Pediatr Crit Care Me
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Pediatr Crit Care Me · Mar 2017
ReviewPathophysiology of Pediatric Multiple Organ Dysfunction Syndrome.
To describe the pathophysiology associated with multiple organ dysfunction syndrome in children. ⋯ Experiment modeling suggests that persistent macrophage activation may be a pathophysiologic basis for multiple organ dysfunction syndrome. Children with multiple organ dysfunction syndrome have 1) reduced cytochrome P450 metabolism inversely proportional to inflammation; 2) increased circulating damage-associated molecular pattern molecules from injured tissues; 3) increased circulating pathogen-associated molecular pattern molecules from infection or endogenous microbiome; and 4) cytokine-driven epithelial, endothelial, mitochondrial, and immune cell dysfunction. Cytochrome P450s metabolize endogenous compounds and xenobiotics, many of which ameliorate inflammation, whereas damage-associated molecular pattern molecules and pathogen-associated molecular pattern molecules alone and together amplify the cytokine production leading to the inflammatory multiple organ dysfunction syndrome response. Genetic and environmental factors can impede inflammation resolution in children with a spectrum of multiple organ dysfunction syndrome pathobiology phenotypes. Thrombocytopenia-associated multiple organ dysfunction syndrome patients have extensive endothelial activation and thrombotic microangiopathy with associated oligogenic deficiencies in inhibitory complement and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13. Sequential multiple organ dysfunction syndrome patients have soluble Fas ligand-Fas-mediated hepatic failure with associated oligogenic deficiencies in perforin and granzyme signaling. Immunoparalysis-associated multiple organ dysfunction syndrome patients have impaired ability to resolve infection and have associated environmental causes of lymphocyte apoptosis. These inflammation phenotypes can lead to macrophage activation syndrome. Resolution of multiple organ dysfunction syndrome requires elimination of the source of inflammation. Full recovery of organ functions is noted 6-18 weeks later when epithelial, endothelial, mitochondrial, and immune cell regeneration and reprogramming is completed.
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Pediatr Crit Care Me · Mar 2017
ReviewPathophysiology of the Gut and the Microbiome in the Host Response.
To describe and summarize the data supporting the gut as the motor driving critical illness and multiple organ dysfunction syndrome presented at the National Institute of Child Health and Human Development MODS Workshop (March 26-27, 2015). ⋯ The understanding of gut dysfunction in critical illness has evolved greatly over time, and the gut is now often considered as the "motor" of critical illness. The association of the gut with critical illness is supported by both animal models and clinical studies. Initially, the association between gut dysfunction and critical illness focused primarily on bacterial translocation into the bloodstream. However, that work has evolved to include other gut-derived products causing distant injury via other routes (e.g., lymphatics). Additionally, alterations in the gut epithelium may be associated with critical illness and influence outcomes. Gut epithelial apoptosis, intestinal hyperpermeability, and perturbations in the intestinal mucus layer have all been associated with critical illness. Finally, there is growing evidence that the intestinal microbiome plays a crucial role in mediating pathology in critical illness. Further research is needed to better understand the role of each of these mechanisms and their contribution to multiple organ dysfunction syndrome in children.