Afebrile status at the time of emergency department visit is associated with delayed antibiotic therapy in patients with sepsis (revised).

OBJECTIVES: To determine whether there is a difference in antibiotic administration time and prognosis in afebrile sepsis patients compared to febrile sepsis patients. METHODS: This was retrospective multicenter observational study. Data collected from three referral hospitals. Data were collected from May 2014 through February 2016 under the SEPSIS-2 criteria and from March 2016 to April 2020 under the newly released SEPSIS-3 criteria. Patients were divided into two groups based on body temperature: afebrile (<37.3 °C) and febrile (≥37.3 °C). The relationship between initial body temperature and 28-day mortality were analyzed using multivariable logistic regression. The subgroup analysis was conducted on patients with complete Hour-1 bundle performance records. RESULTS: We included 4293 patients in this study. Initial body temperatures in 28-day survivors were significantly higher than in 28-day non-survivors (37.5 °C ± 1.2 °C versus 37.1 °C ± 1.2 °C, p < 0.01). Multivariable logistic regression analysis was performed in afebrile and febrile sepsis patients. Adjusted odds ratio of afebrile sepsis patients for 28-day mortality was 1.76 (95% Confidence interval 1.46-2.12). As a result of performing the Hour-1 bundle, the number of patients who received antibiotics within 1 h was smaller in the afebrile sepsis patients (323/2076, 15.6%) than in the febrile sepsis patients (395/2156, 18.3%) (p = 0.02). In the subgroup analysis of patients with complete Hour-1 bundle performance records adjusted odds ratio of afebrile sepsis patients for 28-day mortality was 1.68 (95% Confidence interval 1.34-2.11). The febrile sepsis patients received antibiotics faster than the afebrile sepsis patients (175.5 ± 207.9 versus 209.3 ± 277.9, p < 0.01). CONCLUSIONS: Afebrile sepsis patients were associated with higher 28-day mortality compared to their febrile counterparts and were delayed in receiving antibiotics. This underscores the need for improved early detection and treatment strategies for the afebrile sepsis patients.

Circulating mitochondrial N-formyl peptides contribute to secondary nosocomial infection in patients with septic shock.

Secondary infections typically worsen outcomes of patients recovering from septic shock. Neutrophil [polymorphonuclear leukocytes (PMNs)] migration to secondarily inoculated sites may play a key role in inhibiting progression from local bacterial inoculation to secondary infection. Mitochondrial N-formyl peptide (mtFP) occupancy of formyl peptide receptor-1 (FPR1) has been shown to suppress PMN chemotaxis. Therefore, we studied the association between circulating mtFPs and the development of secondary infection in patients with septic shock. We collected clinical data and plasma samples from patients with septic shock admitted to the intensive care unit for longer than 72 h. Impacts of circulating nicotinamide adenine dinucleotide dehydrogenase subunit-6 (ND6) upon clinical outcomes were analyzed. Next, the role of ND6 in PMN chemotaxis was investigated using isolated human PMNs. Studying plasma samples from 97 patients with septic shock, we found that circulating ND6 levels at admission were independently and highly associated with the development of secondary infection (odds ratio = 30.317, 95% CI: 2.904 to 316.407, P = 0.004) and increased 90-d mortality (odds ratio = 1.572, 95% CI: 1.002 to 2.465, P = 0.049). In ex vivo experiments, ND6 pretreatment suppressed FPR1-mediated PMN chemotactic responses to bacterial peptides in the presence of multiple cytokines and chemokines, despite increased nondirectional PMN movements. Circulating mtFPs appear to contribute to the development of secondary infection and increased mortality in patients with septic shock who survive their early hyperinflammatory phase. The increased susceptibility to secondary infection is probably partly mediated by the suppression of FPR1-mediated PMN chemotaxis to secondary infected sites.

Combination Therapy of Niacin and Apocynin Attenuates Lung Injury During Sepsis in Rats.

