Polymyxin-B hemoperfusion inactivates circulating proapoptotic factors.
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ABSTRACT: Objective
To test the hypothesis that extracorporeal therapy with polymyxin B (PMX-B) may prevent Gram-negative sepsis-induced acute renal failure (ARF) by reducing the activity of proapoptotic circulating factors.Setting
Medical-Surgical Intensive Care Units.Patients and interventions
Sixteen patients with Gram-negative sepsis were randomized to receive standard care (Surviving Sepsis Campaign guidelines) or standard care plus extracorporeal therapy with PMX-B.Measurements and results
Cell viability, apoptosis, polarity, morphogenesis, and epithelial integrity were evaluated in cultured tubular cells and glomerular podocytes incubated with plasma from patients of both groups. Renal function was evaluated as SOFA and RIFLE scores, proteinuria, and tubular enzymes. A significant decrease of plasma-induced proapoptotic activity was observed after PMX-B treatment on cultured renal cells. SOFA and RIFLE scores, proteinuria, and urine tubular enzymes were all significantly reduced after PMX-B treatment. Loss of plasma-induced polarity and permeability of cell cultures was abrogated with the plasma of patients treated with PMX-B. These results were associated to a preserved expression of molecules crucial for tubular and glomerular functional integrity.Conclusions
Extracorporeal therapy with PMX-B reduces the proapoptotic activity of the plasma of septic patients on cultured renal cells. These data confirm the role of apoptosis in the development of sepsis-related ARF.
SUBMITTER: Cantaluppi V
PROVIDER: S-EPMC2517091 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundIn 2010, the EUPHAS 2 collaborative group created a registry with the purpose of recording data from critically ill patients suffering from severe sepsis and septic shock treated with polymyxin-B hemoperfusion (PMX-HP) for endotoxin removal. The aim of the registry was to verify the application of PMX-HP in the daily clinical practice.MethodsThe EUPHAS 2 registry involved 57 centers between January 2010 and December 2014, collecting retrospective data of 357 patients (297 in Europe and 60 in Asia) suffering from severe sepsis and septic shock caused by proved or suspected infection related to Gram negative bacteria. All patients received atleast one cycle of extracorporeal endotoxin removal by PMX-HP.ResultsSeptic shock was diagnosed in 305 (85.4 %) patients. The most common source of infection was abdominal (44.0 %) followed by pulmonary (17.6 %). Gram negative bacteria represented 60.6 % of the pathogens responsible of infection. After 72 h from the first cycle of PMX-HP, some of the SOFA score components significantly improved with respect to baseline: cardiovascular (2.16 ± 1.77 from 3.32 ± 1.29, p < 0.0001), respiratory (1.95 ± 0.95 from 2.40 ± 1.06, p < 0.001) and renal (1.84 ± 1.77 from 2.23 ± 1.62, p = 0.013). Overall 28-day survival rate was 54.5 % (60.4 % in abdominal and 47.5 % in pulmonary infection). Patients with abdominal infection treated with PMX-HP within 24 h from the diagnosis of septic shock had a 28-day survival rate of 64.5 %. Patients showing a significantly cardiovascular improvement after PMX-HP had a 28-survival rate of 75 % in comparison to the 39 % of patients who did not (p < 0.001). Cox regression analysis found the variation of cardiovascular, respiratory and coagulation SOFA to be independent covariates for 28-day survival. In European patients were observed a higher 28-day (58.8 vs. 34.5 %, p = 0.003), ICU (59 vs. 36.7 %, p = 0.006) and hospital survival rate (53.2 vs. 35 %, p = 0.02) than in Asian patients. However, the two populations were highly heterogeneous in terms of source of infection and severity scores at admission.ConclusionThe EUPHAS 2 is the largest registry conducted outside Japan on the clinical use of PMX-HP in septic patients. Data analysis confirmed the feasibility of PMX-HP to treat septic patients in daily clinical practice, showing clinical benefits associated with endotoxin removal without significant adverse events related to the extracorporeal technique.
