clinical data of 86 patients with severe cerebral hemorrhage treated at our hospital between March 2020 and January 2022 were retrospectively analyzed. The patients were grouped according to their treatment plans: the control group consisted of 40 patients who underwent stereotactic aspiration of the spontaneous intracerebral hematoma, whereas the study group consisted of 46 patients who received adjuvant mild therapeutic hypothermia in addition to the aforementioned treatment. Clinical efficacy, neurological function (NIHSS score), daily living ability (BI score), cerebral hematoma, cerebral edema, cerebral hemodynamics (PI, RI, Vm, Vd), inflammatory markers (IL-6, IL-8, TNF-α, hs-CRP), oxidative stress indicators (SOD, MDA, 8-iso-PGF2α), serum-related factors (MMP-9, ICAM-1, ET-1, NO), and prognosis were compared between the groups. The total efficacy rate in the study group (95.65%) was significantly higher than that in the control group (77.50%) (P < 0.05). Post-treatment NIHSS scores, intracranial hematoma volume, perihematoma edema volume, cerebral edema volume, RI, serum IL-6, IL-8, TNF-α, hs-CRP, MDA, and 8-iso-PGF2α levels were significantly lower in both groups, with the study group showing even greater reductions. The BI score and PI, Vm, Vd, SOD, and NO levels were significantly higher in the study group (P < 0.05). At the 6-month follow-up, the prognosis of patients in the intervention group was significantly better than that of patients in the control group (P < 0.05). The combination of mild therapeutic hypothermia with stereotactic aspiration of a spontaneous intracerebral hematoma has demonstrated efficacy in the treatment of severe cerebral hemorrhage. This approach effectively reduces cerebral hematoma and edema, improves daily living ability, alleviates neurological deficits, regulates cerebral hemodynamics, suppresses inflammatory responses and oxidative stress, modulates serum-related factor levels, and enhances patient prognosis.

Mild Therapeutic Hypothermia Alleviated Myocardial Ischemia/Reperfusion Injury via Targeting SLC25A10 to Suppress Mitochondrial Apoptosis

Myocardial ischemia/reperfusion injury (MI/RI) is identified as a severe vascular emergency, and the treatment strategy of MI/RI still needs further improvement. The present study aimed to investigate the potential effects of mild therapeutic hypothermia (MTH) on MI/RI and underlying mechanisms. In ischemia/reperfusion (I/R) rats, MTH treatment significantly improved myocardial injury, attenuated myocardial infarction, and inhibited the mitochondrial apoptosis pathway. The results of proteomics identified SLC25A10 as the main target of MTH treatment. Consistently, SLC25A10 expressions in I/R rat myocardium and hypoxia and reoxygenation (H/R) cardiomyocytes were significantly suppressed, which was effectively reversed by MTH treatment. In H/R cardiomyocytes, MTH treatment significantly improved cell injury, mitochondrial dysfunction, and inhibited the mitochondrial apoptosis pathway, which were partially reversed by SLC25A10 deletion. These findings suggested that MTH treatment could protect against MI/RI by modulating SLC25A10 expression to suppress mitochondrial apoptosis pathway, providing new theoretical basis for clinical application of MTH treatment for MI/RI.Graphical

Circulating Monocyte Chemoattractant Protein-1 in Patients with Cardiogenic Shock Complicating Acute Myocardial Infarction Treated with Mild Hypothermia: A Biomarker Substudy of SHOCK-COOL Trial

