Prognosis Of Septic Patients Research Articles

Renal medullary perfusion differs from that in renal cortex in patients with sepsis associated acute kidney injury and correlates with renal function prognosis: A prospective cohort study.

Renal perfusion status remains poorly studied at the bedside during sepsis associated acute kidney injury (AKI). The aim of the study is to examine renal cortical and medullary perfusion using renal contrast enhanced ultrasound (CEUS) in septic patients. In this single-center, prospective longitudinal study, septic patients were enrolled. Renal ultrasonography was performed within 24 hours of ICU admission (D1), then repeated at D3, D5 and D7. Each measurement consisted of three destruction replenishment sequences that were recorded for delayed analysis with dedicated software (Vuebox). Renal cortex and medulla perfusion were quantified by measuring time to peak (TTP). Receiver operating characteristic (ROC) analysis was used to evaluate 28-day renal prognosis. The study included 149 septic patients, including 70 non-AKI patients and 79 AKI patients. Both renal cortical and medullary TTP was longer in the AKI group than in the non-AKI group. The difference of TTP between renal cortex and medulla in AKI group was higher than that in the non-AKI group (p = 0.000). Medullary TTP on day 3 had the best performance in predicting the prognosis of 28-day renal function (AUC 0.673, 95% confidence interval 0.528-0.818, p = 0.024), and its cut-off value was 45 s with a sensitivity 52.2% and a specificity of 82.1%. Cortical TTP on day 3 also had the performance in predicting the prognosis of 28-day renal function (AUC 0.657, 95% confidence interval 0.514-0.800, p = 0.039), and its cut-off value was 33 s with a sensitivity 78.3% and a specificity of 55.0%. Renal medullary perfusion alterations differ from those in cortex, with the medulla is worse. Simultaneous and dynamic assessment of cortical and medullary microcirculatory flow alterations necessary. TTP on day 3, especially medullary TTP, seems to be a relatively stable and useful indicator, which correlates with 28-day renal function prognosis in septic patients. Early correction of renal cortical and medullary perfusion alterations reduces the incidence of adverse renal events.

Efficacy and safety of calcineurin inhibitors (CNIs) for septic patients in ICU: a cohort study from MIMIC database.

Sepsis is marked by a dysregulated immune response to infection. Calcineurin inhibitors (CNIs), commonly used as immunosuppressants, have unique properties that may help mitigate the overactive immune response in sepsis, potentially leading to better patient outcomes. This study aims to assess whether CNIs improve prognosis in septic patients and to evaluate any associated adverse reactions. We utilized the Medical Information Mart for Intensive Care IV 2.2 (MIMIC-IV 2.2) database to identify septic patients who were treated with CNIs and those who were not. Propensity score matching (PSM) was employed to balance baseline characteristics between the CNI user group and the non-user group. The primary outcome was 28-day mortality, analyzed using the Kaplan-Meier method and Cox proportional hazard regression models to examine the relationship between CNI use and patient survival. From the MIMIC-IV database, 22,517 septic patients were identified. After propensity score matching, a sample of 874 patients was analyzed. The CNI group exhibited a significantly lower 28-day mortality risk compared to the non-user group (HR: 0.26; 95% CI: 0.17, 0.41) in the univariate Cox hazard analysis. Kaplan-Meier survival curves also demonstrated a significantly higher 28- and 365-day survival rate for CNI users compared to non-users (log-rank test p-value = 0.001). No significant association was found between CNI use and an increased risk of new-onset infection (p = 0.144), but an association with mild hypertension (P < 0.001) and liver injury (P < 0.001) was observed. The use of calcineurin inhibitors was associated with reduced short- and long-term mortality in septic patients without an increased incidence of new-onset infections, hyperkalemia, severe hypertension, or acute kidney injury (AKI). However, CNI use may lead to adverse effects, such as liver injury and mild hypertension.

