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1.
Cells ; 10(10)2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34685643

RESUMO

Extracellular vesicles (EVs) have been identified as novel mediators of intercellular communication. They work via delivering the sequestered cargo to cells in the close vicinity, as well as distant sites in the body, regulating pathophysiological processes. Cell death and inflammation are biologically crucial processes in both normal physiology and pathology. These processes are indistinguishably linked with their effectors modulating the other process. For instance, during an unresolvable infection, the upregulation of specific immune mediators leads to inflammation causing cell death and tissue damage. EVs have gained considerable interest as mediators of both cell death and inflammation during conditions, such as sepsis. This review summarizes the types of extracellular vesicles known to date and their roles in mediating immune responses leading to cell death and inflammation with specific focus on sepsis and lung inflammation.


Assuntos
Apoptose , COVID-19/terapia , Morte Celular , Vesículas Extracelulares/metabolismo , Inflamação/metabolismo , Pulmão/patologia , SARS-CoV-2 , Sepse/imunologia , Animais , Biomarcadores/metabolismo , COVID-19/imunologia , Comunicação Celular , Quimiocinas , Exossomos , Humanos , Pulmão/imunologia , Camundongos , Sepse/fisiopatologia
2.
Medicine (Baltimore) ; 100(38): e27235, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34559119

RESUMO

ABSTRACT: To investigate the usefulness of afterload-related cardiac performance (ACP) for assessing cardiac impairment and predicting prognosis in septic patients.Adult patients with sepsis in the intensive care unit were included. Cardiac output, cardiac index, cardiac power index, and ACP were calculated at the time of admission (D0) and 48-72 h after admission (D3). They were correlated with Acute Physiology and Chronic Health Evaluation II and sequential organ failure assessment scores, then the prognostic values were analyzed.A total of 41 patients with sepsis were selected. ACP showed a stronger negative correlation with Acute Physiology and Chronic Health Evaluation II and sequential organ failure assessment scores than cardiac output, cardiac index, and cardiac power index. ACP predicted 28-day mortality with an area under the curve of 0.775 and 0.976 on D0 and D3, respectively. In addition, most non-survivors had emergent cardiac impairment (ACP ≤ 80%) on D0, and cardiac function was deteriorated on D3. Survival analysis showed that the patients with a decreased ACP from D0 to D3 had the highest mortality. The decrease of ACP on D3 was an independent risk factor for mortality (hazard ratio, 11.89; P = .0028).ACP can be used to assess the severity of cardiac impairment in sepsis. Continued decline of ACP during the first 3 days strongly suggests a poor prognosis.


Assuntos
Débito Cardíaco/fisiologia , Prognóstico , Sepse/fisiopatologia , Idoso , Área Sob a Curva , Estado Terminal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Projetos Piloto , Estudos Prospectivos , Curva ROC , Sepse/complicações , Análise de Sobrevida
3.
Int J Mol Sci ; 22(17)2021 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-34502521

RESUMO

BACKGROUND: Sepsis is a serious, heterogeneous clinical entity produced by a severe and systemic host inflammatory response to infection. Methotrexate (MTX) is a folate-antagonist that induces the generation of adenosine and also inhibits JAK/STAT pathway; MTX it is widely used as an anti-inflammatory drug to control the immune system. OBJECTIVE: The aim of this study was to assess the beneficial effects of a single and low dose of MTX in the systemic response and acute lung injury (ALI) induced by sepsis. As in the clinics, we treated our animals with antibiotics and fluids and performed the source control to mimic the current clinic treatment. METHODS AND MAIN RESULTS: Sepsis was induced in rats by a cecal ligation puncture (CLP) procedure. Six hours after induction of sepsis, we proceeded to the source control; fluids and antibiotics were administered at 6 h and 24 h after CLP. MTX (2.5 mg/Kg) was administered 6 h after the first surgery in one CLP experimental group and to one Sham group. A protective effect of MTX was observed through a significant reduction of pro-inflammatory cytokines and a decrease infiltration of inflammatory cells in the lung. In addition, we found a regulation in adenosine receptor A2aR and the metalloproteinases by MTX. CONCLUSION: A single, low dose of MTX attenuates sepsis lung-associated damage by decreasing pro-inflammatory response, infiltration of pro-inflammatory cells and avoiding defective tissue lung remodeling.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Metotrexato/farmacologia , Sepse/tratamento farmacológico , Animais , Anti-Inflamatórios/uso terapêutico , Ceco/patologia , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Ligadura , Pulmão/efeitos dos fármacos , Masculino , Metotrexato/metabolismo , Punções , Ratos , Ratos Sprague-Dawley , Sepse/fisiopatologia
4.
Crit Care Med ; 49(12): 2112-2120, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34582409

