Ischemic stroke outcome after promoting CD4+CD25+ Treg cell migration through CCR4 overexpression in a tMCAO animal model.

The importance of neuroinflammation during the ischemic stroke has been extensively studied. The role of CD4+CD25+ regulatory T (Treg) cells during the recovery phase have shown infarct size reduction and functional improvement, possibly through the mitigation of inflammatory immune responses. We aimed to investigate the molecular factors involved in microglia-Treg cell communication that result in Treg trafficking. First, we observed the migration patterns of CD8+ (cytotoxic) T cells and Treg cells and then searched for chemokines released by activated microglia in an oxygen-glucose deprivation (OGD) model. The transwell migration assay showed increased migration into OGD media for both cell types, in agreement with the increase in chemokines involved in immune cell trafficking from the mouse chemokine profiling array. MSCV retrovirus was transduced to overexpress CCR4 in Treg cells. CCR4-overexpressed Treg cells were injected into the mouse transient middle cerebral artery occlusion (tMCAO) model to evaluate the therapeutic potential via the tetrazolium chloride (TTC) assay and behavioral tests. A general improvement in the prognosis of animals after tMCAO was observed. Our results suggest the increased mobility of CCR4-overexpressed Treg cells in response to microglia-derived chemokines in vitro and the therapeutic potential of Treg cells with increased mobility in cellular therapy.

Baseline eGFR cutoff for increased risk of post-contrast acute kidney injury in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction in the emergency department.

Acute myocardial infarction is an acute-stage disease that requires prompt diagnosis and treatment. Primary percutaneous coronary intervention (pPCI) for ST-elevation myocardial infarction (STEMI) is a high-risk factor for post-contrast acute kidney injury (PC-AKI). This retrospective cohort study analyzed the data of 754 patients with STEMI who underwent pPCI and were integrated into the Fast Interrogation Rule for STEMI critical pathway program between 2015 and 2019. We aimed to determine the optimal cutoff baseline eGFR for identifying a high risk of PC-AKI after multivariable adjustment with statistically significant risk factors. We also compared the incidence rates of PC-AKI between the previous and current diagnostic criteria. The probability of PC-AKI increased when the baseline estimated glomerular filtration rate (eGFR) was ≤ 79mL/min/1.73 m2. The optimal cutoff baseline eGFR for high risk of PC-AKI was found to be an eGFR of ≤ 61 mL/min/1.73 m2 after multivariable adjustment. The current diagnostic criteria more accurately identified the patient group with impaired renal function. Our results have clinically significant implications for identifying patients at a high risk of developing PC-AKI, especially before and after the use of contrast agents in patients who require PCI for STEMI in the emergency department.

Delivery of recombinant sestrin2 ameliorates oxidative stress, mitochondrial damage and renal dysfunction in contrast-induced acute kidney injury.

Although the use of iodinated contrast agents is sometimes unavoidable for accurate diagnosis, contrast-induced acute kidney injury (CI-AKI) is a possible complication of its administration. The pathogenesis of CI-AKI has not been fully elucidated, but oxidative stress is thought to be a major factor. Sestrin2 plays an important role in cellular and mitochondrial homeostasis by regulating oxidative stress. In this study, we aimed to investigate whether recombinant adenovirus containing sestrin2 (RS) can attenuate CI-AKI by reducing oxidative stress in a CI-AKI mice model. Our results showed that RS decreases oxidative stress, pro-inflammatory cytokines (TNF-α, IL-1α, IL-1ß and IL-6) and apoptosis (Bax/Bcl2 and cleaved caspase-3) in the CI-AKI model. Additionally, RS alleviated mitochondrial damage, as evidenced by morphological changes, are restored ATP synthesis. Furthermore, RS administration resulted in a decrease in mitochondrial fission marker (Drp1) that was increased in the CI-AKI model, while the mitochondrial fusion marker (Mfn2) increased, indicating a restoration of mitochondrial dynamics. Decreased relative blood volume, as evaluated on computed tomography (CT), significantly increased compared to the CI-AKI group after RS administration. Finally, renal injury markers such as Kim-1, Ngal, IL-18 also decreased and kidney function was preserved with RS. These results suggested that RS can mitigate the deterioration of renal function in CI-AKI model.

Therapeutic hypothermia for stroke: Unique challenges at the bedside.