Increased serum albumin corrected anion gap levels are associated with poor prognosis in septic patients with liver cirrhosis

The prognosis of septic patients with cirrhosis is worse compared to septic patients without cirrhosis. Early and accurate prognosis determination in patients with cirrhosis and sepsis is pivotal for guiding treatment decisions. The aim of this study was to investigate the association between albumin-corrected anion gap (ACAG) and clinical prognosis of patients with sepsis and cirrhosis. This study extracted data of patients with sepsis and cirrhosis from the Medical Information Mart for Intensive Care (MIMIC-IV) database. A total of 1340 patients (64.6% male) were enrolled. After confounders adjusting, elevated ACAG had a significant association with 28-day mortality (HR1.604; 95% CI 1.258–2.048; P < 0.001). Restricted cubic spline revealed that a linear relationship between ACAG and 28-day mortality (P-nonlinear = 0.089, P-overall = 0.001). According to the ROC curve analysis, the ACAG demonstrated a higher area under the curve (AUC) of 0.703 compared to AG (0.675). Kaplan–Meier analysis revealed higher 28-day mortality in high ACAG group (log-rank test, χ^2 = 175.638, P < 0.001). Furthermore, subgroup analysis showed a significant interaction between ACAG and etiology of cirrhosis (P for interaction = 0.014). Therefore, ACAG could provide clinicians with valuable insights for guiding interventions in this high-risk population.

N-acetyltransferase 10 mediates cognitive dysfunction through the acetylation of GABABR1 mRNA in sepsis-associated encephalopathy

Sepsis-associated encephalopathy (SAE) is a critical neurological complication of sepsis and represents a crucial factor contributing to high mortality and adverse prognosis in septic patients. This study explored the contribution of NAT10-mediated messenger RNA (mRNA) acetylation in cognitive dysfunction associated with SAE, utilizing a cecal ligation and puncture (CLP)-induced SAE mouse model. Our findings demonstrate that CLP significantly upregulates NAT10 expression and mRNA acetylation in the excitatory neurons of the hippocampal dentate gyrus (DG). Notably, neuronal-specific Nat10 knockdown improved cognitive function in septic mice, highlighting its critical role in SAE. Proteomic analysis, RNA immunoprecipitation, and real-time qPCR identified GABABR1 as a key downstream target of NAT10. Nat10 deletion reduced GABABR1 expression, and subsequently weakened inhibitory postsynaptic currents in hippocampal DG neurons. Further analysis revealed that microglia activation and the release of inflammatory mediators lead to the increased NAT10 expression in neurons. Microglia depletion with PLX3397 effectively reduced NAT10 and GABABR1 expression in neurons, and ameliorated cognitive dysfunction induced by SAE. In summary, our findings revealed that after CLP, NAT10 in hippocampal DG neurons promotes GABABR1 expression through mRNA acetylation, leading to cognitive dysfunction.

Association between admission pan-immune-inflammation value and short-term mortality in septic patients: a retrospective cohort study

Pan-Immune-Inflammation Value (PIV) has recently received more attention as a novel indicator of inflammation. We aimed to evaluate the association between PIV and prognosis in septic patients. Data were extracted from the Medical Information Mart for Intensive Care IV database. The primary and secondary outcomes were 28-day and 90-day mortality. The association between PIV and outcomes was assessed by Kaplan–Meier curves, Cox regression analysis, restricted cubic spline curves and subgroup analysis. A total of 11,331 septic patients were included. Kaplan–Meier curves showed that septic patients with higher PIV had lower 28-day survival rate. In multivariable Cox regression analysis, log2-PIV was positively associated with the risk of 28-day mortality [HR (95% CI) 1.06 (1.03, 1.09), P < 0.001]. The relationship between log2-PIV and 28-day mortality was non-linear with a predicted inflection point at 8. To the right of the inflection point, high log2-PIV was associated with an increased 28-day mortality risk [HR (95% CI) 1.13 (1.09, 1.18), P < 0.001]. However, to the left of this point, this association was non-significant [HR (95% CI) 1.01 (0.94, 1.08), P = 0.791]. Similar results were found for 90-day mortality. Our study showed a non-linear relationship between PIV and 28-day and 90-day mortality risk in septic patients.

