METFORMIN MITIGATES SEPSIS-ASSOCIATED PULMONARY FIBROSIS BY PROMOTING AMPK ACTIVATION AND INHIBITING HIF-1α-INDUCED AEROBIC GLYCOLYSIS.

ABSTRACT: Recent research has revealed that aerobic glycolysis has a strong correlation with sepsis-associated pulmonary fibrosis (PF). However, at present, the mechanism and pathogenesis remain unclear. We aimed to test the hypothesis that the adenosine monophosphate-activated protein kinase (AMPK) activation and suppression of hypoxia-inducible factor 1α (HIF-1α)-induced aerobic glycolysis play a central role in septic pulmonary fibrogenesis. Cellular experiments demonstrated that lipopolysaccharide increased fibroblast activation through AMPK inactivation, HIF-1α induction, alongside an augmentation of aerobic glycolysis. By contrast, the effects were reversed by AMPK activation or HIF-1α inhibition. In addition, pretreatment with metformin, which is an AMPK activator, suppresses HIF-1α expression and alleviates PF associated with sepsis, which is caused by aerobic glycolysis, in mice. Hypoxia-inducible factor 1α knockdown demonstrated similar protective effects in vivo . Our research implies that targeting AMPK activation and HIF-1α-induced aerobic glycolysis with metformin might be a practical and useful therapeutic alternative for sepsis-associated PF.

Development and validation of a nomogram to predict the risk of renal replacement therapy among acute kidney injury patients in intensive care unit.

BACKGROUND: There are no universally accepted indications to initiate renal replacement therapy (RRT) among patients with acute kidney injury (AKI). This study aimed to develop a nomogram to predict the risk of RRT among AKI patients in intensive care unit (ICU). METHODS: In this retrospective cohort study, we extracted AKI patients from Medical Information Mart for Intensive Care III (MIMIC-III) database. Patients were randomly divided into a training cohort (70%) and a validation cohort (30%). Multivariable logistic regression based on Akaike information criterion was used to establish the nomogram. The discrimination and calibration of the nomogram were evaluated by Harrell's concordance index (C-index) and Hosmer-Lemeshow (HL) test. Decision curve analysis (DCA) was performed to evaluate clinical application. RESULTS: A total of 7413 critically ill patients with AKI were finally enrolled. 514 (6.9%) patients received RRT after ICU admission. 5194 (70%) patients were in the training cohort and 2219 (30%) patients were in the validation cohort. Nine variables, namely, age, hemoglobin, creatinine, blood urea nitrogen and lactate at AKI detection, comorbidity of congestive heart failure, AKI stage, and vasopressor use were included in the nomogram. The predictive model demonstrated satisfying discrimination and calibration with C-index of 0.938 (95% CI, 0.927-0.949; HL test, P = 0.430) in training set and 0.935 (95% CI, 0.919-0.951; HL test, P = 0.392) in validation set. DCA showed a positive net benefit of our nomogram. CONCLUSION: The nomogram developed in this study was highly accurate for RRT prediction with potential application value.

Association of geriatric nutritional risk index with all-cause hospital mortality among elderly patients in intensive care unit.

