Reverse Shock Index multiplied by Glasgow Coma Scale score as a point-of-care severity assessment for initial trauma management: A nationwide cohort study.

BACKGROUND: Severe trauma patients often require emergent interventions, such as massive transfusion, resuscitative procedures, and surgical procedures, and consume considerable human and medical resources. However, few practical indices can be easily used for emergent interventions. In recent years, it has become clear that rSIG (Reverse Shock Index multiplied by Glasgow Coma Scale [GCS] score), which can be easily calculated from vital signs, is a promising predictor of mortality. However, it is unclear whether rSIG is useful for emergent interventions. METHODS: Data collected by the Japan Trauma Data Bank for adult patients admitted directly from the scene of trauma between April 2019 and December 2020 were analysed. The outcomes were massive transfusion, resuscitative procedures, surgical procedures and emergent interventions. Emergent interventions were defined as the composite outcome of massive transfusion, resuscitative procedures, and surgical procedures. The ability of rSIG to predict massive transfusion was compared with that of the ABC score and FASILA score by receiver-operating characteristic curve analysis. The ability of rSIG to predict resuscitative and surgical procedures was compared with that of the Shock Index (SI), GCS, Triage Revised Trauma score (T-RTS), and Previous Simple Prediction (PSP) score. The ability of rSIG to predict emergent interventions was compared with that of T-RTS, PSP, ABC, and FASILA. In addition to rSIG, rSIM (Reverse Shock Index multiplied by best motor response score) was also analysed as a supplement. RESULTS: The study included 32,201 patients, 6,371 of whom required emergent interventions. The area under the receiver-operating characteristic curve (AUROC) for massive transfusion was highest for rSIG (0.846 [95 % confidence interval 0.832-0.859]) and significantly higher for rSIG than for rSIM, ABC and FASILA (all p < 0.0001). AUROCs for resuscitative and surgical procedures were highest for rSIG (0.777 [0.769-0.785] and 0.731 [0.720-0.741], respectively) and significantly higher than those for rSIM, SI, GCS, T-RTS, and PSP (all p < 0.0001). The AUROC for emergent interventions was highest for rSIG (0.760 [0.753-0.768]) and significantly higher for rSIG than for rSIM, T-RTS, PSP, ABC, or FASILA (all p < 0.0001). CONCLUSIONS: rSIG is a simple and effective point-of-care predictor of emergent interventions during initial management of trauma.

The reverse shock index multiplied by the Glasgow Coma Scale score can predict the need for initial resuscitation in patients suspected of sepsis.

For patients suspected of sepsis, early recognition of the need for initial resuscitation is key in management. This study evaluated the ability of a modified shock index - the reverse shock index multiplied by the Glasgow Coma Scale score (rSIG) - to predict the need for initial resuscitation in patients with sepsis. This retrospective study involved adults with infection who were admitted to a Japanese tertiary care hospital from an emergency department between January and November 2020. The rSIG, modified Early Warning Score (MEWS), quick Sequential Organ Failure Assessment (qSOFA), and original shock index (SI) values were recorded using initial vital signs. The primary outcome was the area under the receiver-operating characteristic curve (AUROC) for the composite outcome consisting of vasopressor use, mechanical ventilation, and 72-h mortality. Secondary outcomes were the AUROCs for each component of the primary outcome and 28-day mortality. As a result, the primary outcome was met by 67 of the 724 patients (9%). The AUROC was significantly higher for the rSIG than for the other tools (rSIG 0.84 [0.78 - 0.88]; MEWS 0.78 [0.71 - 0.84]; qSOFA 0.72 [0.65 - 0.79]; SI 0.80 [0.74 - 0.85]). Compared with MEWS and qSOFA, the rSIG also had a higher AUROC for vasopressor use and mechanical ventilation, but not for 72-h mortality or in-hospital mortality. The rSIG could be a simple and reliable predictor of the need for initial resuscitation in patients suspected of sepsis.

Poor prognosis of patients with severe COVID-19 admitted to an infectious disease intensive care unit during the pandemic caused by the Delta variant in Japan.