Prognostic significance of non-thyroidal illness syndrome in sepsis

Background and objectives. Sepsis is a common diagnosis among ICU patients. Therefore, the present study aimed at assessing the prognostic significance of non-thyroidal illness syndrome (NTIS) in sepsis. Materials and methods. The study was done as a retrospective analysis on adult patients of age greater than 18 years who were admitted with sepsis to an urban tertiary care ICU at Saveetha Medical College and Hospital. Results. The study found that NTIS can manifest as a fall in T3 alone, T4 alone, or both T3 and T4. A combined fall in T3 and T4 strongly correlates with poor primary outcomes (28-day mortality) compared to a fall in either hormone alone. Advancing age in septic patients leads to a greater combined fall in T3 and T4 values and an increased mortality rate, especially among females. The overall mortality rate in this series was 55%, with severe infections and high APACHE II scores contributing to lower hormone levels and higher severity. Conclusion. NTIS should be considered an indicator of poor prognosis in septic patients, necessitating aggressive management. It underscores the importance of assessing TSH alongside T3 and T4 in critically ill patients, although treating NTIS was beyond the scope of this study.

FGF21 ameliorates septic liver injury by restraining proinflammatory macrophages activation through the autophagy/HIF-1α axis

IntroductionSepsis, a systemic immune syndrome caused by severe trauma or infection, poses a substantial threat to the health of patients worldwide. The progression of sepsis is heavily influenced by septic liver injury, which is triggered by infection and cytokine storms, and has a significant impact on the tolerance and prognosis of septic patients. The objective of our study is to elucidate the biological role and molecular mechanism of fibroblast growth factor 21 (FGF21) in the process of sepsis. ObjectivesThis study was undertaken in an attempt to elucidate the function and molecular mechanism of FGF21 in therapy of sepsis. MethodsSerum concentrations of FGF21 were measured in sepsis patients and septic mice. Liver injury was compared between mice FGF21 knockout (KO) mice and wildtype (WT) mice. To assess the therapeutic potential, recombinant human FGF21 was administered to septic mice. Furthermore, the molecular mechanism of FGF21 was investigated in mice with myeloid-cell specific HIF-1α overexpression mice (LyzM-CreDIO-HIF-1α) and myeloid-cell specific Atg7 knockout mice (Atg7△mye). ResultsSerum level of FGF21 was significantly increased in sepsis patients and septic mice. Through the use of recombinant human FGF21 (rhFGF21) and FGF21 KO mice, we found that FGF21 mitigated septic liver injury by inhibiting the initiation and propagation of inflammation. Treatment with rhFGF21 effectively suppressed the activation of proinflammatory macrophages by promoting macroautophagy/autophagy degradation of hypoxia-inducible factor-1α (HIF-1α). Importantly, the therapeutic effect of rhFGF21 against septic liver injury was nullified in LyzM-CreDIO-HIF-1α mice and Atg7△mye mice. ConclusionsOur findings demonstrate that FGF21 considerably suppresses inflammation upon septic liver injury through the autophagy/ HIF-1α axis.

Obesity and septic patient outcomes: Shaping the puzzle through age and sex perspectives

While obesity has been reported as a protective factor in septic patients, little is known about the potential modifying effects of age and sex. The objective of this study is to investigate age and sex-specific associations between obesity and the prognosis of septic patients. A retrospective analysis was conducted on a cohort of 15,464 septic patients, categorized by body mass index (BMI) into four groups: underweight (<18.5kg/m2, n=483), normal (18.5-24.9kg/m2, n=4344), overweight (25-29.9kg/m2, n=4949) and obese (≥30kg/m2, n=5688). Multivariable logistic regression and inverse probability weighting were employed to robustly confirm the protective effect of a higher BMI on 28-day mortality, with normal weight serving as the reference category. Subgroup analyses based on age (young: 18-39, middle-aged: 40-64 and elderly: ≥65) and sex were performed. The findings demonstrate that high BMI independently confers a protective effect against 28-day mortality in septic patients. However, the relationship between BMI and 28-day mortality exhibits a non-linear trend, with a BMI of 34.5kg/m2 displaying the lowest odds ratio. Notably, the survival benefits associated with a high BMI were not observed in the young group. Moreover, being underweight emerges as an independent risk factor for middle-aged and elderly female patients, while in males it is only a risk factor in the elderly group. Interestingly, being overweight and obese were identified as independent protective factors in middle-aged and elderly male patients, but not in females. The effect of BMI on mortality in septic patients varies according to age and sex. Elderly individuals with sepsis may derive more prognostic benefits from obesity.