RESUMO

OBJECTIVES: Sepsis is a common condition in the ICU. Despite much research, its prognosis remains poor. In 2017, a retrospective before/after study reported promising results using a combination of thiamine, ascorbic acid, and hydrocortisone called "metabolic resuscitation cocktail" and several randomized controlled trials assessing its effectiveness were performed. DESIGN: We conducted a systematic review and meta-analysis of randomized controlled trials in septic ICU patients to assess the effects of this combination therapy. SETTING: PubMed, Embase, and the Cochrane library databases were searched from inception to March of 2021. Data were extracted independently by two authors. The main outcome was the change in Sequential Organ Failure Assessment score within 72 hours. Secondary outcomes included renal composite endpoints (acute kidney injury) Kidney Disease - Improving Global Outcome organization stage 3 or need for renal replacement therapy, vasopressor duration, and 28-day mortality. SUBJECTS: We included randomized controlled trials with patients admitted to the ICU with sepsis or septic shock. INTERVENTION: The trials compared a combination of thiamine, ascorbic acid, and hydrocortisone to standard care or placebo in patients admitted to ICU with sepsis or septic shock. MEASUREMENTS AND MAIN RESULTS: We included eight randomized controlled trials (n = 1,335 patients). Within 72 hours, the median of mean improvement was -1.8 and -3.2 in the control and intervention groups, respectively (eight randomized controlled trials, n = 1,253 patients); weighted mean difference -0.82 (95% CI, -1.15 to -0.48). Data were homogeneous and the funnel plot did not suggest any publication bias. Duration of vasopressor requirement was significantly reduced in the intervention group (six randomized controlled trials). There was no evidence of a difference regarding the ICU mortality and the renal composite outcome (acute kidney injury KDIGO 3 or need for renal replacement therapy, seven randomized controlled trials). CONCLUSIONS: Metabolic resuscitation cocktail administrated in ICU septic patients improves change in Sequential Organ Failure Assessment score within 72 hours. However, this improvement is modest and its clinical relevance is questionable. The impact on renal failure and mortality remains unclear.


Assuntos
Ácido Ascórbico/metabolismo , Hidrocortisona/metabolismo , Metabolismo/efeitos dos fármacos , Sepse/tratamento farmacológico , Tiamina/metabolismo , Ácido Ascórbico/farmacologia , Ácido Ascórbico/uso terapêutico , Combinação de Medicamentos , Humanos , Hidrocortisona/farmacologia , Hidrocortisona/uso terapêutico , Ontário , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Sepse/fisiopatologia , Tiamina/farmacologia , Tiamina/uso terapêutico
5.
Biochem Biophys Res Commun ; 577: 38-44, 2021 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-34507063

RESUMO

Sepsis is a life-threatening inflammatory syndrome secondary to infection. Thanks to the advances of antibiotics and life-supporting techniques, the mortality of sepsis has been decreasing in recent decades. Nevertheless, sepsis-associated encephalopathy (SAE) is still common in septic patients, which promotes the mortality of septic patients and results in cognitive dysfunction in survivors. Full understanding and effective medicine in the treatment of SAE is currently scant. Here, we revealed a novel role of cGAS signaling in the pathogenesis of SAE. Deficiency of cGas significantly restored cognitive impairment in sepsis mice model. The restoration may attribute to the recovery of neo-neuron decline that associated with the decrease of activated microglia and astrocytes in the hippocampus of cGas-deficient mice. In addition, type I interferon (IFN) signaling, a downstream of cGAS pathway, was boosted in the hippocampus of septic mice, which was dramatically attenuated by deleting cGas. Moreover, administration of recombinant IFNß markedly reversed the protection of ablation of cGas in the cognitive impairment in sepsis. Collectively, cGAS promotes the pathogenesis of SAE by up-regulating type I IFN signaling. Blocking cGAS may be a promising strategy for preventing encephalopathy in sepsis.


Assuntos
Modelos Animais de Doenças , Nucleotidiltransferases/genética , Encefalopatia Associada a Sepse/genética , Transdução de Sinais/genética , Animais , Animais Recém-Nascidos , Astrócitos/metabolismo , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Interferon Tipo I/metabolismo , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/metabolismo , Neurônios/metabolismo , Nucleotidiltransferases/deficiência , Substâncias Protetoras/metabolismo , Sepse/genética , Sepse/metabolismo , Sepse/fisiopatologia , Encefalopatia Associada a Sepse/metabolismo
6.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361061