During the surge of coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) delta variant, our institution operated an intensive care unit (ICU) for patients with severe COVID-19. The study aim was to determine the survival rate and treatment outcomes of patients with severe COVID-19 treated in the ICU during the surge. A total of 23 consecutive patients with severe COVID-19 were admitted to the ICU between August 5 and October 6, 2021. Patients received multidrug therapy consisting of remdesivir, tocilizumab, heparin, and methylprednisolone. The patients were divided into two groups based on the ordinal scale (OS): a non-invasive oxygen therapy (OS-6) group, and an invasive oxygen therapy (OS-7) group. There were 13 (57%) and 10 (43%) patients in the OS-7 and OS-6 groups, respectively. All patients were unvaccinated. Sixteen patients (70%) were male. The median age was 53 years; the median body mass index (BMI) was 30.3 kg/m2; and the median P/F ratio on admission was 96. The 30-day survival rate was 69% and was significantly poorer in the OS-7 group (54%) than in the OS-6 group (89%; p = 0.05). The prevalence of obesity (p = 0.05) and the Sequential Organ Failure Assessment (SOFA) score on admission (p < 0.01) were significantly higher in the OS-7 group. Seven patients in the OS-7 group (54%) developed bacteremia. A low P/F ratio on admission was a significant unfavorable prognostic factor (hazard ratio: 10.9; p = 0.03). The survival rate was poor, especially in patients requiring invasive oxygen therapy. More measures are needed to improve the treatment outcomes of patients with severe COVID 19.

Autopsy findings of a patient with severe COVID-19 treated with long-term extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation (ECMO) therapy in patients with coronavirus disease 2019 (COVID-19) has a low frequency of use, and thus pathological findings in such patients are valuable. In this case report, a 62-year-old man with a history of hypertension presented with a runny nose. After an at-home COVID-19 positive test, he developed dyspnea and fever. Once admitted to our hospital, his oxygenation worsened, and ECMO was initiated. He died from respiratory failure 69 days after ECMO induction. Macroscopically, the lungs gained mass, were partially consolidated, and were airless. Histological analysis revealed diffuse bronchial epithelial metaplasia and adenoid metaplasia in the alveolar epithelium. Although the lung parenchyma was partially preserved, there was organizing and fibrosis that filled pulmonary alveolus due to COVID-19 and changes resulting from disuse and long-term ECMO.

Extracorporeal membrane oxygenation may decrease the plasma concentration of remdesivir in a patient with severe coronavirus disease 2019.

Remdesivir is an antiviral drug that results in clinical improvement after five days of treatment and accelerates recovery by 31%. No studies have discussed the pharmacokinetic analysis of remdesivir in patients with severe COVID-19 requiring extracorporeal membrane oxygenation (ECMO). A 63-year-old American man who underwent mechanical ventilation and ECMO for severe COVID-19 was administered remdesivir for ten days. The loading dosage was 200 mg at 7 PM on day 12 and 100 mg daily at 0:00 PM from day 13-21, administered within 1 h. The pharmacokinetic analysis was performed. The serum creatinine concentration was within the normal range of 0.5-0.7 mg/dL during treatment. According to the pharmacokinetic analysis, the plasma concentrations of remdesivir and GS-441524 4 h after administration (C4) were 662 ng/mL and 58 ng/mL, respectively, and the concentrations 18 h after administration (C18) were 32 ng/mL and 44 ng/mL, respectively. Therefore, the half-life of remdesivir and GS-441524 was 3.2 and 35.1 h, respectively. Monitoring the plasma concentrations of remdesivir and GS-441524 in patients undergoing ECMO may be necessary.

SLC15A4 mediates M1-prone metabolic shifts in macrophages and guards immune cells from metabolic stress.

