The effect of extracorporeal blood purification on clinical outcomes in sepsis is assumed to be related to modulation of plasma cytokine concentrations. To test this hypothesis directly, we treated rats that had a cecal ligation followed by puncture (a standard model of sepsis) with a modest dose of extracorporeal blood purification that did not result in acute changes in a panel of common cytokines associated with inflammation (TNF-α, IL-1β, IL-6, and IL-10). Pre- and immediate post-treatment levels of these cytokines were unchanged compared to the sham therapy of extracorporeal circulation without blood purifying sorbent. The overall survival to 7 days, however, was significantly better in animals that received extracorporeal blood purification compared to those with a sham procedure. This panel of common plasma cytokines along with alanine aminotransferase and creatinine was significantly lower 72 h following extracorporeal blood purification compared to sham-treated rats. Thus, the effects of this procedure on organ function and survival do not appear to be due solely to immediate changes in the usual measured circulating cytokines. These results may have important implications for the design and conduct of future trials in sepsis including defining alternative targets for extracorporeal blood purification and other therapies.
Objective To compare the acute effects of 0.9% saline versus a balanced electrolyte solution on acute kidney injury in a rat model of sepsis. Design Controlled laboratory experiment. Setting University laboratory. Subjects Sixty adult, male Sprague-Dawley rats. Interventions We induced sepsis by cecal ligation and puncture and randomized animals to receive fluid resuscitation with either 0.9% saline or Plasma-Lyte solution for 4 hours after 18 hours of cecal ligation and puncture (10 mL/kg in the first hour and 5 mL/kg in the next 3 hr). Blood and urine specimens were obtained from baseline, 18 hours after cecal ligation and puncture, immediately after 4 hours fluid resuscitation, and 24 hours later. We measured blood gas, plasma electrolytes, creatinine, interleukin-6, cystatin C, and neutrophil gelatinase-associated lipocalin concentrations. We also analyzed urine for cystatin C and neutrophil gelatinase-associated lipocalin. We used Risk, Injury, Failure, Loss and End-stage criteria for creatinine to assess severity of acute kidney injury. We observed all animals for survival up to 1 day after resuscitation. Surviving animals were killed for kidney histology. Finally, we carried out an identical study in 12 healthy animals. Measurements and Main Results Compared with Plasma-Lyte, 0.9% saline resuscitation resulted in significantly greater blood chloride concentrations (p < 0.05) and significantly decreased pH and base excess. Acute kidney injury severity measured by RIFLE criteria was increased with 0.9% saline compared with Plasma-Lyte resuscitation (p < 0.05), and these results were consistent with kidney histology and biomarkers of acute kidney injury. Twenty-four-hour survival favored Plasma-Lyte resuscitation (76.6% vs 53.3%; p = 0.03). Finally, in healthy animals, we found no differences between fluids and no evidence of acute kidney injury. Conclusion Volume resuscitation with Plasma-Lyte resulted in less acidosis and less kidney injury and improved short-term survival when compared with 0.9% saline in this experimental animal model of sepsis.
Acute kidney injury (AKI) and acute lung injury (ALI) represent serious, complex clinical problems. The combination of AKI and ALI drastically decreases survival. However, detailed knowledge about the interactions between these two organs is scarce. We used two different models of AKI together with P. aeruginosa inhalation to study kidney-lung cross-talk in mice during AKI and bacterial pneumonia. AKI was induced by folic-acid injections or by myohemoglobinuria following i.m. injection of glycerol. To characterize pneumonia, we measured O2-saturation, colony-forming units in lung homogenates, and neutrophil (PMN) recruitment. Plasma creatinine and cystatin C concentrations served to quantify AKI. We also examined lung and kidney histology as well as PMN transmigration and F-actin polymerization. Sub-groups of mice received anti-PMN-antibody or platelet-depleting serum to assess the role of PMN and platelets, respectively. AKI by itself did not cause clinically-relevant ALI. P. aeruginosa-induced pneumonia was PMN-dependent, whereas pneumonia-induced AKI was platelet-dependent. AKI attenuated pulmonary PMN recruitment during pneumonia and worsened pneumonia. Mice with AKI had lower O2-saturations and greater bacterial load than mice without it. PMN from mice with FA-induced AKI also had impaired transmigration and F-actin polymerization in vitro. Our data demonstrate clinically-relevant kidney-lung interactions during AKI and pneumonia, that depend both PMN and platelets.
Sepsis is one of the main causes of death in critically ill patients. The pathophysiology of sepsis is complex and not completely understood. The proinflammatory and anti-inflammatory response leads to cell and organ dysfunction and, in many cases, death. Thus, the goal of the intervention is to restore the homeostasis of circulating mediators rather than to inhibit selectively the proinflammatory or anti-inflammatory mediators. Blood purification has been reported to remove a wide array of inflammatory mediators. The effects are broad-spectrum and auto-regulating. Blood purification has also been demonstrated to restore immune function through improving antigen-presenting capability, adjusting leukocyte recruitment, oxidative burst and phagocytosis, and improving leukocyte responsiveness. A great deal of work has to be done in order to find and optimize the best extracorporeal blood purification therapy for sepsis. New devices specifically target the pathophysiological mechanisms involved in these conditions. High-volume hemofiltration, hemoadsorption, coupled plasma filtration adsorption, and high cutoff membrane are now being tested in septic patients. Preliminary data indicate the feasibility of these modified techniques in sepsis. Their impact on patient prognosis, however, still needs proof by large randomized clinical trials. Finally, the emerging paradigm of sepsis-induced immune suppression provides additional rationale for the development of extracorporeal blood purification therapy for sepsis.
