Normal saline resuscitation worsens lactic acidosis in experimental sepsis

It is well established that infusing large amounts of normal saline causes hyperchloremic acidosis, yet the clinical relevance of this is unknown.\ud \ud We found that infusion of normal saline, compared with a balanced crystalloid, worsens lactic acidosis in experimental sepsis

Leukocyte capture and modulation of cell-mediated immunity during human sepsis: An ex vivo study

Introduction: Promising preclinical results have been obtained with blood purification therapies as adjuvant treatment for sepsis. However, the mechanisms by which these therapies exert beneficial effects remain unclear. Some investigators have suggested that removal of activated leukocytes from the circulation might help ameliorate remote organ injury. We designed an extracorporeal hemoadsorption device capable of capturing both cytokines and leukocytes in order to test the hypothesis that leukocyte capture would alter circulating cytokine profiles and influence immunological cell-cell interactions in whole blood taken from patients with sepsis.Methods: We performed a series of ex vivo studies in 21 patients with septic shock and 12 healthy volunteers. Blood circulated for four hours in closed loops with four specially designed miniaturized extracorporeal blood purification devices including two different hemoadsorption devices and a hemofilter in order to characterize leukocyte capture and to assess the effects of leukocyte removal on inflammation and immune function. Results: Hemoadsorption was selective for removal of activated neutrophils and monocytes. Capture of these cells led to local release of certain cytokines, especially IL-8, and resulted in complex cell-cell interactions involved in cellmediated immunity. Inhibition of cell adherence reversed the cytokine release and the effects on lymphocyte function. Conclusions: Monocyte and neutrophil capture using a sorbent polymer results in upregulation of IL-8 and modulation of cell-mediated immunity. Further studies are needed to understand better these cellular interactions in order to help design better blood purification therapies. © 2013 Rimmelé et al.; licensee BioMed Central Ltd

Modulation of chemokine gradients by apheresis redirects leukocyte trafficking to different compartments during sepsis, studies in a rat model

Introduction: Prior 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.Methods: In 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.Results: Apheresis 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.Conclusions: Our 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. © 2014 Peng et al

Urine/Plasma Neutrophil Gelatinase Associated Lipocalin Ratio Is a Sensitive and Specific Marker of Subclinical Acute Kidney Injury in Mice

Background Detection of acute kidney injury (AKI) is still a challenge if conventional markers of kidney function are within reference range. We studied the sensitivity and specificity of NGAL as an AKI marker at different degrees of renal ischemia. Methods Male C57BL/6J mice were subjected to 10-, 20- or 30-min unilateral renal ischemia, to control operation or no operation, and AKI was evaluated 1 day later by histology, immunohistochemistry, BUN, creatinine, NGAL (plasma and urine) and renal NGAL mRNA expression. Results A short (10-min) ischemia did not alter BUN or kidney histology, but elevated plasma and urinary NGAL level and renal NGAL mRNA expression although to a much smaller extent than longer ischemia. Surprisingly, control operation elevated plasma NGAL and renal NGAL mRNA expression to a similar extent as 10-min ischemia. Further, the ratio of urine to plasma NGAL was the best parameter to differentiate a 10-min ischemic injury from control operation, while it was similar in the non and control-operated groups. Conclusions These results suggest that urinary NGAL excretion and especially ratio of urine to plasma NGAL are sensitive and specific markers of subclinical acute kidney injury in mice

Is exposure to formaldehyde in air causally associated with leukemia?—A hypothesis-based weight-of-evidence analysis

Recent scientific debate has focused on the potential for inhaled formaldehyde to cause lymphohematopoietic cancers, particularly leukemias, in humans. The concern stems from certain epidemiology studies reporting an association, although particulars of endpoints and dosimetry are inconsistent across studies and several other studies show no such effects. Animal studies generally report neither hematotoxicity nor leukemia associated with formaldehyde inhalation, and hematotoxicity studies in humans are inconsistent. Formaldehyde's reactivity has been thought to preclude systemic exposure following inhalation, and its apparent inability to reach and affect the target tissues attacked by known leukemogens has, heretofore, led to skepticism regarding its potential to cause human lymphohematopoietic cancers. Recently, however, potential modes of action for formaldehyde leukemogenesis have been hypothesized, and it has been suggested that formaldehyde be identified as a known human leukemogen. In this article, we apply our hypothesis-based weight-of-evidence (HBWoE) approach to evaluate the large body of evidence regarding formaldehyde and leukemogenesis, attending to how human, animal, and mode-of-action results inform one another. We trace the logic of inference within and across all studies, and articulate how one could account for the suite of available observations under the various proposed hypotheses. Upon comparison of alternative proposals regarding what causal processes may have led to the array of observations as we see them, we conclude that the case fora causal association is weak and strains biological plausibility. Instead, apparent association between formaldehyde inhalation and leukemia in some human studies is better interpreted as due to chance or confounding