Endotoxin removal therapy with Polymyxin B immobilized fiber column: a single center experience from EUPHAS2 registry

Continuous renal replacement therapy; Diagnostic markers; InfectionTerapia de reemplazo renal continua; Marcadores de diagnóstico; InfecciónTeràpia de substitució renal contínua; Marcadors diagnòstics; InfeccióAlthough the precise clinical indication for initiation of PMX-HA is widely debated in the literature, a proper patient selection and timing of treatment delivery might play a critical role in the clinical course of a specific subphenotype of septic shock (endotoxic shock). In light of this view, since 2019, we have introduced in our clinical practice a diagnostic-therapeutic flowchart to select patients that can benefit the most from the treatment proposed. In addition, we reported in this study our experience of PMX-HA in a cohort of critically ill patients admitted to our intensive care unit (ICU). We analyzed a single centre, retrospective, observational web-based database (extracted from the EUPHAS2 registry) of critically ill patients admitted to the ICU between January 2016 and May 2021 who were affected by endotoxic shock. Patients were divided according to the diagnostic-therapeutic flowchart in two groups: Pre-Flowchart (Pre-F) and Post-Flowchart (Post-F). From January 2016 to May 2021, 61 patients were treated with PMX-HA out of 531 patients diagnosed with septic shock and of these, fifty patients (82%) developed AKI during their ICU stay. The most common source of infection was secondary peritonitis (36%), followed by community-acquired pneumonia (29%). Fifty-five (90%) out of 61 patients received a second PMX-HA treatment, with a statistically significant difference between the two groups (78% of the Pre-F vs. 100% of the Post-F group, p = 0.005). In both groups, between T0 and T120, the Endotoxin Activity Assay (EAA) decreased, while the SOFA score, mean arterial pressure (MAP), and Vasoactive Inotropic Score (VIS) improved with no statistically significant difference. Furthermore, when performing a propensity score matching analysis to compare mortality between the two groups, statistically significant lower ICU and 90-day mortalities were observed in the Post-F group [p = 0.016]. Although in this experienced centre data registry, PMX-HA was associated with organ function recovery, hemodynamic improvement, and current EAA level reduction in critically ill patients with endotoxic shock. Following propensity score-matched analysis, ICU mortality and 90-day mortalities were lower in the diagnostic-therapeutic flowchart group when considering two temporal groups based on strict patient selection criteria and timing to achieve PMX. Further Randomised Control Trials focused on centre selection, adequate training and a flowchart of action when assessing extracorporeal blood purification use should be performed.This work was supported by IRRIV (The International Renal Research Institute of Vicenza) Foundation

ADPKD: Prototype of Cardiorenal Syndrome Type 4

The cardiorenal syndrome type 4 (Chronic Renocardiac Syndrome) is characterized by a condition of primary chronic kidney disease (CKD) that leads to an impairment of the cardiac function, ventricular hypertrophy, diastolic dysfunction, and/or increased risk of adverse cardiovascular events. Clinically, it is very difficult to distinguish between CRS type 2 (Chronic Cardiorenal Syndrome) and CRS type 4 (Chronic Renocardiac Syndrome) because often it is not clear whether the primary cause of the syndrome depends on the heart or the kidney. Autosomal dominant polycystic kidney disease (ADPKD), a genetic disease that causes CKD, could be viewed as an ideal prototype of CRS type 4 because it is certain that the primary cause of cardiorenal syndrome is the kidney disease. In this paper, we will briefly review the epidemiology of ADPKD, conventional and novel biomarkers which may be useful in following the disease process, and prevention and treatment strategies

Oxidant and Carbonyl Stress-Related Apoptosis in End-Stage Kidney Disease: Impact of Membrane Flux

Apoptosis is a highly regulated process which mostly affects cell-mediated immunity. In this open-label, randomized, prospective clinical study, we determined the impact in 10 hemodialysis patients treated with high-, medium-, and low-flux membranes on spontaneous or plasma-induced apoptosis, on monocytes, as well as on oxidant and carbonyl stress. High- and medium-flux membranes significantly reduced patients' plasma-dependent proapoptotic activity on U937 monocytic cell lines. Patients who had the highest levels of plasma-induced proapoptotic activity exhibited the highest plasma levels of advanced oxidation protein products (AOPPs) and carbonyls. Plasma carbonyl residues but not AOPPs were significantly lowered. Finally, a significant correlation could be drawn between the extent of plasma-induced proapoptotic activity and both plasma carbonyl and AOPP levels