INTRODUCTION: Oxidative stress contributes to tissue injury through reactive oxygen species-dependent signaling pathways during sepsis. We studied therapeutic benefits of the combination therapy of niacin, which increased reduced glutathione levels, and apocynin, which suppressed reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) activity, in septic rats. MATERIALS AND METHODS: Polymicrobial sepsis was induced through cecal ligation and puncture (CLP) with antibiotics in male Sprague-Dawley rats (n = 189). The rats were randomly divided into sham, CLP, CLP + niacin, CLP + apocynin, and CLP + niacin + apocynin groups. Six hours after CLP, vehicle, niacin (360 mg/kg through the orogastric tube), and/or apocynin (20 mg/kg through intraperitoneal injection) were administered. The occurrence of mortality for 72 h after CLP was observed. Next, a separate set of animals was euthanized at 24 h post-CLP for lung tissue analyses. RESULTS: Combination therapy with niacin and apocynin significantly improved survival in rats with sepsis (75.0% versus 28.8%, P = 0.006) but monotherapy with niacin or apocynin did not. Monotherapy with niacin and apocynin appeared to increase NADPH levels and decrease Nox levels and activity, respectively, but failed to show statistical significances. However, combination therapy significantly decreased Nox levels and activity, increased NADPH and glutathione levels, decreased intranuclear nuclear factor-κB (NF-κB) p65 levels, reduced inflammatory cytokine expression and malondialdehyde levels, and attenuated histological lung injuries. CONCLUSIONS: Combination therapy with niacin and apocynin synergistically attenuated lung injuries and improved survival in rats with sepsis through niacin-induced glutathione redox cycle activation and apocynin-induced Nox suppression.

Modified cardiovascular SOFA score in sepsis: development and internal and external validation.

BACKGROUND: The Sepsis-3 criteria introduced the system that uses the Sequential Organ-Failure Assessment (SOFA) score to define sepsis. The cardiovascular SOFA (CV SOFA) scoring system needs modification due to the change in guideline-recommended vasopressors. In this study, we aimed to develop and to validate the modified CV SOFA score. METHODS: We developed, internally validated, and externally validated the modified CV SOFA score using the suspected infection cohort, sepsis cohort, and septic shock cohort. The primary outcome was 28-day mortality. The modified CV SOFA score system was constructed with consideration of the recently recommended use of the vasopressor norepinephrine with or without lactate level. The predictive validity of the modified SOFA score was evaluated by the discrimination for the primary outcome. Discrimination was assessed using the area under the receiver operating characteristics curve (AUC). Calibration was assessed using the calibration curve. We compared the prognostic performance of the original CV/total SOFA score and the modified CV/total SOFA score to detect mortality in patients with suspected infection, sepsis, or septic shock. RESULTS: We identified 7,393 patients in the suspected cohort, 4038 patients in the sepsis cohort, and 3,107 patients in the septic shock cohort in seven Korean emergency departments (EDs). The 28-day mortality rates were 7.9%, 21.4%, and 20.5%, respectively, in the suspected infection, sepsis, and septic shock cohorts. The model performance is higher when vasopressor and lactate were used in combination than the vasopressor only used model. The modified CV/total SOFA score was well-developed and internally and externally validated in terms of discrimination and calibration. Predictive validity of the modified CV SOFA was significantly higher than that of the original CV SOFA in the development set (0.682 vs 0.624, p < 0.001), test set (0.716 vs 0.638), and all other cohorts (0.648 vs 0.557, 0.674 vs 0.589). Calibration was modest. In the suspected infection cohort, the modified model classified more patients to sepsis (66.0 vs 62.5%) and identified more patients at risk of septic mortality than the SOFA score (92.6 vs 89.5%). CONCLUSIONS: Among ED patients with suspected infection, sepsis, and septic shock, the newly-developed modified CV/total SOFA score had higher predictive validity and identified more patients at risk of septic mortality.

Preexisting Clinical Frailty Is Associated With Worse Clinical Outcomes in Patients With Sepsis.

