Melatonin attenuates sepsis-induced acute kidney injury by promoting mitophagy through SIRT3-mediated TFAM deacetylation.

ABBREVIATIONS: AKI: acute kidney injury; ATP: adenosine triphosphate; BUN: blood urea nitrogen; CLP: cecal ligation and puncture; eGFR: estimated glomerular filtration rate; H&E: hematoxylin and eosin staining; LCN2/NGAL: lipocalin 2; LPS: lipopolysaccharide; LTL: lotus tetragonolobus lectin; mKeima: mitochondria-targeted Keima; mtDNA: mitochondrial DNA; PAS: periodic acid - Schiff staining; RTECs: renal tubular epithelial cells; SAKI: sepsis-induced acute kidney injury; Scr: serum creatinine; SIRT3: sirtuin 3; TFAM: transcription factor A, mitochondrial; TMRE: tetramethylrhodamine.

PDHA1 hyperacetylation-mediated lactate overproduction promotes sepsis-induced acute kidney injury via Fis1 lactylation.

The increase of lactate is an independent risk factor for patients with sepsis-induced acute kidney injury (SAKI). However, whether elevated lactate directly promotes SAKI and its mechanism remain unclear. Here we revealed that downregulation of the deacetylase Sirtuin 3 (SIRT3) mediated the hyperacetylation and inactivation of pyruvate dehydrogenase E1 component subunit alpha (PDHA1), resulting in lactate overproduction in renal tubular epithelial cells. We then found that the incidence of SAKI and renal replacement therapy (RRT) in septic patients with blood lactate ≥ 4 mmol/L was increased significantly, compared with those in septic patients with blood lactate < 2 mmol/L. Further in vitro and in vivo experiments showed that additional lactate administration could directly promote SAKI. Mechanistically, lactate mediated the lactylation of mitochondrial fission 1 protein (Fis1) lysine 20 (Fis1 K20la). The increase in Fis1 K20la promoted excessive mitochondrial fission and subsequently induced ATP depletion, mitochondrial reactive oxygen species (mtROS) overproduction, and mitochondrial apoptosis. In contrast, PDHA1 activation with sodium dichloroacetate (DCA) or SIRT3 overexpression decreased lactate levels and Fis1 K20la, thereby alleviating SAKI. In conclusion, our results show that PDHA1 hyperacetylation and inactivation enhance lactate overproduction, which mediates Fis1 lactylation and exacerbates SAKI. Reducing lactate levels and Fis1 lactylation attenuate SAKI.

Effect of Esmolol on Clinical Outcomes in Critically Ill Patients: Data from the MIMIC-IV Database.

BACKGROUND AND AIMS: Esmolol is a common short-acting drug to control ventricular rate. This study aimed to evaluate the association between use of esmolol and mortality in critically ill patients. METHODS: This is a retrospective cohort study from MIMIC-IV database containing adult patients with a heart rate of over 100 beats/min during the intensive care unit (ICU) stay. Multivariable Cox proportional hazard models and logistic regression were used to explore the association between esmolol and mortality and adjust confounders. A 1:1 nearest neighbor propensity score matching (PSM) was performed to minimize potential cofounding bias. The comparison for secondary outcomes was performed at different points of time using an independent t-test. RESULTS: A total of 30,332 patients were reviewed and identified as critically ill. There was no significant difference in 28-day mortality between two groups before (HR = 0.90, 95% CI = 0.73-1.12, p = 0.343) and after PSM (HR = 0.84, 95% CI = 0.65-1.08, p = 0.167). Similar results were shown in 90-day mortality before (HR = 0.93, 95% CI = 0.75-1.14, p = 0.484) and after PSM (HR = 0.85, 95% CI = 0.67-1.09, p = 0.193). However, esmolol treatment was associated with higher requirement of vasopressor use before (HR = 2.89, 95% CI = 2.18-3.82, p < 0.001) and after PSM (HR = 2.66, 95% CI = 2.06-3.45, p < 0.001). Esmolol treatment statistically reduced diastolic blood pressure (DBP), mean arterial pressure (MAP), and heart rate (all p < 0.001) and increased fluid balance at 24 hours (p < 0.05) but did not significantly lower SBP (p = 0.721). Patients in esmolol group showed no significant difference in lactate levels and daily urine output when compared with those in non-esmolol group when adjusted for confounders (all p > 0.05). CONCLUSION: Esmolol treatment was associated with reduced heart rate and lowered DBP and MAP, which may increase vasopressor use and fluid balance at the timepoint of 24 hours in critically ill patients during ICU stay. However, after adjusting for confounders, esmolol treatment was not associated with 28-day and 90-day mortality.