Should I Supplement Vitamin D in a Patient With Sepsis?

Sepsis is a potentially fatal organ failure produced by the host's immune response to infection. It is critical to identify risk factors associated with a poor prognosis in septic patients in order to develop new therapy options. Vitamin D deficiency (25-hydroxyvitamin cholecalciferol < 20 ng/mL) is common in critical and septic patients. Serum vitamin D concentrations are associated with an increased incidence of mortality in critically ill adult patients. In critically ill patients, vitamin D supplementation (a very high vitamin D 3 or cholecalciferol loading dosage as a single bolus dose ranging from 400,000 to 540,000 IU) is feasible and safe. Some of the trials and their post-hoc analyses evaluating vitamin D supplementation in severely sick individuals, including septic patients, suggested possible benefits in mortality (reduced 28-day mortality in the range of 8.1%-17.5%), and other outcomes (reduction in hospital length in the range from 9 to 18 days, and decrease in duration of mechanical ventilation in the range from 5 to 10 days). Despite the fact that many studies support the provision of vitamin D to septic patients, there are still many studies that contradict this opinion, and there is still debate about the recommendation to use vitamin D in sepsis. A pragmatic clinical approach in severe sepsis could be supplementation of vitamin D if serum levels are diminished (< 30 ng/mL). It appears that a single ultrahigh dose of vitamin D 3 (cholecalciferol) could be administered to the septic patient via an enteral tube, followed by daily or monthly maintenance doses. Parenteral administration might be reserved for a subgroup of septic patients with gastrointestinal, hepatic, or renal dysfunction. Future clinical trials designed exclusively for septic patients are required to assess the potential advantages of vitamin D. Possible impacts of selective activators of vitamin D receptors, such as paricalcitol, should be elucidated in sepsis. This emphasizes the requirement for more study and confirmation of any potential beneficial effects of vitamin D in sepsis.

Prognostic Impact of Left Compared to Right Heart Function in Sepsis and Septic Shock.

This study investigates the prognostic impact of left ventricular ejection fraction (LVEF) and tricuspid annular plane systolic excursion (TAPSE) in patients with sepsis and septic shock. Consecutive patients with sepsis and septic shock were included from 2019 to 2021. LVEF and TAPSE were assessed during the first 24 hours of intensive care unit (ICU) treatment. Patients were stratified by LVEF of less than 45% and greater than or equal to 45%. The primary endpoint was 30 day all-cause mortality. Two hundred ninety-two consecutive patients were included, of which 26% presented with LVEF of less than 45%. Within the entire study cohort (60% vs. 48%; hazard ratio [HR] = 1.414; 95% confidence interval [CI] = 0.999-2.001; p = 0.050) and specifically in patients with sepsis (58% vs. 36%; HR = 1.919; 95% CI = 1.148-3.208; p = 0.013), LVEF of less than 45% was associated with an increased risk of 30 day all-cause mortality, whereas TAPSE of less than 17 mm was not (56% vs. 52%; log rank p = 0.798). Even after multivariable adjustment, LVEF of less than 45% was accompanied by a worse prognosis in septic patients (HR = 1.944; 95% CI = 1.084-3.485; p = 0.026). Contrarily, LVEF < 45% was not accompanied with increased mortality in septic shock patients (63% vs. 67%; log rank p = 0.847; HR = 0.956; 95% CI 0.596-1.533; p = 0.853). In conclusion, impaired LVEF was associated with increased mortality in septic patients without shock, but not in patients with septic shock. In contrast, impaired right ventricular function was not associated with adverse prognosis in both conditions.