Therapeutic hypothermia has shown promise as a means to improving neurological outcomes at several neurological conditions. At the clinical level, it has been shown to improve outcomes in comatose survivors of cardiac arrest and in neonatal hypoxic ischemic encephalopathy, but has yet to be convincingly demonstrated in stroke. While numerous preclinical studies have shown benefit in stroke models, translating this to the clinical level has proven challenging. Major obstacles include cooling patients with typical stroke who are awake and breathing spontaneously but often have significant comorbidities. Solutions around these problems include selective brain cooling and cooling to lesser depths or avoiding hyperthermia. This review will cover the mechanisms of protection by therapeutic hypothermia, as well as recent progress made in selective brain cooling and the neuroprotective effects of only slightly lowering brain temperature. Therapeutic hypothermia for stroke has been shown to be feasible, but has yet to be definitively proven effective. There is clearly much work to be undertaken in this area.

Thrombotic Microangiopathy Score as a New Predictor of Neurologic Outcomes in Patients after Out-of-Hospital Cardiac Arrest.

PURPOSE: Given the morphological characteristics of schistocytes, thrombotic microangiopathy (TMA) score can be beneficial as it can be automatically and accurately measured. This study aimed to investigate whether serial TMA scores until 48 h post admission are associated with clinical outcomes in patients undergoing targeted temperature management (TTM) after out-of-hospital cardiac arrest (OHCA). MATERIALS AND METHODS: We retrospectively evaluated a cohort of 185 patients using a prospective registry. We analyzed TMA scores at admission and after 12, 24, and 48 hours. The primary outcome measures were poor neurological outcome at discharge and 30-day mortality. RESULTS: Increased TMA scores at all measured time points were independent predictors of poor neurological outcomes and 30-day mortality, with TMA score at time-12 showing the strongest correlation [odds ratio (OR), 3.008; 95% confidence interval (CI), 1.707-5.300; p<0.001 and hazard ratio (HR), 1.517; 95% CI, 1.196-1.925; p<0.001]. Specifically, a TMA score ≥2 at time-12 was closely associated with an increased predictability of poor neurological outcomes (OR, 6.302; 95% CI, 2.841-13.976; p<0.001) and 30-day mortality (HR, 2.656; 95% CI, 1.675-4.211; p<0.001). CONCLUSION: Increased TMA scores predicted neurological outcomes and 30-day mortality in patients undergoing TTM after OHCA. In addition to the benefit of being serially measured using an automated hematology analyzer, TMA score may be a helpful tool for rapid risk stratification and identification of the need for intensive care in patients with return of spontaneous circulation after OHCA.

Optimal temperature in targeted temperature management without automated devices using a feedback system: A multicenter study.

PURPOSE: Targeted temperature management (TTM) at 32 °C-36 °C improves patient outcomes following out-of-hospital cardiac arrest (OHCA). TTM using automated temperature management devices with feedback systems (TFDs) is recommended, but the equipment is often unavailable. This study aimed to investigate therapeutic relations between targeted temperatures and TFDs on the outcomes of OHCA patients with TTM. METHODS: This multicenter study analyzed nontraumatic OHCA registry data between October 2015 and June 2020 from 29 institutions. Patients were classified into four groups based on targeted temperatures and TFD implementation: TTM at 33 °C with TFD (33TFD), TTM at 36 °C with TFD (36TFD), TTM at 33 °C without TFD (33NTFD), and TTM at 36 °C without TFD (36NTFD). Clinical outcomes were survival till hospital discharge and neurological status at discharge. RESULTS: A total of 938 patients were included in the analysis. There was an independent association between the 33NTFD patients with the least survival and the worst neurological outcomes among the four groups after adjustment for covariates. However, no significant differences were observed in survival and neurological outcomes among the 33TFD, 36TFD, and 36NTFD groups after adjusting for covariates. Compared to 33NTFD, 36NTFD patients exhibited significantly higher adjusted ORs for survival and favorable neurological status at hospital discharge. CONCLUSION: In OHCA patients receiving TTM without TFDs, the adjusted predicted probability of survival and good neurological outcomes at hospital discharge was greater for TTM at 36 °C than that at 33 °C. This suggests that a TTM of 36 °C rather than 33 °C is associated with more favorable clinical outcomes if TFDs are unavailable.