Background: Malnutrition is associated with poor outcomes for geriatric patients in intensive care unit (ICU). It is important to identify patients at risk of malnutrition and provide individual nutrition support. The assessment of malnutrition risk is not easy for these patients due to their cognitive impairment. Geriatric nutrition risk index (GNRI) is a simple and objective scoring tool to evaluate the risk of malnutrition in elderly patients. In this study, we aimed to see whether GNRI score was appropriate to predict clinical outcomes among geriatric patients in the setting of ICU. Materials and methods: Elderly patients with age ≥ 65 years were extracted from Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Categories based on GNRI were classified as major risk (GNRI <82), moderate risk (GNRI 82 to <92), low risk (GNRI 92 to ≤98), and no risk (GNRI >98). The primary outcome was all-cause hospital mortality. Multivariable Cox proportional hazards regression models and restricted cubic spline were used to investigate associations of GNRI with hospital mortality, respectively. A two-piecewise linear regression model was applied to examine the inflection point of GNRI on hospital mortality. To reduce selection bias, propensity score matching (PSM) was used in a 1:1 ratio. Results: A total of 3,696 geriatric patients were finally included with median age 75 (69, 81) years. The prevalence of major risk was 28.6%. In the fully adjusted model, GNRI categories featured a negative trend with hospital mortality (p for trend = 0.037). Restricted cubic spline analysis demonstrated an L-shaped relationship between GNRI and hospital mortality before and after matching. The inflection point was 78.7. At the left side of inflection point, GNRI levels were significantly negatively associated with hospital mortality (HR = 0.96, 95% CI: 0.94-0.98; p < 0.001) and featured no significant relations at the right side. Multiple linear regression also showed that GNRI was negatively associated with length of stay in hospital. Conclusion: The major risk of malnutrition defined by GNRI was able to predict poor prognosis for geriatric patients admitted to ICU.

Scars of COVID-19: A bibliometric analysis of post-COVID-19 fibrosis.

Background: The coronavirus disease 2019 (COVID-19) becomes a worldwide public health threat. Increasing evidence proves that COVID-19-induced acute injuries could be reversed by a couple of therapies. After that, post-COVID-19 fibrosis (PCF), a sequela of "Long COVID," earns rapidly emerging concerns. PCF is associated with deteriorative lung function and worse quality of life. But the process of PCF remains speculative. Therefore, we aim to conduct a bibliometric analysis to explore the overall structure, hotspots, and trend topics of PCF. Materials and methods: A comprehensive search was performed in the Web of Science core database to collect literature on PCF. Search syntax included COVID-19 relevant terms: "COVID 19," "COVID-19 Virus Disease," "COVID-19 Virus Infection," "Coronavirus Disease-19," "2019 Novel Coronavirus Disease," "2019 Novel Coronavirus Infection," "SARS Coronavirus 2 Infection," "COVID-19 Pandemic," "Coronavirus," "2019-nCoV," and "SARS-CoV-2"; and fibrosis relevant terms: "Fibrosis," "Fibroses," and "Cirrhosis." Articles in English were included. Totally 1,088 publications were enrolled. Searching results were subsequentially exported and collected for the bibliometric analysis. National, organizational, and individual level data were analyzed and visualized through biblioshiny package in the R, VOSviewer software, the CiteSpace software, and the Graphical Clustering Toolkit (gCLUTO) software, respectively. Results: The intrinsic structure and development in the field of PCF were investigated in the present bibliometric analysis. The topmost keywords were "COVID-19" (occurrences, 636) surrounded by "SARS-CoV-2" (occurrences, 242), "coronavirus" (occurrences, 123), "fibrosis" (occurrences, 120), and "pneumonia" (occurrences, 94). The epidemiology, physiopathology, diagnosis, and therapy of PCF were extensively studied. After this, based on dynamic analysis of keywords, hot topics sharply changed from "Wuhan," "inflammation," and "cytokine storm" to "quality of life" and "infection" through burst detection; from "acute respiratory syndrome," "cystic-fibrosis" and "fibrosis" to "infection," "COVID-19," "quality-of-life" through thematic evolution; from "enzyme" to "post COVID." Similarly, co-cited references analysis showed that topics of references with most citations shift from "pulmonary pathology" (cluster 0) to "COVID-19 vaccination" (cluster 6). Additionally, the overview of contributors, impact, and collaboration was revealed. Summarily, the USA stood out as the most prolific, influential, and collaborative country. The Udice French Research University, Imperial College London, Harvard University, and the University of Washington represented the largest volume of publications, citations, H-index, and co-authorships, respectively. Dana Albon was the most productive and cited author with the strongest co-authorship link strength. Journal of Cystic Fibrosis topped the list of prolific and influential journals. Conclusion: Outcomes gained from this study assisted professionals in better realizing PCF and would guide future practices. Epidemiology, pathogenesis, and therapeutics were study hotspots in the early phase of PCF research. As the spread of the COVID-19 pandemic and progress in this field, recent attention shifted to the quality of life of patients and post-COVID comorbidities. Nevertheless, COVID-19 relevant infection and vaccination were speculated to be research trends with current and future interest. International cooperation as well as in-depth laboratory experiments were encouraged to promote further explorations in the field of PCF.