Pathogen Diagnosis Value of Nanopore Sequencing in Severe Hospital-Acquired Pneumonia Patients.

Background: Next-generation sequencing of the metagenome (mNGS) is increasingly used in pathogen diagnosis for infectious diseases due to its short detection time. The time for Oxford Nanopore Technologies (ONT) sequencing-based etiology detection is further shortened compared with that of mNGS, but only a few studies have verified the time advantage and accuracy of ONT sequencing for etiology diagnosis. In 2022, a study confirmed that there was no significant difference in sensitivity and specificity between ONT and mNGS in suspected community-acquired pneumonia patients, which there was no clinical study verified in patients with SHAP. Methods: From October 24 to November 20, 2022, 10 patients with severe hospital-acquired pneumonia (SHAP) in the Nanfang Hospital intensive care unit (ICU) were prospectively enrolled. Bronchoalveolar lavage fluid (BALF) was collected for ONT sequencing, mNGS, and traditional culture. The differences in pathogen detection time and diagnostic agreement among ONT sequencing, mNGS, traditional culture method, and clinical composite diagnosis were compared. Results: Compared with mNGS and the traditional culture method, ONT sequencing had a significant advantage in pathogen detection time (9.6±0.7 h versus 24.7±2.7 h versus 132±58 h, P <0.05). The agreement rate between ONT sequencing and the clinical composite diagnosis was 73.3% (kappa value=0.737, P <0.05). Conclusion: ONT sequencing has a potential advantage for rapidly identifying pathogens.

Dexmedetomidine only regimen for long-term sedation is associated with reduced vasopressor requirements in septic shock patients: A retrospective cohort study from MIMIC-IV database.

Background: Previous studies have shown that dexmedetomidine (DEX) may be associated with reduced vasopressor requirements in septic shock patients, however, long-term DEX-only sedation in reducing vasopressor requirements is still controversial. Methods: A retrospective study was conducted among patients with septic shock on mechanical ventilation using the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. The primary outcome was the ratio of norepinephrine equivalent dose to mean arterial pressure (NEq/MAP) in the first 72 h after DEX or other sedatives for sedation. The secondary outcomes were key organ function parameters, 28-day mortality, and 90-day mortality. Univariate, propensity score matching (PSM), and generalized linear mixed model (GLMM) analyses were performed. Results: DEX was associated with decreased NEq/MAP in the first 72 h (difference = 0.05, 95% CI = -0.02-0.08, p = 0.002) after adjusting for confounders in the GLMM analysis. The DEX group was also associated with a lower heart rate, cardiac output (CO), lactate level, aspartate transaminase (AST) level, and higher PaO2/FiO2 ratio (p < 0.0125). Moreover, DEX only sedation was associated with reduced 90-day mortality (OR = 0.60, 95% CI = 0.37-0.94, p = 0.030). Conclusion: DEX may be associated with decreased vasopressor requirements, improved AST and PaO2/FiO2 levels, and reduced 90-day mortality in patients with septic shock, which warrants further study.

Association between dexmedetomidine administration and outcomes in critically ill patients with sepsis-associated acute kidney injury.