Effectiveness of polymyxin B-immobilized fiber column in sepsis: a systematic review

INTRODUCTION: Severe sepsis and septic shock are common problems in the intensive care unit and carry a high mortality. Endotoxin, one of the principal components on the outer membrane of gram-negative bacteria, is considered important to their pathogenesis. Polymyxin B bound and immobilized to polystyrene fibers (PMX-F) is a medical device that aims to remove circulating endotoxin by adsorption, theoretically preventing the progression of the biological cascade of sepsis. We performed a systematic review to describe the effect in septic patients of direct hemoperfusion with PMX-F on outcomes of blood pressure, use of vasoactive drugs, oxygenation, and mortality reported in published studies. METHODS: We searched PubMed, the Cochrane Collaboration Database, and bibliographies of retrieved articles and consulted with experts to identify relevant studies. Prospective and retrospective observational studies, pre- and post-intervention design, and randomized controlled trials were included. Three authors reviewed all citations. We identified a total of 28 publications - 9 randomized controlled trials, 7 non-randomized parallel studies, and 12 pre-post design studies - that reported at least one of the specified outcome measures (pooled sample size, 1,425 patients: 978 PMX-F and 447 conventional medical therapy). RESULTS: Overall, mean arterial pressure (MAP) increased by 19 mm Hg (95% confidence interval [CI], 15 to 22 mm Hg; p < 0.001), representing a 26% mean increase in MAP (range, 14% to 42%), whereas dopamine/dobutamine dose decreased by 1.8 microg/kg per minute (95% CI, 0.4 to 3.3 microg/kg per minute; p = 0.01) after PMX-F. There was significant intertrial heterogeneity for these outcomes (p < 0.001), which became non-significant when analysis was stratified for baseline MAP. The mean arterial partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) ratio increased by 32 units (95% CI, 23 to 41 units; p < 0.001). PMX-F therapy was associated with significantly lower mortality risk (risk ratio, 0.53; 95% CI, 0.43 to 0.65). The trials assessed had suboptimal method quality. CONCLUSION: Based on this critical review of the published literature, direct hemoperfusion with PMX-F appears to have favorable effects on MAP, dopamine use, PaO2/FiO2 ratio, and mortality. However, publication bias and lack of blinding need to be considered. These findings support the need for further rigorous study of this therapy

Volume Assessment in Mechanically Ventilated Critical Care Patients Using Bioimpedance Vectorial Analysis, Brain Natriuretic Peptide, and Central Venous Pressure

Purpose. Strategies for volume assessment of critically ill patients are limited, yet early goal-directed therapy improves outcomes. Central venous pressure (CVP), Bioimpedance Vectorial Analysis (BIVA), and brain natriuretic peptide (BNP) are potentially useful tools. We studied the utility of these measures, alone and in combination, to predict changing oxygenation. Methods. Thirty-four mechanically ventilated patients, 26 of whom had data beyond the first study day, were studied. Relationships were assessed between CVP, BIVA, BNP, and oxygenation index (O2I) in a cross-sectional (baseline) and longitudinal fashion using both univariate and multivariable modeling. Results. At baseline, CVP and O2I were positively correlated (R = 0.39; P = .021), while CVP and BIVA were weakly correlated (R = −0.38; P = .025). The association between slopes of variables over time was negligible, with the exception of BNP, whose slope was correlated with O2I (R = 0.40; P = .044). Comparing tertiles of CVP, BIVA, and BNP slopes with the slope of O2I revealed only modest agreement between BNP and O2I (kappa = 0.25; P = .067). In a regression model, only BNP was significantly associated with O2I; however, this was strengthened by including CVP in the model. Conclusions. BNP seems to be a valuable noninvasive measure of volume status in critical care and should be assessed in a prospective manner

