History and current status of polymyxin B‐immobilized fiber column for treatment of severe sepsis and septic shock

Abstract Toraymyxin® (Toray Medical Co., Ltd, Tokyo, Japan) has been developed as a direct hemoperfusion column that contains polymyxin B‐immobilized fiber to bind endotoxins in patients’ blood. Toraymyxin was approved by the Japanese National Health Insurance system for the treatment of endotoxemia and septic shock in 1994. Since then, PMX (defined as direct hemoperfusion with Toraymyxin) has been safely used in more than 100 000 cases in emergency and intensive care units in Japan. Toraymyxin is currently available for use in clinical settings in 12 countries outside of Japan. We reviewed and analyzed the development, clinical use, and efficacy of Toraymyxin, and assessed the current status of Toraymyxin use for the treatment of severe sepsis and septic shock. Our review shows that PMX appeared to be effective in improving hemodynamics and respiratory function in septic shock requiring emergency abdominal surgery. Recent large‐scale ranomized controlled trialscould not demonstrate whether prognosis is improved by PMX. However, the latest meta‐analysis revealed that PMX significantly decreased mortality in patients with severe sepsis and septic shock. Combination of PMX with continuous hemodiafiltration and longer duration of PMX might be an effective strategy to improve survival in such patients.

adsorption of circulating endotoxins in the blood. Toraymyxin â (Toray Medical Co., Ltd, Tokyo, Japan) has been developed as a direct hemoperfusion column that contains polymyxin B-immobilized fiber to bind endotoxins in patients' blood.
A narrative literature review was carried out using PubMed, MEDLINE and Google scholar search engines regarding PMX (defined as direct hemoperfusion with Toraymyxin). We describe the history of the development of Toraymyxin and comment on its clinical efficacy and current status with respect to its use for the treatment of severe sepsis and septic shock. A phase I clinical study was started in 1989, and the first clinical report of 16 patients with septic multiple organ failure treated with PMX was published in 1994. 3 PMX was approved by the Japanese National Health Insurance system for the treatment of endotoxemia and septic shock in 1994. 4 Since then, Toraymyxin has been safely used in more than 100 000 cases in emergency and intensive care units in Japan.
Toraymyxin received the CE mark of approval in Europe in 1998.

Results of the first preliminary randomized controlled trial (RCT) in
Europe were published in 2005, showing that treatment with PMX was safe and improves cardiac and renal dysfunction in patients with sepsis or septic shock. 5 The findings of a meta-analysis demonstrated the favorable effects of PMX in 2007. 6 The results of a subsequent RCT in Europe, the EUPHAS study (Early Use of Polymyxin B Hemoperfusion in Abdominal Sepsis), which was conducted in Italy, were published in 2009, showing that PMX results in a significant reduction in sepsis-associated mortality. 7  There are three types of Toraymyxin columns currently available for clinical use in Japan: PMX-20R â (volume, 135 mL), PMX-05R â (40 mL), and PMX-01R â (8 mL) (Figure 3). The first Toraymyxin column to be released was PMX-20R, which was developed for the treatment of septic shock in adults. 4 The second column to be released was PMX-05R in 2005, which was developed for use in pediatric or elderly patients with smaller circulating blood volumes or bodyweight less than 40 kg. 11 Several reports have shown acceptable results by using PMX-05R in pediatric or elderly patients with sepsis. 11 PMX-01R was released for use in newborn or premature infants in 2011. There are a few case reports describing successful clinical experience with the use of PMX-01R in patients with severe sepsis and a bodyweight less than 1000 g. 12,13 Since 1994, Toraymyxin has been used in over 100 000 cases in Japan. There have been no reports of any serious adverse effects.
Despite adverse effects such as clotting of cartridges, thrombocytopenia or hypotension being reported, these incidents are rare. 4 The Toraymyxin column was originally designed to specifically adsorb endotoxins. Plasma endotoxin levels are significantly decreased immediately after PMX compared with pretreatment levels ( Figure 4A). Furthermore, the patients' hyperdynamic state, which is characterized by an increase in cardiac index during endotoxic shock, was returned to normal after treatment ( Figure 4B) 15 A new method for the detection and quantitation of endotoxins is therefore urgently needed.
Recently, a new rapid assay called the endotoxin activity assay (EAA) had been developed, which detects endotoxins in whole blood by using autologous neutrophil-dependent chemiluminescence. 16 The  There are four RCT conducted outside of Japan as listed in Table 1. Vincent et al. 5 25 Clotting problems in the blood circuit during PMX were seldom raised in Japan. The cause of death was also not clarified between the PMX and conventional groups in this study. As such, the conflicting results of the ABDO-MIX study were inconclusive and not definitive.
The EUPHRATES trial conducted in the USA and Canada 9 was designed to address the criticisms of previous studies. Circulating Medicine. 26 The primary endpoint of mortality rate (44.3% in placebo group and 43.75% in PMX group) was not met in full intention-to-treat populations. Analyses of the secondary endpoints in this study are still ongoing and will be reported in the near future.
In their latest meta-analysis, Terayama et al. 27  The effect of PMX on mortality in patients with septic shock requiring CRRT was also examined using the DPC database, demonstrating tive studies also seemed to support the fact that PMX might be effective in patients with a higher baseline mortality risk.
The combination of PMX and continuous hemodiafiltration (CHDF) as CRRT appears to be more beneficial for patients with septic renal dysfunction than CHDF alone; combination treatment significantly decreases the concentration of circulating IL-6 and improves patient survival ( Figure 6A). 30 Figure 6B). 32 The latest meta-analysis 27 and large-scale retrospective studies 28,29 suggested that a beneficial effect with PMX might be higher in patients with a higher baseline mortality risk; such patients required the combination of PMX with CHDF. Further studies are needed to clarify the proper indication and clinical benefits for the combination of PMX and CHDF in patients with septic shock.
Originally, the treatment duration of PMX was set at 2 hours following the results seen in preclinical studies ( Figure 3). Endotoxin adsorption capacity is considered to reach equilibrium at 2 hours after the initiation of perfusion; however, the evident clinical efficacy of longer duration of PMX (>6 hours) has been reported in cases lacking clinical efficacy within 2 hours. 33 25 The respiratory source (17.6%; 63 cases) was, in fact, the second most frequently observed clinical condition in the study.
The 28-day mortality in patients with respiratory infections (52.5%) showed a trend toward a higher mortality rate than in those with abdominal infections (39.4%). Lower respiratory tract infections may have some differences compared to abdominal or urinary sepsis. In the discussion, they described that pulmonary sepsis seemed to respond less to the two sessions of endotoxin removal because source control is better achieved through antibiotic action and the resolution needs a longer time. However, in patients with intraabdominal sepsis, the source control is obtained through surgery and concomitant PMX treatment, achieving a more rapid resolution. 25 Kono et al. 36 reported that a longer duration of PMX is more efficacious for patients with acute exacerbation of interstitial pneumonia