STUDY OBJECTIVE: To investigate the association between dexmedetomidine administration and outcomes in critically ill patients with sepsis-associated acute kidney injury (SA-AKI). DESIGN: A single-center, retrospective, cohort study. SETTING: Intensive care unit (ICU). PATIENTS: A total of 2192 critically ill patients with SA-AKI were included in the analysis, which identified from the Medical Information Mart for Intensive Care (MIMIC-IV) database between 2008 and 2019. INTERVENTIONS: Intravenous infusion of dexmedetomidine. MEASUREMENTS: The primary outcome was recovery of renal function. In-hospital mortality, vasopressor requirements, length of ICU and hospital stay were considered secondary outcomes. The Cox proportional hazards, logistic regression, and linear regression models were used to assess the association between dexmedetomidine and outcomes. Propensity score matching (PSM) analysis was used to match patients receiving dexmedetomidine to those without treatment. MAIN RESULTS: After PSM, 719 matched patient pairs were derived from patients who received dexmedetomidine and those who did not. The administration of dexmedetomidine was associated with a higher rate of renal recovery [61.8% vs. 55.8%, hazard ratio (HR) 1.35; P = 0.01], reduced in-hospital mortality [28.3% vs. 41.3%, HR 0.56; P < 0.001], and prolonged intensive care unit (ICU) stay [15.8d vs 12.6d, HR 2.34; P < 0.001] and hospital stay [23.7d vs 19.7d, HR 4.47; P < 0.001]. No significant difference was found in vasopressor requirements in patients with SA-AKI. Nevertheless, results illustrated that dose receiving between 0.30 and 1.00 µg/kg/h and duration using under 48 h of dexmedetomidine was associated with improvements in renal function recovery in SA-AKI patients. CONCLUSION: Dexmedetomidine administration was associated with improvements in renal function recovery and in-hospital survival in critically ill patients with SA-AKI. The results need to be verified in further randomized controlled trials.

Early pulmonary artery catheterization is not associated with survival benefits in critically ill patients with cardiac disease: An analysis of the MIMIC-IV database.

BACKGROUND: Many studies demonstrated no improved survival in patients with pulmonary artery catheter placement. However, no consistent conclusions have been drawn regarding the impact of pulmonary artery catheter in critically ill patients with heart disease. This study aimed to investigate the association of early pulmonary artery catheter use with 28-day mortality in that population. METHODS: The Multiparameter Intelligent Monitoring in Intensive Care IV (MIMIC-IV) database, a single-center critical care database, was employed to investigate this issue. This study enrolled a total of 11,887 critically ill patients with cardiac disease with or without pulmonary artery catheter insertion. The primary outcome was 28-day mortality. The multivariate regression was modeled to examine the association between pulmonary artery catheter and outcomes. Additionally, we examined the effect modification by cardiac surgeries. Propensity score matching was conducted to validate our findings. RESULTS: No improvement in 28-day mortality was observed among the pulmonary artery catheter group compared to the non-pulmonary artery catheter group (odds ratio 95% confidence interval: 1.18 [1.00-1.38], P = .049). When stratified by cardiac surgeries, the results were consistent. The patients in the pulmonary artery catheter group had fewer ventilation-free days and vasopressor-free days than those in the nonpulmonary artery catheter group after surgery stratification. In the surgical patients, pulmonary artery catheter insertion was not associated with the occurrence of acute kidney injury, and it was associated with a higher daily fluid input (mean difference 95% confidence interval: 0.13 [0.05-0.20], P = .001). In nonsurgical patients, the pulmonary artery catheter group had a higher risk of acute kidney injury occurrence (odds ratio 95% confidence interval: 1.94 [1.32-2.84], P = .001). CONCLUSION: Early pulmonary artery catheter placement is not associated with survival benefits in critically ill patients with cardiac diseases, either in surgical or nonsurgical patients.

Risk Factors for Mortality in Abdominal Infection Patients in ICU: A Retrospective Study From 2011 to 2018.

