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Purpose To test whether the polymyxin B hemoperfusion (PMX HP) fiber column reduces mortality and organ failure in peritonitis-induced septic shock (SS) from abdominal infections. Method Prospective, multicenter, randomized controlled trial in 18 French intensive care units from October 2010 to March 2013, enrolling 243 patients with SS within 12 h after emergency surgery for peritonitis related to organ perforation. The PMX HP group received conventional therapy plus two sessions of PMX HP. Primary outcome was mortality on day 28; secondary outcomes were mortality on day 90 and a reduction in the severity of organ failures based on Sequential Organ Failure Assessment (SOFA) scores. Results Primary outcome: day 28 mortality in the PMX HP group ( n  = 119) was 27.7 versus 19.5 % in the conventional group ( n  = 113), p  = 0.14 (OR 1.5872, 95 % CI 0.8583–2.935). Secondary endpoints: mortality rate at day 90 was 33.6 % in PMX-HP versus 24 % in conventional groups, p  = 0.10 (OR 1.6128, 95 % CI 0.9067–2.8685); reduction in SOFA score from day 0 to day 7 was −5 (−11 to 6) in PMX-HP versus −5 (−11 to 9), p  = 0.78. Comparable results were observed in the predefined subgroups (presence of comorbidity; adequacy of surgery, <2 sessions of hemoperfusion) and for SOFA reduction from day 0 to day 3. Conclusion This multicenter randomized controlled study demonstrated a non-significant increase in mortality and no improvement in organ failure with PMX HP treatment compared to conventional treatment of peritonitis-induced SS.

We report on the effect of hemoadsorption therapy to reduce cytokines in septic patients with respiratory failure. This was a randomized, controlled, open-label, multicenter trial. Mechanically ventilated patients with severe sepsis or septic shock and acute lung injury or acute respiratory distress syndrome were eligible for study inclusion. Patients were randomly assigned to either therapy with CytoSorb hemoperfusion for 6 hours per day for up to 7 consecutive days (treatment), or no hemoperfusion (control). Primary outcome was change in normalized IL-6-serum concentrations during study day 1 and 7. 97 of the 100 randomized patients were analyzed. We were not able to detect differences in systemic plasma IL-6 levels between the two groups (n = 75; p = 0.15). Significant IL-6 elimination, averaging between 5 and 18% per blood pass throughout the entire treatment period was recorded. In the unadjusted analysis, 60-day-mortality was significantly higher in the treatment group (44.7%) compared to the control group (26.0%; p = 0.039). The proportion of patients receiving renal replacement therapy at the time of enrollment was higher in the treatment group (31.9%) when compared to the control group (16.3%). After adjustment for patient morbidity and baseline imbalances, no association of hemoperfusion with mortality was found (p = 0.19). In this patient population with predominantly septic shock and multiple organ failure, hemoadsorption removed IL-6 but this did not lead to lower plasma IL-6-levels. We did not detect statistically significant differences in the secondary outcomes multiple organ dysfunction score, ventilation time and time course of oxygenation.

Background Recent 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. Methods We 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. Results Fifty-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. Conclusion PMX-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 registration ClinicalTrials.gov, NCT02413541 . Registered on 3 March 2015. 

The aim of this proof of concept, prospective, randomized pilot trial was to investigate the effects of extracorporeal cytokine removal (CytoSorb®) applied as a standalone treatment in patients with septic shock. 20 patients with early (<24 h) onset of septic shock of medical origin, on mechanical ventilation, norepinephrine>10 μg/min, procalcitonin (PCT) > 3 ng/mL without the need for renal replacement therapy were randomized into CytoSorb (n = 10) and Control groups (n = 10). CytoSorb therapy lasted for 24 h. Clinical and laboratory data were recorded at baseline (T0), T12, T24, and T48 hours. Overall SOFA scores did not differ between the groups. In the CytoSorb-group norepinephrine requirements and PCT concentration decreased significantly (norepinephrine: CytoSorb: T0 = 0.54[IQR:0.20–1.22], T48 = 0.16[IQR:0.07–0.48], p = .016; Controls: T0 = 0.43[IQR:0.19–0.64], T48 = 0.25[IQR:0.08–0.65] μg/kg/min; PCT: CytoSorb: T0 median = 20.6[IQR: 6.5–144.5], T48 = 5.6[1.9–54.4], p = .004; Control: T0 = 13.2[7.6–47.8], T48 = 9.2[3.8–44.2]ng/mL). Big-endothelin-1 concentrations were also significantly lower in the CytoSorb group (CytoSorb: T0 = 1.3 ± 0.6, *T24 = 1.0 ± 0.4, T48 = 1.4 ± 0.8, *p = .003; Control: T0 = 1.1 ± 0.7, T24 = 1.1 ± 0.6, T48 = 1.2 ± 0.6 pmol/L, p = .115). There were no CytoSorb therapy-related adverse events. This is the first trial to investigate the effects of early extracorporeal cytokine adsorption treatment in septic shock applied without renal replacement therapy. It was found to be safe with significant effects on norepinephrine requirements, PCT and Big-endothelin-1 concentrations compared to controls. Trial registration: The study has been registered on ClinicalTrials.gov, under the registration number of NCT02288975, registered 13 November 2014. •First randomized trial on one single 24-hour period of standalone CytoSorb treatment•Medical patients with septic shock were randomized (CytoSorb treated or control)•Patients were treated for 24 h with CytoSorb in addition to standard treatment•Significant reduction (70%) in norepinephrine requirement, PCT and Big Endothelin-1