Background: There is evidence that monocyte chemoattractant protein-1 (MCP-1) levels reflect the intensity of the inflammatory response in patients with cardiogenic shock (CS) complicating acute myocardial infarction (AMI) and have a predictive value for clinical outcomes. However, little is known about the effect of mild therapeutic hypothermia (MTH) on the inflammatory response in patients with CS complicating AMI. Therefore, we conducted a biomarker study to investigate the effect of MTH on MCP-1 levels in patients with CS complicating AMI. Methods: In the randomized mild hypothermia in cardiogenic shock (SHOCK-COOL) trial, 40 patients with CS complicating AMI were enrolled and assigned to MTH (33 °C) for 24 h or normothermia at a 1:1 ratio. Blood samples were collected at predefined time points at the day of admission/day 1, day 2 and day 3. Differences in MCP-1 levels between and within the MTH and normothermia groups were assessed. Additionally, the association of MCP-1 levels with the risk of all-cause mortality at 30 days was analyzed. Missing data were accounted for by multiple imputation as sensitivity analyses. Results: There were differences in MCP-1 levels over time between patients in MTH and normothermia groups (P for interaction = 0.013). MCP-1 levels on day 3 were higher than on day 1 in the MTH group (day 1 vs day 3: 21.2 [interquartile range, 0.25–79.9] vs. 125.7 [interquartile range, 87.3–165.4] pg/mL; p = 0.006) and higher than in the normothermia group at day 3 (MTH 125.7 [interquartile range, 87.3–165.4] vs. normothermia 12.3 [interquartile range, 0–63.9] pg/mL; p = 0.011). Irrespective of therapy, patients with higher levels of MCP-1 at hospitalization tended to have a decreased risk of all-cause mortality at 30 days (HR, 2.61; 95% CI 0.997–6.83; p = 0.051). Conclusions: The cooling phase of MTH had no significant effect on MCP-1 levels in patients with CS complicating AMI compared to normothermic control, whereas MCP-1 levels significantly increased after rewarming. Trial registration: NCT01890317.

Mild Therapeutic Hypothermia Alters Hemostasis in ST Elevation Myocardial Infarction Patients.

Background and Rationale: Mild therapeutic hypothermia (MTH) is a concept to reduce infarct size and improve outcome after ST-segment elevation myocardial infarction (STEMI). In the STATIM trial, we investigated MTH as an additional therapy for STEMI patients. In the intention-to-treat set, 101 patients were included. No difference in primary and secondary endpoints measured by cardiac magnetic resonance imaging was found. Platelet activation and plasmatic coagulation are key in the pathophysiology of STEMI. In the present study, we investigated the effect of MTH on primary and secondary hemostasis in STEMI patients.Methods and Results: Platelet function and morphology were assessed by routine blood count, aggregometry testing, and flow cytometry. Soluble platelet markers were determined by enzyme-linked immunosorbent assay (ELISA) testing. Plasmatic coagulation was measured throughout the study. Platelet count remained unchanged, irrespective of treatment, whereas platelet size decreased in both patient groups. Platelet aggregometry indicated increased platelet reactivity in the MTH group. Furthermore, higher adenosine diphosphate (ADP) plasma levels were found in MTH patients. Expression of glycoprotein IIb/IIIa was increased on platelets of STEMI patients treated with MTH. Lower patient temperatures correlated with longer clotting times and resulted in reduced pH. Lower pH values were positively correlated with longer clotting times.Conclusion: Present data indicate longer clotting times and higher platelet reactivity in STEMI patients treated with MTH. These changes did not correspond to clinical bleeding events or larger infarct size.

Analysis of microRNA expression in cerebral ischemia/reperfusion after mild therapeutic hypothermia treatment in rats.