Prognostic Nutritional Index as a Predictor of 30-Day Mortality Among Patients Admitted to Intensive Care Unit with Acute Exacerbation of Chronic Obstructive Pulmonary Disease: A Single-Center Retrospective Cohort Study.

BACKGROUND Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is significantly associated with increased mortality. The current study aimed to investigate the predictive ability of the prognostic nutritional index (PNI) in 30-day mortality among AECOPD patients admitted to the ICU. MATERIAL AND METHODS Clinical data were extracted from the Medical Information Mart for Intensive Care-III (MIMIC-III) database. Patients were divided into 3 groups according to the tertiles of PNI. Cox proportional hazard regressions were performed to assess the association between PNI and 30-day mortality. Subgroup analyses were performed to identify the consistency of the association. Receiver operator characteristic (ROC) curve analysis was performed to evaluate the predictive accuracy among PNI, serum albumin, neutrophil-to-lymphocyte (NLR), and platelet-to-lymphocyte ratio (PLR). RESULTS A total of 494 AECOPD patients were included in this study. The mean age was 70.8±10.4 years old. Kaplan-Meier analysis showed ongoing divergence in rates of mortality among tertiles (p<0.001). After adjusting for confounders, high PNI tertile was an independent favorable predictor of 30-day mortality (HR=0.39; 95% CI, 0.19-0.80; p=0.011) compared to low tertile reference. Subgroup analysis showed that the predictive ability of PNI was especially suitable for patients aged >70 years and with mechanical ventilation. The cut-off value of PNI was 31.8 with sensitivity 62.3% and specificity 64.1%. The area under the ROC of PNI (0.642, 95% CI, 0.560 to 0.717) was better than that of serum albumin, NLR, and PLR. CONCLUSIONS PNI could serve as a simple and reliable prognostic biomarker for AECOPD patients in the ICU.

Favorable Outcomes of Anticoagulation With Unfractioned Heparin in Sepsis-Induced Coagulopathy: A Retrospective Analysis of MIMIC-III Database.

Backgrounds: Anticoagulation in sepsis-associated disseminated intravascular coagulation (DIC) remains uncertain. The aim of this study was to investigate whether unfractioned heparin (UFH) could improve clinical outcomes in patients with sepsis-induced coagulopathy (SIC). Methods: Septic patients with SIC were identified from the Medical Information Mart for Intensive Care (MIMIC)-III database. Cox-proportional hazards model, logistic regression model and linear regression were used to assess the associations between UFH administration and 28-day mortality, hospital mortality, occurrence of bleeding complications and length of stay, respectively. Propensity score matching (PSM) analysis was used to match the imbalance between patients in the UFH group and the control group. Patients were further stratified according to SIC score and Simplified Acute Physiology Score II (SAPS II). Results: A total of 1,820 septic patients with SIC were included in the data analysis. After PSM, 652 pairs of patients were matched between the patients in the UFH group and the control group. UFH was significantly associated with reduced 28-day mortality (HR, 0.323, 95% CI, 0.258-0.406; p < 0.001) and hospital mortality (HR, 0.380, 95% CI, 0.307-0.472; p < 0.001) without increasing the risks of intracranial hemorrhage (OR, 1.480, 95% CI, 0.955-2.294; p = 0.080) or gastrointestinal bleeding (OR, 1.094, 95% CI, 0.503-2.382; p = 0.820). For subgroup analysis, it didn't change the favorable results of UFH on mortality and UFH didn't increase the risk of hemorrhage in patients with severe disease. Conclusions: The analysis of MIMIC-III database indicated that anticoagulant therapy with UFH may be associated with a survival benefit in patients with SIC.

