-
American Journal of Respiratory and... Dec 2023Assessing the early use of video-assisted thoracoscopic surgery (VATS) or intrapleural enzyme therapy (IET) in pleural infection requires a phase III randomized... (Randomized Controlled Trial)
Randomized Controlled Trial
Early Video-assisted Thoracoscopic Surgery or Intrapleural Enzyme Therapy in Pleural Infection: A Feasibility Randomized Controlled Trial. The Third Multicenter Intrapleural Sepsis Trial-MIST-3.
Assessing the early use of video-assisted thoracoscopic surgery (VATS) or intrapleural enzyme therapy (IET) in pleural infection requires a phase III randomized controlled trial (RCT). To establish the feasibility of randomization in a surgery-versus-nonsurgery trial as well as the key outcome measures that are important to identify relevant patient-centered outcomes in a subsequent RCT. The MIST-3 (third Multicenter Intrapleural Sepsis Trial) was a prospective multicenter RCT involving eight U.K. centers combining on-site and off-site surgical services. The study enrolled all patients with a confirmed diagnosis of pleural infection and randomized those with ongoing pleural sepsis after an initial period (as long as 24 h) of standard care to one of three treatment arms: continued standard care, early IET, or a surgical opinion with regard to early VATS. The primary outcome was feasibility based on >50% of eligible patients being successfully randomized, >95% of randomized participants retained to discharge, and >80% of randomized participants retained to 2 weeks of follow-up. The analysis was performed per intention to treat. Of 97 eligible patients, 60 (62%) were randomized, with 100% retained to discharge and 84% retained to 2 weeks. Baseline demographic, clinical, and microbiological characteristics of the patients were similar across groups. Median times to intervention were 1.0 and 3.5 days in the IET and surgery groups, respectively ( = 0.02). Despite the difference in time to intervention, length of stay (from randomization to discharge) was similar in both intervention arms (7 d) compared with standard care (10 d) ( = 0.70). There were no significant intergroup differences in 2-month readmission and further intervention, although the study was not adequately powered for this outcome. Compared with VATS, IET demonstrated a larger improvement in mean EuroQol five-dimension health utility index (five-level edition) from baseline (0.35) to 2 months (0.83) ( = 0.023). One serious adverse event was reported in the VATS arm. This is the first multicenter RCT of early IET versus early surgery in pleural infection. Despite the logistical challenges posed by the coronavirus disease (COVID-19) pandemic, the study met its predefined feasibility criteria, demonstrated potential shortening of length of stay with early surgery, and signals toward earlier resolution of pain and a shortened recovery with IET. The study findings suggest that a definitive phase III study is feasible but highlights important considerations and significant modifications to the design that would be required to adequately assess optimal initial management in pleural infection.The trial was registered on ISRCTN (number 18,192,121).
Topics: Humans; Thoracic Surgery, Video-Assisted; Feasibility Studies; Communicable Diseases; Pleural Diseases; Sepsis; Enzyme Therapy
PubMed: 37820359
DOI: 10.1164/rccm.202305-0854OC -
Intensive Care Medicine Jan 2024Ilofotase alfa is a human recombinant alkaline phosphatase with reno-protective effects that showed improved survival and reduced Major Adverse Kidney Events by 90 days... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Ilofotase alfa is a human recombinant alkaline phosphatase with reno-protective effects that showed improved survival and reduced Major Adverse Kidney Events by 90 days (MAKE90) in sepsis-associated acute kidney injury (SA-AKI) patients. REVIVAL, was a phase-3 trial conducted to confirm its efficacy and safety.
METHODS
In this international double-blinded randomized-controlled trial, SA-AKI patients were enrolled < 72 h on vasopressor and < 24 h of AKI. The primary endpoint was 28-day all-cause mortality. The main secondary endpoint was MAKE90, other secondary endpoints were (i) days alive and free of organ support through day 28, (ii) days alive and out of the intensive care unit (ICU) through day 28, and (iii) time to death through day 90. Prior to unblinding, the statistical analysis plan was amended, including an updated MAKE90 definition.