BackgroundThis study aimed to explore the molecular mechanism of mild hypothermia in in the treatment of cerebral ischemia, microRNA (miRNA) microarrays and bioinformatics analysis were employed to examine the miRNA expression profiles of rats with mild therapeutic hypothermia after middle cerebral artery occlusion (MCAO).MethodsMCAO was induced in Male Sprague–Dawley rats. Mild hypothermia treatment began from the onset of ischemia and maintained for 3 hours. miRNA expressions following focal cerebral ischemia and mild hypothermia treatment were profiled using microarray technology. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to analyze the functions of the target genes in mild therapeutic hypothermia after MCAO. 60 min before MCAO, mimics and inhibitor of miR-291b were injected into the right lateral ventricle respectively, then the infarct volume and neuronal apoptosis were analyzed.ResultsSix upregulated miRNAs and 6 downregulated miRNAs were detected 4 hours after mild therapeutic hypothermia, and after 24 hours, 41 and 10 miRNAs were upregulated and downregulated, respectively. The target genes of the differentially expressed genes were mainly related with multicellular organism development and the mucin type O-glycan biosynthesis pathway was the most enriched KEGG pathway. Among the differentially expressed miRNAs, miR-291b was selected to assess the effects of mild therapeutic hypothermia in MCAO rats. At 24 hours after mild therapeutic hypothermia, miR-291b overexpression was proved to exhibit neuroprotective effects.ConclusionsThe results showed that miRNAs might play a pivotal role in mild therapeutic hypothermia in cerebral ischemia/reperfusion injury. Further understanding of the mechanism and function of miRNAs would help to illuminate the mechanism of mild therapeutic hypothermia in cerebral ischemia/reperfusion injury.

The Effect of Mild Hypothermia on Nogo-A and Neurological Function in the Brain after Cardiopulmonary Resuscitation in Rats

Objective We investigated the dynamic changes of Nogo-A protein in brain and the effects of mild therapeutic hypothermia (MTH) on its expression after cardiopulmonary resuscitation (CPR). Methods: Western-blotting and neurological scoring of 45 rats subjected to cardiac arrest and CPR with and without MTR were performed to investigate the changes in the expression of Nogo-A protein in the hippocampus and cortex over a period of time ranging from 6 h to 72 h after restoration of spontaneous circulation (ROSC). Results: Nogo-A expression levels were increased at 6 h after CPR in the hippocampus and cortex, peaked at 24 h in the cortex, and at 48 h in the hippocampus. The expression of Nogo-A in the MTR group was significantly lower at 12 h (p < 0.05) compared to those with no MTR after ROSC. Conclusions: MTR blunts the expression of Nogo-A protein in the hippocampus and cortex after cardiac arrest and resuscitation, and MTR may provide cerebral protection after ischemia.

Abstract 106: Differential Effects of Mild Therapeutic Hypothermia Against Normothermia for Post-Cardiac Arrest Syndrome According to the Severity Scale

Introduction: There are few studies on the differential effects of mild therapeutic hypothermia (MTH) according to the risk class in post-cardiac arrest syndrome (PCAS) patients. Objective: The aim of this study was to evaluate the differential effects of MTH against therapeutic normothermia (TN) for PCAS patients according to our risk classification tool (rCAST). Methods: We used data from the out-of-hospital cardiac arrest (OHCA) registry of the Japanese Association for Acute Medicine (JAAM), which is a multi-center, prospective registry of OHCA patients who were transported to critical care medical centers or hospitals with an emergency care department across Japan. We classified eligible PCAS patients treated with MTH or TN on the basis of our rCAST score which was previously developed by us: low severity group (≤5.5), moderate severity group (6-14), and high severity group (≥14.5). The differential effects of MTH vs. TN for their neurological outcome in the 3 severity categories were evaluated by interaction analysis, and the effect of MTH vs. TN in each group was assessed by multivariate logistic regression analysis and propensity score analysis. The good neurological outcome was defined as a Cerebral Performance Categories score ≤2 at 30 days. Results: Among 12,024 OHCA patients in the registry, data of 460 PCAS patients treated by MTH or TN were analyzed (96 patients; the low score, 192; the moderate score, and 172; the high score group). There was a statistically significant interaction effect between MTH/TN and their neurological outcome at 30 days in the 3 categories (p = 0.022). MTH was significantly associated with good neurological outcome at 30 days in PCAS patients of moderate severity group both in the multivariate logistic regression analysis (adjusted odds ratio, 3.09; 95% confidence interval, 1.13-8.49; p = 0.029) and the propensity score analysis (p = 0.030), while it was not in low and high severity group. Conclusions: The effect of MTH in PCAS patients differed according to the severity of PCAS, and MTH was significantly associated with a good neurological outcome as compared to TN in the moderate severity group.

