Glycocalyx and sepsis-induced alterations in vascular permeability

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

Changes in ceftriaxone pharmacokinetics/pharmacodynamics during the early phase of sepsis: a prospective, experimental study in the rat

Abstract Background Sepsis is characterized by the loss of the perm-selectivity properties of the glomerular filtration barrier (GFB) with consequent albuminuria. We examined whether the pharmacokinetics–pharmacodynamics (PK/PD) of ceftriaxone (CTX), an extensively protein-bound 3rd generation cephalosporin, is altered during early sepsis and whether an increase in urinary loss of bound-CTX, due to GFB alteration, can occur in this condition. Methods A prospective, experimental, randomized study was carried out in adult male Sprague–Dawley rats. Sepsis was induced by cecal ligation and puncture (CLP). Rats were divided into two groups: Sham-operated and CLP. CTX (100 mg i.p., equivalent to 1 g dose in humans) was administered in order to measure plasma and lung CTX concentrations at several time-points: baseline and 1, 2, 4 and 6 h after administration. CTX was measured by High Performance Liquid Chromatography (HPLC). The morphological status of the sialic components of the GFB barrier was assessed by lectin histo-chemistry. Monte Carlo simulation was performed to calculate the probability of target attainment (PTA >90%) for 80 and 100% of Tfree > minimum inhibitory concentration (MIC) for 80 and 100% of dosing interval. Measurements and main results After CLP, sepsis developed in rats as documented by the growth of polymicrobial flora in the peritoneal fluid (≤1 × 101 CFU in sham rats vs 5 × 104–1 × 105 CFU in CLP rats). CTX plasma concentrations were higher in CLP than in sham rats at 2 and 4 h after administration (difference at 2 h was 47.3, p = 0.012; difference at 4 h was 24.94, p = 0.004), while lung penetration tended to be lower. An increased urinary elimination of protein-bound CTX occurred (553 ± 689 vs 149 ± 128 mg/L, p < 0.05; % of bound/total CTX 22 ± 6 in septic rats vs 11 ± 4 in sham rats, p < 0.01) and it was associated with loss of the GFB sialic components. According to Monte Carlo simulation a PTA > 90% for 100% of the dosing interval was reached neither for sham nor CLP rats using MIC = 1 mg/L, the clinical breakpoint for Enterobacteriacee. Conclusions Sepsis causes changes in the PK of CTX and an alteration in the sialic components of the GFB, with consequent loss of protein-bound CTX. Among factors that can affect drug pharmacokinetics during the early phases of sepsis, urinary loss of both free and albumin–bound antimicrobials should be considered

Sialic acids and hyaluronan expression in the renal tubulointerstitial space of rat in an experimental sepsis model

Sialic acids and hyaluronan play important roles in maintaining structure and functionality of the kidney tubulointerstitial space. In several investigations, performed on some renal pathologies, morpho-functional changes of the tubulointerstitial space showed correlation with altered expression of these anionic components; no data are available on the expression of these molecules in this space during sepsis. Therefore, the aim of this study was to evaluate the expression of sialic acids and hyaluronan in the renal tubulointerstitial space in the early stages of an experimental animal model of polymicrobial sepsis. Experiments were performed on adult male rats assigned to two groups: 1) sham-operated (n=20); 2) Caecal Ligation and Puncture (CLP) (clinically model of polymicrobial infection that mimics human sepsis) (n=25). The groups were divided into 3 subgroups related to 3 time points after CLP or sham-operated: t1=0 h, t2=3 h and t3=7 h. For evidence of sepsis TNF-α plasma level was measured and microbiology of peritoneal fluid was examined with bacteriologic techniques. Urinary protein levels were measured to test the renal functional damage. Kidney samples of each group were processed to analyse the morphology, sialic acids expression, by using lectin histochemistry, and hyaluronan expression, by using immunohistochemistry. The results showed that plasma TNF-α level significantly increased after CLP induction when compared to sham-operated animals. Bacteriologic techniques revealed a polymicrobial infection after CLP. The proteinuria was significantly increased in CLP group. Morphological changes, such as edema and epithelial lesions, were observed in the tubulointerstitium space in CLP group. Lectin histochemistry showed decrease of sialic acids in the tubular wall of septic rats with respect to the control ones. The largest amount of acetylated sialic acid was evidenced in the sepsis group. Immunohistochemistry demonstrated hyaluronan presence only in the medullary interstitium in the control group; in the septic rats hyaluronan appeared also in the cortical interstitium and tubular wall. The findings indicate the existence of a correlation between sialic acids and hyaluronan altered expression and morpho-functional changes in the kidney tubulointerstitial space during sepsis. In addition, an important role of these anionic molecules in protection/ defence and repairing processes may be suggested