RESUMO

Sepsis is a sustained systemic inflammatory condition involving multiple organ failures caused by dysregulated immune response to infections. Sepsis induces substantial changes in energy demands at the cellular level leading to metabolic reprogramming in immune cells and stromal cells. Although sepsis-associated organ dysfunction and mortality have been partly attributed to the initial acute hyperinflammation and immunosuppression precipitated by a dysfunction in innate and adaptive immune responses, the late mortality due to metabolic dysfunction and immune paralysis currently represent the major problem in clinics. It is becoming increasingly recognized that intertissue and/or intercellular metabolic crosstalk via endocrine factors modulates maintenance of homeostasis, and pathological events in sepsis and other inflammatory diseases. Exosomes have emerged as a novel means of intercellular communication in the regulation of cellular metabolism, owing to their capacity to transfer bioactive payloads such as proteins, lipids, and nucleic acids to their target cells. Recent evidence demonstrates transfer of intact metabolic intermediates from cancer-associated fibroblasts via exosomes to modify metabolic signaling in recipient cells and promote cancer progression. Here, we review the metabolic regulation of endothelial cells and immune cells in sepsis and highlight the role of exosomes as mediators of cellular metabolic signaling in sepsis.


Assuntos
Células Endoteliais/patologia , Exossomos/patologia , Imunossupressão , Inflamação/patologia , Doenças Metabólicas/patologia , Sepse/fisiopatologia , Animais , Humanos , Inflamação/imunologia , Doenças Metabólicas/etiologia
8.
Br J Anaesth ; 127(4): 577-586, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34332740

RESUMO

BACKGROUND: Excess mitochondrial reactive oxygen species (mROS) in sepsis is associated with organ failure, in part by generating inflammation through the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. We determined the impact of a mitochondrial-targeted antioxidant (MitoTEMPO) on mitochondrial dysfunction in renal proximal tubular epithelial cells, peritoneal immune cell function ex vivo, and organ dysfunction in a rat model of sepsis. METHODS: The effects of MitoTEMPO were assessed ex vivo using adenosine triphosphate and lipopolysaccharide-stimulated rat peritoneal immune cells and fresh rat kidney slices exposed to serum from septic rats. We assessed mROS production and phagocytotic capacity (flow cytometry), mitochondrial functionality (multiphoton imaging, respirometry), and NLRP3 inflammasome activation in cell culture. The effect of MitoTEMPO on organ dysfunction was evaluated in a rat model of faecal peritonitis. RESULTS: MitoTEMPO decreased septic serum-induced mROS (P<0.001) and maintained normal reduced nicotinamide adenine dinucleotide redox state (P=0.02) and mitochondrial membrane potential (P<0.001) in renal proximal tubular epithelial cells ex vivo. In lipopolysaccharide-stimulated peritoneal immune cells, MitoTEMPO abrogated the increase in mROS (P=0.006) and interleukin-1ß (IL-1ß) (P=0.03) without affecting non-mitochondrial oxygen consumption or the phagocytotic-induced respiratory burst (P>0.05). In vivo, compared with untreated septic animals, MitoTEMPO reduced systemic IL-1ß (P=0.01), reduced renal oxidative stress as determined by urine isoprostane levels (P=0.04), and ameliorated renal dysfunction (reduced serum urea (P<0.001) and creatinine (P=0.05). CONCLUSIONS: Reduction of mROS by a mitochondria-targeted antioxidant reduced IL-1ß, and protected mitochondrial, cellular, and organ functionality after septic insults.


Assuntos
Antioxidantes/farmacologia , Inflamação/tratamento farmacológico , Compostos Organofosforados/farmacologia , Piperidinas/farmacologia , Sepse/tratamento farmacológico , Animais , Modelos Animais de Doenças , Inflamassomos/metabolismo , Inflamação/patologia , Interleucina-1beta/metabolismo , Nefropatias/tratamento farmacológico , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peritonite/tratamento farmacológico , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Sepse/fisiopatologia
9.
PLoS One ; 16(8): e0249868, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34460853

RESUMO

Sepsis is a potentially life-threatening condition that requires prompt recognition and treatment. Recently, heart rate variability (HRV), a measure of the cardiac autonomic regulation derived from short electrocardiogram tracings, has been found to correlate with sepsis mortality. This paper presents using novel heart rate n-variability (HRnV) measures for sepsis mortality risk prediction and comparing against current mortality prediction scores. This study was a retrospective cohort study on patients presenting to the emergency department of a tertiary hospital in Singapore between September 2014 to April 2017. Patients were included if they were above 21 years old and were suspected of having sepsis by their attending physician. The primary outcome was 30-day in-hospital mortality. Stepwise multivariable logistic regression model was built to predict the outcome, and the results based on 10-fold cross-validation were presented using receiver operating curve analysis. The final predictive model comprised 21 variables, including four vital signs, two HRV parameters, and 15 HRnV parameters. The area under the curve of the model was 0.77 (95% confidence interval 0.70-0.84), outperforming several established clinical scores. The HRnV measures may have the potential to allow for a rapid, objective, and accurate means of patient risk stratification for sepsis severity and mortality. Our exploration of the use of wealthy inherent information obtained from novel HRnV measures could also create a new perspective for data scientists to develop innovative approaches for ECG analysis and risk monitoring.