OBJECTIVES: Frailty is a multidimensional syndrome or state of increased vulnerability to poor resolution of homoeostasis following a stressor event. Frailty is common in patients with sepsis. Sepsis and frailty are both associated with older age and chronic medical conditions. However, there is limited evidence about the direct association between frailty and sepsis. The aim of this study is to determine the association between preexisting clinical frailty and clinical outcomes in patients with sepsis. DESIGN: A nationwide propensity score-matched cohort study analyzing data prospectively collected between September 2019 and February 2020. SETTING: Nineteen tertiary or university-affiliated hospitals in South Korea. PATIENTS: Adult patients who were diagnosed with sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Frailty status was assessed using the Clinical Frailty Scale. All patients were classified as "frail" (Clinical Frailty Scale score, 5-9) or "nonfrail" (Clinical Frailty Scale score, 1-4). Propensity score matching identified comparable nonfrail patients. The primary outcome was inhospital mortality. Multivariable logistic regression analysis was used to evaluate the association between frailty and inhospital mortality. The propensity score-matched cohort comprised 468 nonfrail patients and 468 frail patients; all covariate imbalances were alleviated. In the matched cohort (mean age, 69 ± 14 yr), 27.2% had septic shock at presentation. Inhospital mortality was 34.2% in the frail group and 26.9% in the nonfrail group (p = 0.019). The adjusted odds ratio for inhospital mortality in the frail group compared with the nonfrail group was 2.00 (95% CI, 1.39-2.89; p < 0.001). Among the patients who survived to discharge, the frail group was less likely to be discharged home compared with the nonfrail group, 64.0% versus 81.3%, respectively (p < 0.001). CONCLUSIONS: In patients with sepsis, preexisting clinical frailty is associated with worse clinical outcomes than that in nonfrail patients, including inhospital mortality and discharge to home.

Hypernatremia is associated with poor long-term neurological outcomes in out-of-hospital cardiac arrest survivors.

BACKGROUND: Brain oedema after cardiac arrest is strongly associated with poor neurological outcomes. Excessive sodium supplementation may increase serum osmolarity and facilitate brain oedema development in cardiac arrest survivors. We aimed to investigate the association of serum sodium levels with long-term neurological outcomes in out-of-hospital cardiac arrest (OHCA) survivors. METHODS: This retrospective observational study used a multicentre prospective cohort registry of OHCA survivors collected between December 2013 and February 2018. We analyzed the association of serum sodium levels at the return of spontaneous circulation (ROSC) (Sodium 0H) and at 24 h after ROSC (Sodium 24H) with 1-year neurological outcomes in OHCA survivors. Patients with 1-year cerebral performance categories (CPC) 1 and 2 were included in the good outcome group while those with CPC 3, 4, and 5 were included in the poor outcome group. RESULTS: Among 277 patients, 84 (30.3%) and 193 (69.7%) were in the good and poor outcome groups, respectively. Compared with the good outcome group, the poor outcome group showed significantly higher Sodium 24H levels (140 mEq/L vs. 137.4 mEq/L, p < 0.001). Increased serum sodium levels per 1 mEq/L increased the risk of poor 1-year CPC by 13% (adjusted odds ratio = 1.13; 95% CI, 1.04⎼1.23; p = 0.004). CONCLUSIONS: Relatively high Sodium 24H levels showed a strong and independent association with poor long-term neurological outcomes in OHCA survivors. These findings may be applied in therapeutic strategies for improving neurological outcomes in OHCA survivors.

Serum total carbon dioxide as a prognostic factor for 28-day mortality in patients with sepsis.

OBJECTIVE: Metabolic acidosis is commonly associated with the disease severity in patients with sepsis or septic shock. This study was performed to investigate the association between serum total carbon dioxide (TCO2) concentration and 28-day mortality in patients with sepsis. METHODS: This study was a multicenter retrospective cohort study of patients with sepsis or septic shock. The relationships between serum TCO2 and 28-day mortality, bicarbonate, pH, lactate, and anion gap were determined with cubic spline curves. The patients were divided into four groups according to their serum TCO2 concentration: Group I (TCO2 > 20 mmol/l), Group II (15 < TCO2 ≤ 20 mg/dl), Group III (10 < TCO2 ≤ 15 mmol/l), and Group IV (TCO2 ≤ 10 mmol/l). RESULTS: A total of 3168 patients were included in the analysis, and the overall mortality rate was 24.1%. Serum TCO2 concentrations below 20 mmol/l showed an almost linear correlation with mortality as well as with lactate, bicarbonate, and pH. The 28-day mortality rates of Group I, II, III, and IV were 18.3%, 23.6%, 32.6%, and 50.0%, respectively (p < .001). In Multivariable Cox proportional hazard regression analysis, the groups with lower serum TCO2 concentrations had a higher risk of 28-day mortality compared with Group I: Group II (Hazard ratio (HR), 1.35; 95% confidence interval (CI), 1.11-1.64), Group III (HR, 1.74; 95% CI, 1.37-2.21), and Group IV (HR, 2.72; 95% CI, 2.03-3.64). CONCLUSIONS: Serum TCO2 concentrations of 20 mmol/l or less were associated with 28-day mortality in patients with sepsis.