Recombinant Klotho Protein Ameliorates Myocardial Ischemia/Reperfusion Injury by Attenuating Sterile Inflammation.

Currently, no effective therapy and potential target have been elucidated for preventing myocardial ischemia and reperfusion injury (I/R). We hypothesized that the administration of recombinant klotho (rKL) protein could attenuate the sterile inflammation in peri-infarct regions by inhibiting the extracellular release of high mobility group box-1 (HMGB1). This hypothesis was examined using a rat coronary artery ligation model. Rats were divided into sham, sham+ rKL, I/R, and I/R+ rKL groups (n = 5/group). Administration of rKL protein reduced infarct volume and attenuated extracellular release of HMGB1 from peri-infarct tissue after myocardial I/R injury. The administration of rKL protein inhibited the expression of pro-inflammatory cytokines in the peri-infarct regions and significantly attenuated apoptosis and production of intracellular reactive oxygen species by myocardial I/R injury. Klotho treatment significantly reduced the increase in the levels of circulating HMGB1 in blood at 4 h after myocardial ischemia. rKL regulated the levels of inflammation-related proteins. This is the first study to suggest that exogenous administration of rKL exerts myocardial protection effects after I/R injury and provides new mechanistic insights into rKL that can provide the theoretical basis for clinical application of new adjunctive modality for critical care of acute myocardial infarction.

Relationship between time of emergency department admission and adherence to the Surviving Sepsis Campaign bundle in patients with septic shock.

BACKGROUND: Nighttime hospital admission is often associated with increased mortality risk in various diseases. This study investigated compliance rates with the Surviving Sepsis Campaign (SSC) 3-h bundle for daytime and nighttime emergency department (ED) admissions and the clinical impact of compliance on mortality in patients with septic shock. METHODS: We conducted an observational study using data from a prospective, multicenter registry for septic shock provided by the Korean Shock Society from 11 institutions from November 2015 to December 2017. The outcome was the compliance rate with the SSC 3-h bundle according to the time of arrival in the ED. RESULTS: A total of 2049 patients were enrolled. Compared with daytime admission, nighttime admission was associated with higher compliance with the administration of antibiotics within 3 h (adjusted odds ratio (adjOR), 1.326; 95% confidence interval (95% CI), 1.088-1.617, p = 0.005) and with the complete SSC bundle (adjOR, 1.368; 95% CI, 1.115-1.678; p = 0.003), likely to result from the increased volume of all patients and sepsis patients admitted during daytime hours. The hazard ratios of the completion of SSC bundle for 28-day mortality and in-hospital mortality were 0.750 (95% CI 0.590-0.952, p = 0.018) and 0.714 (95% CI 0.564-0.904, p = 0.005), respectively. CONCLUSION: Septic shock patients admitted to the ED during the daytime exhibited lower sepsis bundle compliance than those admitted at night. Both the higher number of admitted patients and the higher patients to medical staff ratio during daytime may be factors that are responsible for lowering the compliance.

Effect of Prehospital Epinephrine on Out-of-Hospital Cardiac Arrest Outcomes: A Propensity Score-Matched Analysis.

PURPOSE: A pilot project using epinephrine at the scene under medical control is currently underway in Korea. This study aimed to determine whether prehospital epinephrine administration is associated with improved survival and neurological outcomes in out-of-hospital cardiac arrest (OHCA) patients who received epinephrine during cardiopulmonary resuscitation (CPR) in the emergency department. MATERIALS AND METHODS: This retrospective observational study used a nationwide multicenter OHCA registry. Patients were classified into two groups according to whether they received epinephrine at the scene or not. The associations between prehospital epinephrine use and outcomes were assessed using propensity score (PS)-matched analysis. Multivariable logistic regression analysis was performed using PS matching. The same analysis was repeated for the subgroup of patients with non-shockable rhythm. RESULTS: PS matching was performed for 1084 patients in each group. Survival to discharge was significantly decreased in the patients who received prehospital epinephrine [odds ratio (OR) 0.415, 95% confidence interval (CI) 0.250-0.670, p<0.001]. However, no statistical significance was observed for good neurological outcome (OR 0.548, 95% CI 0.258-1.123, p=0.105). For the patient subgroup with non-shockable rhythm, prehospital epinephrine was also associated with lower survival to discharge (OR 0.514, 95% CI 0.306-0.844, p=0.010), but not with neurological outcome (OR 0.709, 95% CI 0.323-1.529, p=0.382). CONCLUSION: Prehospital epinephrine administration was associated with decreased survival rates in OHCA patients but not statistically associated with neurological outcome in this PS-matched analysis. Further research is required to investigate the reason for the detrimental effect of epinephrine administered at the scene.