Assuntos
Serviço Hospitalar de Emergência , Frequência Cardíaca , Sepse/mortalidade , Idoso , Eletrocardiografia , Serviço Hospitalar de Emergência/estatística & dados numéricos , Feminino , Frequência Cardíaca/fisiologia , Mortalidade Hospitalar , Humanos , Masculino , Valor Preditivo dos Testes , Estudos Retrospectivos , Medição de Risco/métodos , Sepse/fisiopatologia
10.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200950

RESUMO

Sepsis is a major health problem worldwide. It is a time-dependent disease, with a high rate of morbidity and mortality. In this sense, an early diagnosis is essential to reduce these rates. The progressive increase of both the incidence and prevalence of sepsis has translated into a significant socioeconomic burden for health systems. Currently, it is the leading cause of noncoronary mortality worldwide and represents one of the most prevalent pathologies both in hospital emergency services and in intensive care units. In this article, we review the role of both endothelial dysfunction and neutrophil dysregulation in the physiopathology of this disease. The lack of a key symptom in sepsis makes it difficult to obtain a quick and accurate diagnosis of this condition. Thus, it is essential to have fast and reliable diagnostic tools. In this sense, the use of biomarkers can be a very important alternative when it comes to achieving these goals. Both new biomarkers and treatments related to endothelial dysfunction and neutrophil dysregulation deserve to be further investigated in order to open new venues for the diagnosis, treatment and prognosis of sepsis.


Assuntos
Endotélio Vascular/patologia , Neutrófilos/patologia , Sepse/fisiopatologia , Animais , Humanos , Sepse/etiologia
11.
Biomed Res Int ; 2021: 9969344, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34327242

RESUMO

Objective: We want to explore the changing law of circulating histones in the acute stage of urosepsis and to find more sensitive and specific biomarkers for diagnosing urosepsis as early as possible. Methods: Twenty healthy male New Zealand rabbits were randomly divided into 4 groups (N = 5): the control group, sham group, model group of LPS 600 µg/kg, and model group of LPS 1000 µg/kg. Heart rate (HR), respiration rate (RR), rectal temperature (T), and mean arterial pressure (MAP) were examined at 1, 3, 6, 12, and 24 hours after operation. Besides, peripheral blood cell counts (RBC, WBC, PLT, and Hb) and C reaction protein (CRP) were tested at 1, 3, and 6 hours after operation, while the levels of histone H3, MMP-9, TIMP-1, and procalcitonin (PCT) in the serum were tested at 1, 3, and 6 hours after operation by ELISA. The heart, left lung, liver, and left kidney were harvested for HE stain and observed to research the pathological change of these tissues. Results: (1) The general status of rabbits: rabbits in the control and sham groups came out in 2 h after operation and regain to drink and eat in 12-24 h after operation. State of the rabbits in the control group was better than that in the sham group. Rabbits in the model groups were languid after operation and stopped to drink and eat. (2) Vital signs of rabbits: there was no statistic difference in HR (P = 0.238) and RR (P = 0.813) among all groups. MAP of the model groups decreased at 3 h postoperative, but transient (P < 0.001). The T of the LPS 1000 group decreased at 6 h postoperative (P = 0.003). (3) The change of biomarkers: H3 level of the LPS groups in the serum increased at 1 h postoperative (P < 0.01); MMP-9 of the LPS 1000 group increased at 1 h postoperative (P < 0.01); WBC of the model groups decreased at 3 h postoperative (P < 0.05); PLT of the LPS 1000 group is significantly increased at 1 h postoperative (P < 0.05); no statistic difference was found in CRP, PCT, and TIMP-1 among all groups. (4) Pathological sections: no abnormal performance was found in the control and sham groups. Glomerulus of the model groups was out of shape and necrosis with obvious renal tubule expansion. Pulmonary pathology showed alveolar septum diffuse increased and inflammatory infiltrate. Change of the LPS 1000 group was more serious than that of the LPS 600 group. Conclusions: Ligating the ureter after an injection of 1000 µg/kg LPS into the ureter of the rabbit can establish the animal model of urosepsis. Histone H3 increase immediately at 1 h postoperative and are promised to be biomarkers of urosepsis, which are more effective than WBC, CRP, and PCT.


