Shock : molecular, cellular, and systemic pathobiological aspects and therapeutic approaches : the official journal the Shock Society, the European Shock Society, the Brazilian Shock Society, the International Federation of Shock Societies
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Despite widespread use, there is currently no consensus on how extracorporeal blood purification therapies should be applied or studied in patients with sepsis. One major obstacle has been the lack of clear descriptions of specific sepsis phenotypes tied to mechanisms that would permit the identification of molecular targets. Current evidence suggests that sepsis-related morbidity and mortality involve widely different clinical phenotypes that variably include mitochondrial dysfunction, abnormalities of vascular biology including endothelial dysfunction and coagulopathy, epithelial dysfunction, and immune suppression and dysregulation. ⋯ Thus, the purpose of the fourteenth international consensus conference of acute dialysis quality initiative was to develop consensus for a conceptual model of sepsis-induced organ failure that can be treated by extracorporeal blood purification and possibly also with drugs or other therapies. We assembled a group of experts from around the world and used a modified Delphi method to reach consensus. Specific findings and recommendations for future research are provided in the four accompanying papers.
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Sepsis affects practically all aspects of endothelial cell (EC) function and is thought to be the key factor in the progression from sepsis to organ failure. Endothelial functions affected by sepsis include vasoregulation, barrier function, inflammation, and hemostasis. These are among other mechanisms often mediated by glycocalyx shedding, such as abnormal nitric oxide metabolism, up-regulation of reactive oxygen species generation due to down-regulation of endothelial-associated antioxidant defenses, transcellular communication, proteases, exposure of adhesion molecules, and activation of tissue factor. ⋯ In this context, we discuss the response of the endothelial cell lining to sepsis in the kidney, liver, and lung. Finally, we discuss evidence as to whether the EC response to sepsis is adaptive or maladaptive. This study is a result of an Acute Dialysis Quality Initiative XIV Sepsis Workgroup meeting held in Bogota, Columbia, between October 12 and 15, 2014.
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Mitochondria are an essential part of the cellular infrastructure, being the primary site for high-energy adenosine triphosphate production through oxidative phosphorylation. Clearly, in severe systemic inflammatory states, like sepsis, cellular metabolism is usually altered, and end organ dysfunction is not only common, but also predictive of long-term morbidity and mortality. ⋯ In this review, the authors address five primary questions centered on the role of mitochondria in sepsis. This review should be used both as a summary source in placing mitochondrial physiology within the context of acute illness and as a focal point for addressing new research into diagnostic and treatment opportunities these insights provide.
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Organ dysfunction induced by sepsis has been consistently associated with worse outcome and death. Regardless of the organ compromised, epithelial dysfunction is present throughout the body, affecting those organs that contain epithelia like the skin, lungs, liver, gut, and kidneys. ⋯ Epithelial injury in this context is not only an explanatory real pathophysiologic event, but also represents a source of biomarkers that have been explored to identify organ compromise earlier, predict outcome, and even to test novel therapeutic interventions such as blood purification. However, this remains largely experimental, and despite promising results, work is still required to better understand the response of the epithelial cells to sepsis, to define their role in adaptation to insults, to comprehend the interorgan cross-talk that occurs in these circumstances, and to exploit these aspects in pursuit of targeted therapies like blood purification, which may improve outcome for these patients in the future.
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Cells of the innate and adaptive immune systems play a critical role in the host response to sepsis. Moreover, their accessibility for sampling and their capacity to respond dynamically to an acute threat increases the possibility that leukocytes might serve as a measure of a systemic state of altered responsiveness in sepsis. The working group of the 14th Acute Dialysis Quality Initiative (ADQI) conference sought to obtain consensus on the characteristic functional and phenotypic changes in cells of the innate and adaptive immune system in the setting of sepsis. ⋯ Regarding adaptive immunity, sepsis-induced apoptosis leads to lymphopenia in patients with septic shock and it involves all types of T cells (CD4, CD8, and Natural Killer) except T regulatory cells, thus favoring immunosuppression. Finally, numerous promising therapies targeting the host immune response to sepsis are under investigation. These potential treatments can have an effect on the number of immune cells, the proportion of cell subtypes, and the cell function.