Background Septic shock is common and has unacceptably high morbidity, mortality, and associated cost with numerous failed attempts at developing effective therapies. Endotoxin, one of the most potent mediators of sepsis, is found in high levels in approximately 50% of patients with septic shock. Polymyxin B (PMX) hemoperfusion has been shown in numerous studies to successfully remove endotoxin and potentially improve outcomes. EUPHRATES (Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized controlled trial of Adults Treated for Endotoxemia and Septic shock) is a theragnostic trial (matching blood measurement to treatment capability) of PMX hemoperfusion in patients with septic shock and confirmed endotoxemia as measured by the endotoxin activity assay (EAA). Methods EUPHRATES is a pivotal regulatory trial that is multi-centered, placebo-controlled and blinded. The trial is being conducted in fifty ICUs in the United States and Canada and is powered to enroll 360 patients. Patients with persistent septic shock despite adequate fluid resuscitation on vasopressors for more than 2 and less than 30 hours are eligible for measurement of the EAA. Those with EAA ≥0.60 are eligible to be randomized to treatment with two sessions of PMX hemoperfusion 24 hours apart. The primary endpoint for the trial is 28-day all-cause mortality. Discussion Unique features of the trial include absence of systemic inflammatory response (SIRS) criteria as a requirement for inclusion, use of the EAA to confirm endotoxemia as a requisite for treatment, and use of a detailed “façade” hemoperfusion event as a blinding mechanism. The outcomes of the second interim analysis included a resizing of the trial to 650 patients and the addition of an exclusion criterion of subjects with multiple organ dysfunction score (MODS) ≤ 9. Results are anticipated in 2016. Trial registration Clinicaltrials.gov identifier: NCT01046669 . Registered: January 8, 2010.

Multiple organ failure following a septic event derives from immune dysregulation. Many of the mediators of this process are humoral factors (cytokines), which could theoretically be cleared by direct adsorption through a process called hemoperfusion. Hemoperfusion through devices, which bind specific molecules like endotoxin or theoretically provide non-specific adsorption of pro-inflammatory mediators has been attempted and studied for several decades with variable results. More recently, technological evolution has led to the increasing application of adsorption due to more biocompatible and possibly more efficient biomaterials. As a result, new indications are developing in this field, and novel tools are available for clinical use. This narrative review will describe current knowledge regarding technical concepts, safety, and clinical results of hemoperfusion. Finally, it will focus on the most recent literature regarding adsorption applied in critically ill patients and their indications, including recent randomized controlled trials and future areas of investigation.Clinical trials for the assessment of efficacy of hemoperfusion in septic patients should apply the explanatory approach. This includes a highly selected homogenous patient population. Enrichment criteria such as applying genetic signature and molecular biomarkers allows the identification of subphenotypes of patients. The intervention must be delivered by a multidisciplinary team of trained personnel. The aim is to maximize the signals for efficacy and safety. In a homogenous cohort, confounding uncontrolled variables are less likely to exist. Trials with highly selected populations have a high internal validity but poor generalizability. The parallel design described in the figure is robust and usually is required by regulatory agencies for the approval of a new treatment. Allocation concealment and randomization are key to minimize bias such as confirmation bias, observer bias. The intervention should be delivered following a strict protocol. Deviations from the protocol might negatively influence the potential effects of the therapies. Surrogates such as cytokine measurement are adequate primary outcomes in phase 3 trials with small sample size because there is a higher likelihood of finding positive results concerning surrogate markers than in respect with clinical outcomes. Once a trial shows positive results concerning surrogate markers, a rationale for another phase 3 trial exploring clinical outcomes is built, justifying the allocation of financial sources to the intended trial.