To identify the risk factors related to the patient's 28-day mortality, we retrospectively reviewed the records of patients with intra-abdominal infections admitted to the ICU of Nanfang Hospital, Southern Medical University from 2011 to 2018. Multivariate Cox proportional hazard regression analysis was used to identify independent risk factors for mortality. Four hundred and thirty-one patients with intra-abdominal infections were analyzed in the study. The 28-day mortality stepwise increased with greater severity of disease expression: 3.5% in infected patients without sepsis, 7.6% in septic patients, and 30.9% in patients with septic shock (p < 0.001). In multivariate analysis, independent risk factors for 28-day mortality were underlying chronic diseases (adjusted HR 3.137, 95% CI 1.425-6.906), high Sequential Organ Failure Assessment (SOFA) score (adjusted HR 1.285, 95% CI 1.160-1.424), low hematocrit (adjusted HR 1.099, 95% CI 1.042-1.161), and receiving more fluid within 72 h (adjusted HR 1.028, 95% CI 1.015-1.041). Compared to the first and last 4 years, the early use of antibiotics, the optimization of IAT strategies, and the restriction of positive fluid balance were related to the decline in mortality of IAIs in the later period. Therefore, underlying chronic diseases, high SOFA score, low hematocrit, and receiving more fluid within 72 h after ICU admission were independent risk factors for patients' poor prognosis.

Remimazolam reduces sepsis-associated acute liver injury by activation of peripheral benzodiazepine receptors and p38 inhibition of macrophages.

BACKGROUND: Remimazolam is a novel ester-type benzodiazepine with ultrafast onset of sedation effect and fast recovery of consciousness. It has potential advantages in the sedation of sepsis-associated acute liver injury (SALI) patients. However, the effect and mechanism of remimazo lam on inflammation in the liver have not yet been elucidated. This study investigated the anti-inflammatory effects and mechanisms of remimazolam on SALI both in vivo and in vitro. METHODS: Lipopolysaccharide (LPS) plus galactosamine treated rat model and LPS-challenged RAW264.7 cells model were constructed to simulate SALI. Next, the models were used to explore the efficacy of remimazolam treatment on SALI. Benzodiazepine receptor inhibitor, PK11195, was also employed. Hepatic injury was assessed by quantifying levels of transaminases, examining liver pathology, and calculating the number of inflammatory cells in the liver. Inflammatory response was evaluated by determining levels of pro-inflammatory cytokines and chemokines in blood, as well as p38 phosphorylation (p-p38) in the liver. RESULTS: SALIrat models showed significant liver damage as manifested by increased levels of transaminases, proinflammatory cytokines, chemokines, and p-38. Remimazolam treatment reduced the liver injury and pathological changes, suppressed pro-inflammatory reactions, and elevated p-p38. The protective effect of remimazolam on liver injury was significantly blocked by PK11195. In LPS-stimulated RAW264.7 cells, it was found that treatment with remimazolam reduced the inflammatory response in LPS-treated cells in a time-dependent manner and decreased the level of p-p38. These results suggest that PK11195 can block remimazolam-induced inhibition of proinflammatory cytokine release and p-38 phosphorylation. CONCLUSIONS: This study shows that remimazolam can attenuate inflammatory response in SALI, which may be associated with activation of peripheral benzodiazepine receptors and inhibition of p38 phosphorylation in macrophages.

A Prediction Model for Assessing Prognosis in Critically Ill Patients with Sepsis-associated Acute Kidney Injury.

