The aim of this study is to compare the discriminant function of multiple organ dysfunction score (MODS) and sequential organ failure assessment (SOFA) components in predicting the Intensive Care Unit (ICU) mortality and neurologic outcome.

A rare case of Francisella hispaniensis infection associated with seawater exposure occurred in a deep-sea diving fisherman in Zhejiang, China. He had skin and soft tissue infection that progressed to bacteremia and multiple organ failure. Moxifloxacin treatment cleared the infections, but the patient suffered a sequela of heart damage.

Multiple organ failure syndrome (MOFS) is a pathology associated to unspecified and severe trauma, characterized by elevated morbidity and mortality. The complex inflammatory MOFS-related reactions generate important ischemia-reperfusion responses in the induction of this syndrome. Nitric oxide elevation, through the activation of cyclic guanosine monophosphate (cGMP), has the potential of counteracting the typical systemic vasoconstriction, and platelet-induced hypercoagulation. Tadalafil would possibly act protectively by reducing cGMP degradation with consequent diffuse vasodilatation, besides reduction of platelet-induced hypercoagulation, thus, preventing multiple organ failure syndrome development.

Multiple organ failure is the commonest cause of death in septic patients.

Sepsis is one of the major complications of surgery resulting in high morbidity and mortality, but there are no specific therapies for sepsis-induced organ dysfunction. Data obtained under Gene Expression Omnibus accession GSE131761 were re-analyzed and showed an increased gene expression of Janus Kinase 2 (JAK2) and Signal Transducer and Activator of Transcription 3 (STAT3) in the whole blood of post-operative septic patients. Based on these results, we hypothesized that JAK/STAT activation may contribute to the pathophysiology of septic shock and, hence, investigated the effects of baricitinib (JAK1/JAK2 inhibitor) on sepsis-induced cardiac dysfunction and multiple-organ failure (MOF). In a mouse model of post-trauma sepsis induced by midline laparotomy and cecal ligation and puncture (CLP), 10-week-old male (n=32) and female (n=32) C57BL/6 mice received baricitinib (1mg/kg; i.p.) or vehicle at 1h or 3h post-surgery. Cardiac function was assessed at 24h post-CLP by echocardiography in vivo, and the degree of MOF was analyzed by determination of biomarkers in the serum. The potential mechanism underlying both the cardiac dysfunction and the effect of baricitinib was analyzed by western blot analysis in the heart. Trauma and subsequent sepsis significantly depressed the cardiac function and induced multiple-organ failure, associated with an increase in the activation of JAK2/STAT3, NLRP3 inflammasome and NF- κβ pathways in the heart of both male and female animals. These pathways were inhibited by the administration of baricitinib post the onset of sepsis. Moreover, treatment with baricitinib at 1h or 3h post-CLP protected mice from sepsis-induced cardiac injury and multiple-organ failure. Thus, baricitinib may be repurposed for trauma-associated sepsis.

Introduction: Chronic Heart failure (CHF) is a highly prevalent disease that leads to significant morbidity and mortality. Diffuse vasculopathy is a commonmorbidity associated with CHF. Increased vascular permeability leading to plasma extravasation (PEx) occurs in surrounding tissues following endothelial dysfunction. Such micro- and macrovascular complications develop over time and lead to edema, inflammation, and multi-organ dysfunction in CHF. However, a systemic examination of PEx in vital organs among different time windows of CHF has never been performed. In the present study, we investigated time-dependent PEx in several major visceral organs including heart, lung, liver, spleen, kidney, duodenum, ileum, cecum, and pancreas between sham-operated and CHF rats induced by myocardial infarction (MI). Methods: Plasma extravasation was determined by colorimetric evaluation of Evans Blue (EB) concentrations at 3 days, ∼10 weeks and 4 months following MI. Results: Data show that cardiac PEx was initially high at day 3 post MI and then gradually decreased but remained at a moderately high level at ∼10 weeks and 4 months post MI. Lung PEx began at day 3 and remained significantly elevated at both ∼10 weeks and 4 months post MI. Spleen PExwas significantly increased at ∼10 weeks and 4 months but not on day 3 post MI. Liver PEx occurred early at day 3 and remain significantly increased at ∼10 weeks and 4 months post MI. For the gastrointestinal (GI) organs including duodenum, ileum and cecum, there was a general trend that PEx level gradually increased following MI and reached statistical significance at either 10 weeks or 4 months post MI. Similar to GI PEx, renal PEx was significantly elevated at 4 months post MI. Discussion: In summary, we found that MI generally incites a timedependent PEx of multiple visceral organs. However, the PEx time window for individual organs in response to the MI challenge was different, suggesting that different mechanisms are involved in the pathogenesis of PEx in these vital organs during the development of CHF.

