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Critical Care (London, England) Sep 2023One of five global deaths are attributable to sepsis. Hyperferritinemic sepsis (> 500 ng/mL) is associated with increased mortality in single-center studies. Our...
BACKGROUND
One of five global deaths are attributable to sepsis. Hyperferritinemic sepsis (> 500 ng/mL) is associated with increased mortality in single-center studies. Our pediatric research network's objective was to obtain rationale for designing anti-inflammatory clinical trials targeting hyperferritinemic sepsis.
METHODS
We assessed differences in 32 cytokines, immune depression (low whole blood ex vivo TNF response to endotoxin) and thrombotic microangiopathy (low ADAMTS13 activity) biomarkers, seven viral DNAemias, and macrophage activation syndrome (MAS) defined by combined hepatobiliary dysfunction and disseminated intravascular coagulation, and mortality in 117 children with hyperferritinemic sepsis (ferritin level > 500 ng/mL) compared to 280 children with sepsis without hyperferritinemia. Causal inference analysis of these 41 variables, MAS, and mortality was performed.
RESULTS
Mortality was increased in children with hyperferritinemic sepsis (27/117, 23% vs 16/280, 5.7%; Odds Ratio = 4.85, 95% CI [2.55-9.60]; z = 4.728; P-value < 0.0001). Hyperferritinemic sepsis had higher C-reactive protein, sCD163, IL-22, IL-18, IL-18 binding protein, MIG/CXCL9, IL-1β, IL-6, IL-8, IL-10, IL-17a, IFN-γ, IP10/CXCL10, MCP-1/CCL2, MIP-1α, MIP-1β, TNF, MCP-3, IL-2RA (sCD25), IL-16, M-CSF, and SCF levels; lower ADAMTS13 activity, sFasL, whole blood ex vivo TNF response to endotoxin, and TRAIL levels; more Adenovirus, BK virus, and multiple virus DNAemias; and more MAS (P-value < 0.05). Among these variables, only MCP-1/CCL2 (the monocyte chemoattractant protein), MAS, and ferritin levels were directly causally associated with mortality. MCP-1/CCL2 and hyperferritinemia showed direct causal association with depressed ex vivo whole blood TNF response to endotoxin. MCP-1/CCL2 was a mediator of MAS. MCP-1/CCL2 and MAS were mediators of hyperferritinemia.
CONCLUSIONS
These findings establish hyperferritinemic sepsis as a high-risk condition characterized by increased cytokinemia, viral DNAemia, thrombotic microangiopathy, immune depression, macrophage activation syndrome, and death. The causal analysis provides rationale for designing anti-inflammatory trials that reduce macrophage activation to improve survival and enhance infection clearance in pediatric hyperferritinemic sepsis.
Topics: Humans; Child; Hyperferritinemia; Macrophage Activation Syndrome; Sepsis; Cytokines; Ferritins
PubMed: 37674218
DOI: 10.1186/s13054-023-04628-x -
Journal of Personalized Medicine Nov 2023This article looks at the challenges of sedoanalgesia for sepsis patients, and argues for a personalised approach. Sedation is a necessary part of treatment for patients... (Review)
Review
This article looks at the challenges of sedoanalgesia for sepsis patients, and argues for a personalised approach. Sedation is a necessary part of treatment for patients in intensive care to reduce stress and anxiety and improve long-term prognoses. Sepsis patients present particular difficulties as they are at increased risk of a wide range of complications, such as multiple organ failure, neurological dysfunction, septic shock, ARDS, abdominal compartment syndrome, vasoplegic syndrome, and myocardial dysfunction. The development of any one of these complications can cause the patient's rapid deterioration, and each has distinct implications in terms of appropriate and safe forms of sedation. In this way, the present article reviews the sedative and analgesic drugs commonly used in the ICU and, placing special emphasis on their strategic administration in sepsis patients, develops a set of proposals for sedoanalgesia aimed at improving outcomes for this group of patients. These proposals represent a move away from simplistic approaches like avoiding benzodiazepines to more "objective-guided sedation" that accounts for a patient's principal pathology, as well as any comorbidities, and takes full advantage of the therapeutic arsenal currently available to achieve personalised, patient-centred treatment goals.
PubMed: 38138868
DOI: 10.3390/jpm13121641 -
Frontiers in Immunology 2023Sepsis related injury has gradually become the main cause of death in non-cardiac patients in intensive care units, but the underlying pathological and physiological...