BRD3308 suppresses macrophage oxidative stress and pyroptosis via upregulating acetylation of H3K27 in sepsis-induced acute lung injury

Abstract Background Sepsis-induced acute lung injury (ALI) leads to severe hypoxemia and respiratory failure, contributing to poor prognosis in septic patients. Endotoxin dissemination triggers oxidative stress and the release of inflammatory cytokines in macrophages, initiating diffuse alveolar damage. The role of epigenetic histone modifications in organ injury is increasingly recognized. The present study aimed to investigate the use of a histone modification inhibitor to alleviate sepsis-induced ALI, revealing a new strategy for improving sepsis patient survival. Methods In vivo models of ALI were established through the intraperitoneal injection of lipopolysaccharide and cecal ligation and puncture surgery. Furthermore, the disease process was simulated in vitro by stimulating Tamm-Horsfall protein-1 (THP-1) cells with lipopolysaccharide. Hematoxylin and eosin staining, blood gas analysis and pulmonary function tests were utilized to assess the extent of lung tissue damage. Western blot analysis, real-time polymerase chain reaction, enzyme-linked immunosorbent assay and immunofluorescence were used to measure the levels and distribution of the indicated indicators within cells and tissues. Reactive oxygen species and autophagic flux alterations were detected using specific probes. Results BRD3308, which is a inhibitor of histone deacetylase 3, improved lung tissue damage, inflammatory infiltration and edema in ALI by inhibiting Nod-like receptor protein3-mediated pyroptosis in macrophages. By upregulating autophagy, BRD3308 improved the disruption of redox balance in macrophages and reduced the accumulation of reactive oxygen species. Mechanistically, BRD3308 inhibited histone deacetylase 3 activity by binding to it and altering its conformation. Following histone deacetylase 3 inhibition, acetylation of H3K27 was significantly increased. Moreover, the increase in H3K27Ac led to the upregulation of autophagy-related gene 5, a key component of autophagosomes, thereby activating autophagy. Conclusions BRD3308 inhibits oxidative stress and pyroptosis in macrophages by modulating histone acetylation, thereby preventing sepsis-induced ALI. The present study provides a potential strategy and theoretical basis for the clinical treatment of sepsis-induced ALI.

Different subtypes of nonthyroidal illness syndrome on the prognosis of septic patients: a two-centered retrospective cohort study.

Nonthyroidal illness syndrome (NTIS) is a common endocrine dysfunction predicting unfavorable outcomes in critical illness. The objective of the study is to evaluate the association between different NTIS subtypes with outcomes in septic patients. Septic patients in two Chinese academic centers from October 2012 and October 2022 are enrolled in analysis. Multivariable regressions are used to assess associations between NTIS and outcomes. Outcomes include in-hospital mortality, length of stay in hospital (LOS), non-invasive ventilation failure and weaning failure. Patients with NTIS are categorized into 4 types according to the different levels of FT4 and TSH. The association between different NTIS subtypes and mortality are further analyzed. Survival curve is plotted using the Kaplan-Meier method. After screening, a total of 1226 septic patients with complete thyroid hormones result are eventually enrolled. Among them, 520 (42.4%) patients are diagnosed as NTIS. In multivariable regression analysis, NTIS is independently associated with increased 30-days mortality (OR=1.759, CI 1.009-3.104, p=0.047), but has no association with 60-days mortality (OR=1.524, CI 0.893-2.618, p=0.123), 90-days mortality (OR=1.411, CI 0.831-2.408, p=0.203), LOS, non-invasive ventilation failure or weaning failure. In NTIS subtypes, NTIS patients with low FT3 and TSH levels, regardless of the FT4 values, have significantly higher mortality than euthyroid patients (30-days mortality, OR= 6.488, CI 1.546-27.808, p=0.01; 60-days mortality, OR=3.973, CI 1.006-15.579, p=0.046; 90-days mortality, OR=3.849, CI 0.977-15.088, p=0.051). This result is consistent in patients with low FT3 and FT4 levels, regardless of the TSH values (30-days mortality, OR=3.349, CI 1.402-7.957, p=0.006; 60-days mortality, OR= 2.594, CI 1.122-5.930, p=0.024; 90-days mortality, OR=2.55, CI 1.110-5.804, p=0.025). There is no survival difference between NTIS patients with low FT3 only and euthyroid patients. Survival plot shows the worst prognosis is in NTIS patients with low FT3, FT4 and TSH level. NTIS is frequent in sepsis. A reduction of FT3 together with FT4 or TSH, but not FT3 only, is associated with an increased risk of mortality.