Management of Bivalirudin Anticoagulation Therapy for Extracorporeal Membrane Oxygenation in Heparin-Induced Thrombocytopenia: A Case Report and a Systematic Review.

Extracorporeal membrane oxygenation (ECMO) can provide respiratory and cardiac support to patients in reversible devastated conditions. Heparin is the mainstay for anticoagulation during ECMO. Bivalirudin, a direct thrombin blocker, may represent an effective alternative for patients suffering from heparin-induced thrombocytopenia (HIT). We present the first case of a Chinese patient who experienced HIT and received bivalirudin anticoagulation during ECMO. In addition, we present a systematic review for this topic. We searched PubMed, EMBASE, and Cochrane Library (up to April 20, 2020) for studies that included patients undergoing ECMO, presenting with HIT, requiring bivalirudin treatment, and reporting relevant outcomes. The literature review yielded 15 studies involving 123 patients, amongst whom 58 patients were confirmed or suspected HIT patients, and 76 patients received bivalirudin as an anticoagulant for ECMO. Twelve studies were included for quantitative synthesis, and 46 patients were retrieved. The mean age of these patients was 46 years, and 30 patients were males. The average maintenance rate of bivalirudin was 0.27 ± 0.37 mg/kg/h, in order to maintain a target of activated clotting time (ACT) of 160-220 s. Additionally, bivalirudin doses in patients with continuous renal replacement therapies (CRRT) and patients without CRRT were 0.15 ± 0.06 mg/kg/h vs 0.28 ± 0.36 mg/kg/h, respectively (p=0.15). Most of the patients with confirmed HIT improved platelet counts in 3.3 ± 2.8 days after switching to bivalirudin anticoagulation. The patient-level data showed that 29 cases survived, 1 reported major bleeding, and 4 reported thrombotic events. Bivalirudin might be a promising optimal choice for ECMO anticoagulation in patients with HIT. A tailored protocol for management of bivalirudin treatment during ECMO should be developed with caution. Further prospective studies are necessary to standardise the use of bivalirudin. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, identifier CRD42020160907.

The efficacy of extracorporeal membrane oxygenation in liver transplantation from non-heart-beating donors: A systemic review and meta-analysis.

BACKGROUND: A systematic review and meta-analysis was made to see whether extracorporeal membrane oxygenation (ECMO) in liver transplantation could improve non-heart-beating donors (NHBDs) recipients' outcomes compared with donors after brain death (DBDs) recipients. METHODS: We searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials for eligible studies. The study eligible criteria are cohort or case-control studies using ECMO in all NHBDs; studies involved a comparison group of DBDs; and studies evaluated 1-year graft and patient survival rate in NHBDs and DBDs groups. RESULTS: Four studies with 704 patients fulfilled the inclusion criteria. The pooled odds ratio (OR) of 1-year patient survival rate in NHBDs recipients compared with DBDs recipients was 0.8 (95% confidence interval [CI], 0.41-1.55). The pooled OR of 1-year graft survival rate in NHBDs recipients compared with DBDs recipients was 0.46 (95% CI, 0.26-0.81). NHBDs recipients were at greater risks to the occurrence of primary nonfunction (PNF) (OR = 7.12, 95% CI, 1.84-27.52) and ischemic cholangiopathy (IC) (OR = 9.46, 95% CI, 2.76-32.4) than DBDs recipients. CONCLUSIONS: ECMO makes 1-year patient survival acceptable in NHBDs recipients. One-year graft survival rate was lower in NHBDs recipients than in DBDs recipients. Compared with DBDs recipients, the risks to develop PNF and IC were increased among NHBDs recipients.