The amino acid and oligopeptide transporter Solute carrier family 15 member A4 (SLC15A4), which resides in lysosomes and is preferentially expressed in immune cells, plays critical roles in the pathogenesis of lupus and colitis in murine models. Toll-like receptor (TLR)7/9- and nucleotide-binding oligomerization domain-containing protein 1 (NOD1)-mediated inflammatory responses require SLC15A4 function for regulating the mechanistic target of rapamycin complex 1 (mTORC1) or transporting L-Ala-γ-D-Glu-meso-diaminopimelic acid, IL-12: interleukin-12 (Tri-DAP), respectively. Here, we further investigated the mechanism of how SLC15A4 directs inflammatory responses. Proximity-dependent biotin identification revealed glycolysis as highly enriched gene ontology terms. Fluxome analyses in macrophages indicated that SLC15A4 loss causes insufficient biotransformation of pyruvate to the tricarboxylic acid cycle, while increasing glutaminolysis to the cycle. Furthermore, SLC15A4 was required for M1-prone metabolic change and inflammatory IL-12 cytokine productions after TLR9 stimulation. SLC15A4 could be in close proximity to AMP-activated protein kinase (AMPK) and mTOR, and SLC15A4 deficiency impaired TLR-mediated AMPK activation. Interestingly, SLC15A4-intact but not SLC15A4-deficient macrophages became resistant to fluctuations in environmental nutrient levels by limiting the use of the glutamine source; thus, SLC15A4 was critical for macrophage's respiratory homeostasis. Our findings reveal a mechanism of metabolic regulation in which an amino acid transporter acts as a gatekeeper that protects immune cells' ability to acquire an M1-prone metabolic phenotype in inflammatory tissues by mitigating metabolic stress.

SARS-CoV-2 Leakage From the Gas Outlet Port During Extracorporeal Membrane Oxygenation for COVID-19.

Patients with the coronavirus disease 2019 (COVID-19) sometimes develop refractory respiratory failure and may require venovenous extracorporeal membrane oxygenation (VV-ECMO). It is known that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is sometimes present in the blood of COVID-19 patients. VV-ECMO is often used for several weeks, and plasma leaks can occur, albeit rarely. Hence, in terms of infection control, a concern is that SARS-CoV-2 may leak from the gas outlet port of the oxygenator during ECMO support of critically ill COVID-19 patients. The aim of this study was to clarify whether SARS-CoV-2 leaks from the oxygenator during ECMO support. Five patients with critical COVID-19 pneumonia were placed on VV-ECMO. Silicone-coated polypropylene membrane oxygenators were used in the ECMO circuits for these patients. SARS-CoV-2 ribonucleic acid (RNA) was measured by quantitative reverse transcription polymerase chain reaction in serum and at the gas outlet port of the ECMO circuit at the time of circuit replacement or liberation from ECMO. SARS-CoV-2 RNA was detected in the gas outlet port of the ECMO circuit for three of the five patients. None of the medical staff involved in the care of these five patients has been infected with COVID-19. In conclusion, SARS-CoV-2 could leak to the gas outlet port of the ECMO circuit through silicone-coated polypropylene membranes during ECMO support of critically ill COVID-19 patients.

Impact of frailty on protocol-based weaning from mechanical ventilation in patients with sepsis: a retrospective cohort study.

AIM: Frailty has been shown to be associated with prolonged mechanical ventilation (MV). However, due to limited physiological data, it has been unclear how frailty affects weaning from MV in septic patients subjected to a specific weaning protocol. METHODS: This was a single-center retrospective cohort study. The study included patients with sepsis on MV who underwent protocol-based weaning between August 2015 and December 2018. Frailty was defined as a Clinical Frailty Scale score 4 or more. The association between frailty and weaning was evaluated. RESULTS: Ninety-nine eligible patients were identified and categorized as frail (n = 67) or not frail (n = 32). The duration of MV was significantly longer in the frail group (8 days versus 5 days, P < 0.01). In multivariate analysis, frailty was independently associated with duration of MV (regression coefficient 17.97, 95% confidence interval 1.77-34.17) and successful weaning (hazard ratio 0.60, 95% confidence interval 0.36-1.00). There was no significant between-group difference in duration until the first separation attempt or reintubation rate. Respiratory failure was significantly more common in the frail group as a cause of weaning failure, whereas airway failure was common in both groups. CONCLUSION: Frailty was independently associated with a longer duration of MV in patients with sepsis who underwent protocol-based weaning. Frail patients were more likely to fail spontaneous breathing trials than nonfrail patients during the weaning process, although the risk after extubation was similar.

Corticosteroid therapy for severe COVID-19 pneumonia: optimal dose and duration of administration.