Mild Hypothermia in Cardiogenic Shock Complicating Myocardial Infarction.

Experimental trials suggest improved outcome by mild therapeutic hypothermia for cardiogenic shock after acute myocardial infarction. The objective of this study was to investigate the hemodynamic effects of mild therapeutic hypothermia in patients with cardiogenic shock complicating acute myocardial infarction. Patients (n=40) with cardiogenic shock undergoing primary percutaneous coronary intervention without classic indications for mild therapeutic hypothermia underwent randomization in a 1:1 fashion to mild therapeutic hypothermia for 24 hours or control. The primary end point was cardiac power index at 24 hours; secondary end points included other hemodynamic parameters and serial measurements of arterial lactate. No relevant differences were observed for the primary end point of cardiac power index at 24 hours (mild therapeutic hypothermia versus control: 0.41 [interquartile range, 0.31-0.52] versus 0.36 [interquartile range, 0.31-0.48] W/m2; P=0.50; median difference, -0.025 W/m2; 95% CI, -0.12 to 0.06). Similarly, all other hemodynamic measurements were not statistically different. Arterial lactate levels at 6, 8, and 10 hours were significantly higher in patients in the mild therapeutic hypothermia group with a slower decline ( P for interaction=0.03). There were no differences in 30-day mortality (60% versus 50%; hazard ratio, 1.27; 95% CI, 0.55-2.94; P=0.55). In this randomized trial, mild therapeutic hypothermia failed to show a substantial beneficial effect on cardiac power index at 24 hours in patients with cardiogenic shock after acute myocardial infarction. URL: https://www.clinicaltrials.gov . Unique identifier: NCT01890317.

Differential effect of mild therapeutic hypothermia depending on the findings of hypoxic encephalopathy on early CT images in patients with post-cardiac arrest syndrome

IntroductionThe aim of this study was to evaluate the differential effects of mild therapeutic hypothermia (MTH) in post-cardiac arrest syndrome (PCAS) patients depending on the presence/absence of hypoxic encephalopathy (HE) in the early brain CT images obtained before the initiation of MTH. MethodsWe conducted a retrospective review of the data of a total of 129 patients with PCAS who were treated by MTH (34 °C) or normothermia treatment (NT) (35 °C or 36 °C), and had undergone brain CT examination prior to the initiation of these treatments. We divided the subjects into 4 groups, namely, the HE(−)/MTH, HE(−)/NT, HE(+)/MTH, and HE(+)/NT groups, for evaluating the interaction effect between the two variables. Then, we compared the neurological outcomes between the HE(−)/MTH and HE(−)/NT groups by multivariate logistic analysis. Good outcome was defined as a Cerebral Performance Category score of ≤2 at 30 days. ResultsThe percentages of subjects with a good outcome in the HE(−)/MTH and HE(−)/NT group were 68.9% (42/61) and 36.1% (13/36), respectively (p = .003), while those in the HE(+)/MTH and HE(+)/NT groups were lower, at 7.4% (2/27) and 20.0% (1/5), respectively (p = .410), suggesting a statistically significant interaction effect between the two variables (pinteraction = 0.002). In the HE(−) group, MTH was associated with a higher odds ratio of a good outcome as compared to NT (OR 6.80, 95% CI 1.19–38.96, p = .031). ConclusionsThe effect of MTH in patients with PCAS differed depending on the presence/absence of evidence of HE on the early CT images.

Transcriptome Analysis of Gene Expression Provides New Insights into the Effect of Mild Therapeutic Hypothermia on Primary Human Cortical Astrocytes Cultured under Hypoxia.