Predictive model for diagnosing central lesions in emergency department patients with isolated dizziness who undergo diffusion-weighted magnetic resonance imaging.

OBJECTIVES: Only 5% to 10% of patients who visit the emergency department (ED) with isolated dizziness without neurologic abnormalities may have central lesions; however, it is important to distinguish central lesions through brain imaging. This study was conducted to create a nomogram to provide an objective medical basis for selectively performing magnetic resonance imaging (MRI) among patients with isolated dizziness. METHODS: This retrospective observational study enrolled patients who visited the ED of a tertiary hospital with isolated dizziness and underwent diffusion-weighted MRI and subsequently consulted with the departments of neurology, neurosurgery, or otorhinolaryngology. Multivariable logistic regression analysis was performed to identify risk factors in patients diagnosed with central lesions to create a nomogram with the significant variables. RESULTS: Of the 1,078 patients who were screened, 119 were diagnosed with central lesions. Significant variables in the multivariable logistic regression analysis were albumin levels (odds ratio [OR] = 0.339, 95% confidence interval [CI] = 0.188 to 0.610, p = 0.0003), inorganic phosphate levels (OR = 0.891, 95% CI = 0.832 to 0.954, p = 0.0010), history of ischemic stroke (OR = 3.170, 95% CI = 1.807 to 5.560, p < 0.0001), presyncope (OR = 3.152, 95% CI = 1.184 to 8.389, p = 0.0216), and nystagmus (OR = 0.365, 95% CI = 0.237 to 0.561, p < 0.0001). The area under the receiver operating characteristic curve of the nomogram created with these variables was 0.7315 (95% CI = 0.6842 to 0.7788, p < 0.0001). CONCLUSIONS: Albumin, inorganic phosphate, previous stroke, presyncope, and nystagmus were associated with the predictive diagnosis of central lesions among patients admitted to the ED with isolated dizziness. The novel nomogram created using these variables can help in objectively determining the need for MRI in patients presenting with isolated dizziness to the ED.

Targeted Temperature Management at 36 °C Shows Therapeutic Effectiveness via Alteration of Microglial Activation and Polarization After Ischemic Stroke.

Ischemic injury leads to cell death and inflammatory responses after stroke. Microglia especially play a crucial role in this brain inflammation. Targeted temperature management (TTM) at 33 °C has shown neuroprotective effects against many acute ischemic injuries. However, it has also shown some adverse effects in preclinical studies. Therefore, we explored the neuroprotective effect of TTM at 36 °C in the ischemic brain. To confirm the neuroprotective effects of hypothermia, mice were subjected to a permanent stroke and then treated with one of the TTM paradigms at 33 and 36 °C. For comparison of TTM at 33 and 36 °C, we examined neuronal cell death and inflammatory response, including activation and polarization of microglia in the ischemic brain. TTM at 33 and 36 °C showed neuroprotective effects in comparison with normal body temperature (NT) at 37.5 °C. Mice under TTM at 33 and 36 °C showed ~ 45-50% fewer TUNEL-positive cells than those under NT. In IVIS spectrum CT, the activation of microglia/macrophage in CX3CR1GFP mice reduced after TTM at 33 and 36 °C in comparison with that after NT on day 7 after ischemic stroke. The number of Tmem119-positive cells under TTM at 33 and 36 °C was ~ 45-50% lower than that in mice under NT. TTM at 33 and 36 °C also increased the ratio of CD206-/CD86-positive cells than the ratio of CD86-/CD206-positive cells by ~ 1.2-fold. Thus, TTM at 33 and 36 °C could equivalently decrease the expression of certain cytokines after ischemic stroke. Our study suggested that TTM at 33 or 36 °C produces equivalent neuroprotective effects by attenuating cell death and by altering microglial activation and polarization. Therefore, TTM at 36 °C can be considered for its safety and effectiveness in ischemic stroke.

Delta neutrophil index and shock index can stratify risk for the requirement for massive transfusion in patients with primary postpartum hemorrhage in the emergency department.