RESULTS
Six hundred fifty patients were treated and analyzed for safety; and 649 for efficacy data (ilofotase alfa n = 330; placebo n = 319). The observed mortality rates in the ilofotase alfa and placebo groups were 27.9% and 27.9% at 28 days, and 33.9% and 34.8% at 90 days. The trial was stopped for futility on the primary endpoint. The observed proportion of patients with MAKE90A and MAKE90B were 56.7% and 37.4% in the ilofotase alfa group vs. 64.6% and 42.8% in the placebo group. Median [interquartile range (IQR)] days alive and free of organ support were 17 [0-24] and 14 [0-24], number of days alive and discharged from the ICU through day 28 were 15 [0-22] and 10 [0-22] in the ilofotase alfa and placebo groups, respectively. Adverse events were reported in 67.9% and 75% patients in the ilofotase and placebo group.
CONCLUSION
Among critically ill patients with SA-AKI, ilofotase alfa did not improve day 28 survival. There may, however, be reduced MAKE90 events. No safety concerns were identified.
Topics: Humans; Acute Kidney Injury; Alkaline Phosphatase; Intensive Care Units; Sepsis
PubMed: 38172296
DOI: 10.1007/s00134-023-07271-w -
Intensive Care Medicine Sep 2023The Acute Disease Quality Initiative (ADQI) Workgroup recently released a consensus definition of sepsis-associated acute kidney injury (SA-AKI), combining Sepsis-3 and... (Observational Study)
Observational Study
Sepsis-associated acute kidney injury in the intensive care unit: incidence, patient characteristics, timing, trajectory, treatment, and associated outcomes. A multicenter, observational study.
PURPOSE
The Acute Disease Quality Initiative (ADQI) Workgroup recently released a consensus definition of sepsis-associated acute kidney injury (SA-AKI), combining Sepsis-3 and Kidney Disease Improving Global Outcomes (KDIGO) AKI criteria. This study aims to describe the epidemiology of SA-AKI.
METHODS
This is a retrospective cohort study carried out in 12 intensive care units (ICUs) from 2015 to 2021. We studied the incidence, patient characteristics, timing, trajectory, treatment, and associated outcomes of SA-AKI based on the ADQI definition.
RESULTS
Out of 84,528 admissions, 13,451 met the SA-AKI criteria with its incidence peaking at 18% in 2021. SA-AKI patients were typically admitted from home via the emergency department (ED) with a median time to SA-AKI diagnosis of 1 day (interquartile range (IQR) 1-1) from ICU admission. At diagnosis, most SA-AKI patients (54%) had a stage 1 AKI, mostly due to the low urinary output (UO) criterion only (65%). Compared to diagnosis by creatinine alone, or by both UO and creatinine criteria, patients diagnosed by UO alone had lower renal replacement therapy (RRT) requirements (2.8% vs 18% vs 50%; p < 0.001), which was consistent across all stages of AKI. SA-AKI hospital mortality was 18% and SA-AKI was independently associated with increased mortality. In SA-AKI, diagnosis by low UO only, compared to creatinine alone or to both UO and creatinine criteria, carried an odds ratio of 0.34 (95% confidence interval (CI) 0.32-0.36) for mortality.
CONCLUSION
SA-AKI occurs in 1 in 6 ICU patients, is diagnosed on day 1 and carries significant morbidity and mortality risk with patients mostly admitted from home via the ED. However, most SA-AKI is stage 1 and mostly due to low UO, which carries much lower risk than diagnosis by other criteria.
Topics: Humans; Retrospective Studies; Incidence; Creatinine; Intensive Care Units; Acute Kidney Injury; Sepsis
PubMed: 37432520
DOI: 10.1007/s00134-023-07138-0 -
Clinical and Translational Medicine Oct 2023Despite all modern advances in medicine, an effective drug for treating sepsis has yet to be found. The discovery of CMPK2 spurred hopes for the treatment of sepsis....