Hypothermia is increasingly used as a therapeutic measure to treat brain injury. However, the cellular mechanisms underpinning its actions are complex and are not yet fully elucidated. Astrocytes are the most abundant cell type in the brain and are likely to play a critical role. In this study, transcriptional changes and the protein expression profile of human primary cortical astrocytes cultured under hypoxic conditions for 6 h were investigated. Cells were treated either with or without a mild hypothermic intervention 2 h post-insult to mimic the treatment of patients following traumatic brain injury (TBI) and/or stroke. Using human gene expression microarrays, 411 differentially expressed genes were identified following hypothermic treatment of astrocytes following a 2 h hypoxic insult. KEGG pathway analysis indicated that these genes were mainly enriched in the Wnt and p53 signaling pathways, which were inhibited following hypothermic intervention. The expression levels of 168 genes involved in Wnt signaling were validated by quantitative real-time-PCR (qPCR). Among these genes, 10 were up-regulated and 32 were down-regulated with the remainder unchanged. Two of the differentially expressed genes (DEGs), p38 and JNK, were selected for validation at the protein level using cell based ELISA. Hypothermic intervention significantly down-regulated total protein levels for the gene products of p38 and JNK. Moreover, hypothermia significantly up-regulated the phosphorylated (activated) forms of JNK protein, while downregulating phosphorylation of p38 protein. Within the p53 signaling pathway, 35 human apoptosis-related proteins closely associated with Wnt signaling were investigated using a Proteome Profiling Array. Hypothermic intervention significantly down-regulated 18 proteins, while upregulating one protein, survivin. Hypothermia is a complex intervention; this study provides the first detailed longitudinal investigation at the transcript and protein expression levels of the molecular effects of therapeutic hypothermic intervention on hypoxic human primary cortical astrocytes. The identified genes and proteins are targets for detailed functional studies, which may help to develop new treatments for brain injury based on an in-depth mechanistic understanding of the astrocytic response to hypoxia and/or hypothermia.

Combination Treatment with Methylene Blue and Hypothermia in Global Cerebral Ischemia.

Therapeutic hypothermia (TH) is the most potent therapeutic strategy for global cerebral ischemia (GCI), usually induced by cardiac arrest. TH has been shown both to suppress the delayed neuronal cell death in the vulnerable hippocampal CA1 subregion and to improve neurological outcomes in experimental animals after GCI. However, given the multiple adverse effects resulting from TH, application of such a therapy is typically limited. In recent years, methylene blue (MB) has emerged as a potential therapeutic drug for the treatment of neurodegenerative diseases. In this study, we investigated the beneficial effects of mild TH combined with MB treatment after GCI. We report that both the neuronal survival in the hippocampal CA1 region and the hippocampus-dependent spatial learning and memory in the combined treatment animals were enhanced compared to those in the single treatment animals. Mechanistic studies revealed that combined TH and MB treatment significantly attenuated mitochondrial dysfunction induced by GCI in the hippocampus CA1 region. The combined treatment also markedly suppressed GCI-induced reactive gliosis and inflammation and reduced oxidative stress while enhancing the antioxidant capacity of hippocampal CA1 neurons. Finally, combining TH and MB synergistically attenuated the intrinsic cytochrome c/caspase-3 apoptotic pathway induced by GCI. Our results suggest that TH and MB act synergistically to protect the ischemic brain and suppress cognitive impairment caused by GCI.