Renal ischemia reperfusion (IR) injury is a major cause of acute kidney injury (AKI) that is often complicated by multiple organ failure of the liver and intestine. The mineralocorticoid receptor (MR) is activated in patients with renal failure associated with glomerular and tubular damage. We thus investigated whether canrenoic acid (CA), a mineralocorticoid receptor (MR) antagonist, protects against AKI-induced hepatic and intestinal injury, suggesting the underlying mechanisms. Mice were divided into five groups: sham mice, mice subjected to renal IR, and mice pretreated with canrenoic acid (CA; 1 or 10 mg/kg) 30 min prior to renal IR. At 24 h after renal IR, the levels of plasma creatinine, alanine aminotransferase and aldosterone were measured, and structural changes and inflammatory responses of the kidney, liver, and intestine were analyzed. We found that CA treatment reduced plasma creatinine levels, tubular cell death and oxidative stress induced by renal IR. CA treatment also decreased renal neutrophil infiltration and inflammatory cytokine expression and inhibited the release of high-mobility group box 1 induced by renal IR. Consistently, CA treatment reduced renal IR-induced plasma alanine transaminase, hepatocellular injury and neutrophil infiltration, and inflammatory cytokine expression. CA treatment also decreased small intestinal cell death, neutrophil infiltration and inflammatory cytokine expression induced by renal IR. Taken together, we conclude that MR antagonism by CA treatment protects against multiple organ failure in the liver and intestine after renal IR.

Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death. Acute mortality from AP-MODS exceeds 20% (ref. 3), and the lifespans of those who survive the initial episode are typically shorter than those of the general population. There are no specific therapies available to protect individuals from AP-MODS. Here we show that kynurenine-3-monooxygenase (KMO), a key enzyme of tryptophan metabolism, is central to the pathogenesis of AP-MODS. We created a mouse strain that is deficient for Kmo (encoding KMO) and that has a robust biochemical phenotype that protects against extrapancreatic tissue injury to the lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the kynurenine substrate led to the discovery of the oxazolidinone GSK180 as a potent and specific inhibitor of KMO. The binding mode of the inhibitor in the active site was confirmed by X-ray co-crystallography at 3.2 Å resolution. Treatment with GSK180 resulted in rapid changes in the levels of kynurenine pathway metabolites in vivo, and it afforded therapeutic protection against MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS, and they open up a new area for drug discovery in critical illness.

Sepsis is a common cause of acute renal failure (ARF). The incidence of sepsis increases dramatically after 50 years of age; however, most ARF studies are performed in young mice.

Several recommendations and data on the treatment of acute necrotizing pancreatitis (ANP) are conflicting and different surgical approaches continue to exist. We conducted a study on 148 patients with ANP, who were divided into two groups: the main group (n = 95) when the tactics of the step-up approach were applied with the principles of the concept of Enhanced Recovery After Surgery (ERAS) in order to determine this approach on effectiveness in reducing complications and 30-day mortality (2017-2022); the comparison group (n = 53) when the same tactic of the treatment was used without ERAS principles (2015-2016). Treatment time for the main group in the intensive care unit was minimized (p ≤ 0.004); it has been shown to reduce the frequency of complications in these patients (p < 0.001) requiring conservative or surgical treatment without general anaesthesia (Clavien-Dindo I-IIIa); no statistically significant differences were observed for the total incidence of Clavien-Dindo IIIb-IVb complications (p > 0.05); the median duration of treatment for patients in the primary group was 23 days, and in the reference group-34 days (p ≤ 0.003). Pancreatic infections have been observed in 92 (62.2%) patients and gram-negative bacteria predominated in the overall pathogen structure with 222 (70.7%) strains. The only evidence of multiple organ failure before (AUC = 0.814) and after surgery (AUC = 0.931) was found to be predictive of mortality. Antibiotic sensitivity of all isolated bacteria better understood local epidemiology and identified the most effective antibiotics when treating patients.

Postinjury multiple organ failure (MOF) is the leading cause of late death in trauma patients. Although MOF was first described 50 years ago, its definition, epidemiology, and change in incidence over time are poorly understood. We aimed to describe the incidence of MOF in the context of different MOF definitions, study inclusion criteria, and its change over time.

Sepsis is caused by systemic infection and is a major health concern as it is the primary cause of death from infection. It is the leading cause of mortality worldwide and there are no specific effective treatments for sepsis. Gene deletion of the neutral solute channel Aquaporin 9 (AQP9) normalizes oxidative stress and improves survival in a bacterial endotoxin induced mouse model of sepsis. In this study we described the initial characterization and effects of a novel small molecule AQP9 inhibitor, RG100204, in a cecal ligation and puncture (CLP) induced model of polymicrobial infection. In vitro, RG100204 blocked mouse AQP9 H2O2 permeability in an ectopic CHO cell expression system and abolished the LPS induced increase in superoxide anion and nitric oxide in FaO hepatoma cells. Pre-treatment of CLP-mice with RG100204 (25 mg/kg p.o. before CLP and then again at 8 h after CLP) attenuated the hypothermia, cardiac dysfunction (systolic and diastolic), renal dysfunction and hepatocellular injury caused by CLP-induced sepsis. Post-treatment of CLP-mice with RG100204 also attenuated the cardiac dysfunction (systolic and diastolic), the renal dysfunction caused by CLP-induced sepsis, but did not significantly reduce the liver injury or hypothermia. The most striking finding was that oral administration of RG100204 as late as 3 h after the onset of polymicrobial sepsis attenuated the cardiac and renal dysfunction caused by severe sepsis. Immunoblot quantification demonstrated that RG100204 reduced activation of the NLRP3 inflammasome pathway. Moreover, myeloperoxidase activity in RG100204 treated lung tissue was reduced. Together these results indicate that AQP9 may be a novel drug target in polymicrobial sepsis.