Mortality in patients with paraquat (PQ) poisoning is related to plasma PQ levels. Concentrations lower than 5,000 ng/mL are considered critical but curable. This study assessed the effects of hemoperfusion (HP) and continuous renal replacement therapy (CRRT) on the survival of PQ-poisoned patients with plasma PQ levels below 5,000ng/mL. We analyzed the records of 164 patients with PQ poisoning who were treated at the First Affiliated Hospital of Wenzhou Medical University in China between January 2011 and May 2015. We divided these patients into six sub-groups based on baseline plasma PQ levels and treatment, compared their clinical characteristics, and analyzed their survival rates. Patient sub-groups did not differ in terms of age, sex, time between poisoning and hospital admission, or time to first gavage. Biochemical indicators improved over time in all sub-groups following treatment, and the combined HP and CRRT treatment yielded better results than HP or CRRT alone. Fatality rates in the three treatment sub-groups did not differ among patients with baseline plasma PQ levels of 50-1,000 ng/mL, but in patients with 1,000-5,000 ng/mL levels, the mortality rate was 59.2% (HP treatment group), 48% (CRRT treatment group), and 37.9% (combined treatment group). Mortality rates were higher 10-30 days after hospitalization than in the first 10 days after admission. In the early stages of PQ poisoning, CRRT is effective in reducing patient fatality rates, particularly when combined with HP. Our data could be useful in increasing survival in acute PQ poisoning patients.

Reducing the number of immunosuppressive cells in blood is a potential strategy for activating anti-tumor immunity, which provides a promising approach to cancer treatment. In this study, we developed an adsorbent designed to selectively target and adsorb lymphocytes expressing latency-associated peptide (LAP), which is abundantly expressed on the surface of CD4 + regulatory T cells (Tregs) and CD14 + monocytes. We investigated whether diethylenetriamine-conjugated polysulfone adsorbent-based direct hemoperfusion (DHP) enhances anti-tumor immunity in a rat cancer model with KDH-V liver cells. Our findings revealed that DHP significantly reduced LAP + Tregs in both peripheral blood and tumor tissues in treated mice. Consequently, cytotoxic T-lymphocytes increased in tumor-bearing rats. The anti-tumor effect was negated by the addition of cells detached from the absorbent, indicating that these cells play a crucial role in inhibiting the observed therapeutic effect. The results suggest that depleting LAP + immunosuppressive cells in blood can enhance anti-tumor immunity and improve survival of patients.

Background The purpose of this study was to investigate whether polymyxin B hemoperfusion (PMX-HP) improves the survival of patients with septic shock. Methods This 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. Results Of 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). Conclusions Our results strongly suggest that PMX-HP reduces all-cause hospital mortality and length of ICU stay in patients with septic shock.

Background Delayed administration of polymyxin B hemoperfusion (PMX-HP) for septic shock could diminish its efficacy in real-world clinical settings. Methods BEAT-SHOCK (BEst Available Treatment for septic SHOCK) registry is a prospective registry consisting of 309 adult patients with septic shock requiring high-dose norepinephrine (≥ 0.2 μg/kg/min). This predetermined analysis included 82 patients treated with PMX-HP. They were grouped according to the median time from intensive care unit (ICU) admission to administration of PMX-HP: the early administration group (n = 40) and the late administration group (n = 42). The primary outcome was short-term hemodynamic status, including mean arterial pressure and vasoactive-inotropic score (VIS; calculated from doses of dopamine, dobutamine, norepinephrine, epinephrine, vasopressin, milrinone, and levosimendan) within 48 h after ICU admission. Results The median time from ICU admission to administration of PMX-HP was 265 min (interquartile range [IQR]: 113–480). The median ages were 70 (IQR: 59–81) and 72 (IQR: 64–80) years ( P  = 0.77), and 21/40 (53%) and 25/42 (60%) patients were male ( P  = 0.52) in the early and late administration groups, respectively. The dose of norepinephrine at ICU admission was 0.33 (IQR: 0.24–0.47) and 0.30 (IQR: 0.22–0.34) μg/kg/min in the early and late administration groups, respectively ( P  = 0.17). Within 48 h after ICU admission, mean arterial pressure was significantly higher at 6 h and 8 h, and VIS was significantly lower at 8 h and thereafter in the early administration group. Within a 28-day period, there were 23 (IQR: 21–25) and 21 (IQR: 0–24) vasopressor/inotrope-free days ( P  = 0.027), and 18 (IQR: 1–23) and 14 (IQR: 0–19) ICU-free days ( P  = 0.025) in the early and late administration groups, respectively. The cumulative mortality at 90 days was 15.3% in the early administration group and 31.3% in the late administration group (adjusted hazard ratio 0.38; 95% confidence interval 0.13–1.09). Conclusions In patients with septic shock, early administration of PMX-HP was associated with higher mean arterial pressure and lower VIS within 48 h after ICU admission. Additionally, it may be associated with an improved clinical course, represented by more ICU-free and vasopressor/inotrope-free days. Trial registration UMIN Clinical Trial Registry on 1 November 2019 (registration no. UMIN000038302).