Severe COVID-19 is associated with a hyperinflammatory state, and corticosteroid therapy may be effective. We review the recent literature and discuss the appropriate dose and duration of corticosteroid therapy. Low-dose corticosteroid therapy is often used to treat COVID-19. However, several doses of methylprednisolone (or prednisolone) have been attempted, ranging from about 40 mg/day to 2 mg/kg/day. Doses may need to be adjusted depending on severity. Corticosteroid therapy is generally administered for a short period over several days. However, COVID-19-induced respiratory failure is often prolonged, so longer administration may be considered. Careful monitoring for complications due to corticosteroid therapy is vital.

Metoclopramide versus sumatriptan in the treatment of migraine in the emergency department: a single-center, open-label, cluster-randomized controlled non-inferiority trial.

Migraine is a common disease seen in the emergency department (ED). Triptans, which are recommended in therapeutic guidelines for migraine, have some contraindications and possible severe side effects. Metoclopramide, which is commonly used as an antiemetic, also seems to have pain-relieving effects for migraine. In this article, we will introduce a study in progress, which investigates whether metoclopramide 10 mg intravenously (IV) is non-inferior to sumatriptan 3 mg subcutaneously (SQ) as migraine treatment in the ED. This study is a single-center, open-label, cluster-randomized controlled trial of 80 patients with migraine attacks to investigate the non-inferiority of metoclopramide to sumatriptan. The patients will be cluster-randomized monthly into metoclopramide 10 mg IV and sumatriptan 3 mg SQ arms. The primary outcome will be change in Numerical Rating Scale score for headache at 1 h after baseline. In discussion, if our hypothesis is confirmed, metoclopramide can be considered as first-line medication for migraine attacks in ED settings.

Identification of Cell-Surface Proteins Endocytosed by Human Brain Microvascular Endothelial Cells In Vitro.

Cell-surface proteins that can endocytose into brain microvascular endothelial cells serve as promising candidates for receptor-mediated transcytosis across the blood-brain barrier (BBB). Here, we comprehensively screened endocytic cell-surface proteins in hCMEC/D3 cells, a model of human brain microvascular endothelial cells, using surface biotinylation methodology and sequential window acquisition of all theoretical fragment-ion spectra-mass spectrometry (SWATH-MS)-based quantitative proteomics. Using this method, we identified 125 endocytic cell-surface proteins from hCMEC/D3 cells. Of these, 34 cell-surface proteins were selectively internalized into human brain microvascular endothelial cells, but not into human umbilical vein endothelial cells (HUVECs), a model of human peripheral microvascular endothelial cells. Two cell-surface proteins, intercellular adhesion molecule-1 (ICAM1) and podocalyxin (PODXL), were identified as BBB-localized endocytic cell-surface proteins in humans, using open mRNA and protein databases. Immunohistochemical evaluation confirmed PODXL expression in the plasma membrane of hCMEC/D3 cells and revealed that anti-PODXL antibody-labeled cell-surface PODXL internalized into hCMEC/D3 cells. Immunohistochemistry further revealed that PODXL is localized at the luminal side of human brain microvessels, supporting its potential suitability for translational applications. In conclusion, our findings highlight novel endocytic cell-surface proteins capable of internalizing into human brain microvascular endothelial cells. ICAM1 or PODXL targeted antibody or ligand-labeled biopharmaceuticals and nanocarriers may provide effective targeted delivery to the brain across the BBB for the treatment of central nervous system (CNS) diseases.

Cyclocreatine Transport by SLC6A8, the Creatine Transporter, in HEK293 Cells, a Human Blood-Brain Barrier Model Cell, and CCDSs Patient-Derived Fibroblasts.