Peroxisome proliferator-activated receptor (PPAR)-beta/delta is a nuclear receptor transcription factor that regulates gene expression in many important biological processes. It is expressed ubiquitously, especially white adipose tissue, heart, muscle, intestine, placenta and macrophages but many of its functions are unknown. Saturated and polyunsaturated fatty acids activate PPAR-beta/delta, but physiological ligands have not yet been identified. In the present study, we investigated the anti-inflammatory effects of PPAR-beta/delta activation, through the use of GW0742 (0,3 mg/kg 10% Dimethyl sulfoxide (DMSO) i.p), a synthetic high affinity ligand, on the development of zymosan-induced multiple organ failure (MOF).

Septic patients treated in the intensive care unit (ICU) often develop multiple organ failure including persistent skeletal muscle dysfunction which results in the patient's protracted recovery process. We have demonstrated that muscle mitochondrial enzyme activities are impaired in septic ICU patients impairing cellular energy balance, which will interfere with muscle function and metabolism. Here we use detailed phenotyping and genomics to elucidate mechanisms leading to these impairments and the molecular consequences.

We previously reported the Bruton's tyrosine kinase (BTK) inhibitors ibrutinib and acalabrutinib improve outcomes in a mouse model of polymicrobial sepsis. Now we show that genetic deficiency of the BTK gene alone in Xid mice confers protection against cardiac, renal, and liver injury in polymicrobial sepsis and reduces hyperimmune stimulation ("cytokine storm") induced by an overwhelming bacterial infection. Protection is due in part to enhanced bacterial phagocytosis in vivo, changes in lipid metabolism and decreased activation of NF-κB and the NLRP3 inflammasome. The inactivation of BTK leads to reduced innate immune cell recruitment and a phenotypic switch from M1 to M2 macrophages, aiding in the resolution of sepsis. We have also found that BTK expression in humans is increased in the blood of septic non-survivors, while lower expression is associated with survival from sepsis. Importantly no further reduction in organ damage, cytokine production, or changes in plasma metabolites is seen in Xid mice treated with the BTK inhibitor ibrutinib, demonstrating that the protective effects of BTK inhibitors in polymicrobial sepsis are mediated solely by inhibition of BTK and not by off-target effects of this class of drugs.

Sepsis remains a common condition with high mortality when multiple organ failure develops. The evidence for therapeutic plasma exchange (TPE) in this setting is promising but inconclusive. Our study aims to evaluate the efficacy of adjunct TPE for septic shock with multiple organ failure compared to standard therapy alone.

Drug-induced hypersensitivity syndrome (DIHS), including Stevens-Johnson syndrome (SJS), is a severe rash that often develops 2-6 weeks after the intake of the causative drug; however, its diagnosis is sometimes difficult. This article describes a case in which a patient with DIHS-induced multiple organ failure was successfully treated with blood purification therapy.

Multiple organ failure (MOF) is a serious complication of moderately severe (MASP) and severe acute pancreatitis (SAP). This study aimed to develop and assess three machine-learning models to predict MOF.

Multiple organ failure (MOF) may lead to an increased mortality rate of moderately severe (MSAP) or severe acute pancreatitis (SAP). This study is aimed to use machine learning to predict the risk of MOF in the course of disease.

The widespread occurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a pandemic of coronavirus disease 2019 (COVID-19). The S spike protein of SARS-CoV-2 binds with angiotensin-converting enzyme 2 (ACE2) as a functional "receptor" and then enters into host cells to replicate and damage host cells and organs. ACE2 plays a pivotal role in the inflammation, and its downregulation may aggravate COVID-19 via the renin-angiotensin system, including by promoting pathological changes in lung injury and involving inflammatory responses. Severe patients of COVID-19 often develop acute respiratory distress syndrome and multiple organ dysfunction/failure with high mortality that may be closely related to the hyper-proinflammatory status called the "cytokine storm." Massive cytokines including interleukin-6, nuclear factor kappa B (NFκB), and tumor necrosis factor alpha (TNFα) released from SARS-CoV-2-infected macrophages and monocytes lead inflammation-derived injurious cascades causing multi-organ injury/failure. This review summarizes the current evidence and understanding of the underlying mechanisms of SARS-CoV-2, ACE2 and inflammation co-mediated multi-organ injury or failure in COVID-19 patients.