Clinical Application of the Standard Q COVID-19 Ag Test for the Detection of SARS-CoV-2 Infection.

We evaluated the Standard Q COVID-19 Ag test for the diagnosis of coronavirus disease 2019 (COVID-19) compared to the reverse transcription-polymerase chain reaction (RT-PCR) test. We applied both tests to patients who were about to be hospitalized, had visited an emergency room, or had been admitted due to COVID-19 confirmed by RT-PCR. Two nasopharyngeal swabs were obtained; one was tested by RT-PCR and the other by the Standard Q COVID-19 Ag test. A total of 118 pairs of tests from 98 patients were performed between January 5 and 11, 2021. The overall sensitivity and specificity for detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for the Standard Q COVID-19 Ag test compared to RT-PCR were 17.5% (95% confidence interval [CI], 8.8-32.0%) and 100% (95% CI, 95.3-100.0%). Analysis of the results using RT-PCR cycle thresholds of ≤ 30 or ≤ 25 increased the sensitivity to 26.9% (95% CI, 13.7-46.1%), and 41.1% (95% CI, 21.6-64.0%), respectively.

Multiplexed Plasma Immune Mediator Signatures Can Differentiate Sepsis From NonInfective SIRS: American Surgical Association 2020 Annual Meeting Paper.

OBJECTIVES: Sepsis and sterile both release "danger signals' that induce the systemic inflammatory response syndrome (SIRS). So differentiating infection from SIRS can be challenging. Precision diagnostic assays could limit unnecessary antibiotic use, improving outcomes. METHODS: After surveying human leukocyte cytokine production responses to sterile damage-associated molecular patterns (DAMPs), bacterial pathogen-associated molecular patterns, and bacteria we created a multiplex assay for 31 cytokines. We then studied plasma from patients with bacteremia, septic shock, "severe sepsis," or trauma (ISS ≥15 with circulating DAMPs) as well as controls. Infections were adjudicated based on post-hospitalization review. Plasma was studied in infection and injury using univariate and multivariate means to determine how such multiplex assays could best distinguish infective from noninfective SIRS. RESULTS: Infected patients had high plasma interleukin (IL)-6, IL-1α, and triggering receptor expressed on myeloid cells-1 (TREM-1) compared to controls [false discovery rates (FDR) <0.01, <0.01, <0.0001]. Conversely, injury suppressed many mediators including MDC (FDR <0.0001), TREM-1 (FDR <0.001), IP-10 (FDR <0.01), MCP-3 (FDR <0.05), FLT3L (FDR <0.05), Tweak, (FDR <0.05), GRO-α (FDR <0.05), and ENA-78 (FDR <0.05). In univariate studies, analyte overlap between clinical groups prevented clinical relevance. Multivariate models discriminated injury and infection much better, with the 2-group random-forest model classifying 11/11 injury and 28/29 infection patients correctly in out-of-bag validation. CONCLUSIONS: Circulating cytokines in traumatic SIRS differ markedly from those in health or sepsis. Variability limits the accuracy of single-mediator assays but machine learning based on multiplexed plasma assays revealed distinct patterns in sepsis- and injury-related SIRS. Defining biomarker release patterns that distinguish specific SIRS populations might allow decreased antibiotic use in those clinical situations. Large prospective studies are needed to validate and operationalize this approach.

Development and validation of the VitaL CLASS score to predict mortality in stage IV solid cancer patients with septic shock in the emergency department: a multi-center, prospective cohort study.

BACKGROUND: Clinical decision-making of invasive high-intensity care for critically ill stage IV cancer patients in the emergency department (ED) is challenging. A reliable and clinically available prognostic score for advanced cancer patients with septic shock presented at ED is essential to improve the quality of intensive care unit care. This study aimed to develop a new prognostic score for advanced solid cancer patients with septic shock available early in the ED and to compare the performance to the previous severity scores. METHODS: This multi-center, prospective cohort study included consecutive adult septic shock patients with stage IV solid cancer. A new scoring system for 28-day mortality was developed and validated using the data of development (January 2016 to December 2017; n = 469) and validation sets (January 2018 to June 2019; n = 428). The developed score's performance was compared to that of the previous severity scores. RESULTS: New scoring system for 28-day mortality was based on six variables (score range, 0-8): vital signs at ED presentation (respiratory rate, body temperature, and altered mentation), lung cancer type, and two laboratory values (lactate and albumin) in septic shock (VitaL CLASS). The C-statistic of the VitaL CLASS score was 0.808 in the development set and 0.736 in the validation set, that is superior to that of the Sequential Organ Failure Assessment score (0.656, p = 0.01) and similar to that of the Acute Physiology and Chronic Health Evaluation II score (0.682, p = 0.08). This score could identify 41% of patients with a low-risk group (observed 28-day mortality, 10.3%) and 7% of patients with a high-risk group (observed 28-day mortality, 73.3%). CONCLUSIONS: The VitaL CLASS score could be used for both risk stratification and as part of a shared clinical decision-making strategy for stage IV solid cancer patients with septic shock admitting at ED within several hours.