PURPOSE: Cyclocreatine, a creatine analog, is a candidate drug for treating patients with cerebral creatine deficiency syndromes (CCDSs) caused by creatine transporter (CRT, SLC6A8) deficiency, which reduces brain creatine level. The purpose of this study was to clarify the characteristics of cyclocreatine transport in HEK293 cells, which highly express endogenous CRT, in hCMEC/D3 cells, a human blood-brain barrier (BBB) model, and in CCDSs patient-derived fibroblasts with CRT mutations. METHODS: Cells were incubated at 37°C with [14C]cyclocreatine (9 µM) and [14C]creatine (9 µM) for specified periods of times in the presence or absence of inhibitors, while the siRNAs were transfected by lipofection. Protein expression and mRNA expression were quantified using targeted proteomics and quantitative PCR, respectively. RESULTS: [14C]Cyclocreatine was taken up by HEK293 cells in a time-dependent manner, while exhibiting saturable kinetics. The inhibition and siRNA knockdown studies demonstrated that the uptake of [14C]cyclocreatine by both HEK293 and hCMEC/D3 cells was mediated predominantly by CRT as well as [14C]creatine. In addition, uptake of [14C]cyclocreatine and [14C]creatine by the CCDSs patient-derived fibroblasts was found to be largely reduced. CONCLUSION: The present study suggests that cyclocreatine is a CRT substrate, where CRT is the predominant contributor to influx of cyclocreatine into the brain at the BBB. Our findings provide vital insights for the purposes of treating CCDSs patients using cyclocreatine.

High-Flow Nasal Cannula May Not Reduce the Re-Intubation Rate Compared With a Large-Volume Nebulization-Based Humidifier.

BACKGROUND: High-flow nasal cannula (HFNC) therapy may reduce the re-intubation rate compared with conventional oxygen therapy. However, HFNC has not been sufficiently compared with conventional oxygen therapy with a heated humidifier, even though heated humidification is beneficial for facilitating airway clearance. METHODS: This study was a single-center, open-label, randomized controlled trial. We randomized subjects with respiratory failure after extubation to either HFNC group or to a large-volume humidified nebulization-based nebulizer. The primary end point was the re-intubation rate within 7 d after extubation. RESULTS: We could not recruit enough subjects for the sample size we designed, therefore, we analyzed 69 subjects (HFNC group, 30 subjects; nebulizer group, 39 subjects). The re-intubation rate within 7 d was not significantly different between the HFNC and nebulizer groups (5/30 subjects [17%] and 6/39 subjects [15%], respectively; P > .99). [Formula: see text]/set [Formula: see text] at 24 h after extubation was also not significantly different between the respective groups (264 ± 105 mm Hg in the HFNC group vs 224 ± 53 mm Hg in the nebulizer group; P = .07). CONCLUSIONS: Compared with a large-volume nebulization-based humidifier, HFNC may not reduce the re-intubation rate within 7 d. However, because of insufficient statistical power, further studies are needed to reach a conclusion.

Derivation of a model to predict mortality in urban patients with accidental hypothermia: a retrospective observational study.

AIM: Accidental hypothermia in urban settings is associated with high mortality rates. However, the predictors of mortality remain under discussion. The purpose of this study was to evaluate prognostic factors and develop a prediction model in patients with accidental hypothermia in urban settings. METHODS: We retrospectively reviewed medical records in patients with hypothermia brought to our hospital by ambulance in a 7-year study period. Patients' records of survival discharge or in-hospital death and clinical data were collected from medical records. We analyzed factors to predict in-hospital death using multiple logistic regression analysis. Recursive partitioning analysis was used to construct a prediction model using predictors from multiple logistic regression analysis. RESULTS: In the study period, 192 patients were included in this study. Of them, 154 patients were discharged alive and 38 patients died. Multiple logistic regression analysis revealed that in-hospital death was related to Glasgow Coma Scale (GCS) score, prothrombin time - international normalized ratio (PT-INR) value, and fibrin degradation product (FDP). Recursive partitioning analysis revealed that patients with accidental hypothermia could be divided into four groups: very high risk (FDP ≥ 14 µg/mL, PT-INR ≥ 1.4), high risk (FDP ≥ 14 µg/mL, PT-INR < 1.4), moderate risk (FDP < 14 µg/mL, GCS < 10), and low risk (FDP < 14 µg/mL, GCS ≥ 10). CONCLUSION: High FDP and PT-INR values and low GCS score on arrival at the emergency department were associated with in-hospital mortality in urban patients with hypothermia. A simple prediction model for grouping risk was developed using these predictors.

Tandem Mass Spectrometry Imaging Reveals Distinct Accumulation Patterns of Steroid Structural Isomers in Human Adrenal Glands.