BACKGROUND
Despite all modern advances in medicine, an effective drug for treating sepsis has yet to be found. The discovery of CMPK2 spurred hopes for the treatment of sepsis. However, CMPK2-untapped target inhibitors are still an enormous obstacle that has hindered the CMPK2-centric treatment of sepsis.
METHODS
Here, we found that the CMPK2 gene is highly expressed in the whole blood of sepsis patients by RNA-Seq. First, recombinant CMPK2 was purified by a eukaryotic expression purification system, and the activity of recombinant CMPK2 was detected by the ADP-GLO assay. Second, we developed an affinity MS strategy combined with quantitative lysine reactivity profiling to discover CMPK2 ligands from the active ingredients of Chinese herbs. In addition, the dissociation constant K of the ligand and the target protein CMPK2 was further detected by microscale thermophoresis technology. Third, we used this strategy to identify a naturally sourced small molecule, dracorhodin (DP). Using mass spectrometry-based quantitative lysine reactivity profiling combined with a series of mutant tests, the results show that K265 acts as a bright hotspot of DP inhibition of CMPK2. Fourth, immune-histochemical staining, ELISAs, RT-qPCR, flow cytometry and immunoblotting were used to illustrate the potential function and related mechanism of DP in regulating sepsis injury.
RESULTS
Our results suggest that DP exerts powerful anti-inflammatory effects by regulating the NLRP3 inflammasome via the lipopolysaccharide (LPS)-induced CMPK2 pathway. Strikingly, DP significantly attenuated LPS-induced sepsis in a mouse model, but its effect was weakened in mice with myeloid-specific Cmpk2 ablation.
CONCLUSION
We provide a new framework that provides more valuable information for new therapeutic approaches to sepsis, including the establishment of screening strategies and the development of target drugs to provide a theoretical basis for ultimately improving clinical outcomes for sepsis patients. Collectively, these findings reveal that DP is a promising CMPK2 inhibitor for the treatment of sepsis.
Topics: Humans; Animals; Mice; Lipopolysaccharides; Lysine; Inflammation; Sepsis
PubMed: 37859535
DOI: 10.1002/ctm2.1449 -
Frontiers in Immunology 2023Degradation of the endothelial glycocalyx is critical for sepsis-associated lung injury and pulmonary vascular permeability. We investigated whether sulodexide, a...
BACKGROUND
Degradation of the endothelial glycocalyx is critical for sepsis-associated lung injury and pulmonary vascular permeability. We investigated whether sulodexide, a precursor for the synthesis of glycosaminoglycans, plays a biological role in glycocalyx remodeling and improves endothelial barrier dysfunction in sepsis.
METHODS
The number of children with septic shock that were admitted to the PICU at Children's Hospital of Fudan University who enrolled in the study was 28. On days one and three after enrollment, venous blood samples were collected, and heparan sulfate, and syndecan-1 (SDC1) were assayed in the plasma. We established a cell model of glycocalyx shedding by heparinase III and induced sepsis in a mouse model via lipopolysaccharide (LPS) injection and cecal ligation and puncture (CLP). Sulodexide was administrated to prevent endothelial glycocalyx damage. Endothelial barrier function and expression of endothelial-related proteins were determined using permeability, western blot and immunofluorescent staining. The survival rate, histopathology evaluation of lungs and wet-to-dry lung weight ratio were also evaluated.
RESULTS
We found that circulating SDC1 levels were persistently upregulated in the non-alive group on days 1 and 3 and were positively correlated with IL-6 levels. Receiver operating characteristic curve analysis showed that SDC1 could distinguish patients with mortality. We showed that SDC1-shedding caused endothelial permeability in the presence of heparinase III and sepsis conditions. Mechanistically, sulodexide (30 LSU/mL) administration markedly inhibited SDC1 shedding and prevented endothelial permeability with zonula occludens-1 (ZO-1) upregulation via NF-κB/ZO-1 pathway. In mice with LPS and CLP-induced sepsis, sulodexide (40 mg/kg) administration decreased the plasma levels of SDC1 and increased survival rate. Additionally, sulodexide alleviated lung injury and restored endothelial glycocalyx damage.