BACKGROUND: Postpartum hemorrhage (PPH) constitutes a major risk for maternal mortality and morbidity. Unfortunately, the severity of PPH can be underestimated because it is difficult to accurately measure blood loss by visual estimation. The delta neutrophil index (DNI), which reflects circulating immature granulocytes, is automatically calculated in hematological analyzers. We evaluated the significance of the DNI in predicting hemorrhage severity based on the requirement for massive transfusion (MT) in patients with PPH. METHODS: We retrospectively analyzed data from a prospective registry to evaluate the association between the DNI and MT. Moreover, we assessed the predictive ability of the combination of DNI and shock index (SI) for the requirement for MT. MT was defined as a transfusion of ≥10 units of red blood cells within 24 h of PPH. In total, 278 patients were enrolled in this study and 60 required MT. RESULTS: Multivariable logistic regression revealed that the DNI and SI were independent predictors of MT. The optimal cut-off values of ≥3.3% and ≥1.0 for the DNI and SI, respectively, were significantly associated with an increased risk of MT (DNI: positive likelihood ratio [PLR] 3.54, 95% confidence interval [CI] 2.5-5.1 and negative likelihood ratio [NLR] 0.48, 95% CI 0.4-0.7; SI: PLR 3.21, 95% CI 2.4-4.2 and NLR 0.31, 95% CI 0.19-0.49). The optimal cut-off point for predicted probability was calculated for combining the DNI value and SI value with the equation derived from logistic regression analysis. Compared with DNI or SI alone, the combination of DNI and SI significantly improved the specificity, accuracy, and positive likelihood ratio of the MT risk. CONCLUSION: The DNI and SI can be routinely and easily measured in the ED without additional costs or time and can therefore, be considered suitable parameters for the early risk stratification of patients with primary PPH.

Glycyrrhizin ameliorating sterile inflammation induced by low-dose radiation exposure.

Glycyrrhizin (GL) is a direct inhibitor of HMGB1 which acts as an alarmin when excreted into the extracellular space. High-dose radiation in radiotherapy induces collateral damage to the normal tissue, which can be mitigated by GL inhibiting HMGB1. The purpose of this study was to assess changes in HMGB1 and pro-inflammatory cytokines and to evaluate the protective effect of GL after low-dose radiation exposure. BALB/c mice were irradiated with 0.1 Gy (n = 10) and 1 Gy (n = 10) with GL being administered to half of the mice (n = 5, respectively) before irradiation. Blood and spleen samples were harvested and assessed for oxidative stress, HMGB1, pro-inflammatory cytokines, and cell viability. HMGB1 and pro-inflammatory cytokines increased and cell viability decreased after irradiation in a dose-dependent manner. Oxidative stress also increased after irradiation, but did not differ between 0.1 Gy and 1 Gy. With the pretreatment of GL, oxidative stress, HMGB1, and all of the pro-inflammatory cytokines decreased while cell viability was preserved. Our findings indicate that even low-dose radiation can induce sterile inflammation by increasing serum HMGB1 and pro-inflammatory cytokines and that GL can ameliorate the sterile inflammatory process by inhibiting HMGB1 to preserve cell viability.

Protective effect of glycyrrhizin, a direct HMGB1 inhibitor, on post-contrast acute kidney injury.

Post contrast-acute kidney injury (PC-AKI) is defined as the deterioration of renal function after administration of iodinated contrast media. HMGB1 is known to play an important role in the development of acute kidney injury. The purpose of this study was to investigate the association between HMGB1 and PC-AKI and the protective effect of glycyrrhizin, a direct inhibitor of HMGB1, in rats. Rats were divided into three groups: control, PC-AKI and PC-AKI with glycyrrhizin. Oxidative stress was measured with MDA levels and H2DCFDA fluorescence intensity. The mRNA expressions of pro-inflammatory cytokines (IL-1α, IL-1ß, IL-6 and TNF-α) and kidney injury markers (KIM-1, NGAL and IL-18) were assessed using RT-PCR and ELISA in kidney tissue. In addition, the serum and intracellular protein levels of HMGB1were analyzed with the enzyme-linked immunosorbent assay (ELISA) and western blotting. Histologic changes were assessed with H&E staining using the transmission electron microscope (TEM). Moreover, serum creatinine (SCr), blood urea nitrogen (BUN) and lactate dehydrogenase (LDH) levels were assessed. Oxidative stress, pro-inflammatory cytokines, kidney injury markers and LDH were significantly higher in PC-AKI compared to the controls, but were lower in PC-AKI with glycyrrhizin. Intracellular and serum HMGB1 levels significantly increased after contrast media exposure, whereas they markedly decreased after glycyrrhizin pretreatment. SCr and BUN also decreased in PC-AKI with glycyrrhizin compared to PC-AKI. In PC-AKI, we could frequently observe tubular dilatation with H&E staining and cytoplasmic vacuoles on TEM, whereas these findings were attenuated in PC-AKI with glycyrrhizin. Our findings indicate that HMGB1 plays an important role in the development of PC-AKI and that glycyrrhizin has a protective effect against renal injury and dysfunction by inhibiting HMGB1 and reducing oxidative stress.