OBJECTIVE
Sepsis related injury has gradually become the main cause of death in non-cardiac patients in intensive care units, but the underlying pathological and physiological mechanisms remain unclear. The Third International Consensus Definitions for Sepsis and Septic Shock (SEPSIS-3) definition emphasized organ dysfunction caused by infection. Neutrophil extracellular traps (NETs) can cause inflammation and have key roles in sepsis organ failure; however, the role of NETs-related genes in sepsis is unknown. Here, we sought to identify key NETs-related genes associate with sepsis.
METHODS
Datasets GSE65682 and GSE145227, including data from 770 patients with sepsis and 54 healthy controls, were downloaded from the GEO database and split into training and validation sets. Differentially expressed genes (DEGs) were identified and weighted gene co-expression network analysis (WGCNA) performed. A machine learning approach was applied to identify key genes, which were used to construct functional networks. Key genes associated with diagnosis and survival of sepsis were screened out. Finally, mouse and human blood samples were collected for RT-qPCR verification and flow cytometry analysis. Multiple organs injury, apoptosis and NETs expression were measured to evaluated effects of sulforaphane (SFN).
RESULTS
Analysis of the obtained DEGs and WGCNA screened a total of 3396 genes in 3 modules, and intersection of the results of both analyses with 69 NETs-related genes, screened out seven genes (, , , , , , ) using machine learning algorithms. Of these, and were independent predictors of poor survival in patients with sepsis. Administration of SFN significantly alleviated murine lung NETs expression and injury, accompanied by whole blood CYBB mRNA level.
CONCLUSION
CYBB and FCAR may be reliable biomarkers of survival in patients with sepsis, as well as potential targets for sepsis treatment. SFN significantly alleviated NETs-related organs injury, suggesting the therapeutic potential by targeting CYBB in the future.
Topics: Humans; Animals; Mice; Extracellular Traps; Sepsis; Shock, Septic; Biomarkers; Gene Expression Profiling; NADPH Oxidase 2
PubMed: 37901228
DOI: 10.3389/fimmu.2023.1253833 -
Diabetologia Feb 2024The overactivation of the mineralocorticoid receptor (MR) promotes pathophysiological processes related to multiple physiological systems, including the heart,... (Review)
Review
The overactivation of the mineralocorticoid receptor (MR) promotes pathophysiological processes related to multiple physiological systems, including the heart, vasculature, adipose tissue and kidneys. The inhibition of the MR with classical MR antagonists (MRA) has successfully improved outcomes most evidently in heart failure. However, real and perceived risk of side effects and limited tolerability associated with classical MRA have represented barriers to implementing MRA in settings where they have been already proven efficacious (heart failure with reduced ejection fraction) and studying their potential role in settings where they might be beneficial but where risk of safety events is perceived to be higher (renal disease). Novel non-steroidal MRA have distinct properties that might translate into favourable clinical effects and better safety profiles as compared with MRA currently used in clinical practice. Randomised trials have shown benefits of non-steroidal MRA in a range of clinical contexts, including diabetic kidney disease, hypertension and heart failure. This review provides an overview of the literature on the systemic impact of MR overactivation across organ systems. Moreover, we summarise the evidence from preclinical studies and clinical trials that have set the stage for a potential new paradigm of MR antagonism.
Topics: Humans; Diabetic Nephropathies; Heart Failure; Mineralocorticoid Receptor Antagonists; Mineralocorticoids; Naphthyridines; Receptors, Mineralocorticoid
PubMed: 38127122
DOI: 10.1007/s00125-023-06031-1 -
Cell Death Discovery Feb 2024Mitochondria produce adenosine triphosphate and potentially contribute to proinflammatory responses and cell death. Mitophagy, as a conservative phenomenon, scavenges... (Review)
Review
Mitochondria produce adenosine triphosphate and potentially contribute to proinflammatory responses and cell death. Mitophagy, as a conservative phenomenon, scavenges waste mitochondria and their components in the cell. Recent studies suggest that severe infections develop alongside mitochondrial dysfunction and mitophagy abnormalities. Restoring mitophagy protects against excessive inflammation and multiple organ failure in sepsis. Here, we review the normal mitophagy process, its interaction with invading microorganisms and the immune system, and summarize the mechanism of mitophagy dysfunction during severe infection. We highlight critical role of normal mitophagy in preventing severe infection.
PubMed: 38374038
DOI: 10.1038/s41420-024-01844-4 -
Journal of Vascular Surgery Oct 2023Multiple organ failure (MOF) is associated with poor outcomes and increased mortality in sepsis and trauma. There are limited data regarding MOF in patients after...
BACKGROUND
Multiple organ failure (MOF) is associated with poor outcomes and increased mortality in sepsis and trauma. There are limited data regarding MOF in patients after ruptured abdominal aortic aneurysm (rAAA) repair. We aimed to identify the contemporary prevalence and characteristics of patients with rAAA with MOF.
