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Frontiers in Immunology 2023Sepsis 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....
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 , 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.
Topics: Humans; Mice; Male; Female; Animals; Multiple Organ Failure; Mice, Inbred C57BL; Heart Diseases; Sepsis
PubMed: 37781388
DOI: 10.3389/fimmu.2023.1223014 -
Blood Mar 2016Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell...
Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS with multi-organ failure (MOF) is associated with >80% mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies. This phase 3 study investigated safety and efficacy of defibrotide in patients with established hepatic VOD/SOS and advanced MOF. Patients (n = 102) given defibrotide 25 mg/kg per day were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by blinded independent reviewers. Baseline characteristics between groups were well balanced. The primary endpoint was survival at day +100 post-HSCT; observed rates equaled 38.2% in the defibrotide group and 25% in the controls (23% estimated difference; 95.1% confidence interval [CI], 5.2-40.8;P= .0109, using a propensity-adjusted analysis). Observed day +100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% for controls (19% difference using similar methodology; 95.1% CI, 3.5-34.6;P= .0160). Defibrotide was generally well tolerated with manageable toxicity. Related adverse events (AEs) included hemorrhage or hypotension; incidence of common hemorrhagic AEs (including pulmonary alveolar [11.8% and 15.6%] and gastrointestinal bleeding [7.8% and 9.4%]) was similar between the defibrotide and control groups, respectively. Defibrotide was associated with significant improvement in day +100 survival and CR rate. The historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality. This trial was registered at www.clinicaltrials.gov as #.
Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Cohort Studies; Female; Fibrinolytic Agents; Hepatic Veno-Occlusive Disease; Humans; Infant; Infant, Newborn; Male; Middle Aged; Multiple Organ Failure; Polydeoxyribonucleotides; Severity of Illness Index; Young Adult
PubMed: 26825712
DOI: 10.1182/blood-2015-10-676924 -
Blood Purification 2019
Topics: Critical Care; Humans; Multiple Organ Failure; Sepsis
PubMed: 30974439
DOI: 10.1159/000499786 -
Circulation Feb 2020Fulminant myocarditis (FM) is an uncommon syndrome characterized by sudden and severe diffuse cardiac inflammation often leading to death resulting from cardiogenic...
Fulminant myocarditis (FM) is an uncommon syndrome characterized by sudden and severe diffuse cardiac inflammation often leading to death resulting from cardiogenic shock, ventricular arrhythmias, or multiorgan system failure. Historically, FM was almost exclusively diagnosed at autopsy. By definition, all patients with FM will need some form of inotropic or mechanical circulatory support to maintain end-organ perfusion until transplantation or recovery. Specific subtypes of FM may respond to immunomodulatory therapy in addition to guideline-directed medical care. Despite the increasing availability of circulatory support, orthotopic heart transplantation, and disease-specific treatments, patients with FM experience significant morbidity and mortality as a result of a delay in diagnosis and initiation of circulatory support and lack of appropriately trained specialists to manage the condition. This scientific statement outlines the resources necessary to manage the spectrum of FM, including extracorporeal life support, percutaneous and durable ventricular assist devices, transplantation capabilities, and specialists in advanced heart failure, cardiothoracic surgery, cardiac pathology, immunology, and infectious disease. Education of frontline providers who are most likely to encounter FM first is essential to increase timely access to appropriately resourced facilities, to prevent multiorgan system failure, and to tailor disease-specific therapy as early as possible in the disease process.
Topics: American Heart Association; Arrhythmias, Cardiac; Extracorporeal Membrane Oxygenation; Female; Heart Transplantation; Humans; Multiple Organ Failure; Myocarditis; Practice Guidelines as Topic; Shock, Cardiogenic; United States
PubMed: 31902242
DOI: 10.1161/CIR.0000000000000745 -
Life Sciences May 2021A novel infectious disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was detected in December 2019 and declared as a global... (Review)
Review
A novel infectious disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was detected in December 2019 and declared as a global pandemic by the World Health. Approximately 15% of patients with COVID-19 progress to severe pneumonia and eventually develop acute respiratory distress syndrome (ARDS), septic shock and/or multiple organ failure with high morbidity and mortality. Evidence points towards a determinant pathogenic role of members of the renin-angiotensin system (RAS) in mediating the susceptibility, infection, inflammatory response and parenchymal injury in lungs and other organs of COVID-19 patients. The receptor for advanced glycation end-products (RAGE), a member of the immunoglobulin superfamily, has important roles in pulmonary pathological states, including fibrosis, pneumonia and ARDS. RAGE overexpression/hyperactivation is essential to the deleterious effects of RAS in several pathological processes, including hypertension, chronic kidney and cardiovascular diseases, and diabetes, all of which are major comorbidities of SARS-CoV-2 infection. We propose RAGE as an additional molecular target in COVID-19 patients for ameliorating the multi-organ pathology induced by the virus and improving survival, also in the perspective of future infections by other coronaviruses.