Assuntos
Diagnóstico Precoce , Histonas/sangue , Sepse/sangue , Sepse/diagnóstico , Animais , Pressão Arterial , Temperatura Corporal , Proteína C-Reativa/metabolismo , Modelos Animais de Doenças , Contagem de Leucócitos , Lipopolissacarídeos , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Especificidade de Órgãos , Contagem de Plaquetas , Pró-Calcitonina/sangue , Curva ROC , Coelhos , Sensibilidade e Especificidade , Sepse/patologia , Sepse/fisiopatologia , Inibidor Tecidual de Metaloproteinase-1/sangue , Sinais Vitais
12.
Biomed Pharmacother ; 138: 111524, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34311527

RESUMO

BACKGROUND: Sepsis-associated cardiac dysfunction results in increased mortality. Hyperoside (Hyp) is a flavonoid, showing significant anti-inflammatory effects. However, its pharmacological effects on sepsis-induced cardiac dysfunction remain unknown. In this study, we attempted to explore whether Hyp could prevent cardiac dysfunction and its underlying mechanisms. METHODS: We established a mice mode of sepsis by cecal ligation and puncture (CLP) treatment, and constructed a cell model of myocardial injury by lipopolysaccharide (LPS) stimulation. The cardiac function indicators and the inflammatory cytokine levels were measured. Effect of Hyp on cardiomyocyte viability was evaluated using MTT assay. The expression and functional role of microRNA-21 (miR-21), a documented molecule that regulated by Hyp, was evaluated in the constructed models, and the potential targets of miR-21 were predicted. RESULTS: Hyp alleviated the impaired cardiac function and stimulated inflammation caused by CLP in the in vivo sepsis model, and alleviated the LPS-induced decrease in cell viability and increase in inflammation of cardiomyocytes. Additionally, Hyp significantly inhibited the expression of miR-21 in LPS-induced cardiomyocytes, and the increased cell viability and decreased inflammation caused by Hyp in the in vitro model could be reversed by miR-21 overexpression. In animal model of sepsis, the protective influence of Hyp against sepsis-induced cardiac dysfunction was attenuated by miR-21 upregulation. CONCLUSION: Our findings demonstrated that Hyp may serve as a promising natural drug for the treatment of sepsis-associated cardiac dysfunction, and its protective role may exerted through regulating cardiomyocyte viability and inflammation by suppressing miR-21.


Assuntos
Anti-Inflamatórios/farmacologia , Cardiopatias/prevenção & controle , MicroRNAs/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Quercetina/análogos & derivados , Sepse/tratamento farmacológico , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Cardiopatias/metabolismo , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Quercetina/farmacologia , Sepse/metabolismo , Sepse/patologia , Sepse/fisiopatologia , Transdução de Sinais
13.
Crit Care ; 25(1): 251, 2021 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-34274013

RESUMO

BACKGROUND: Meropenem dosing for septic critically patients is difficult due to pathophysiological changes associated with sepsis as well as supportive symptomatic therapies. A prospective single-center study assessed whether fluid retention alters meropenem pharmacokinetics and the achievement of the pharmacokinetic/pharmacodynamic (PK/PD) targets for efficacy. METHODS: Twenty-five septic ICU patients (19 m, 6f) aged 32-86 years with the mean APACHE II score of 20.2 (range 11-33), suffering mainly from perioperative intra-abdominal or respiratory infections and septic shock (n = 18), were investigated over three days after the start of extended 3-h i.v. infusions of meropenem q8h. Urinary creatinine clearance (CLcr) and cumulative fluid balance (CFB) were measured daily. Plasma meropenem was measured, and Bayesian estimates of PK parameters were calculated. RESULTS: Eleven patients (9 with peritonitis) were classified as fluid overload (FO) based on a positive day 1 CFB of more than 10% body weight. Compared to NoFO patients (n = 14, 11 with pneumonia), the FO patients had a lower meropenem clearance (CLme 8.5 ± 3.2 vs 11.5 ± 3.5 L/h), higher volume of distribution (V1 14.9 ± 3.5 vs 13.5 ± 4.1 L) and longer half-life (t1/2 1.4 ± 0.63 vs 0.92 ± 0.54 h) (p < 0.05). Over three days, the CFB of the FO patients decreased (11.7 ± 3.3 vs 6.7 ± 4.3 L, p < 0.05) and the PK parameters reached the values comparable with NoFO patients (CLme 12.4 ± 3.8 vs 11.5 ± 2.0 L/h, V1 13.7 ± 2.0 vs 14.0 ± 5.1 L, t1/2 0.81 ± 0.23 vs 0.87 ± 0.40 h). The CLcr and Cockroft-Gault CLcr were stable in time and comparable. The correlation with CLme was weak to moderate (CLcr, day 3 CGCLcr) or absent (day 1 and 2 CGCLcr). Dosing with 2 g meropenem q8h ensured adequate concentrations to treat infections with sensitive pathogens (MIC 2 mg/L). The proportion of pre-dose concentrations exceeding the MIC 8 mg/L and the fraction time with a target-exceeding concentration were higher in the FO group (day 1-3 f Cmin > MIC: 67 vs 27%, p < 0.001; day 1%f T > MIC: 79 ± 17 vs 58 ± 17, p < 0.05). CONCLUSIONS: These findings emphasize the importance of TDM and a cautious approach to augmented maintenance dosing of meropenem to patients with FO infected with less susceptible pathogens, if guided by population covariate relationships between CLme and creatinine clearance.