MILD HYPOTHERMIA IN CARDIOGENIC SHOCK COMPLICATING MYOCARDIAL INFARCTION: THE RANDOMIZED SHOCK-COOL PILOT TRIAL

Background —Experimental trials suggest improved outcome by mild therapeutic hypothermia for cardiogenic shock following acute myocardial infarction. The objective of this study was to inves-tigate hemodynamic effects of mild therapeutic hypothermia in patients with cardiogenic shock complicating acute myocardial infarction. Methods —Patients (n=40) with cardiogenic shock undergoing primary percutaneous coronary in-tervention without classical indication for mild therapeutic hypothermia underwent randomization in a 1:1 fashion to mild therapeutic hypothermia for 24 h or control. The primary endpoint was cardiac power index at 24 h; secondary endpoints included other hemodynamic parameters as well as serial measurements of arterial lactate. Results —No relevant differences were observed for the primary endpoint cardiac power index at 24 h (mild therapeutic hypothermia vs. control: 0.41 [interquartile range 0.31-0.52] vs. 0.36 [inter-quartile range 0.31-0.48] W/m 2 ; p=0.50, median difference -0.025 [95% confidence interval -0.12 to 0.06 W/m 2 ]). Similarly, all other hemodynamic measurements were not statistically different. Arterial lactate levels at 6, 8 and 10 hours were significantly higher in patients in the MTH group with a slower decline (p for interaction 0.03). There were no differences in 30-day mortality: (60 vs. 50%, hazard ratio 1.27 [95% confidence interval 0.55-2.94]; p=0.55). Conclusions —In this randomized trial mild therapeutic hypothermia failed to show a substantial beneficial effect in patients with cardiogenic shock after acute myocardial infarction on cardiac power index at 24 h. Clinical Trial Registration —URL: www.clinicaltrials.gov Unique Identifier: NCT01890317

Decompressive Craniectomy in a Patient with Severe Traumatic Brain Injury during Mild Therapeutic Hypothermia

Mild Therapeutic Hypothermia (MTH) and decompressive craniectomy are therapeutic measures used for the treatment of intracranial hypertension (ICHT) refractory to medical treatment and cerebrospinal fluid drainage. One of the side effects of MTH is the increased risk of coagulopathy, thus the performance of neurosurgical procedures in these cases is very controversial.We present the case of a patient with traumatic brain injury and ICHT refractory to medical treatment, in which moderate therapeutic hypothermia was initiated. After a transient improvement, the patient presented ICHT again, requiring a decompressive craniotomy while keeping the patient in moderate hypothermia. Due to the history of traumatic brain injury and the use of MTH, we decided on the use of viscoelastic tests as goal-directed therapy to assess haemostasis prior to surgery.

Editor's Choice- Inside the cold heart: A review of therapeutic hypothermia cardioprotection.

Targeted temperature management has been originally used to reduce neurological injury and improve outcome in patients after out-of-hospital cardiac arrest. Myocardial infarction remains a major cause of death in the world and several investigators are studying the effect of mild therapeutic hypothermia during an acute cardiac ischemic injury. A search on MEDLINE, Scopus and EMBASE databases was conducted to obtain data regarding the cardioprotective properties of therapeutic hypothermia. Preclinical studies have shown that therapeutic hypothermia provides a cardioprotective effect in animals. The proposed pathways for the cardioprotective effects of therapeutic hypothermia include stabilization of mitochondrial permeability, production of nitric oxide, equilibration of reactive oxygen species, and calcium channels homeostasis. Clinical trials in humans have yielded controversial results. Current trials are therefore seeking to combine therapeutic hypothermia with other treatment modalities in order to improve the outcomes of patients with acute ischemic injury. This article provides a review of the hypothermia effects on the cardiovascular system, from the basic science of physiological changes in the human body and molecular mechanisms of cardioprotection to the bench of clinical trials with therapeutic hypothermia in patients with acute ischemic injury.

Therapeutic hypothermia and outcomes in paediatric out-of-hospital cardiac arrest: A nationwide observational study

ObjectivesThis study aimed to analyse the association between mild therapeutic hypothermia (MTH) and outcomes in paediatric patients who survived out-of-hospital cardiac arrest (OHCA) by using their initial electrocardiogram (ECG) rhythm, which is the key factor used to predict prognosis in paediatric OHCA. MethodsThis cross-sectional observational study utilised the registry of paediatric OHCA patients who survived to admission from 2008 to 2014 in the national OHCA database. MTH was defined as all cooling methods applied after the return of spontaneous circulation. Primary and secondary outcomes were survival to discharge and good neurologic recovery, respectively. Multivariable logistic regression analysis with an interaction term between MTH and the initial ECG at the scene was conducted to calculate adjusted odds ratios (AORs) and 95% confidence intervals (CIs) after adjusting for potential confounders. ResultsAmong the 663 enrolled patients, the rates of survival to discharge and good neurological recovery in the MTH and non-MTH groups were similar, at 48.1% vs. 40.2% (P=0.17, AOR 1.05 [0.59–1.88]) and 22.2% vs. 8.7% (P=0.45, AOR 1.22 [0.59–2.51]). In the interaction model, the AORs of MTH in shockable rhythm vs. non-shockable rhythm for survival to discharge (AOR 0.62 [0.15–2.52] vs. 1.17 [0.62–2.2]) and good neurological recovery (0.42 [0.12–1.45] vs. 2.22 [0.83–5.98]) were not significantly different. ConclusionMTH and the effect of MTH across the initial ECG at the scene were not significantly associated with survival or good neurologic recovery in paediatric OHCA survivors.