Formyl Peptide Receptor-1 Blockade Prevents Receptor Regulation by Mitochondrial Danger-Associated Molecular Patterns and Preserves Neutrophil Function After Trauma.

OBJECTIVES: Trauma predisposes to systemic sterile inflammation (systemic inflammatory response syndrome) as well as infection, but the mechanisms linking injury to infection are poorly understood. Mitochondrial debris contains formyl peptides. These bind formyl peptide receptor-1, trafficking neutrophils to wounds, initiating systemic inflammatory response syndrome, and wound healing. Bacterial formyl peptides, however, also attract neutrophils via formyl peptide receptor-1. Thus, mitochondrial formyl peptides might suppress neutrophils antimicrobial function. Also, formyl peptide receptor-1 blockade used to mitigate systemic inflammatory response syndrome might predispose to sepsis. We examined how mitochondrial formyl peptides impact neutrophils functions contributing to antimicrobial responses and how formyl peptide receptor-1 antagonists affect those functions. DESIGN: Prospective study of human and murine neutrophils and clinical cohort analysis. SETTING: University research laboratory and level 1 trauma center. PATIENTS: Trauma patients, volunteer controls. ANIMAL SUBJECTS: C57Bl/6, formyl peptide receptor-1, and formyl peptide receptor-2 knockout mice. INTERVENTIONS: Human and murine neutrophils functions were activated with autologous mitochondrial debris, mitochondrial formyl peptides, or bacterial formyl peptides followed by chemokines or leukotrienes. The experiments were repeated using formyl peptide receptor-1 antagonist cyclosporin H, "designer" human formyl peptide receptor-1 antagonists (POL7178 and POL7200), or anti-formyl peptide receptor-1 antibodies. Mouse injury/lung infection model was used to evaluate effect of formyl peptide receptor-1 inhibition. MEASUREMENTS AND MAIN RESULTS: Human neutrophils cytosolic calcium, chemotaxis, reactive oxygen species production, and phagocytosis were studied before and after exposure to mitochondrial debris, mitochondrial formyl peptides, and bacterial formyl peptides. Mitochondrial formyl peptide and bacterial formyl peptides had similar effects on neutrophils. Responses to chemokines and leukotrienes were suppressed by prior exposure to formyl peptides. POL7200 and POL7178 were specific antagonists of human formyl peptide receptor-1 and more effective than cyclosporin H or anti-formyl peptide receptor-1 antibodies. Formyl peptides inhibited mouse neutrophils responses to chemokines only if formyl peptide receptor-1 was present. Formyl peptide receptor-1 blockade did not inhibit neutrophils bacterial phagocytosis or reactive oxygen species production. Cyclosporin H increased bacterial clearance in lungs after injury. CONCLUSIONS: Formyl peptides both activate and desensitize neutrophils. Formyl peptide receptor-1 blockade prevents desensitization, potentially both diminishing systemic inflammatory response syndrome and protecting the host against secondary infection after tissue trauma or primary infection.

Pulse Oximeter Plethysmograph Variation During Hemorrhage in Beta-Blocker-Treated Swine.

