-
Contributions To Nephrology 2023Major trauma care has seen significant improvements in early mortality, reflecting improvements in prehospital techniques for hemorrhage control and speed of access to... (Review)
Review
Major trauma care has seen significant improvements in early mortality, reflecting improvements in prehospital techniques for hemorrhage control and speed of access to specialized trauma centers. However, many patients then go on to die in the intensive care unit (ICU), and improvements in immediate trauma care are presenting intensivists with greater numbers of severely injured patients who might previously have died shortly after injury. It is theorized that, despite initial survival, these patients deteriorate due to massive release of damage associated molecular patterns (DAMPs) after traumatic and ischemic tissue injury. These trigger a vicious cycle of overactive pro- and anti-inflammatory pathways, leading to organ dysfunction and immunoparesis. Extracorporeal hemoperfusion, with its ability to adsorb both DAMPs and inflammatory mediators from the bloodstream, has the potential to break this cycle and could, in theory, then prevent early death or organ dysfunction in the ICU. However, currently, there has been little research around the indications for, and efficacy of, this therapy in the setting of polytrauma. Here we outline potential molecular targets, summarize existing exploratory studies, and suggest areas for future research required to establish the benefits of hemoperfusion as an adjunct therapy in major polytrauma.
Topics: Humans; Multiple Organ Failure; Hemoperfusion; Multiple Trauma; Hemorrhage
PubMed: 37263242
DOI: 10.1159/000527570 -
Critical Care Clinics Apr 2020Thrombocytopenia-associated multiple organ failure is a clinical phenotype encompassing a spectrum of syndromes associated with disseminated microvascular thromboses.... (Review)
Review
Thrombocytopenia-associated multiple organ failure is a clinical phenotype encompassing a spectrum of syndromes associated with disseminated microvascular thromboses. Autopsies performed in patients that died with thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, or disseminated intravascular coagulation reveal specific findings that can differentiate these 3 entities. Significant advancements have been made in our understanding of the pathologic mechanisms of these syndromes. Von Willebrand factor and ADAMTS-13 play a central role in thrombotic thrombocytopenic purpura. Shiga toxins and the complement pathway drive the hemolytic uremic syndrome pathology. Tissue factor activity is vital in the development of disseminated intravascular coagulation.
Topics: Disseminated Intravascular Coagulation; Genetic Predisposition to Disease; Hemolytic-Uremic Syndrome; Humans; Multiple Organ Failure; Phenotype; Plasma Exchange; Thrombocytopenia
PubMed: 32172819
DOI: 10.1016/j.ccc.2019.12.010 -
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 -
Expert Review of Respiratory Medicine Sep 2020
Topics: Betacoronavirus; COVID-19; Coronavirus Infections; Global Health; Humans; Incidence; Multiple Organ Failure; Pandemics; Pneumonia, Viral; SARS-CoV-2; Survival Rate
PubMed: 32567404
DOI: 10.1080/17476348.2020.1778470 -
Contributions To Nephrology 2023Sepsis is a life-threatening syndrome initiated by a dysregulated host response to infection. Maladaptive inflammatory burst damages host tissues and causes organ... (Review)
Review
Sepsis is a life-threatening syndrome initiated by a dysregulated host response to infection. Maladaptive inflammatory burst damages host tissues and causes organ dysfunction, the burden of which has been demonstrated as the paramount predictor of worse clinical outcomes. In this setting, septic shock represents the most lethal complication of sepsis and implies profound alterations of both the cardiovascular system and cellular metabolism with consequent high mortality rate. Although an increasing amount of evidence attempts to characterize this clinical condition, the complexity of multiple interconnections between underlying pathophysiological pathways requires further investigations. Accordingly, most therapeutic interventions remain purely supportive and should be integrated in light of the continuous organ cross-talk, in order to match a patient's specific needs. In this context, different organ supports may be combined to replace multiple organ dysfunctions through the application of sequential extracorporeal therapy in sepsis (SETS). In this chapter, we provide an overview of sepsis-induced organ dysfunction, focusing on the pathophysiological pathways that are triggered by endotoxin. Based on the need to apply specific blood purification techniques in specific time windows with different targets, we suggest a sequence of extracorporeal therapies. Accordingly, we reported the hypothesis that sepsis-induced organ dysfunction may benefit the most from SETS. Finally, we point out basic principles of this innovative approach and describe a multifunctional platform that allows SETS, in order to make clinicians aware of this new therapeutic frontier for critically ill patients.