Therapeutic hypothermia protects against ischemia-induced impairment of synaptic plasticity following juvenile cardiac arrest in sex-dependent manner

Pediatric cardiac arrest (CA) often leads to poor neurologic outcomes, including deficits in learning and memory. The only approved treatment for CA is therapeutic hypothermia, although its utility in the pediatric population remains unclear. This study analyzed the effect of mild therapeutic hypothermia after CA in juvenile mice on hippocampal neuronal injury and the cellular model of learning and memory, termed long-term potentiation (LTP). Juvenile mice were subjected to cardiac arrest and cardiopulmonary resuscitation (CA/CPR) followed by normothermia (37°C) and hypothermia (30°C, 32°C). Histological injury of hippocampal CA1 neurons was performed 3days after resuscitation using hematoxylin and eosin (H&E) staining. Field excitatory post-synaptic potentials (fEPSPs) were recorded from acute hippocampal slices 7days after CA/CPR to determine LTP. Synaptic function was impaired 7days after CA/CPR. Mice exposed to hypothermia showed equivalent neuroprotection, but exhibited sexually dimorphic protection against ischemia-induced impairment of LTP. Hypothermia (32°C) protects synaptic plasticity more effectively in females, with males requiring a deeper level of hypothermia (30°C) for equivalent protection. In conclusion, male and female juvenile mice exhibit equivalent neuronal injury following CA/CPR and hypothermia protects both males and females. We made the surprising finding that juvenile mice have a sexually dimorphic response to mild therapeutic hypothermia protection of synaptic function, where males may need a deeper level of hypothermia for equivalent synaptic protection.

Limited effect of mild therapeutic hypothermia on outcome after prolonged resuscitation

BackgroundMild therapeutic hypothermia interferes with multiple cascades of the ischaemia/reperfusion injury that is known as primary mechanism for brain damage after cardiac arrest. First resuscitation attempts and the duration of resuscitation efforts will initiate and aggravate this pathophysiology. Therefore we investigated the interaction between the duration of basic and advanced life support and outcome after cardiac arrest in patients treated with or without mild therapeutic hypothermia. MethodsThis retrospective cohort study included patients 18 years of age or older suffering a witnessed out-of-hospital cardiac arrest with presumed cardiac cause, which remained comatose after restoration of spontaneous circulation. The basic and advanced life support ‘low-flow’ time, categorized into four quartiles (0–11, 12–17, 18–28, ≥29min), was correlated with neurological outcome. ResultsOut of 1103 patients 613 were cooled to a target temperature of 33±1°C for 24h. In the three quartiles with ‘low-flow’ time up to 28min cooling was associated with >2-fold odds of favourable neurological outcome. In the fourth quartile with ‘low-flow’ time of ≥29min cooling had no influence on neurological outcome (OR: 0.73; 95% CI: 0.38–1.4, test for interaction p<0.01). ConclusionThe duration of resuscitation efforts, defined as ‘low-flow’ time, influences the effectiveness of mild therapeutic hypothermia in terms of neurologic outcome. Patients with low to moderate ‘low-flow’ time benefit most from this treatment.