Topics: Animals; COVID-19; Drug Discovery; Humans; Molecular Targeted Therapy; Multiple Organ Failure; Receptor for Advanced Glycation End Products; Renin-Angiotensin System; SARS-CoV-2; Signal Transduction; COVID-19 Drug Treatment
PubMed: 33636175
DOI: 10.1016/j.lfs.2021.119251 -
The Journal of Trauma and Acute Care... May 2023Postinjury multiple organ failure (MOF) is the leading cause of late death in trauma patients. Although MOF was first described 50 years ago, its definition,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
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.
METHODS
Cochrane Library, EMBASE, MEDLINE, PubMed, and Web of Science databases were searched for articles published between 1977 and 2022 in English and German. Random-effects meta-analysis was performed when applicable.
RESULTS
The search returned 11,440 results, of which 842 full-text articles were screened. Multiple organ failure incidence was reported in 284 studies that used 11 unique inclusion criteria and 40 MOF definitions. One hundred six studies published from 1992 to 2022 were included. Weighted MOF incidence by publication year fluctuated from 11% to 56% without significant decrease over time. Multiple organ failure was defined using four scoring systems (Denver, Goris, Marshall, Sequential Organ Failure Assessment [SOFA]) and 10 different cutoff values. Overall, 351,942 trauma patients were included, of whom 82,971 (24%) developed MOF. The weighted incidences of MOF from meta-analysis of 30 eligible studies were as follows: 14.7% (95% confidence interval [CI], 12.1-17.2%) in Denver score >3, 12.7% (95% CI, 9.3-16.1%) in Denver score >3 with blunt injuries only, 28.6% (95% CI, 12-45.1%) in Denver score >8, 25.6% (95% CI, 10.4-40.7%) in Goris score >4, 29.9% (95% CI, 14.9-45%) in Marshall score >5, 20.3% (95% CI, 9.4-31.2%) in Marshall score >5 with blunt injuries only, 38.6% (95% CI, 33-44.3%) in SOFA score >3, 55.1% (95% CI, 49.7-60.5%) in SOFA score >3 with blunt injuries only, and 34.8% (95% CI, 28.7-40.8%) in SOFA score >5.
CONCLUSION
The incidence of postinjury MOF varies largely because of lack of a consensus definition and study population. Until an international consensus is reached, further research will be hindered.
LEVEL OF EVIDENCE
Systematic Review and Meta-analysis; Level III.
Topics: Humans; Adult; Multiple Organ Failure; Incidence; Multiple Trauma; Organ Dysfunction Scores; Wounds, Nonpenetrating
PubMed: 36809374
DOI: 10.1097/TA.0000000000003923 -
Annals of Surgery Aug 1992Multiple organ failure (MOF) has reached epidemic proportions in most intensive care units and is fast becoming the most common cause of death in the surgical intensive... (Review)
Review
Multiple organ failure (MOF) has reached epidemic proportions in most intensive care units and is fast becoming the most common cause of death in the surgical intensive care unit. Furthermore, in spite of the development of successive generations of new and more powerful antibiotics and increasing sophisticated techniques of organ support, our ability to salvage patients once MOF has become established has not appreciably improved over the last two decades. Clearly, new therapeutic strategies aimed at preventing or limiting the development of the physiologic abnormalities that induce organ failure are needed to improve survival in these critically ill patients. Based on our rapidly increasing knowledge of the mechanisms of MOF and the fruits of molecular biology, a number of new therapeutic approaches are in various stages of development. To effectively use these new therapeutic options as they become available, it is necessary to have a clear understanding of the pathophysiology of MOF. Thus, the goals of this review are to integrate the vast amount of new information on the basic biology of MOF and to focus special attention on the potential therapeutic consequences of these recent advances in our understanding of this complex and perplexing syndrome.