BACKGROUND: Beta-blockers blunt the stress response to hemorrhage. Our aim was to investigate the feasibility of noninvasive pulse oximeter plethysmographic waveform variation (PoPV) for predicting blood volume loss in an esmolol-treated swine hemorrhagic shock model. MATERIALS AND METHODS: Controlled hemorrhage was induced in eight male domestic pigs. In four pigs, a total of 15% and 30% blood volume was drawn step-by-step over 10 min in each step (controlled hemorrhage-only pigs). In the other four pigs, the heart rate (HR) was reduced and maintained by 30% from baseline by esmolol infusion before controlled hemorrhage (esmolol-treated pigs). Diagnostic abilities of HR, pulse pressure variation (PPV), PoPV, and mean arterial pressure for 15% and 30% blood volume loss were determined by the area under the receiver operating characteristic curve (AUC). RESULTS: PoPV was well correlated with PPV in controlled hemorrhage-only pigs (r = 0.717) and esmolol-treated pigs (r = 0.532). In controlled hemorrhage-only pigs, HR (AUC = 0.841 and 0.864), PPV (0.878 and 0.843), and PoPV (0.779 and 0.793) accurately predicted 15% and 30% of blood volume loss. In esmolol-treated pigs, the diagnostic ability of HR was decreased (AUC = 0.766 and 0.733). However, diagnostic abilities of PPV (0.848 and 0.804) and PoPV (0.808 and 0.842) were not deteriorated. CONCLUSIONS: The diagnostic ability of HR for blood volume loss was blunted by esmolol. However, those of PPV and PoPV were not altered. PoPV may be considered to be a useful noninvasive tool to predict blood volume loss in injured patients taking beta-blockers.

Emergency physician-based intensive care unit for critically ill patients visiting emergency department.

BACKGROUND: To provide a prompt and optimal intensive care to critically ill patients visiting our emergency department (ED), we set up and ran a specific type of emergency intensive care unit (EICU) managed by emergency physician (EP) intensivists. We investigated whether this EICU reduced the time interval from ED arrival to ICU transfer (ED-ICU interval) without altering mortality. METHODS: This was a retrospective study conducted in a tertiary referral hospital. We collected data from ED patients who were admitted to the EICU (EICU group) and other ICUs including medical, surgical, and cardiopulmonary ICUs (other ICUs group), from August 2014 to July 2017. We compared these two groups with respect to demographic findings, including the Acute Physiology and Chronic Health Evaluation II (APACHE II) score, ED-ICU interval, ICU mortality, and hospital mortality. RESULTS: Among the 3440 critically ill patients who visited ED, 1815 (52.8%) were admitted to the EICU during the study period. The ED-ICU interval for the EICU group was significantly shorter than that for the other ICUs group by 27.5% (5.0 ±â€¯4.9 vs. 6.9 ±â€¯5.4 h, p < 0.001). In multivariable analysis, the ICU mortality (odds ratio = 1.062, 95% confidence interval 0.862-1.308, p = 0.571) and hospital mortality (odds ratio = 1.093, 95% confidence interval 0.892-1.338, p = 0.391) of the EICU group were not inferior to those of the other ICUs group. CONCLUSIONS: The EICU run by EP intensivists reduced the time interval from ED arrival to ICU transfer without altering hospital mortality.

Relative tachycardia is associated with poor outcomes in post-cardiac arrest patients regardless of therapeutic hypothermia.

BACKGROUND: To investigate whether the relationship between heart rate and neurological outcome is independent of therapeutic hypothermia (TH) and whether heart rate is related to hemodynamic instability post-cardiac arrest. METHODS: Retrospective review of an out-of-hospital cardiac arrest registry was performed. The primary exposure was heart rate quartiles at 24 h post-cardiac arrest. The primary outcome was a poor neurological outcome, which was defined as having a cerebral performance category (CPC) of 3-5 at 28 days. Secondary outcomes were mean blood pressure and serum lactate at 24 h and Sequential Organ Failure Assessment (SOFA) scores at admission. RESULTS: In total, 155 patients were enrolled. The proportion of patients with a poor CPC was significantly greater in higher heart rate quartiles; similar results were observed in patients who did and did not undergo TH. Serum lactate levels at 24 h were significantly higher in the 3rd and 4th quartile groups than in the 1st quartile group. Additionally, SOFA scores were significantly higher in the 4th quartile group than in the 1st and 3rd quartile groups. CONCLUSIONS: Relative tachycardia is associated with poor neurological outcomes in post-cardiac arrest patients, independent of TH, and with higher serum lactate levels and admission SOFA scores.

Niacin and Selenium Attenuate Brain Injury After Cardiac Arrest in Rats by Up-Regulating DJ-1-Akt Signaling.