Advances in the Study of Immunosuppressive Mechanisms in Sepsis.

Sepsis is a life-threatening disease caused by a systemic infection that triggers a dysregulated immune response. Sepsis is an important cause of death in intensive care units (ICUs), poses a major threat to human health, and is a common cause of death in ICUs worldwide. The pathogenesis of sepsis is intricate and involves a complex interplay of pro- and anti-inflammatory mechanisms that can lead to excessive inflammation, immunosuppression, and potentially long-term immune disorders. Recent evidence highlights the importance of immunosuppression in sepsis. Immunosuppression is recognized as a predisposing factor for increased susceptibility to secondary infections and mortality in patients. Immunosuppression due to sepsis increases a patient's chance of re-infection and increases organ load. In addition, antibiotics, fluid resuscitation, and organ support therapy have limited impact on the prognosis of septic patients. Therapeutic approaches by suppressing excessive inflammation have not achieved the desired results in clinical trials. Research into immunosuppression has brought new hope for the treatment of sepsis, and a number of therapeutic approaches have demonstrated the potential of immunostimulatory therapies. In this article, we will focus on the mechanisms of immunosuppression and markers of immune monitoring in sepsis and describe various targets for immunostimulatory therapy in sepsis.

Stattic ameliorates the cecal ligation and puncture-induced cardiac injury in septic mice via IL-6-gp130-STAT3 signaling pathway

AimSepsis-induced cardiac dysfunction is the leading cause of higher morbidity and mortality with poor prognosis in septic patients. Our recent previous investigation provides evidence of the hallmarks of signal transducer and activator of transcription3 (STAT3) activation in sepsis and targeting of STAT3 with Stattic, a small-molecule inhibitor of STAT3, has beneficial effects in various septic tissues. We investigated the possible cardioprotective effects of Stattic on cardiac inflammation and dysfunction in mice with cecal ligation and puncture (CLP)-induced sepsis. Main methodsA polymicrobial sepsis model was induced by CLP in mice and Stattic (25 mg/kg) was intraperitoneally given at one and twelve hours after CLP operation. The cecum was exposed in sham-control mice without CLP. After 18 h of surgery, electrocardiogram (ECG) for anaesthized mice was registered followed by collecting of samples of blood and tissues for bimolecular and histopathological assessments. Myeloperoxidase, a marker of neutrophil infiltration, was assessed immunohistochemically. Key findingsCLP profoundly impaired cardiac functions as evidenced by ECG changes in septic mice as well as elevation of cardiac enzymes, and inflammatory markers with myocardial histopathological and immunohistochemical alterations. While, Stattic markedly reversed the CLP-induced cardiac abnormalities and restored the cardiac function by its anti-inflammatory activities. SignificanceStattic treatment had potential beneficial effects against sepsis-induced cardiac inflammation, dysfunction and damage. Its cardioprotective effects were possibly attributed to its anti-inflammatory activities by targeting STAT3 and downregulation of IL-6 and gp130. Our investigations suggest that Stattic could be a promising target for management of cardiac sepsis and inflammation-related cardiac damage.

3-Hydroxybutyrate ameliorates sepsis-associated acute lung injury by promoting autophagy through the activation of GPR109α in macrophages

BackgroundSepsis is a systemic inflammatory disease caused by multiple pathogens, with the most commonly affected organ being the lung. 3-Hydroxybutyrate plays a protective role in inflammatory diseases through autophagy promotion; however, the exact mechanism remains unexplored. MethodOur study used the MIMIC-III database to construct a cohort of ICU sepsis patients and figure out the correlation between the level of ketone bodies and clinical prognosis in septic patients. In vivo and in vitro models of sepsis were used to reveal the role and mechanism of 3-hydroxybutyrate in sepsis-associated acute lung injury (sepsis-associated ALI). ResultHerein, we observed a strong correlation between the levels of ketone bodies and clinical prognosis in patients with sepsis identified using the MIMIC- III database. In addition, exogenous 3-hydroxybutyrate supplementation improved the survival rate of CLP-induced sepsis in mice by promoting autophagy. Furthermore, 3-hydroxybutyrate treatment protected against sepsis-induced lung damage. We explored the mechanism underlying these effects. The results indicated that 3-hydroxybutyrate upregulates autophagy levels by promoting the transfer of transcription factor EB (TFEB) to the macrophage nucleus in a G-protein-coupled receptor 109 alpha (GPR109α) dependent manner, upregulating the transcriptional level of ultraviolet radiation resistant associated gene (UVRAG) and increasing the formation of autophagic lysosomes. Conclusion3-Hydroxybutyrate can serve as a beneficial therapy for sepsis-associated ALI through the upregulation of autophagy. These results may provide a basis for the development of promising therapeutic strategies for sepsis-associated ALI.