CONLUSIONS
In conclusion, our data suggest that SDC1 predicts prognosis in children with septic shock and sulodexide may have therapeutic potential for the treatment of sepsis-associated endothelial dysfunction.
Topics: Animals; Mice; Endothelial Cells; Shock, Septic; Capillary Permeability; Glycocalyx; Lipopolysaccharides; Lung Injury; Sepsis; Glycosaminoglycans; Body Weight
PubMed: 37614234
DOI: 10.3389/fimmu.2023.1172892 -
International Journal of Molecular... Nov 2023Endotoxin, also referred to as lipopolysaccharide (LPS), is a potent stimulator of the inflammatory cascade which may progress to sepsis and septic shock. The term... (Review)
Review
Endotoxin, also referred to as lipopolysaccharide (LPS), is a potent stimulator of the inflammatory cascade which may progress to sepsis and septic shock. The term endotoxic septic shock has been used for patients who have a clinical phenotype that is characterized by high endotoxin activity in addition to a high burden of organ failure; especially a pattern of organ failure including hepatic dysfunction, acute kidney injury, and various forms of endothelial dysfunction. Endotoxic septic shock has been a target for drug therapy for decades with no success. A likely barrier to their success was the inability to quantify endotoxin in the bloodstream. The Endotoxin Activity Assay (EAA) is positioned to change this landscape. In addition, medical devices using adsorptive technology in an extra-corporeal circulation has been shown to remove large quantities of endotoxin from the bloodstream. Focusing on the use of EAA to determine high concentrations of endotoxin will allow patients with endotoxic septic shock to be identified quickly and these patients may benefit most from removal of endotoxin using extracorporeal methods.
Topics: Humans; Shock, Septic; Sepsis; Endotoxins; Lipopolysaccharides
PubMed: 38003374
DOI: 10.3390/ijms242216185 -
Journal of Infection in Developing... Nov 2023Ochrobactrum species are emerging Gram-negative, non-fermenting bacteria with low virulence. Infection with the Ochrobactrum species is commonly nosocomial and has been...
Ochrobactrum species are emerging Gram-negative, non-fermenting bacteria with low virulence. Infection with the Ochrobactrum species is commonly nosocomial and has been reported in patients with indwelling medical devices and implants. Among the species of Ochrobactrum infecting humans, Ochrobactrum anthropic and Ochrobactrum intermedium are the commonest ones. We present a case of septicemia caused by Ochrobactrum intermedium in a 75-year-old patient with lower limb cellulitis. This report describes the epidemiology, clinical manifestations, laboratory diagnosis, antibiotic susceptibility pattern, and treatment of Ochrobactrum infections.
Topics: Humans; Aged; Ochrobactrum; Sepsis
PubMed: 38064389
DOI: 10.3855/jidc.17185 -
International Journal of Epidemiology Aug 2023Increased iron stores have been associated with elevated risks of different infectious diseases, suggesting that iron supplementation may increase the risk of...
OBJECTIVES
Increased iron stores have been associated with elevated risks of different infectious diseases, suggesting that iron supplementation may increase the risk of infections. However, these associations may be biased by confounding or reverse causation. This is important, since up to 19% of the population takes iron supplementation. We used Mendelian randomization (MR) to bypass these biases and estimate the causal effect of iron on infections.
METHODS
As instrumental variables, we used genetic variants associated with iron biomarkers in two genome-wide association studies (GWASs) of European ancestry participants. For outcomes, we used GWAS results from the UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative or 23andMe, for seven infection phenotypes: 'any infections', combined, COVID-19 hospitalization, candidiasis, pneumonia, sepsis, skin and soft tissue infection (SSTI) and urinary tract infection (UTI).