Topics: Humans; Multiple Organ Failure; Sepsis; Shock, Septic; Critical Illness; Syndrome
PubMed: 37290408
DOI: 10.1159/000527573 -
Anesthesia and Analgesia Dec 2020Despite substantial advances in anesthesia safety within the past decades, perioperative mortality remains a prevalent problem and can be considered among the top causes... (Review)
Review
Despite substantial advances in anesthesia safety within the past decades, perioperative mortality remains a prevalent problem and can be considered among the top causes of death worldwide. Acute organ failure is a major risk factor of morbidity and mortality in surgical patients and develops primarily as a consequence of a dysregulated inflammatory response and insufficient tissue perfusion. Neurological dysfunction, myocardial ischemia, acute kidney injury, respiratory failure, intestinal dysfunction, and hepatic impairment are among the most serious complications impacting patient outcome and recovery. Pre-, intra-, and postoperative arrangements, such as enhanced recovery after surgery programs, can contribute to lowering the occurrence of organ dysfunction, and mortality rates have improved with the advent of specialized intensive care units and advances in procedures relating to extracorporeal organ support. However, no specific pharmacological therapies have proven effective in the prevention or reversal of perioperative organ injury. Therefore, understanding the underlying mechanisms of organ dysfunction is essential to identify novel treatment strategies to improve perioperative care and outcomes for surgical patients. This review focuses on recent knowledge of pathophysiological and molecular pathways leading to perioperative organ injury. Additionally, we highlight potential therapeutic targets relevant to the network of events that occur in clinical settings with organ failure.
Topics: Acute Kidney Injury; Heart Diseases; Humans; Liver Diseases; Multiple Organ Failure; Perioperative Care; Postoperative Complications; Risk Factors
PubMed: 33186161
DOI: 10.1213/ANE.0000000000005191 -
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 -
United European Gastroenterology Journal Mar 2021
Topics: Disease Progression; Humans; Multiple Organ Failure; Pancreatitis; Risk Factors
PubMed: 33871927
DOI: 10.1002/ueg2.12056 -
FEBS Letters Aug 2020Sepsis as life-threatening organ dysfunction caused by microorganisms represents a dreadful challenge for the immune system. The role of the complement system as major... (Review)
Review
Sepsis as life-threatening organ dysfunction caused by microorganisms represents a dreadful challenge for the immune system. The role of the complement system as major column of innate immunity has been extensively studied in various sepsis models, but its translational value remains in the dark. Complement activation products, such as C3a and C5a, and their corresponding receptors provide useful diagnostic tools and promising targets to improve organ function and outcome. However, a monotherapeutic complement intervention irrespective of the current immune function seems insufficient to reverse the complex sepsis mechanisms. Indeed, sepsis-induced disturbances of cross talking complement, coagulation, and fibrinolytic cascades lead to systemic 'thromboinflammation', ultimately followed by multiple-organ failure. We propose to reliably monitor the complement function in the patient and to re-establish the immune balance by patient-tailored combined therapies, such as complement and Toll-like receptor inhibition. Our working hypothesis aims at blocking the 'explosive' innate immune recognition systems early on before downstream mediators are released and the inflammatory response becomes irreversible, a strategy that we name 'upstream approach'.
Topics: Animals; Complement Activation; Complement C3a; Complement C5a; Humans; Multiple Organ Failure; Sepsis
PubMed: 32621378
DOI: 10.1002/1873-3468.13881 -
Military Medical Research Oct 2023Hypoxic-ischemic injury is a common pathological dysfunction in clinical settings. Mitochondria are sensitive organelles that are readily damaged following ischemia and... (Review)
Review
Hypoxic-ischemic injury is a common pathological dysfunction in clinical settings. Mitochondria are sensitive organelles that are readily damaged following ischemia and hypoxia. Dynamin-related protein 1 (Drp1) regulates mitochondrial quality and cellular functions via its oligomeric changes and multiple modifications, which plays a role in mediating the induction of multiple organ damage during hypoxic-ischemic injury. However, there is active controversy and gaps in knowledge regarding the modification, protein interaction, and functions of Drp1, which both hinder and promote development of Drp1 as a novel therapeutic target. Here, we summarize recent findings on the oligomeric changes, modification types, and protein interactions of Drp1 in various hypoxic-ischemic diseases, as well as the Drp1-mediated regulation of mitochondrial quality and cell functions following ischemia and hypoxia. Additionally, potential clinical translation prospects for targeting Drp1 are discussed. This review provides new ideas and targets for proactive interventions on multiple organ damage induced by various hypoxic-ischemic diseases.
Topics: Humans; Dynamins; Hypoxia; Ischemia; Mitochondria; Multiple Organ Failure
PubMed: 37833768
DOI: 10.1186/s40779-023-00482-8