OBJECTIVES: To determine neuroprotective effects and mechanism of the combination therapy of niacin and selenium in cardiac arrest rats. DESIGN: Prospective laboratory study. SETTING: University laboratory. SUBJECTS: Rat cortex neurons and male Sprague-Dawley rats (n = 68). INTERVENTIONS: In rat cortex neurons underwent 90 minutes of oxygen-glucose deprivation and 22.5 hours of reoxygenation, effects of the combination therapy of niacin (0.9 mM) and selenium (1.5 µM) were investigated. The role of DJ-1 was determined using DJ-1 knockdown cells. In cardiac arrest rats, posttreatment effects of the combination therapy of niacin (360 mg/kg) and selenium (60 µg/kg) were evaluated. MEASUREMENTS AND MAIN RESULTS: In oxygen-glucose deprivation and 22.5 hours of reoxygenation cells, combination therapy synergistically activated the glutathione redox cycle by a niacin-induced increase in glutathione reductase and a selenium-induced increase in glutathione peroxidase activities and reduced hydrogen peroxide level. It increased phosphorylated Akt and intranuclear Nuclear factor erythroid 2-related factor 2 expression and attenuated neuronal injury. However, these benefits were negated by DJ-1 knockdown. In cardiac arrest rats, combination therapy increased DJ-1, phosphorylated Akt, and intranuclear nuclear factor erythroid 2-related factor 2 expression, suppressed caspase 3 cleavage, and attenuated histologic injury in the brain tissues. It also improved the 7-day Neurologic Deficit Scales from 71.5 (66.0-74.0) to 77.0 (74.-80.0) (p = 0.02). CONCLUSIONS: The combination therapy of clinically relevant doses of niacin and selenium attenuated brain injury and improved neurologic outcome in cardiac arrest rats. Its benefits were associated with reactive oxygen species reduction and subsequent DJ-1-Akt signaling up-regulation.

Prognosis of patients excluded by the definition of septic shock based on their lactate levels after initial fluid resuscitation: a prospective multi-center observational study.

BACKGROUND: Septic shock can be defined both by the presence of hyperlactatemia and need of vasopressors. Lactate levels should be measured after volume resuscitation (as per the Sepsis-3 definition). However, currently, no studies have evaluated patients who have been excluded by the new criteria for septic shock. The aim of this study was to determine the clinical characteristics and prognosis of these patients, based on their lactate levels after initial fluid resuscitation. METHODS: This observational study was performed using a prospective, multi-center registry of septic shock, with the participation of 10 hospitals in the Korean Shock Society, between October 2015 and February 2017. We compared the 28-day mortality between patients who were excluded from the new definition (defined as lactate level <2 mmol/L after volume resuscitation) and those who were not (≥2 mmol/L after volume resuscitation), from among a cohort of patients with refractory hypotension, and requiring the use of vasopressors. Other outcome variables such as in-hospital mortality, intensive care unit (ICU) stay (days), Sequential Organ Failure Assessment (SOFA) scores and Acute Physiology and Chronic Health Evaluation (APACHE) II scores were also analyzed. RESULTS: Of 567 patients with refractory hypotension, requiring the use of vasopressors, 435 had elevated lactate levels, while 83 did not have elevated lactate levels (either initially or after volume resuscitation), and 49 (8.2%) had elevated lactate levels initially, which normalized after fluid resuscitation. Thus, these 49 patients were excluded by the new definition of septic shock. These patients, in whom perfusion was restored, demonstrated significantly lower age, platelet count, and initial and subsequent lactate levels (all p < 0.01). Similarly, significantly lower 28-day mortality was observed in these patients than in those who had not been excluded (8.2% vs 25.5%, p = 0.02). In-hospital mortality and the maximum SOFA score were also significantly lower in the excluded patients group (p = 0.03, both). CONCLUSIONS: It seems reasonable for septic shock to be defined by the lactate levels after volume resuscitation. However, owing to the small number of patients in whom lactate levels were improved, further study is warranted.

Prognostic performance of Emergency Severity Index (ESI) combined with qSOFA score.