Predictive Model of Good Clinical Outcomes in Patients Undergoing Coronary Angiography after Out-of-Hospital Cardiac Arrest: A Prospective, Multicenter Observational Study Conducted by the Korean Cardiac Arrest Research Consortium.

This observational study aimed to develop novel nomograms that predict the benefits of coronary angiography (CAG) after resuscitating patients with out-of-hospital cardiac arrest (OHCA) regardless of the electrocardiography findings and to perform an external validation of these models. Data were extracted from a prospective, multicenter registry of resuscitated patients with OHCA (October 2015-June 2018). New nomograms were developed based on variables associated with survival discharge and neurologic outcomes; their analysis included 723 and 709 patients, respectively. Patient age (p < 0.001), prehospital defibrillation by emergency medical technicians (EMTs) (p = 0.003), prehospital return of spontaneous circulation (ROSC) (p = 0.02), and time from collapse to ROSC (p < 0.001) were associated with survival discharge. Patient age (p < 0.001), prehospital defibrillation by EMTs (p < 0.001), and time from collapse to ROSC (p < 0.001) were associated with neurologic outcomes. The new nomogram had a good predictive performance, with an area under the curve (AUC) of 0.8832 (95% confidence interval (CI): 0.8358-0.9305) for survival discharge and an AUC of 0.9048 (95% CI: 0.8627-0.9469) for neurologic outcomes. Novel nomograms that predict survival discharge and good neurological outcomes after CAG in patients with OHCA were developed and validated; they can be quickly and easily applied to identify patients who will benefit from CAG.

Transient Global Ischemia-Induced Brain Inflammatory Cascades Attenuated by Targeted Temperature Management.

Sudden cardiac arrest leads to a significantly increased risk of severe neurological impairment and higher mortality rates in survivors due to global brain tissue injury caused by prolonged whole-body ischemia and reperfusion. The brain undergoes various deleterious cascading events. Among these damaging mechanisms, neuroinflammation plays an especially crucial role in the exacerbation of brain damage. Clinical guidelines indicate that 33 °C and 36 °C are both beneficial for targeted temperature management (TTM) after cardiac arrest. To clarify the mechanistic relationship between TTM and inflammation in transient global ischemia (TGI) and determine whether 36 °C produces a neuroprotective effect comparable to 33 °C, we performed an experiment using a rat model. We found that TTM at 36 °C and at 33 °C attenuated neuronal cell death and apoptosis, with significant improvements in behavioral function that lasted for up to 72 h. TTM at 33 °C and 36 °C suppressed the propagation of inflammation including the release of high mobility group box 1 from damaged cells, the activation and polarization of the microglia, and the excessive release of activated microglia-induced inflammatory cytokines. There were equal neuroprotective effects for TTM at 36 °C and 33 °C. In addition, hypothermic complications and should be considered safe and effective after cardiac arrest.

Usefulness of chloride levels for fluid resuscitation in patients undergoing targeted temperature management after out-of-hospital cardiac arrest.