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| S-EPMC8246724 | biostudies-literature
Project description:ObjectivesTo evaluate the use of direct hemoperfusion with polymyxin B-immobilized fiber (PMX-DHP) as adjunctive therapy during pediatric patients with septic shock.DesignProspective observational study.SettingNine-bed PICUs at university referral hospital.PatientsChildren (30 d to 15 yr) with septic shock and Pediatric Logistic Organ Dysfunction (PELOD)-2 score greater than or equal to 10 or Pediatric Risk of Mortality (PRISM) 3 score greater than or equal to 15, who were also receiving at least one inotrope.InterventionPatients received 2-4 hour treatment with PMX-DHP 20R column on 2 consecutive days.Measurements and main resultsWe enrolled six children aged 21-167 months old (median, 99-mo old), with a body weight of 10-50 kg (median, 28 kg). All six patients had both PELOD-2 greater than or equal to 10 and PRISM-3 greater than or equal to 15, required invasive mechanical ventilation, and received standard treatment for septic shock before enrollment. We observed significant improvement in PELOD-2 score from baseline to 72 hours after the start of PMX-DHP (mean [95% CI] from 14.3 [12.2-16.5] to 6.0 [0.3-11.7]; p = 0.006). The vasoactive inotropic score (VIS) and lactate concentration also significantly decreased from baseline to 72 hours (VIS, 60 mmol/L [25-95 mmol/L] to 4.0 mmol/L [44.1-12 mmol/L]; p = 0.003; lactate, 2.4 mmol/L [1.0-3.8 mmol/L] to 1.0 mmol/L [0.5-1.5 mmol/L]; p = 0.01). Five of six patients survived. There was no device-related adverse event in these patients.ConclusionsIn this case series of treatment with PMX-DHP as adjunctive therapy in children with refractory septic shock and high baseline severity, we have shown that patient recruitment is feasible. We have also found that clinical hemodynamic and severity of illness scores at 72 hours may be potential end points for testing in future randomized controlled trials.
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Project description:BackgroundDirect hemoperfusion with polymyxin B-immobilized fiber (PMX-DHP) has been widely used for patients with septic shock around the world, but the prognostic factors have not been fully understood. We conducted a retrospective analysis to determine the prognostic factors in patients with septic shock who underwent PMX-DHP.MethodsTwenty-nine patients with septic shock who underwent PMX-DHP were included in the study. The patients were divided into groups based on survival (n = 23) and non-survival (n = 6) 28 days after PMX-DHP, and the clinical data for the two groups before and after PMX-DHP were compared.ResultsIn non-survivors, the vasopressor dependency index before PMX-DHP was significantly higher (p = 0.046), and the leukocyte count before PMX-DHP was significantly lower (p = 0.024) than in survivors. Furthermore, base excess after PMX-DHP was significantly lower in non-survivors (p = 0.007) than in survivors. The optimal cutoff points of the vasopressor dependency index, leukocyte count, and base excess identified by receiver operating characteristic curves were 0.499/mmHg, 1360/μL, and -6.4 mmol/L, respectively. And the score using these three cutoffs, termed the prognostic score, was related to the prognosis of septic shock patients who underwent PMX-DHP (area under the curve = 0.946).ConclusionsThe prognostic score, using three parameters which are immediately and readily available in early phase after starting PMX-DHP, might be useful to predict the prognosis of these patients.
| S-EPMC4908858 | biostudies-literature
Project description:BackgroundThe purpose of this study was to investigate whether polymyxin B hemoperfusion (PMX-HP) improves the survival of patients with septic shock.MethodsThis was a retrospective, multicenter study conducted on patients treated during a 3-year period. We performed propensity-score analyses of the Japan Septic Disseminated Intravascular Coagulation (JSEPTIC DIC) study database. The study included data on 1723 patients with septic shock aged 16 years or older. Furthermore, we divided patients into to PMX-HP- and non-PMX-HP-treated groups. The primary endpoint was all-cause hospital mortality; secondary endpoints included intensive care unit (ICU) mortality and number of ICU-free days (ICUFDs) in the first 28 days.ResultsOf 1,723 eligible patients, 522 had received PMX-HP. Propensity score matching created 262 matched pairs (i.e., 262 patients in each of the non-PMX-HP and PMX-HP groups). The proportion of all-cause hospital mortality was significantly lower in the PMX-HP group than in the non-PMX-HP group (32.8% vs. 41.2%; odds ratio (OR): 0.681; 95% confidence interval (CI): 0.470-0.987; P?=?0.042). The number of ICUFD in the first 28 days was significantly higher in the PMX-HP group than in the non-PMX-HP group (18 (0-22) vs. 14 (0-22) days, respectively; P?=?0.045). On the other hand, there was no significant difference in ICU mortality between the two groups (21.8% vs. 24.4%; OR: 0.844; CI: 0.548-1.300; P?=?0.443).ConclusionsOur results strongly suggest that PMX-HP reduces all-cause hospital mortality and length of ICU stay in patients with septic shock.