Assuntos
Meropeném/farmacocinética , Farmacocinética , Sepse/tratamento farmacológico , Equilíbrio Hidroeletrolítico/efeitos dos fármacos , APACHE , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/metabolismo , Antibacterianos/farmacocinética , Teorema de Bayes , Estado Terminal/terapia , República Tcheca , Feminino , Humanos , Unidades de Terapia Intensiva/organização & administração , Unidades de Terapia Intensiva/estatística & dados numéricos , Masculino , Meropeném/metabolismo , Pessoa de Meia-Idade , Estudos Prospectivos , Sepse/fisiopatologia
14.
Clin Neurophysiol ; 132(9): 2075-2082, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34284242

RESUMO

OBJECTIVE: In critical care, continuous EEG (cEEG) monitoring is useful for delirium diagnosis. Although visual cEEG analysis is most commonly used, automatic cEEG analysis has shown promising results in small samples. Here we aimed to compare visual versus automatic cEEG analysis for delirium diagnosis in septic patients. METHODS: We obtained cEEG recordings from 102 septic patients who were scored for delirium six times daily. A total of 1252 cEEG blocks were visually analyzed, of which 805 blocks were also automatically analyzed. RESULTS: Automatic cEEG analyses revealed that delirium was associated with 1) high mean global field power (p < 0.005), mainly driven by delta activity; 2) low average coherence across all electrode pairs and all frequencies (p < 0.01); 3) lack of intrahemispheric (fronto-temporal and temporo-occipital regions) and interhemispheric coherence (p < 0.05); and 4) lack of cEEG reactivity (p < 0.005). Classification accuracy was assessed by receiver operating characteristic (ROC) curve analysis, revealing a slightly higher area under the curve for visual analysis (0.88) than automatic analysis (0.74) (p < 0.05). CONCLUSIONS: Automatic cEEG analysis is a useful supplement to visual analysis, and provides additional cEEG diagnostic classifiers. SIGNIFICANCE: Automatic cEEG analysis provides useful information in septic patients.


Assuntos
Cuidados Críticos/métodos , Delírio/fisiopatologia , Eletroencefalografia/métodos , Monitorização Fisiológica/métodos , Sepse/fisiopatologia , Idoso , Estudos de Coortes , Delírio/diagnóstico , Delírio/terapia , Feminino , Humanos , Masculino , Sepse/diagnóstico , Sepse/terapia
15.
Mol Cell Biol ; 41(10): e0033221, 2021 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-34309413

RESUMO

Evidence exists reporting that saikosaponin-d (Sa) can prevent experimental sepsis, and this study aims to illustrate the molecular events underlying its renoprotective effects on lipopolysaccharide (LPS)-induced renal inflammation simulating sepsis. Through network pharmacology analysis and bioinformatics analysis, we identified that Sa may influence sepsis development by mediating TCF7. Dual luciferase reporter gene and chromatin immunoprecipitation (ChIP) assays were used to explore the interactions between TCF7, FOSL1, and matrix metalloproteinase 9 (MMP9). The experimental data suggest that Sa attenuated LPS-induced renal injury, as evidenced by the reduced production of proinflammatory cytokines as well as cell apoptosis in the renal tissues of LPS-induced mice. Mechanically, Sa inhibited FOSL1 by inhibiting TCF7, which reduced the expression of inflammatory factors in renal cells. TCF7 activated the FOSL1 expression and consequently promoted the expression of MMP9. Also, Sa reduced cell apoptosis and the expression of inflammatory factors by inhibiting the TCF7/FOSL1/MMP9 axis in vivo. In conclusion, Sa suppresses FOSL1 transcription by downregulating TCF7, thereby inhibiting MMP9 expression and ultimately reducing the renal inflammation and cell apoptosis induced by sepsis.