OBJECTIVE: Chloride is an important electrolyte in the body. In this study, we aimed to evaluate the associations between chloride levels on emergency department (ED) admission and neurologic outcomes by stratifying patients undergoing targeted temperature management (TTM) after out-of-hospital cardiac arrest (OHCA) into three groups (hyper/normo/hypochloremia); we also assessed the effect of changes in chloride levels from baseline over time on outcomes. METHODS: This retrospective, observational cohort study of 346 patients was conducted between 2011 and 2019. The chloride levels were categorized as hypochloremia, normochloremia, and hyperchloremia by predetermined definitions. The primary endpoint was poor neurologic outcomes after hospital discharge. We evaluated the associations between chloride levels on ED admission and neurologic outcomes and assess the effect of changes in chloride levels over time on clinical outcomes. RESULTS: On ED admission, compared with normochloremia, hypochloremia was significantly associated with unfavorable neurologic outcomes (OR, 2.668; 95% CI, 1.217-5.850, P = 0.014). Over time, unfavorable neurologic outcomes were significantly associated with increases in chloride levels in the hyperchloremia and normochloremia groups after ED admission. The rates of poor neurologic outcomes in the hyperchloremia and normochloremia groups were increased by 14.2% at Time-12, 20.1% at Time-24, and 9.3% at Time-48 with a 1-mEq/L increase in chloride levels. CONCLUSION: In clinical practice, chloride levels can be routinely and serially measured cost-effectively. Thus, baseline chloride levels may be a promising tool for rapid risk stratification of patients after OHCA. For fluid resuscitation after cardiac arrest, a chloride-restricted solution may be an early therapeutic strategy.

Targeted temperature management at 33°C or 36℃ induces equivalent myocardial protection by inhibiting HMGB1 release in myocardial ischemia/reperfusion injury.

Acute myocardial infarction (AMI) is lethal and causes myocardial necrosis via time-dependent ischemia due to prolonged occlusion of the infarct-related artery. No effective therapy or potential therapeutic targets can prevent myocardial ischemia/reperfusion (I/R) injury. Targeted temperature management (TTM) may reduce peri-infarct regions by inhibiting the extracellular release of high mobility group box-1 (HMGB1) as a primary mediator of the innate immune response. We used a rat left anterior descending (LAD) coronary artery ligation model to determine if TTM at 33°C and 36°C had similar myocardial protective effects. Rats were divided into sham, LAD I/R+37°C normothermia, LAD I/R+33°C TTM, and LAD I/R+36°C TTM groups (n = 5 per group). To verify the cardioprotective effect of TTM by specifically inhibiting HMGB1, rats were assigned to sham, LAD I/R, and LAD I/R after pre-treatment with glycyrrhizin (known as a pharmacological inhibitor of HMGB1) groups (n = 5 per group). Different target temperatures of 33°C and 36°C caused equivalent reductions in infarct volume after myocardial I/R, inhibited the extracellular release of HMGB1 from infarct tissue, and suppressed the expression of inflammatory cytokines from peri-infarct regions. TTM at 33°C and 36°C significantly attenuated the elevation of cardiac troponin, a sensitive and specific marker of heart muscle damage, after injury. Similarly, glycyrrhizin alleviated myocardial damage by suppressing the extracellular release of HMGB1. TTM at 33°C and 36°C had equivalent myocardial protective effects by similar inhibiting HMGB1 release against myocardial I/R injury. This is the first study to suggest that a target core temperature of 36°C is applicable for cardioprotection.

Inter-Hospital Transfer after Return of Spontaneous Circulation Shows no Correlation with Neurological Outcomes in Cardiac Arrest Patients Undergoing Targeted Temperature Management in Cardiac Arrest Centers.

This study evaluated whether inter-hospital transfer (IHT) after the return of spontaneous circulation (ROSC) was associated with poor neurological outcomes after 6 months in post-cardiac-arrest patients treated with targeted temperature management (TTM). We used data from the Korean Hypothermia Network prospective registry from November 2015 to December 2018. These out-of-hospital cardiac arrest (OHCA) patients had either received post-cardiac arrest syndrome (PCAS) care at the same hospital or had been transferred from another hospital after ROSC. The primary endpoint was the neurological outcome 6 months after cardiac arrest. Subgroup analyses were performed to determine differences in the time from ROSC to TTM induction according to the electrocardiography results after ROSC. We enrolled 1326 patients. There were no significant differences in neurological outcomes between the direct visit and IHT groups. In patients without ST elevation, the mean time to TTM was significantly shorter in the direct visit group than in the IHT group. IHT after achieving ROSC was not associated with neurologic outcomes after 6 months in post-OHCA patients treated with TTM, even though TTM induction was delayed in transferred patients.