IntroductionPrior work suggests that leukocyte trafficking is determined by local chemokine gradients between the nidus of infection and the plasma. We recently demonstrated that therapeutic apheresis can alter immune mediator concentrations in the plasma, protect against organ injury, and improve survival. Here we aimed to determine whether the removal of chemokines from the plasma by apheresis in experimental peritonitis changes chemokine gradients and subsequently enhances leukocyte localization into the infected compartment, and away from healthy tissues.MethodsIn total, 76 male adult Sprague–Dawley rats weighing 400 g to 600 g were included in this study. Eighteen hours after inducing sepsis by cecal ligation and puncture, we randomized these rats to apheresis or sham treatment for 4 hours. Cytokines, chemokines, and leukocyte counts from blood, peritoneal cavity, and lung were measured. In a separate experiment, we labeled neutrophils from septic donor animals and injected them into either apheresis or sham-treated animals. All numeric data with normal distributions were compared with one-way analysis of variance, and numeric data not normally distributed were compared with the Mann–Whitney U test.ResultsApheresis significantly removed plasma cytokines and chemokines, increased peritoneal fluid-to-blood chemokine (C-X-C motif ligand 1, ligand 2, and C-C motif ligand 2) ratios, and decreased bronchoalveolar lavage fluid-to-blood chemokine ratios, resulting in enhanced leukocyte recruitment into the peritoneal cavity and improved bacterial clearance, but decreased recruitment into the lung. Apheresis also reduced myeloperoxidase activity and histologic injury in the lung, liver, and kidney. These Labeled donor neutrophils exhibited decreased localization in the lung when infused into apheresis-treated animals.ConclusionsOur results support the concept of chemokine gradient control of leukocyte trafficking and demonstrate the efficacy of apheresis to target this mechanism and reduce leukocyte infiltration into the lung.
Objective To explore the relationships between bactericidal antimicrobial treatment of sepsis, inflammatory response, severity of AKI, and outcomes. Design Controlled laboratory experiment. Setting University laboratory. Interventions Sepsis was induced by cecal ligation and puncture (CLP) in 52 rats and was treated with either bactericidal antibiotics (ampicillin/sulbactam) or placebo (saline). Serial blood specimens were obtained after CLP for serum creatinine, interleukin (IL)-6, and neutrophil gelatinase-associated lipocalin (NGAL) concentrations. RIFLE criteria were used to assess severity of AKI. All animals were observed for survival up to one week. In a separate experiment, 6 healthy animals were given antibiotics and renal function was assessed. Another 12 animals were sacrificed 2 days after laparotomy for kidney histology. Measurements and Main Results Survival in the placebo group was 50% compared to 81.8% in the antibiotic group (P <0.05). Most animals (93%) without antibiotics developed AKI, of which 39% exhibited greater than a 3-fold rise in serum creatinine (RIFLE-F). Furthermore survival decreased as AKI severity increased. Surprisingly, all antibiotic-treated animals developed AKI, of which 68.6% reached RIFLE-F. However, renal dysfunction was less persistent in these animals. Patterns of plasma IL-6 were similar to creatinine with higher concentrations seen earlier in antibiotic-treated animals but with faster resolution. IL-6 concentration at 24 hrs was independently associated with the development of RIFLE-F. Histological findings were consistent with functional parameters showing that antibiotics worsened AKI. Conclusion In polymicrobial sepsis bactericidal antibiotics resulted in more inflammation and more severe AKI. However, resolution of inflammation and AKI was faster with antibiotics and correlated best with survival. These results suggest that transient worsening of renal function may be an expected consequence of sepsis therapy. These findings also question the value of peak severity of AKI as a primary endpoint and suggest that resolution of AKI may be more appropriate.
For older people with disabilities environmental design will become increasingly important to their quality of life as they expect supportive structures within community settings to facilitate their functioning, independence and well-being. This paper reports on photovoice research to amplify the issues one older woman with mobility limitations as a result of visual and neurological challenges experienced in a small city located in the south central part of the USA. The use of photovoice to illuminate these issues was one substudy of a larger scale project focusing on positive aging in this small city, the home to a large state-assisted university. The authors, which includes Linda, the principal photovoice researcher, offer a rationale guiding photovoice, describe the photovoice method the participatory research model incorporated, identify the environmental inequities the participant experienced in her community and immediate living situation, and document the affordances she developed to support her mobility, safety and quality of life. The authors then discuss how a community exhibit supported dissemination of the participant's photovoice content to the general community, and the outcomes the participant experienced in the form of empowerment and environmental enhancements ensuing from the combined influence of photovoice and community-based dissemination of her findings.
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