Effective Combination Therapy of Polymyxin‐B Direct Hemoperfusion and Recombinant Thrombomodulin for Septic Shock Accompanied by Disseminated Intravascular Coagulation: A Historical Controlled Trial

Abstract

Disseminated intravascular coagulation (DIC) and multiple organ failure often occur via the crosstalk between inflammation and coagulation, which is mediated by High Mobility Group Box 1 (HMGB1). In septic shock, Polymyxin-B direct hemoperfusion (PMX-DHP) ameliorates hemodynamics by endogenous cannabinoid adsorption and improves pulmonary oxygenation by indirect cytokine reduction through the adsorption of activated mononuclear cells. However, PMX-DHP has no direct effect on HMGB1 circulating in the plasma. In cases with DIC, recombinant thrombomodulin (rTM), an effective drug for DIC, exerts not only anticoagulation but also antiinflammatory properties via direct anti-HMGB1 activity. Therefore, a combination of PMX-DHP and rTM is expected to block the vicious cycle of a cytokine storm ending up with multiple organ failure in DIC. The aim of this study was to investigate the efficacy of combination therapy for septic shock associated with DIC. This study comprised 22 consecutive patients with sepsis-induced DIC who received PMX-DHP. The initial eight patients were treated without rTM (historical control group), and the following 14 patients were given rTM (rTM group). The baseline Sequential Organ Failure Assessment (SOFA) score or age was not different between both groups. Sixtyday survival rate in the rTM group was significantly higher than that in the control group (85.7% vs. 37.5%, P = 0.015). A combination of PMX-DHP and rTM may be effective in septic shock accompanied by DIC and is expected to improve survival rates.

Exacerbation of prothrombin time-international normalized ratio before second polymyxin B cartridge hemoperfusion predicts poor outcome of patients with severe sepsis and/or septic shock

“…According to the results shown in Table 2, because the SOFA score, diastolic blood pressure, mean arterial pressure and systolic blood pressure were improved by PMX therapy in both groups, PT-INR is well known to be an important marker of disseminated intravascular coagulation (DIC) [16][17][18]. Because the relationship between DIC and SS is merely regarded as the two sides of the same coin [19], treatment for DIC and SS should be performed synchronously using not only anti-coagulant therapies [20] but also blood purification. In addition, because DIC is related to the pathophysiology of sepsis and progression of multiple organ dysfunction syndrome (MODS), inhibition of coagulation activity is also important for effective therapy [21,22].…”

Plasma Adsorption Membranes Are Able to Efficiently Remove High Mobility Group Box-1 (HMGB-1)

“…In DIC and multiple organ failure, HMGB-1 levels are significantly increased, which accelerates the chain reactions that lead to cytokine storm. Since PMX-DHP therapy does not directly reduce the amount of HMGB-1, its therapeutic effect on these severe conditions is limited 31 . However, PMX-DHP does adsorb early mediators in sepsis that are upstream of HMGB-1, which eventually decreases the concentration of HMGB-1.…”

Sphingosine-1-Phosphate (S1P) Is a Feasible Biomarker in Predicting the Efficacy of Polymyxin B-Immobilized Fiber Direct Hemoperfusion (PMX-DHP) in Patients with Septic Shock

“…High Mobility Group Box 1 (HMGB1), which is secreted from macrophages and monocytes, mediates inflammatory cytokines 10 . It is also known to trigger disseminated intravascular coagulation (DIC) and sepsis by deterioration of the coagulation system 11 . Other biomarkers include: Anandamide (N-arachidonoylethanolamine, AEA) and 2-arachidonoylglycerol (2-AG), endogenous agonists of cannabinoid receptors that are reported to be increased in patients with septic shock 12 ; The plasminogen activator inhibitor-1 (PAI-1), the principal inhibitor of tissue plasminogen activator (tPA) and urokinase (uPA), which regulates the plasminogen activator to initiate fibrinolysis 13,14 ; and Protein C (PC) which regulates blood clot size and prevents the downstream coagulation pathway through the proteolytic inactivation of the procoagulant co-factors Vllla and Va 15 .…”