Protective effect of resin adsorption on septic plasma-induced tubular injury

Introduction: A pro-apoptotic effect of circulating mediators on renal tubular epithelial cells has been involved in the pathogenesis of sepsis-associated acute kidney injury (AKI). Adsorption techniques have been showed to efficiently remove inflammatory cytokines from plasma. The aim of this study was to evaluate the efficiency of the hydrophobic resin Amberchrom CG161 M to adsorb from septic plasma soluble mediators involved in tubular injury. Methods: We enrolled in the study 10 critically ill patients with sepsis-associated AKI and we evaluated the effects of their plasma on granulocyte adhesion, apoptosis and functional alterations of cultured human kidney tubular epithelial cells. We established an in vitro model of plasma adsorption and we studied the protective effect of unselective removal of soluble mediators by the Amberchrom CG161 M resin on septic plasma-induced tubular cell injury. Results: Plasma from septic patients induced granulocyte adhesion, apoptosis and altered polarity in tubular cells. Plasma adsorption significantly decreased these effects and abated the concentrations of several soluble mediators. The inhibition of granulocyte adhesion to tubular cells was associated with the down-regulation of ICAM-1 and CD40. Resin adsorption inhibited tubular cell apoptosis induced by septic plasma by down-regulating the activation of caspase-3, 8, 9 and of Fas/death receptor-mediated signalling pathways. The alteration of cell polarity, morphogenesis, protein reabsorption and the down-regulation of the tight junction molecule ZO-1, of the sodium transporter NHE3, of the glucose transporter GLUT-2 and of the endocytic receptor megalin all induced by septic plasma were significantly reduced by resin adsorption. Conclusions: Septic plasma induced a direct injury of tubular cells by favouring granulocyte adhesion, by inducing cell apoptosis and by altering cell polarity and function. All these biological effects are related to the presence of circulating inflammatory mediators that can be efficiently removed by resin adsorption with a consequent limitation of tubular cell injury

Heart-Kidney Biomarkers in Patients Undergoing Cardiac Stress Testing

We examined association of inducible myocardial perfusion defects with cardiorenal biomarkers, and of diminished left ventricular ejection fraction (LVEF) with kidney injury marker plasma neutrophil gelatinase-associated lipocalin (NGAL). Patients undergoing nuclear myocardial perfusion stress imaging were divided into 2 groups. Biomarkers were analyzed pre- and poststress testing. Compared to the patients in the low ischemia group (n = 16), the patients in the high ischemia group (n = 18) demonstrated a significantly greater rise in cardiac biomarkers plasma BNP, NT-proBNP and cTnI. Subjects were also categorized based on pre- or poststress test detectable plasma NGAL. With stress, the group with no detectable NGAL had a segmental defect score 4.2 compared to 8.2 (P = .06) in the detectable NGAL group, and 0.9 vs. 3.8 (P = .03) at rest. BNP rose with stress to a greater degree in patients with detectable NGAL (10.2 vs. 3.5 pg/mL, P = .03). LVEF at rest and with stress was significantly lower in the detectable NGAL group; 55.8 versus 65.0 (P = .03) and 55.1 vs. 63.8 (P = .04), respectively. Myocardial perfusion defects associate with biomarkers of cardiac stress, and detectable plasma NGAL with significantly lower LVEF, suggesting a specific heart-kidney link

B-Type Natriuretic Peptide in the Critically Ill with Acute Kidney Injury

Introduction. Acute kidney injury (AKI) is common in the intensive care unit (ICU) and associated with poor outcome. Plasma B-type natriuretic peptide (BNP) is a biomarker related to myocardial overload, and is elevated in some ICU patients. There is a high prevalence of both cardiac and renal dysfunction in ICU patients. Aims. To investigate whether plasma BNP levels in the first 48 hours were associated with AKI in ICU patients. Methods. We studied a cohort of 34 consecutive ICU patients. Primary outcome was presence of AKI on presentation, or during ICU stay. Results. For patients with AKI on presentation, BNP was statistically higher at 24 and 48 hours than No-AKI patients (865 versus 148 pg/mL; 1380 versus 131 pg/mL). For patients developing AKI during 48 hours, BNP was statistically higher at 0, 24 and 48 hours than No-AKI patients (510 versus 197 pg/mL; 552 versus 124 pg/mL; 949 versus 104 pg/mL). Conclusion. Critically ill patients with AKI on presentation or during ICU stay have higher levels of the cardiac biomarker BNP relative to No-AKI patients. Elevated levels of plasma BNP may help identify patients with elevated risk of AKI in the ICU setting. The mechanism for this cardiorenal connection requires further investigation