BACKGROUND: Sepsis-associated acute kidney injury (SA-AKI) is a common problem in critically ill patients and is associated with high morbidity and mortality. Early prediction of the survival of hospitalized patients with SA-AKI is necessary, but a reliable and valid prediction model is still lacking. METHODS: We conducted a retrospective cohort analysis based on a training cohort of 2,066 patients enrolled from the Multiparameter Intelligent Monitoring in Intensive Care Database III (MIMIC III) and a validation cohort of 102 patients treated at Nanfang Hospital of Southern Medical University. Least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression analysis were used to identify predictors for survival. Areas under the ROC curves (AUC), the concordance index (C-index), and calibration curves were used to evaluate the efficiency of the prediction model (SAKI) in both cohorts. RESULTS: The overall mortality of SA-AKI was approximately 18%. Age, admission type, liver disease, metastatic cancer, lactate, BUN/SCr, admission creatinine, positive culture, and AKI stage were independently associated with survival and combined in the SAKI model. The C-index in the training and validation cohorts was 0.73 and 0.72. The AUC in the training cohort was 0.77, 0.72, and 0.70 for the 7-day, 14-day, and 28-day probability of in-hospital survival, respectively, while in the external validation cohort, it was 0.83, 0.73, and 0.67. SAPSII and SOFA scores showed poorer performance. Calibration curves demonstrated a good consistency. CONCLUSIONS: Our SAKI model has predictive value for in-hospital mortality of SA-AKI in critically ill patients and outperforms generic scores.

Melatonin Attenuates Sepsis-Induced Small-Intestine Injury by Upregulating SIRT3-Mediated Oxidative-Stress Inhibition, Mitochondrial Protection, and Autophagy Induction.

Melatonin reportedly alleviates sepsis-induced multi-organ injury by inducing autophagy and activating class III deacetylase Sirtuin family members (SIRT1-7). However, whether melatonin attenuates small-intestine injury along with the precise underlying mechanism remain to be elucidated. To investigate this, we employed cecal ligation and puncture (CLP)- or endotoxemia-induced sepsis mouse models and confirmed that melatonin treatment significantly prolonged the survival time of mice and ameliorated multiple-organ injury (lung/liver/kidney/small intestine) following sepsis. Melatonin partially protected the intestinal barrier function and restored SIRT1 and SIRT3 activity/protein expression in the small intestine. Mechanistically, melatonin treatment enhanced NF-κB deacetylation and subsequently reduced the inflammatory response and decreased the TNF-α, IL-6, and IL-10 serum levels; these effects were abolished by SIRT1 inhibition with the selective blocker, Ex527. Correspondingly, melatonin treatment triggered SOD2 deacetylation and increased SOD2 activity and subsequently reduced oxidative stress; this amelioration of oxidative stress by melatonin was blocked by the SIRT3-selective inhibitor, 3-TYP, and was independent of SIRT1. We confirmed this mechanistic effect in a CLP-induced sepsis model of intestinal SIRT3 conditional-knockout mice, and found that melatonin preserved mitochondrial function and induced autophagy of small-intestine epithelial cells; these effects were dependent on SIRT3 activation. This study has shown, to the best of our knowledge, for the first time that melatonin alleviates sepsis-induced small-intestine injury, at least partially, by upregulating SIRT3-mediated oxidative-stress inhibition, mitochondrial-function protection, and autophagy induction.

Risk Factors for Enterococcal Intra-Abdominal Infections and Outcomes in Intensive Care Unit Patients.

Background: To investigate the risk factors for enterococcal intra-abdominal infections (EIAIs) and the association between EIAIs and outcomes in intensive care unit (ICU) patients. Methods: We reviewed retrospectively the records of patients with intra-abdominal infections admitted to the Department of Critical Care Medicine at Nanfang Hospital, Southern Medical University, China, from January 2011 to December 2018. Patients with intra-abdominal infections were divided into enterococcal and non-enterococcal groups based on whether enterococci were isolated from intra-abdominal specimens. Results: A total of 431 patients with intra-abdominal infections were included, of whom 119 were infected with enterococci and 312 were infected with non-enterococci. Enterococci were isolated in 27.6% of patients, accounting for 24.5% (129/527) of all clinical bacterial isolates. Post-operative abdominal infection (adjusted odds ratio [OR], 2.361; p = 0.004), intestinal infection (adjusted OR, 2.703; p < 0.001), Mannheim Peritonitis Index score (MPI; adjusted OR, 1.052; p = 0.015), and use of antibiotic agents within the previous 90 days (adjusted OR, 1.880; p = 0.025) were associated with an increased risk of EIAIs. Compared with patients without enterococcal infection, ICU patients with enterococcal infection had a higher risk of failure of initial clinical therapy (49.6% vs. 24.2%; p < 0.001) and longer hospital stays (33 days [19, 48] vs. 18 days [12, 29]; p < 0.001). Enterococcal infection was associated with increased 28-day mortality, in-hospital mortality, and ICU mortality. However, no difference was found in length of ICU stay between the two groups. Additionally, there was no difference in ICU mortality, hospital mortality, or 28-day mortality in patients infected with enterococcus who did or did not receive empirical anti-enterococcal therapy. Conclusion: Post-operative abdominal infection, intestinal infection, MPI score, and use of antibiotic agents within the previous 90 days were independent risk factors for enterococcal infection. Enterococcal infection was associated with reduced short-term survival in ICU patients.