Effects of mild therapeutic hypothermia on acute kidney injury after cardiopulmonary resuscitation

About the effect of mild therapeutic hypothermia on renal function after cardiopulmonary resuscitation little data exists. From animal and human studies it is known that renal function might be impaired, which is not reflected by serum creatinine levels if creatinine production is reduced.

At what level of unconsciousness is mild therapeutic hypothermia indicated for out-of-hospital cardiac arrest: a retrospective, historical cohort study.

BackgroundAppropriate patient selection is very important when initiating mild therapeutic hypothermia (MTH) for patients following out-of-hospital cardiac arrest, and the extent of unconsciousness at implementation must be defined in such cases. However, there are no clear standards regarding the level of unconsciousness at which MTH would be beneficial. The effects of MTH in patients with different degrees of unconsciousness according to the motor response score of the Glasgow Coma Scale (GCS) were investigated.MethodsThe subjects consisted of witnessed non-traumatic adult out-of-hospital cardiac arrest patients admitted to our institute from April 2002 to August 2011. The patients were divided into six groups according to the GCS motor response score: 1 (GCS M1), 2 (GCS M2), 3 (GCS M3), 4 (GCS M4), 5 (GCS M5), and 6 (GCS M6). The neurological outcome was evaluated at 30 days after hospital admission using the Cerebral Performance Category. Chi-squared Automatic Interaction Detection (CHAID) analysis was performed to estimate the threshold GCS M level where therapeutic hypothermia is indicated. Odds ratios were then calculated by multiple logistic-regression analysis using factors including GCS M5–6 and MTH.ResultsA total of 289 patients were enrolled in this study. CHAID analysis demonstrated two points of significant increase in percentage of good recovery at 30 days after admission, dividing the GCS M categories into three groups. Patients classified with a GCS motor response score of 5 or higher had the highest percentage of good recovery. The odds ratio for good recovery (CPC1–2) was 2.901 (95 % CI 1.460–5.763, P = 0.002) for MTH, and that for GCS M5–6 was 159.835 (95 % CI 33.592–760.513, P < 0.001).ConclusionsMTH may be unnecessary in patients with a GCS motor response score of 5 or higher. Consequently, because there are post cardiac arrest patients with a GCS motor response score of 4 or lower who benefit from MTH, MTH may be limited to patients with a GCS motor response score of 4 or lower.

The effect of mild therapeutic hypothermia on good neurological recovery after out-of-hospital cardiac arrest according to location of return of spontaneous circulation: A nationwide observational study

BackgroundMild therapeutic hypothermia (MTH) has been known to be associated with good neurological recovery after out-of-hospital cardiac arrest (OHCA). Prehospital return of spontaneous circulation (P-ROSC) is associated with better hospital outcomes than ROSC at emergency department (ED-ROSC). The study aims to examine the association between MTH by location of ROSC and good neurological recovery after OHCA. MethodsAdult OHCA cases with presumed cardiac etiology who survived to hospital admission were collected from a nationwide cardiac registry between 2008 and 2013. MTH was defined as a case receiving hypothermia procedure regardless of procedure method. Primary outcome was good neurological recovery with cerebral performance category score of 1 and 2. Multivariable logistic regression analysis was performed adjusting for potential confounders with an interaction term between MTH and location of ROSC to calculate adjusted odds ratios (AORs) and 95% confidence intervals (CIs). ResultsAmong 11,158 patients survived to admission, good neurological recovery was 23.6% (399/1691) in MTH vs. 15.0% (1400/9316) in non-MTH (p<0.001), and 58.2% (1074/1864) in P-ROSC vs. 7.9% (725/9161) in ED-ROSC (p<0.001). There was a significant association between MTH and good neurological recovery (AOR=1.32, 95% CI=1.11–1.57). In the interaction model, AOR of MTH and interaction effect with P-ROSC and ED-ROSC was 0.78 (0.58–2.70) and 1.68 (1.34–1.98), respectively. ConclusionMTH was significantly associated with good neurological recovery among OHCA survivors. In the interaction model, MTH showed significant benefits in patient group with ROSC at ED, not in P-ROSC group.