METHODS
We retrospectively reviewed patients with rAAA who underwent repair (2010-2020) at our multihospital institution. Patients who died within the first 2 days after repair were excluded. MOF was quantified by modified (excluding hepatic system) Denver, Sequential Organ Failure Assessment (SOFA) score, and Multiple Organ Dysfunction Score (MODS) for postoperative days 3 to 5 to determine the prevalence of MOF. MOF was defined as a Denver score of >3, dysfunction in two or more organ systems by SOFA score, or a MODS score of >8. Kaplan-Meier curves and log-rank testing were used to evaluate differences in 30-day mortality between multiple organ failure and patients without MOF. Logistic regression was used to assess predictors of MOF.
RESULTS
Of 370 patients with rAAA, 288 survived past two days (mean age, 73±10.1 years; 76.7% male; 44.1% open repair), and 143 had data for MOF calculation recorded. From postoperative days 3 to 5, 41 (14.24%) had MOF by Denver, 26 (9.03%) by SOFA, and 39 (13.54%) by MODS criteria. Among these scoring systems, pulmonary and neurological systems were impacted most commonly. Among patients with MOF, pulmonary derangement occurred in 65.9% (Denver), 57.7% (SOFA), and 56.4% (MODS). Similarly, neurological derangement occurred in 92.3% (SOFA) and 89.7% (MODS), but renal derangement occurred in 26.8% (Denver), 23.1% (SOFA), and 10.3% (MODS). MOF by all three scoring systems was associated with increased 30-day mortality (Denver: 11.3% vs 41.5% [P < .01]; DOFA: 12.6% vs 46.2% [P < .01]; MODS: 12.5% vs 35.9% [P < .01]), as was MOF by any criteria (10.8% vs 35.7 %; P < .01). Patients with MOF were more likely to have a higher body mass index (55.9±26.6 vs 49.0±15.0; P = .011) and to have had a preoperative stroke (17.9% vs 6.0%; P = .016). Patients with MOF were less likely to have undergone endovascular repair (30.4% vs 62.1%; P < .001). Endovascular repair was protective against MOF (any criteria) on multivariate analysis (odds ratio, 0.23; 95% confidence interval, 0.08-0.64; P = .019) after adjusting for age, gender, and presenting systolic blood pressure.
CONCLUSIONS
MOF occurred in only 9% to 14% of patients after rAAA repair, but was associated with a three-fold increase in mortality. Endovascular repair was associated with a reduced MOF incidence.
Topics: Humans; Male; Middle Aged; Aged; Aged, 80 and over; Female; Multiple Organ Failure; Retrospective Studies; Endovascular Procedures; Blood Pressure; Aortic Aneurysm, Abdominal; Aortic Rupture; Treatment Outcome; Risk Factors; Blood Vessel Prosthesis Implantation
PubMed: 37385354
DOI: 10.1016/j.jvs.2023.06.011 -
Frontiers in Molecular Biosciences 2023Fibrosis could happen in every organ, leading to organic malfunction and even organ failure, which poses a serious threat to global health. Early treatment of fibrosis... (Review)
Review
Fibrosis could happen in every organ, leading to organic malfunction and even organ failure, which poses a serious threat to global health. Early treatment of fibrosis has been reported to be the turning point, therefore, exploring potential correlates in the pathogenesis of fibrosis and how to reverse fibrosis has become a pressing issue. As a mechanism-sensitive cationic calcium channel, turns on in response to changes in the lipid bilayer of the plasma membrane. exerts multiple biological roles, including inhibition of inflammation, cytoskeletal stabilization, epithelial-mesenchymal transition, stromal stiffness, and immune cell mechanotransduction, interestingly enough. These processes are closely associated with the development of fibrotic diseases. Recent studies have shown that deletion or knockdown of attenuates the onset of fibrosis. Therefore, in this paper we comprehensively describe the biology of this gene, focusing on its potential relevance in pulmonary fibrosis, renal fibrosis, pancreatic fibrosis, and cardiac fibrosis diseases, except for the role of drugs (agonists), increased intracellular calcium and mechanical stress using this gene in alleviating fibrosis.
PubMed: 37900917
DOI: 10.3389/fmolb.2023.1270979 -
Current Opinion in Critical Care Aug 2023Critical illness imposes a severe insult on the body, with various stressors triggering pronounced cell damage. This compromises cellular function, leading to a high... (Review)
Review
PURPOSE OF REVIEW
Critical illness imposes a severe insult on the body, with various stressors triggering pronounced cell damage. This compromises cellular function, leading to a high risk of multiple organ failure. Autophagy can remove damaged molecules and organelles but appears insufficiently activated during critical illness. This review discusses insight into the role of autophagy in critical illness and the involvement of artificial feeding in insufficient autophagy activation in critical illness.
