The high mobility group box 1 protein (HMGB1) is an alarmin that plays an important role in sepsis and has been recognized as a promising target with a wide therapeutic window; however, no drugs and devices are currently in practical use. We hypothesized that hemofilters composed of porous membranes or cytokine-adsorbing membranes could remove HMGB1 from the blood. We performed experimental hemofiltration in vitro using four types of hemofilters composed of different membranes specifically designed for continuous hemofiltration. The test solution was a 1000-mL substitution fluid containing 100 µg of HMGB1 and 35 g of bovine serum albumin. Experimental hemofiltration was conducted for 360 min in a closed loop circulation system. Among the four membranes, surface-treated polyacrylonitrile (AN69ST) showed the highest capacity to adsorb HMGB1; it adsorbed nearly 100 µg of HMGB1 in the initial 60 min and showed a markedly high clearance rate (60.8 ± 5.0 mL/min) at 15 min. The polymethylmethacrylate membrane had half of the adsorption capacity of the AN69ST membrane. Although the highest sieving coefficient for HMGB1 was obtained with the high cut-off polyarylethersulfone membrane, which correlated with a constant filtrate clearance rate, albumin loss was observed. However, no such removal of both HMGB1 and albumin was observed with the polysulfone membrane and tubing. We conclude that continuous hemofiltration using the AN69ST membrane is a promising approach for HMGB1-related sepsis.
Chronic critical illness is a global clinical issue affecting millions of sepsis survivors annually. Survivors report chronic skeletal muscle weakness and development of new functional limitations that persist for years. To delineate mechanisms of sepsis-induced chronic weakness, we first surpassed a critical barrier by establishing a murine model of sepsis with ICU-like interventions that allows for the study of survivors. We show that sepsis survivors have profound weakness for at least 1 month, even after recovery of muscle mass. Abnormal mitochondrial ultrastructure, impaired respiration and electron transport chain activities, and persistent protein oxidative damage were evident in the muscle of survivors. Our data suggest that sustained mitochondrial dysfunction, rather than atrophy alone, underlies chronic sepsis-induced muscle weakness. This study emphasizes that conventional efforts that aim to recover muscle quantity will likely remain ineffective for regaining strength and improving quality of life after sepsis until deficiencies in muscle quality are addressed.
Polymyxin B-immobilized fiber column direct hemoperfusion (PMX-DHP) therapy is widely used for the treatment of severe sepsis and septic shock, and is generally performed for 2 h. Although previous studies demonstrated the efficacy of PMX-DHP therapy, it currently remains unclear whether its optimal duration is 2 h. This retrospective study analyzed 37 patients with septic shock who showed a poor clinical response to 2 h of PMX-DHP, and underwent a longer duration of this therapy. The mean duration of PMX-DHP therapy was 15.8 ± 7.9 h, and none of the patients developed adverse events, which enabled the therapy to be performed safely. The pressure catecholamine index [CAIP = catecholamine index/mean arterial pressure; catecholamine index = dopamine + dobutamine + (adrenaline + noradrenaline) × 100 μg/kg per min], as an indicator of hemodynamics, improved significantly in the survival group in the period between the start and 24 h after the end of PMX-DHP therapy (P < 0.01), and between 2 h after the start of and the end of this therapy (P < 0.05). In addition, the P/F ratio improved significantly in the group of surviving patients with acute respiratory distress syndrome (ARDS) in the period between the start and 24 h after the end of PMX-DHP therapy (P < 0.01), and between 2 h after the start of and the end of this therapy (P < 0.01). These results suggest that a longer duration of PMX-DHP therapy can be expected to improve the hemodynamics and pulmonary oxygenation capacity of patients with severe sepsis/septic shock. Strict prospective studies are needed in the future.
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