Assuntos
Ácido Oleanólico/análogos & derivados , Saponinas/farmacologia , Sepse/tratamento farmacológico , Injúria Renal Aguda/genética , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Humanos , Inflamação/tratamento farmacológico , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Nefrite/tratamento farmacológico , Ácido Oleanólico/metabolismo , Ácido Oleanólico/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Saponinas/metabolismo , Sepse/fisiopatologia
16.
Crit Care ; 25(1): 202, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112226

RESUMO

BACKGROUND: The mechanisms driving acute kidney injury (AKI) in critically ill COVID-19 patients are unclear. We collected kidney biopsies from COVID-19 AKI patients within 30 min after death in order to examine the histopathology and perform mRNA expression analysis of genes associated with renal injury. METHODS: This study involved histopathology and mRNA analyses of postmortem kidney biopsies collected from patients with COVID-19 (n = 6) and bacterial sepsis (n = 27). Normal control renal tissue was obtained from patients undergoing total nephrectomy (n = 12). The mean length of ICU admission-to-biopsy was 30 days for COVID-19 and 3-4 days for bacterial sepsis patients. RESULTS: We did not detect SARS-CoV-2 RNA in kidney biopsies from COVID-19-AKI patients yet lung tissue from the same patients was PCR positive. Extensive acute tubular necrosis (ATN) and peritubular thrombi were distinct histopathology features of COVID-19-AKI compared to bacterial sepsis-AKI. ACE2 mRNA levels in both COVID-19 (fold change 0.42, p = 0.0002) and bacterial sepsis patients (fold change 0.24, p < 0.0001) were low compared to control. The mRNA levels of injury markers NGAL and KIM-1 were unaltered compared to control tissue but increased in sepsis-AKI patients. Markers for inflammation and endothelial activation were unaltered in COVID-19 suggesting a lack of renal inflammation. Renal mRNA levels of endothelial integrity markers CD31, PV-1 and VE-Cadherin did not differ from control individuals yet were increased in bacterial sepsis patients (CD31 fold change 2.3, p = 0.0006, PV-1 fold change 1.5, p = 0.008). Angiopoietin-1 mRNA levels were downregulated in renal tissue from both COVID-19 (fold change 0.27, p < 0.0001) and bacterial sepsis patients (fold change 0.67, p < 0.0001) compared to controls. Moreover, low Tie2 mRNA expression (fold change 0.33, p = 0.037) and a disturbed VEGFR2/VEGFR3 ratio (fold change 0.09, p < 0.0001) suggest decreased microvascular flow in COVID-19. CONCLUSIONS: In a small cohort of postmortem kidney biopsies from COVID-19 patients, we observed distinct histopathological and gene expression profiles between COVID-19-AKI and bacterial sepsis-AKI. COVID-19 was associated with more severe ATN and microvascular thrombosis coupled with decreased microvascular flow, yet minimal inflammation. Further studies are required to determine whether these observations are a result of true pathophysiological differences or related to the timing of biopsy after disease onset.


Assuntos
COVID-19/patologia , Expressão Gênica/genética , Rim/patologia , Rim/fisiopatologia , Sepse/patologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , COVID-19/genética , COVID-19/fisiopatologia , Estado Terminal/terapia , Feminino , Humanos , Unidades de Terapia Intensiva/organização & administração , Unidades de Terapia Intensiva/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Sepse/genética , Sepse/fisiopatologia , Escala Psicológica Aguda Simplificada
17.
Life Sci ; 279: 119662, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34081989

RESUMO

AIM: Early and prompt treatment of sepsis by effective antibiotics against susceptible organisms may be lifesaving. However, increased antibiotic resistance and side effects of chemotherapeutic agents limiting their tolerability result in a restricted use of medications. This has led to an increased search for solution oriented novel treatments and therapeutic targets, as well as investigations on the pathogenesis and physiology of sepsis. In this study, we aimed to examine the antioxidant and anti-inflammatory effects of fosfomycin in sepsis resulting from other causes. MAIN METHODS: Sprague Dawley rats were assigned into three groups. Randomly selected control rats received intraperitoneal saline solution only. Only caecal puncture and ligation were carried out in the caecal ligation and puncture (CLP) group, while in the CLP + fosfomycin group (CLP + FOS), together with sepsis due to caecal puncture and ligation, 500 mg/kg of FOS was administered intraperitoneally (i.p.). KEY FINDINGS: As compared to the control group, elevated TBARS and TNF-α levels as well as increased expression of NF-kB/p65 and TLR-4 and reduced -SH levels were found in the lung tissue of CLP rats. On the other hand, TBARS and TNF-α levels were reduced and NF-kB/p65 and TLR-4 expressions were decreased together with increase in total -SH levels among CLP + FOS (500 mg/kg i.p.) rats. SIGNIFICANCE: FOS treatment may represent a promising agent in terms of reducing the sepsis-related lung injury due to its antimicrobial effects as well as its antioxidant and anti-inflammatory properties.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Fosfomicina/farmacologia , Inflamação/complicações , Estresse Oxidativo , Substâncias Protetoras/farmacologia , Sepse/fisiopatologia , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/patologia , Animais , Antibacterianos/farmacologia , Antioxidantes/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley
18.
Biomed Res Int ; 2021: 5520051, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34136567