Visualizing tissue distribution of steroid hormones is a promising application of MALDI mass spectrometry imaging (MSI). On-tissue chemical derivatization using Girard's T reagent has enhanced the ionization efficiency of steroids. However, discriminating between structural isomers with distinct bioactivities remains a challenge. Herein, we used ion trap MS/tandem MS (MS3) to distinguish a mineralcorticoid aldosterone (Aldo) and a glucocorticoid cortisol (F), from their structural isomers. Our method is also useful to detect hybrid steroids (18-hydroxycortisol [18-OHF] and 18-oxocortisol) with sufficient signal-to-noise ratio. The clinical applicability of the tandem MS method was evaluated by analyzing F, Aldo, and 18-OHF distributions in human adrenal glands. In such clinical specimens, small Aldo-producing cell clusters (APCCs) were identified and were first found to produce a high level of Aldo and not to contain F. Moreover, a part of APCCs produced 18-OHF, presumably converted from F by APCC-specific CYP11B2 activity. Catecholamine species were also visualized with another derivatization reagent (TAHS), and those profiling successfully discriminated pheochromocytoma species. These tandem MSI-methods, coupled with on-tissue chemical derivatization has proven to be useful for detecting low-abundance steroids, including Aldo and hybrid steroids and thus identifying steroid hormone-producing lesions.

Large-Scale Quantitative Comparison of Plasma Transmembrane Proteins between Two Human Blood-Brain Barrier Model Cell Lines, hCMEC/D3 and HBMEC/ciß.

Transmembrane (TM) proteins localized at the plasma membrane, such as transporters and receptors, play important roles in regulating the selective permeability of the blood-brain barrier (BBB). The purpose of the present study was to clarify the differences in the expression levels of TM proteins in the plasma membrane between two established human BBB model cell lines, hCMEC/D3 and HBMEC/ciß, in order to assist researchers in selecting the most appropriate cell line for particular purposes. We first confirmed that plasma membranes could be enriched sufficiently for a quantitative proteomics study by using the Plasma Membrane Protein Extraction Kit provided by BioVision with a modified protocol. This method was applied to hCMEC/D3 and HBMEC/ciß cells, and fractions were used for untargeted quantitative proteomics based on sequential window acquisition of all theoretical fragment-ion spectra. In the plasma membrane fractions, 345 TM proteins were quantified, among which 135 showed significant expression differences between the two cell lines. In hCMEC/D3 cells, amino acid transporters SNAT1, SNAT2, SNAT5, ASCT1, CAT1, and LAT1; adenosine 5'-triphosphate-binding cassette transporters P-gp and MRP4; and GLUT1 were more highly expressed. The transferrin receptor expression was also 4.56-fold greater in hCMEC/D3 cells. In contrast, HBMEC/ciß cells expressed greater levels of IgG transporter neonatal Fc receptor, as well as tight-junction proteins PECAM1, JAM1, JAM3, and ESAM. Our results suggest that hCMEC/D3 cells have greater efflux transport, amino acid transport, and transferrin receptor-mediated uptake activities, whereas HBMEC/ciß cells have greater IgG-transport activity and tight-junction integrity.

Study protocol for single-center, open-label, randomized controlled trial to clarify the preventive efficacy of electrical stimulation for muscle atrophy after trauma.

BACKGROUND: Management of trauma involves long-term bed rest even when muscle strength in the lower extremities is preserved. Prolonged bed rest reduces muscle mass and causes muscle atrophy. A recent study reported the efficacy of rehabilitation using electrical muscle stimulation (EMS) for muscle strength maintenance in intensive care unit patients with disturbance of consciousness. However, despite the expected benefits of EMS in maintaining muscle strength, little is known about its efficacy in trauma patients. METHODS/DESIGN: A single-center, open-label, randomized controlled trial of 40 patients with pelvic fracture to test the effectiveness of 14 days of EMS. The primary outcome will be change in cross-sectional area of the thigh muscle between pre and post intervention, as measured on computed tomography images. We will analyze the primary endpoint by analysis of covariance (ANCOVA) and analyze the secondary endpoints in an exploratory manner. CONCLUSION: If our hypothesis is confirmed, this study will provide evidence that the use of EMS can be effective in preventing muscle atrophy. TRIAL REGISTRATION: UMIN registration number: UMIN000030190 . Registered on 1 December 2017.