RESULTS
Most of our analyses showed increasing iron (measured by its biomarkers) was associated with only modest changes in the odds of infectious outcomes, with all 95% odds ratios confidence intervals within the 0.88 to 1.26 range. However, for the three predominantly bacterial infections (sepsis, SSTI, UTI), at least one analysis showed a nominally elevated risk with increased iron stores (P <0.05).
CONCLUSION
Using MR, we did not observe an increase in risk of most infectious diseases with increases in iron stores. However for bacterial infections, higher iron stores may increase odds of infections. Hence, using genetic variation in iron pathways as a proxy for iron supplementation, iron supplements are likely safe on a population level, but we should continue the current practice of conservative iron supplementation during bacterial infections or in those at high risk of developing them.
Topics: Humans; Genome-Wide Association Study; Mendelian Randomization Analysis; COVID-19; Iron; Biomarkers; Sepsis; Communicable Diseases; Polymorphism, Single Nucleotide
PubMed: 36773317
DOI: 10.1093/ije/dyad010 -
Medizinische Klinik, Intensivmedizin... Dec 2023Sepsis is one of the most frequent causes of death worldwide, but the recording of population-based epidemiology is challenging, which is why reliable data on sepsis... (Review)
Review
BACKGROUND
Sepsis is one of the most frequent causes of death worldwide, but the recording of population-based epidemiology is challenging, which is why reliable data on sepsis incidence and mortality are only available in a few, mostly highly-resourced countries.
OBJECTIVE
The aim of this narrative review is to provide an overview of sepsis epidemiology worldwide and in Germany based on current literature, to identify challenges in this research area, and to give an outlook on future developments.
MATERIALS AND METHODS
Selective literature review. PubMed and Google Scholar were searched for current literature. The results were processed narratively.
RESULTS
Based on modeling studies or meta-analyses of prospective studies, global annual sepsis incidence was found to be 276-678/100,000 persons. Case fatality ranged from 22.5 to 26.7%. However, current data sources have several limitations, as administrative data of selected individual countries-mostly with high income-were used as their basis. In these administrative data, sepsis is captured with limited validity. Prospective studies using clinical data often have limited comparability or lack population reference.
CONCLUSION
There is a lack of reliable data sources and definitions to monitor the epidemiology of sepsis and collect reliable global estimates. Increased policy efforts and new scientific approaches are needed to improve our understanding of sepsis epidemiology, identify vulnerable populations, and develop and target effective interventions.
Topics: Humans; Prospective Studies; Sepsis; Incidence; Germany
PubMed: 37975898
DOI: 10.1007/s00063-023-01088-7 -
International Journal of Molecular... Aug 2023Severe hemostatic disturbances and impaired fibrinolysis occur in sepsis. In the most serious cases, the dysregulation of fibrinolysis contributes to septic shock,... (Review)
Review
Severe hemostatic disturbances and impaired fibrinolysis occur in sepsis. In the most serious cases, the dysregulation of fibrinolysis contributes to septic shock, disseminated intravascular coagulation (DIC), and death. Therefore, an analysis of circulating concentrations of pro- and anti-fibrinolytic mediators could be a winning strategy in both the diagnosis and the treatment of sepsis. However, the optimal cutoff value, the timing of the measurements, and their combination with coagulation indicators should be further investigated. The purpose of this review is to summarize all relevant publications regarding the role of the main components of the plasminogen activation system (PAS) in the pathophysiology of sepsis. In addition, the clinical value of PAS-associated biomarkers in the diagnosis and the outcomes of patients with septic syndrome will be explored. In particular, experimental and clinical trials performed in emergency departments highlight the validity of soluble urokinase plasminogen activator receptor (suPAR) as a predictive and prognostic biomarker in patients with sepsis. The measurements of PAI-I may also be useful, as its increase is an early manifestation of sepsis and may precede the development of thrombocytopenia. The upcoming years will undoubtedly see progress in the use of PAS-associated laboratory parameters.
Topics: Humans; Plasminogen; Sepsis; Shock, Septic; Fibrinolysis; Serine Proteases; Biomarkers
PubMed: 37569751
DOI: 10.3390/ijms241512376