RESUMO

The aim of this study was to investigate the effect of cardiac troponin I-interacting kinase (TNNI3K) on sepsis-induced myocardial dysfunction (SIMD) and further explore the underlying molecular mechanisms. In this study, a lipopolysaccharide- (LPS-) induced myocardial injury model was used. qRT-PCR was performed to detect the mRNA expression of TNNI3K. Western blot was conducted to quantitatively detect the expression of TNNI3K and apoptosis-related proteins (Bcl-2, Bax, and caspase-3). ELISA was performed to detect the content of lactate dehydrogenase (LDH) and creatine kinase (CK). TUNEL assay was used to detect the apoptosis of H9C2 cells. In LPS-induced H9C2 cells, TNNI3K was up regulated. Besides, the CK activity, the content of LDH, and the apoptosis of H9C2 cells were significantly increased after treatment with LPS. Silencing TNNI3K decreased the LDH release activity and CK activity and inhibited apoptosis of H9C2 cell. Further research illustrated that si-TNNI3K promoted the protein expression of Bcl-2 and decreased the protein expression of Bax and cleaved caspase-3. The study concluded that TNNI3K was upregulated in LPS-induced H9C2 cells. Importantly, functional research findings indicated that silencing TNNI3K alleviated LPS-induced H9C2 cell injury by regulating apoptosis-related proteins.


Assuntos
Apoptose , Insuficiência Cardíaca/metabolismo , Miocárdio/patologia , Proteínas Tirosina Quinases/metabolismo , Sepse/metabolismo , Sepse/fisiopatologia , Animais , Caspase 3/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Inativação Gênica , Insuficiência Cardíaca/etiologia , Lipopolissacarídeos/metabolismo , RNA Mensageiro/metabolismo , Ratos , Sepse/complicações , Transfecção , Regulação para Cima , Proteína X Associada a bcl-2/metabolismo
19.
Am J Emerg Med ; 49: 268-272, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34171722

RESUMO

OBJECTIVE: This study aims to compare the composite outcome of progression to septic shock between 30 mL/kg/ideal body weight (IBW) versus 30 mL/kg/non-IBW fluid resuscitation dosing strategies in obese patients with severe sepsis. METHODS: We retrospectively evaluated obese patients admitted to an academic tertiary care center for the management of severe sepsis. Patients were included if they had a fluid bolus order placed using the sepsis order set between Oct 2018 and Sept 2019. The primary objective was the composite of progression to septic shock, defined as either persistent hypotension within 3 h after the conclusion of the 30 mL/kg fluid bolus administration or the initiation of vasopressor(s) within 6 h of the bolus administration. RESULTS: Of 72 included patients, 49 (68%) were resuscitated using an IBW-based and 23 (32%) using a non-IBW-based dosing strategy. There were similar rates of progression to septic shock in the IBW and non-IBW groups (18% vs. 26%; p = 0.54). Median ICU and hospital LOS in the IBW group versus non-IBW group were (0 [IQR 0] vs. 0 [IQR 0 to 4] days; p = 0.13) and (6 [IQR 3 to 10] vs. 8 [IQR 5 to 12] days; p = 0.07), respectively. In-hospital mortality rates were similar between the groups. CONCLUSIONS: Our study results suggest that in obese septic patients, fluid administration using an IBW-dosing strategy did not affect the progression to septic shock.


Assuntos
Relação Dose-Resposta a Droga , Hidratação/normas , Obesidade/complicações , Sepse/terapia , Idoso , Feminino , Hidratação/métodos , Hidratação/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Obesidade/fisiopatologia , Ressuscitação/métodos , Ressuscitação/normas , Ressuscitação/estatística & dados numéricos , Estudos Retrospectivos , Sepse/epidemiologia , Sepse/fisiopatologia
20.
Methods Mol Biol ; 2321: 121-135, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34048012

RESUMO

The translation of preclinical results into successful clinical therapies remains a challenge in sepsis research. One reason for this lack of translation might be the discrepancy between preclinical models and the clinical reality: nonresuscitated young healthy rodents in contrast to elderly comorbid patients in an intensive care unit. We introduce the mouse intensive care unit (MICU) as a concept to address the lack of resuscitation in preclinical studies as one of the limiting issues in translational research. The MICU reflects standard procedures of the clinical intensive care unit: fluid resuscitation, lung-protective mechanical ventilation, and hemodynamic monitoring and management, all tailored to organ- and function-specific targets. Thus, the MICU gives an experimental animal the intermediate possibility of recovery and survival due to "patient" management, which is not reflected in less complex experimental scenarios, which either result in acute survival or death.


Assuntos
Estudos Clínicos como Assunto/métodos , Camundongos/fisiologia , Animais , Hemodinâmica/fisiologia , Unidades de Terapia Intensiva , Pulmão/fisiopatologia , Respiração Artificial/métodos , Ressuscitação/métodos , Sepse/fisiopatologia , Pesquisa Médica Translacional/métodos
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