OBJECTIVE: We conducted this study to investigate whether ESI combined with qSOFA score (ESI+qSOFA) predicts hospital outcome better than ESI alone in the emergency department (ED). METHODS: This was a retrospective study for patients aged over 15years who visited an ED of a tertiary referral hospital from January 1st, 2015 to December 31st, 2015. We calculated and compared predictive performances of ESI alone and ESI+qSOFA for prespecified outcomes. The primary outcome was hospital mortality, and the secondary outcome was composite outcome of in-hospital mortality and ICU admission. We calculated in-hospital mortality rates by positive qSOFA in each subgroup divided according to ESI levels (1, 2, 3, 4+5). RESULTS: 43,748 patients were enrolled. The area under receiver-operating characteristics curves were higher in ESI+qSOFA than in ESI alone for both mortality and composite outcome (0.786 vs. 0.777, P<.001 for mortality; 0.778 vs. 0.774, P<.001 for composite outcome). In each subgroup divided by ESI levels, patients with positive qSOFA had significantly higher in-hospital mortality rate compared to those with negative qSOFA (20.4% vs. 14.7%, P=.117 in ESI level 1 subgroup; 11.3% vs. 2.7%, P=.001 in ESI level 2 subgroup; 2.3% vs. 0.4%, P<.001 in ESI level 3 subgroup; 0.0% vs. 0.0% in ESI level 4 or 5 subgroup). CONCLUSION: The prognostic performance of ESI+qSOFA for in-hospital mortality was significantly higher than that of ESI alone. Within each subgroup, patients with positive qSOFA had higher in-hospital mortality compared to those with negative qSOFA.

Protective effect of hemopexin on systemic inflammation and acute lung injury in an endotoxemia model.

BACKGROUND: Hemopexin (HPX) has been identified as an anti-inflammatory agent, but its role in endotoxemia is unclear. The purpose of this study was to determine whether HPX suppresses systemic and lung inflammation in a mouse model of endotoxemia. MATERIALS AND METHODS: At 30 min of intraperitoneal administration of lipopolysaccharide (LPS; 10 mg/kg), either distilled water (LPS-only treated animals) or HPX (5 mg/kg) was injected into mice via the tail vein, and the survival rates were analyzed after 36 h. Furthermore, the serum levels of tumor necrosis factor-α, interleukin-6 (IL-6), and HPX were determined at 0, 3, and 6 h, and the expression levels and DNA binding activities of phosphorylated cytoplasmic inhibitor κB-α, nuclear factor-κB (NF-κB), and the p65 subunit of NF-κB were evaluated and compared with the rates of histologic lung injury after 6 h. RESULTS: Serum tumor necrosis factor-α and interleukin-6 levels were decreased in HPX-treated animals at 3 and 6 h (P < 0.05). HPX suppressed the NF-κB pathway (P < 0.05) and reduced acute lung injury at 6 h, and 36 h after initial treatment, the survival rate was higher in HPX-treated animals than that in LPS-treated animals (P < 0.05). CONCLUSIONS: HPX downregulated proinflammatory cytokine production and acute lung injury as well as improved survival rates in a mouse model of endotoxemia. These effects were associated with HPX-mediated suppression of the NF-κB pathway.

Long-term survival of out-of-hospital cardiac arrest patients with malignancy.

BACKGROUND: The aim of this study was to investigate whether the 1-year survival rate of out-of-hospital cardiac arrest (OHCA) patients with malignancy was different from that of those without malignancy. METHODS: All adult OHCA patients were retrospectively analyzed in a single institution for 6years. The primary outcome was 1-year survival, and secondary outcomes were sustained return of spontaneous circulation (ROSC), survival to hospital admission, survival to discharge and discharge with a good neurological outcome (CPC 1 or 2). Kaplan-Meier survival analysis and Cox proportional hazard regression analysis were performed to test the effect of malignancy. RESULTS: Among 341 OHCA patients, 59 patients had malignancy (17.3%). Sustained ROSC, survival to admission, survival to discharge and discharge with a good CPC were not different between the two groups. The 1-year survival rate was lower in patients with malignancy (1.7% vs 11.4%; P=0.026). Kaplan-Meier survival analysis revealed that patients with malignancy had a significantly lower 1-year survival rate when including all patients (n=341; P=0.028), patients with survival to admission (n=172, P=0.002), patients with discharge CPC 1 or 2 (n=18, P=0.010) and patients with discharge CPC 3 or 4 (n=57, P=0.008). Malignancy was an independent risk factor for 1-year mortality in the Cox proportional hazard regression analysis performed in patients with survival to admission and survival to discharge. CONCLUSIONS: Although survival to admission, survival to discharge and discharge with a good CPC rate were not different, the 1-year survival rate was significantly lower in OHCA patients with malignancy than in those without malignancy.