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| S-EPMC8473472 | biostudies-literature
Project description:BackgroundRecent randomized trials have not found that polymyxin B hemoperfusion (PMX-HP) improves outcomes for patients with sepsis. However, it remains unclear whether the therapy could provide benefit for highly selected patients. Monocyte human leukocyte antigen (mHLA-DR) expression, a critical step in the immune response, is decreased during sepsis and leads to worsening sepsis outcomes. One recent study found that PMX-HP increased mHLA-DR expression while another found that the treatment removed HLA-DR-positive cells.MethodsWe conducted a randomized controlled trial in patients with blood endotoxin activity assay (EAA) level ≥ 0.6. Patients in the PMX-HP group received a 2-h PMX-HP treatment plus standard treatment for 2 consecutive days. Patients in the non-PMX-HP group received only standard treatment. The primary outcome compared the groups on median change in mHLA-DR expression between day 3 and baseline. Secondary outcomes compared the groups on the mean or median change in CD11b expression, neutrophil chemotaxis, presepsin, cardiovascular Sequential Organ Failure Assessment (CVS SOFA) score, vasopressor dose, and EAA level between day 3 and baseline. We further compared the groups on mortality, ICU-free days, ventilator-free days, dialysis dependence status, renal recovery, serum creatinine, vasopressor-free days, and major adverse kidney events (MAKE 28), measured on day 28.ResultsFifty-nine patients were randomized to PMX-HP (n = 29) and non-PMX-HP (n = 30) groups. At baseline, mHLA-DR expression, CD11b, neutrophil chemotaxis, and clinical parameters were comparable between groups. The median change in mHLA-DR expression between day 3 and baseline was higher in PMX-HP patients than in patients receiving standard therapy alone (P = 0.027). The mean change in CD11b between day 3 and baseline was significantly lower in the PMX-HP group than in the non-PMX-HP group (P = 0.002). There were no significant changes from baseline in neutrophil chemotaxis, presepsin, CVS SOFA scores, vasopressor doses, or EAA level between groups. On day 28 after enrollment, mortality, ICU-free days, ventilator-free days, dialysis dependence status, renal recovery, serum creatinine, vasopressor-free days, and MAKE 28 were comparable between groups.ConclusionPMX-HP improved mHLA-DR expression in severe sepsis patients. Future studies should examine the potential benefit of PMX-HP in patients with low mHLA-DR expression.Trial registrationClinicalTrials.gov, NCT02413541 . Registered on 3 March 2015.
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Project description:Autophagy and apoptosis are two important and interconnected stress-response mechanisms. However, the molecular interplay between these two pathways is not fully understood. To study the fate and function of autophagic proteins at the onset of apoptosis, we used a cellular model system in which autophagy precedes apoptosis. IL-3 depletion of Ba/F3 cells caused caspase (casp)-mediated cleavage of Beclin-1 and PI3KC3, two crucial components of the autophagy-inducing complex. We identified two casp cleavage sites in Beclin-1, TDVD(133) and DQLD(149), cleavage at which yields fragments lacking the autophagy-inducing capacity. Noteworthy, the C-terminal fragment, Beclin-1-C, localized predominantly at the mitochondria and sensitized the cells to apoptosis. Moreover, on isolated mitochondria, recombinant Beclin-1-C was able to induce the release of proapoptotic factors. These findings point to a mechanism by which casp-dependent generation of Beclin-1-C creates an amplifying loop enhancing apoptosis upon growth factor withdrawal.
| S-EPMC3032505 | biostudies-literature
Project description:BackgroundSeptic shock is a leading cause of death in critical patients. In patients with gram-negative septic shock, hemoperfusion with polymyxin B aims to remove endotoxins from plasma. We analyzed the clinical and biological response to hemoperfusion in patients with septic shock and acute kidney injury.MethodsThis prospective case-control study in the medical-surgical intensive care unit of a university hospital included consecutive adults patients with septic shock and suspected gram-negative bacteria infection with elevated plasma endotoxin activity (EAA?>?0.6 EU/ml) and acute kidney injury requiring continuous renal replacement therapy (CRRT). At onset of septic shock, half underwent CRRT plus hemoperfusion with polymyxin B for two hours a day during two consecutive days (hemoperfusion group) and half received only CRRT (control group). We measured clinical, physiological, and biological parameters (EAA, C-reactive protein, procalcitonin, and cytokines) daily during the first 5 days.ResultsWe included 18 patients (male, 33%; mean age, 67.5; mean SOFA score, 11.3). Abdominal infections predominated (50% had peritonitis). At the beginning of CRRT, RIFLE classification was "failure" for 72% and "injury" for 28%. Baseline characteristics did not differ between groups. Patients in the hemoperfusion group required longer mechanical ventilation (12.4 vs. 9.4 days, p?=?0.03) and CRRT (8.5 vs. 6 days, p?=?0.01) than in the control group. Noradrenaline doses, lactate, procalcitonin, and C-reactive protein decreased in both groups. At day 5, EAA was significantly lower in the hemoperfusion group (0.58 EU/ml vs. 0.73 EU/ml in controls, p?=?0.03). There were no significant differences between groups in other biomarkers or ICU mortality (33.3% in the treatment group vs. 44.4% in the control group, p?=?0.5). No adverse effects of hemoperfusion were observed.ConclusionsHemoperfusion with polymyxin B added to CRRT resulted in faster decrease in endotoxin levels, but we observed no improvements in clinical, physiological, or biological parameters.
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