Topics: Bacterial Infections; Critical Care; Cytokines; Humans; Intensive Care Units; Intestines; Lymphocyte Activation; Macrophage Activation; Microcirculation; Multiple Organ Failure; Respiratory Distress Syndrome; Shock, Septic; Wound Infection
PubMed: 1503516
DOI: 10.1097/00000658-199208000-00002 -
Clinics in Liver Disease Aug 2014The Model for End-Stage Liver Disease (MELD) has been the single best predictor of outcome of the progression of cirrhosis. Acute-on-chronic liver failure (ACLF) has... (Review)
Review
The Model for End-Stage Liver Disease (MELD) has been the single best predictor of outcome of the progression of cirrhosis. Acute-on-chronic liver failure (ACLF) has been proposed as an alternative path in the natural history of cirrhosis. ACLF occurs in patients with chronic liver disease and is characterized by a precipitating event, resulting in acute deterioration in liver function, multiorgan system failure, and high short-term mortality. In this review, the natural course of patients with ACLF, especially as it relates to management of cirrhotic patients on the transplant waiting list, and its impact on liver transplantation outcomes are defined.
Topics: End Stage Liver Disease; Humans; Liver Cirrhosis; Liver Failure, Acute; Liver Transplantation; Models, Biological; Multiple Organ Failure; Prognosis; Risk Factors
PubMed: 25017076
DOI: 10.1016/j.cld.2014.05.004 -
Critical Care Clinics Jan 2017The development of organ dysfunction (OD) is related to the intensity and balance between trauma-induced simultaneous, opposite inflammatory responses. Early... (Review)
Review
The development of organ dysfunction (OD) is related to the intensity and balance between trauma-induced simultaneous, opposite inflammatory responses. Early proinflammation via innate immune system activation may cause early OD, whereas antiinflammation, via inhibition of the adaptive immune system and apoptosis, may induce immunoparalysis, impaired healing, infections, and late OD. Patients discharged with low-level OD may develop the persistent inflammation-immunosuppression catabolism syndrome. Although the incidence of multiple organ failure has decreased over time, it remains morbid, lethal, and resource intensive. However, single OD, especially acute lung injury, remains frequent. Treatment is limited, and prevention remains the mainstay strategy.
Topics: Humans; Inflammation; Multiple Organ Failure; Risk Factors; Wounds and Injuries
PubMed: 27894496
DOI: 10.1016/j.ccc.2016.08.006 -
Pediatric Critical Care Medicine : a... Mar 2017To summarize the epidemiology and outcomes of children with multiple organ dysfunction syndrome as part of the Eunice Kennedy Shriver National Institute of Child Health... (Review)
Review
OBJECTIVE
To summarize the epidemiology and outcomes of children with multiple organ dysfunction syndrome as part of the Eunice Kennedy Shriver National Institute of Child Health and Human Development multiple organ dysfunction syndrome workshop (March 26-27, 2015).
DATA SOURCES
Literature review, research data, and expert opinion.
STUDY SELECTION
Not applicable.
DATA EXTRACTION
Moderated by an experienced expert from the field, issues relevant to the epidemiology and outcomes of children with multiple organ dysfunction syndrome were presented, discussed, and debated with a focus on identifying knowledge gaps and research priorities.
DATA SYNTHESIS
Summary of presentations and discussion supported and supplemented by the relevant literature.
CONCLUSIONS
A full understanding the epidemiology and outcome of multiple organ dysfunction syndrome in children is limited by inconsistent definitions and populations studied. Nonetheless, pediatric multiple organ dysfunction syndrome is common among PICU patients, occurring in up to 57% depending on the population studied; sepsis remains its leading cause. Pediatric multiple organ dysfunction syndrome leads to considerable short-term morbidity and mortality. Long-term outcomes of multiple organ dysfunction syndrome in children have not been well studied; however, studies of adults and children with other critical illnesses suggest that the risk of long-term adverse sequelae is high. Characterization of the long-term outcomes of pediatric multiple organ dysfunction syndrome is crucial to identify opportunities for improved treatment and recovery strategies that will improve the quality of life of critically ill children and their families. The workshop identified important knowledge gaps and research priorities intended to promote the development of standard definitions and the identification of modifiable factors related to its occurrence and outcome.
Topics: Child; Critical Care; Critical Illness; Global Health; Humans; Incidence; Intensive Care Units, Pediatric; Multiple Organ Failure; Prevalence; Risk Factors; Treatment Outcome
PubMed: 28248829
DOI: 10.1097/PCC.0000000000001047