Novel Insights into the Molecular Features and Regulatory Mechanisms of Mitochondrial Dynamic Disorder in the Pathogenesis of Cardiovascular Disease.

Mitochondria maintain mitochondrial homeostasis through continuous fusion and fission, that is, mitochondrial dynamics, which is precisely mediated by mitochondrial fission and fusion proteins, including dynamin-related protein 1 (Drp1), mitofusin 1 and 2 (Mfn1/2), and optic atrophy 1 (OPA1). When the mitochondrial fission and fusion of cardiomyocytes are out of balance, they will cause their own morphology and function disorders, which damage the structure and function of the heart, are involved in the occurrence and progression of cardiovascular disease such as ischemia-reperfusion injury (IRI), septic cardiomyopathy, and diabetic cardiomyopathy. In this paper, we focus on the latest findings regarding the molecular features and regulatory mechanisms of mitochondrial dynamic disorder in cardiovascular pathologies. Finally, we will address how these findings can be applied to improve the treatment of cardiovascular disease.

[Role of deacetylase sirtuins in sepsis: beneficial or harmful?]

OBJECTIVE: Sepsis, life-threatening organ dysfunction caused by a dysregulated host response to infection, is a major public health concern. To date, the mechanism of sepsis is not completely understood, which is still a huge task ahead of numerous clinical and laboratory researchers. Recently, increasing evidences show that deacetylase sirtuins play an important role in sepsis and the function of sirtuins are varied in different stages of sepsis. More importantly, the mechanism of sirutins is not fully understood. The sirtuins family is composed by sirtuin 1-7 members. Among them, sirtuin 1 is widely reported. In addition to sirtuin 1, other members of sirtuins are also involved in the regulation of inflammation or metabolism signaling following sepsis. Of note, the sirtuins may interact with each other and form a precious control mechanism. Herein, we tried to summarize the recent paper from PubMed, to explain the possible mechanism of distinct role of sirtuin 1/2, to generalize the downstream effects of sirtuin 3 action, and to describe the interactions among sirtuins members on sepsis, which might be helpful for our future research and potential clinical applications.

Emerging Evidence concerning the Role of Sirtuins in Sepsis.

Sepsis, a dysregulated host response to infection, is a major public health concern. Though experimental and clinical studies relating to sepsis are increasing, the mechanism of sepsis is not completely understood. To date, numerous studies have shown that sirtuins (silent mating type information regulation 2 homolog), which belong to the class III histone deacetylases, may have a varied, or even opposite, effect in the pathogenesis of sepsis. Notably, downstream mechanisms of sirtuins are not fully understood. The sirtuin family consists of sirtuins 1-7; among them, sirtuin 1 (SIRT1) is the most studied one, during the development of sepsis. Furthermore, other sirtuin members are also confirmed to be involved in the regulation of inflammatory or metabolic signaling following sepsis. In addition, sirtuins may interact with each other to form a precise regulatory mechanism in different phases of sepsis. Therefore, in this review, by accumulating data from PubMed, we intend to explain the role of sirtuin in sepsis, which we hope will pave the way for further experimental study and the potential future clinical applications of sirtuins.