Some Suggestions from PK/PD Principles to Contain Resistance in the Clinical Setting—Focus on ICU Patients and Gram-Negative Strains

The containment of the phenomenon of resistance towards antimicrobials is a priority, especially in preserving molecules acting against Gram-negative pathogens, which represent the isolates more frequently found in the fragile population of patients admitted to Intensive Care Units. Antimicrobial therapy aims to prevent resistance through several actions, which are collectively known as &ldquo;antimicrobial stewardship&rdquo;, to be taken together, including the application of pharmacokinetic/pharmacodynamic (PK/PD) principles. PK/PD application has been shown to prevent the emergence of resistance in numerous experimental studies, although a straight translation to the clinical setting is not possible. Individualized antibiotic dosing and duration should be pursued in all patients, and even more especially when treating intensive care unit (ICU) septic patients in whom optimal exposure is both difficult to achieve and necessary. In this review, we report on the available data that support the application of PK/PD parameters to contain the development of resistance and we give some practical suggestions that can help to translate the benefit of PK/PD application to the bedside

Minimum anesthetic volume in regional anesthesia by using ultrasound-guidance

Abstract The ultrasound guidance in regional anesthesia ensures the visualization of needle placement and the spread of Local Anesthetics. Over the past few years there was a substantial interest in determining the Minimum Effective Anesthetic Volume necessary to accomplish surgical anesthesia. The precise and real-time visualization of Local Anesthetics spread under ultrasound guidance block may represent the best requisite for reducing Local Anesthetics dose and Local Anesthetics-related effects. We will report a series of studies that have demonstrated the efficacy of ultrasound guidance blocks to reduce Local Anesthetics and obtain surgical anesthesia as compared to block performed under blind or electrical nerve stimulation technique. Unfortunately, the results of studies are widely divergent and not seem to indicate a dose considered effective, for each block, in a definitive way; but it is true that, through the use of ultrasound guidance, it is possible to reduce the dose of anesthetic in the performance of anesthetic blocks

Volume mínimo de anestésico em anestesia regional guiada por ultrassom

ResumoO uso de ultrassom em anestesia regional permite visualizar a colocação da agulha e a propagação dos anestésicos locais.Nos últimos anos houve um grande interesse em determinar o volume mínimo eficaz de anestésico necessário para fazer a anestesia cirúrgica. A visualização precisa e em tempo real da difusão dos anestésicos locais com o uso de ultrassom pode ser o melhor requisito para reduzir a dose e os efeitos relacionados aos anestésicos locais.Revisamos uma série de estudos que relataram a eficácia de bloqueios guiados por ultrassom para reduzir o uso de anestésicos locais e obter anestesia cirúrgica, em comparação com bloqueios feitos com a técnica às cegas e de estimulação elétrica de nervos.Infelizmente, os resultados dos estudos são muito divergentes e não parecem indicar uma dose considerada eficaz para cada bloqueio de modo definitivo, mas é verdade que, com o auxílio do ultrassom, é possível reduzir a dose dos anestésicos em bloqueios.AbstractThe ultrasound guidance in regional anesthesia ensures the visualization of needle placement and the spread of Local Anesthetics.Over the past few years there was a substantial interest in determining the Minimum Effective Anesthetic Volume necessary to accomplish surgical anesthesia. The precise and real‐time visualization of Local Anesthetics spread under ultrasound guidance block may represent the best requisite for reducing Local Anesthetics dose and Local Anesthetics‐related effects.We will report a series of studies that have demonstrated the efficacy of ultrasound guidance blocks to reduce Local Anesthetics and obtain surgical anesthesia as compared to block performed under blind or electrical nerve stimulation technique.Unfortunately, the results of studies are widely divergent and not seem to indicate a dose considered effective, for each block, in a definitive way; but it is true that, through the use of ultrasound guidance, it is possible to reduce the dose of anesthetic in the performance of anesthetic blocks

Minimum anesthetic volume in regional anesthesia by using ultrasound-guidance

Abstract The ultrasound guidance in regional anesthesia ensures the visualization of needle placement and the spread of Local Anesthetics. Over the past few years there was a substantial interest in determining the Minimum Effective Anesthetic Volume necessary to accomplish surgical anesthesia. The precise and real-time visualization of Local Anesthetics spread under ultrasound guidance block may represent the best requisite for reducing Local Anesthetics dose and Local Anesthetics-related effects. We will report a series of studies that have demonstrated the efficacy of ultrasound guidance blocks to reduce Local Anesthetics and obtain surgical anesthesia as compared to block performed under blind or electrical nerve stimulation technique. Unfortunately, the results of studies are widely divergent and not seem to indicate a dose considered effective, for each block, in a definitive way; but it is true that, through the use of ultrasound guidance, it is possible to reduce the dose of anesthetic in the performance of anesthetic blocks