PO-05-161 ACQUIRED LONG QT SYNDROME IN SEPSIS-INDUCED MYOCARDIAL INJURY: INVESTIGATION ON CLINICAL CHARACTERISTICS AND MECHANISM VIA ION CHANNEL REPROGRAMMING

Sepsis-induced cardiomyopathy (SIC) is one major cause of death in sepsis. Evidence of various cardiac arrhythmias in septic patients has been reported previously. Acquired QT prolongation (aQTP) is associated with an increased risk of polymorphic VT and Torsade de Pointes. However, data on the clinical analysis of aQTP, or acquired long QT syndrome (aLQTS) in sepsis and their potential mechanism is limited. We aimed to investigate the prevalence and characteristics of aQTP/aLQTS in sepsis and explore the underlying mechanism. Patients diagnosed with sepsis from 2018 to 2022 were enrolled. Occurrence of aQTP as well as cardiac arrhythmias were described. Correlation analysis was performed to investigate associated factors, followed analysis on prognosis. Mouse model for SIC was thereafter established, in which bulk-RNA sequencing of the heart was performed. The gene expression of myocardial tissue was then determined by RT-quantitative polymerase chain reaction. Biostatistical analysis based on Gene Expression Omnibus database were performed. Among 110 patients diagnosed with sepsis, aQTP was found in 13 (11.8%) subjects with a mean QTc of 502 msec, in which 2 typical aLQTS cases with progressive QTP was observed to develop electrical storm during sepsis following pacemaker implantation and esophagectomy, respectively. In correlation analysis, the prevalence of aQTP was found statistically associated with heart failure (p=0.009) and all-cause shock (p=0.02). As for primary endpoints, aLQTS was shown relevant with the length of ICU stay (p=0.037) and as an independent risk factor for all-cause death (p=0.026) in sepsis. Sequencing of myocardium on SIC mice revealed multiple genes associated with electrical ion channels were significantly altered in SIC, e.g., KCNQ1 (p<0.001, R2=0.84), KCNJ5(p<0.001, R2=0.97), SCN5A (p<0.001, R2=0.86), CALMl4 (p-0038, R2=0.36) etc., which affect cardiac repolarization by regulating potassium, sodium and calcium channels, and was in accordance with the results of qPCR for the hub genes. Externally validation based on GEO database demonstrated similar results. aQTP is not infrequently observed in sepsis-induced myocardial injury, which is associated with poor prognosis in septic patients. It requires more clinical awareness of regular monitoring for related aLQTS and other complications. Sepsis-induced myocardial inflammation may have an impact on the expression of multiple genes related to myocardial repolarization.

Platelet Indices: Is it a Reliable Biomarker in Viral Infections?

Platelets are non-nucleated blood cells that are essential for maintaining hemostasis. While platelet activation and increased platelet numbers (thrombocytosis) are associated with a higher risk of thrombotic events, low platelet counts (thrombocytopenia) and a variety of platelet function abnormalities are associated with a higher risk of bleeding. Platelets and their activation state have been proven in recent years to influence innate and adaptive immune responses, and low platelet counts have been identified as a surrogate indicator for poor prognosis in septic patients. Platelet activation frequently occurs in conjunction with viral infections. Viruses, on the other hand, can interact directly with platelets and megakaryocytes, modulating their function. All these factors contribute to platelet activation, which leads to increased platelet consumption and elimination, as well as thrombocytopenia, which is common during viral infection Platelets and their secreted products have been demonstrated to suppress infection and aid virus persistence in the presence of certain viruses, making platelets a double-edged sword during viral infections. In this review we have highlighted about what is currently known about platelet interactions with various types of viruses, virus effects on platelet activation, as well as platelet-mediated regulation of innate and adaptive immune responses.

