Endothelial cells line the inner portion of the heart, blood vessels, and lymphatic vessels; a basal membrane of extracellular matrix lines the extraluminal side of endothelial cells. The apical side of endothelial cells is the site for the glycocalyx, which is a complex network of macromolecules, including cell-bound proteoglycans and sialoproteins. Sepsis-associated alterations of this structure may compromise endothelial permeability with associated interstitial fluid shift and generalized edema. Indeed, in sepsis, the glycocalyx acts as a target for inflammatory mediators and leukocytes, and its ubiquitous nature explains the damage of tissues that occurs distant from the original site of infection. Inflammatory-mediated injury to glycocalyx can be responsible for a number of specific clinical effects of sepsis, including acute kidney injury, respiratory failure, and hepatic dysfunction. Moreover, some markers of glycocalyx degradation, such as circulating levels of syndecan or selectins, may be used as markers of endothelial dysfunction and sepsis severity. Although a great deal of experimental evidence shows that alteration of glycocalyx is widely involved in endothelial damage caused by sepsis, therapeutic strategies aiming at preserving its integrity did not significantly improve the outcome of these patients.
Low-dose hydrocortisone seems to reduce MACR and serum C-reactive protein but not procalcitonin in patients with severe sepsis. Further studies are needed to confirm these results and to understand the underlying molecular mechanisms.
The present study shows that a) during aortic surgery, the genes for interleukin-6 and for the components of the local renin-angiotensin system (angiotensinogen, angiotensin-converting enzyme, and angiotensin type 1 receptor subtype) are activated early in the ischemic muscle, and activation persists during reperfusion; b) interleukin-6 plasma concentration increases only in patients with tissue ischemia (aortic abdominal aneurysm), whereas no changes are detectable in patients with abdominal surgery; and finally c) the occurrence of systemic inflammatory reaction with increased interleukin-6 plasma concentrations is followed by impaired pulmonary function.
Post-operative patients developing sepsis, unlike those with an uncomplicated postoperative evolution, showed an increase in glomerular permeability which was revealed by MACR. The increase in the MACR was positively correlated to the increase in SOFA score, while it had no relation to the PaO2/FIO2 ratio.
IntroductionIncreased vascular permeability represents one of the hallmarks of sepsis. In the kidney, vascular permeability is strictly regulated by the 'glomerular filtration barrier' (GFB), which is comprised of glomerular endothelium, podocytes, their interposed basement membranes and the associated glycocalyx. Although it is likely that the GFB and its glycocalyx are altered during sepsis, no study has specifically addressed this issue. The aim of this study was to evaluate whether albuminuria -- the hallmark of GFB perm-selectivity -- occurs in the initial stage of sepsis and whether it is associated with morphological and biochemical changes of the GFB.MethodsCecal ligation and puncture (CLP) was used to induce sepsis in the rat. Tumor necrosis factor (TNF)-alpha levels in plasma and growth of microorganisms in the peritoneal fluid were evaluated at 0, 3 and 7 hours after CLP or sham-operation. At the same times, kidney specimens were collected and structural and ultrastructural alterations in the GFB were assessed. In addition, several components of GFB-associated glycocalyx, syndecan-1, hyluronan (HA) and sialic acids were evaluated by immunofluorescence, immunohistochemistry and lectin histochemistry techniques. Serum creatinine and creatinine clearance were measured to assess kidney function and albuminuria for changes in GFB permeability. Analysis of variance followed by Tukey's multiple comparison test was used.ResultsSeptic rats showed increased TNF-alpha levels and growth of microorganisms in the peritoneal fluid. Only a few renal corpuscles had major ultrastructural and structural alterations and no change in serum creatinine or creatinine clearance was observed. Contrarily, urinary albumin significantly increased after CLP and was associated with diffuse alteration in the glycocalyx of the GFB, which consisted in a decrease in syndecan-1 expression and in HA and sialic acids contents. Sialic acids were also changed in their structure, exhibiting a higher degree of acetylation.ConclusionsIn its initial phase, sepsis is associated with a significant alteration in the composition of the GFB-associated glycocalyx, with loss of GFB perm-selectivity as documented by albumin leakage into urine.
The more favourable pharmacokinetic profile of imipenem compared with meropenem in critically ill patients with sepsis might balance the possibly greater potency demonstrated in vitro for meropenem against Gram-negative strains. Hence, the clinical efficacy of the two carbapenems depends mostly on their correct dosage.
Propofol (2,6-diisopropylphenol) is one of the most popular agents used for induction of anesthesia and long-term sedation, owing to its favorable pharmacokinetic profile, which ensures a rapid recovery even after prolonged administration. A neuroprotective effect, beyond that related to the decrease in cerebral metabolic rate for oxygen, has been shown to be present in many in vitro and in vivo established experimental models of mild/moderate acute cerebral ischemia. Experimental studies on traumatic brain injury are limited and less encouraging. Despite the experimental results and the positive effects on cerebral physiology (propofol reduces cerebral blood flow but maintains coupling with cerebral metabolic rate for oxygen and decreases intracranial pressure, allowing optimal intraoperative conditions during neurosurgical operations), no clinical study has yet indicated that propofol may be superior to other anesthetics in improving the neurological outcome following acute cerebral injury. Therefore, propofol cannot be indicated as an established clinical neuroprotectant per se, but it might play an important role in the so-called multimodal neuroprotection, a global strategy for the treatment of acute injury of the brain that includes preservation of cerebral perfusion, temperature control, prevention of infections, and tight glycemic control.
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