RECENT FINDINGS
Animal studies manipulating autophagy have shown its protective effects against kidney, lung, liver, and intestinal injury after several critical insults. Autophagy activation also protected peripheral, respiratory, and cardiac muscle function, despite aggravated muscle atrophy. Its role in acute brain injury is more equivocal. Animal and patient studies showed that artificial feeding suppressed autophagy activation in critical illness, particularly with high protein/amino acid doses. Feeding-suppressed autophagy may explain short and long-term harm by early enhanced calorie/protein feeding in large randomized controlled trials.
SUMMARY
Insufficient autophagy during critical illness is at least partly explained by feeding-induced suppression. This may explain why early enhanced nutrition failed to benefit critically ill patients or even induced harm. Safe, specific activation of autophagy avoiding prolonged starvation opens perspectives for improving outcomes of critical illness.
Topics: Animals; Humans; Critical Illness; Autophagy; Nutritional Support; Nutritional Status; Liver
PubMed: 37306474
DOI: 10.1097/MCC.0000000000001056 -
JAMA Network Open Aug 2023The Sepsis Prediction Model (SPM) is a proprietary decision support tool created by Epic Systems; it generates a predicting sepsis score (PSS). The model has not...
IMPORTANCE
The Sepsis Prediction Model (SPM) is a proprietary decision support tool created by Epic Systems; it generates a predicting sepsis score (PSS). The model has not undergone validation against existing sepsis prediction tools, such as Systemic Inflammatory Response Syndrome (SIRS), Sequential Organ Failure Assessment (SOFA), or quick Sepsis-Related Organ Failure Asessement (qSOFA).
OBJECTIVE
To assess the validity and timeliness of the SPM compared with SIRS, qSOFA, and SOFA.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective cohort study included all adults admitted to 5 acute care hospitals in a single US health system between June 5, 2019, and December 31, 2020. Data analysis was conducted from March 2021 to February 2023.
MAIN OUTCOMES AND MEASURES
A sepsis event was defined as receipt of 4 or more days of antimicrobials, blood cultures collected within ±48 hours of initial antimicrobial, and at least 1 organ dysfunction as defined by the organ dysfunction criteria optimized for the electronic health record (eSOFA). Time zero was defined as 15 minutes prior to qualifying antimicrobial or blood culture order.
RESULTS
Of 60 507 total admissions, 1663 (2.7%) met sepsis criteria, with 1324 electronic health record-confirmed sepsis (699 [52.8%] male patients; 298 [22.5%] Black patients; 46 [3.5%] Hispanic/Latinx patients; 945 [71.4%] White patients), 339 COVID-19 sepsis (183 [54.0%] male patients; 98 [28.9%] Black patients; 36 [10.6%] Hispanic/Latinx patients; and 189 [55.8%] White patients), and 58 844 (97.3%; 26 632 [45.2%] male patients; 12 698 [21.6%] Black patients; 3367 [5.7%] Hispanic/Latinx patients; 40 491 White patients) did not meet sepsis criteria. The median (IQR) age was 63 (51 to 73) years for electronic health record-confirmed sepsis, 69 (60 to 77) years for COVID-19 sepsis, and 60 (42 to 72) years for nonsepsis admissions. Within the vendor recommended threshold PSS range of 5 to 8, PSS of 8 or greater had the highest balanced accuracy for classifying a sepsis admission at 0.79 (95% CI, 0.78 to 0.80). Change in SOFA score of 2 or more had the highest sensitivity, at 0.97 (95% CI, 0.97 to 0.98). At a PSS of 8 or greater, median (IQR) time to score positivity from time zero was 68.00 (6.75 to 605.75) minutes. For SIRS, qSOFA, and SOFA, median (IQR) time to score positivity was 7.00 (-105.00 to 08.00) minutes, 74.00 (-22.25 to 599.25) minutes, and 28.00 (-108.50 to 134.00) minutes, respectively.
CONCLUSIONS AND RELEVANCE
In this cohort study of hospital admissions, balanced accuracy of the SPM outperformed other models at higher threshold PSS; however, application of the SPM in a clinical setting was limited by poor timeliness as a sepsis screening tool as compared to SIRS and SOFA.
Topics: Adult; Humans; Male; Middle Aged; Aged; Female; Systemic Inflammatory Response Syndrome; Cohort Studies; Multiple Organ Failure; Organ Dysfunction Scores; Retrospective Studies; COVID-19; Sepsis
PubMed: 37624600
DOI: 10.1001/jamanetworkopen.2023.29729