Association between the volume of fluid resuscitation and mortality modified by disease severity in patients with sepsis in ICU: a retrospective cohort study

ObjectiveThe important effect modifiers of high disease severity on the relationship between the different volumes of early fluid resuscitation and prognosis in septic patients are unknown. Thus, this study was...

Untargeted metabolomic profiling of sepsis-induced cardiac dysfunction.

Sepsis is a life-threatening condition secondary to infection that evolves into a dysregulated host response and is associated with acute organ dysfunction. Sepsis-induced cardiac dysfunction is one of the most complex organ failures to characterize. This study performed comprehensive metabolomic profiling that distinguished between septic patients with and without cardiac dysfunction. Plasma samples collected from 80 septic patients were analysed by untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomics. Principal component analysis (PCA), partial least squares discrimination analysis (PLS-DA), and orthogonal partial least square discriminant analysis (OPLS-DA) were applied to analyse the metabolic model between septic patients with and without cardiac dysfunction. The screening criteria for potential candidate metabolites were as follows: variable importance in the projection (VIP) >1, P < 0.05, and fold change (FC) > 1.5 or < 0.7. Pathway enrichment analysis further revealed associated metabolic pathways. In addition, we constructed a subgroup metabolic analysis between the survivors and non-survivors according to 28-day mortality in the cardiac dysfunction group. Two metabolite markers, kynurenic acid and gluconolactone, could distinguish the cardiac dysfunction group from the normal cardiac function group. Two metabolites, kynurenic acid and galactitol, could distinguish survivors and non-survivors in the subgroup analysis. Kynurenic acid is a common differential metabolite that could be used as a candidate for both diagnosis and prognosis for septic patients with cardiac dysfunction. The main associated pathways were amino acid metabolism, glucose metabolism and bile acid metabolism. Metabolomic technology could be a promising approach for identifying diagnostic and prognostic biomarkers of sepsis-induced cardiac dysfunction.

Immune checkpoint molecule Tim-3 promotes NKT cell apoptosis and predicts poorer prognosis in Sepsis

BackgroundSepsis is a leading cause of death among critically ill patients, which is defined as life-threatening organ dysfunction caused by a deregulated host immune response to infection. Immune checkpoint molecule Tim-3 plays important and complex roles in regulating immune responses and in inducing immune tolerance. Although immune checkpoint blockade would be expected as a promising therapeutic strategy for sepsis, but the underlying mechanism remain unknown, especially under clinical conditions. MethodsTim-3 expression and apoptosis in NKT cells were compared in septic patients (27 patients with sepsis and 28 patients with septic shock). Phenotypic and functional characterization of Tim-3+ NKT cells were analysed, and then the relationship between Tim-3 + NKT cells and clinical prognosis were investigated in septic patients. α-lactose (Tim-3/Galectin-9 signalling inhibitor) and Tim-3 mutant mice (targeting mutation of the Tim-3 cytoplasmic domain) were utilized to evaluate the protective effect of Tim-3 signalling blockade following septic challenge. ResultsThere is a close correlation between Tim-3 expression and the functional status of NKT cells in septic patients, Upregulated Tim-3 expression promoted NKT cell activation and apoptosis during the early stage of sepsis, and it was associated with worse disease severity and poorer prognosis in septic patients. Blockade of the Tim-3/Galectin-9 signal axis using α-lactose inhibited in vitro apoptosis of NKT cells isolated from septic patients. Impaired activity of Tim-3 protected mice following septic challenge. ConclusionsOverall, these findings demonstrated that immune checkpoint molecule Tim-3 in NKT cells plays a critical role in the immunopathogenesis of septic patients. Blockade of immune checkpoint molecule Tim-3 may be a promising immunomodulatory strategy in future clinical practice for the management of sepsis.