PMX-DHP Treatment Research Articles

When should polymyxin B‐immobilized polystyrene column be introduced to improve COVID‐19 prognosis?

Increased cytokine levels are involved in severe COVID-19. Moreover, apheresis is used to prevent or alleviate organ damage in moderate to severe COVID-19 patients. In particular, targets for removal are circulating mediators, including cytokines and damage-associated molecular patterns (DAMPs). Direct hemoperfusion using a polymyxin B-immobilized polystyrene column (PMX-DHP) selectively adsorbs endotoxins and various endogenous substances. We previously evaluated the efficacy and safety of PMX-DHP in COVID-19 patients that required oxygen support (N = 12) [1]. On Day 14 after the first treatment, disease severity decreased in 58.3% of patients. Additionally, the P/F ratio increased on Days 4 and 8. Cytokine measurements before and after PMX-DHP revealed decreased IL-6 levels. In which stage of COVID-19 should we start PMX treatment? In our observational study, seven patients were on ventilator or extracorporeal membrane oxygenation (ECMO) at the time of PMX treatment, and five of them (71.4%) survived. Furthermore, out of five patients receiving oxygen at the time of PMX treatment, four of them (80.0%) survived. Unfortunately, three patients died. The COVID-19 Clinical Practice Guide in Japan (6th Edition) [2] states that PMX-DHP treatment should be considered in certain cases due to its suppression of excessive inflammatory reactions in the “early stage before multiple organ failure progresses.” Remarkably, PMX-DHP improves prognosis in sepsis patients with sequential organ failure assessment (SOFA) scores of 7–9, 10–12. However, PMX-DHP does not affect prognosis in sepsis patients with SOFA 0–6, 13–15, 16–24 [3]. Therefore, we believe that PMX-DHP should be considered in patients with moderate disease II when oxygen demand appears (Figure 1). Finally, it is unclear if PMX is effective in patients with severe COVID-19. In this stage, multiple infections are a major problem and endotoxin removal plays an important role. De Rosa et al. performed PMX-DHP in 12 COVID-19 patients on invasive mechanical ventilation. In COVID-19 patients with sepsis, the SOFA score was improved at 120 h after the procedure, and the endotoxin activity assay (EAA) decreased from 0.78 to 0.60 [4]. Recently, we measured EAA before and after PMX-DHP in COVID-19 patients at our hospital; EAA in patients with high EAA tended to decrease after PMX treatment (unpublished data). Proposed mechanisms of action of PMX-DHP on COVID-19 include cytokine regulation, oxygenation enhancement by removal of activated neutrophils, and adsorption and removal of endotoxins. In addition to the vaccines, antiviral drugs, immunosuppressive agents, and neutralizing antibody therapies that are being applied clinically. However, certain cases may become severe. Subsequently, we initiated a prospective multicenter study. This study is ongoing and we hope to obtain valuable results to provide insight on the apt time to implement. This work was supported in part by Grants-in-Aid for Research from the National Center for Global Health and Medicine (20A-2008, 21A2002). The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

The effects of direct hemoperfusion with polymyxin B-immobilized fiber in patients with acute exacerbation of interstitial lung disease.

BackgroundAcute exacerbation of interstitial lung disease (AE-ILD) causes clinically significant deterioration and has an extremely poor prognosis with high mortality. Recently, several studies reported the effectiveness of direct hemoperfusion with a polymyxin B-immobilized fiber column (PMX-DHP) in patients with AE-ILD as a potential therapy. This study describes the clinical effectiveness and safety of PMX-DHP in patients with AE-ILD. MethodsWe retrospectively reviewed the medical records of 10 patients (11 episodes) with AE-ILD treated with PMX-DHP from January 2018 to June 2019. We compared laboratory and physiologic data of the ratio of partial pressure arterial oxygen to fraction of inspired oxygen (P/F ratio) and level of inflammatory markers before and after implementation of PMX-DHP. ResultsTen patients were included according to the 2016 revised definition of acute exacerbation of idiopathic pulmonary fibrosis (IPF). Nine patients had IPF and one patient had fibrotic nonspecific interstitial pneumonia. Most patients (90.9%) were treated with a steroid pulse, and four patients (36.4%) were treated with an immunosuppressant. The median number of PMX-DHP cycles was 2, and the median duration of each cycle was 6 hours. After PMX-DHP, the mean P/F ratio improved (86 [range, 63–106] vs. 145 [86–260], P=0.030) and interleukin-6 and c-reactive protein decreased (79 [35–640] vs. 10 [5–25], P=0.018 and 14 [4–21] vs. 5 [2–6], P=0.019, respectively). The 30-day mortality rate was 27.3% and the 90-day mortality rate was 72.7%.ConclusionsPMX-DHP treatment improved P/F ratio and reduced inflammatory markers in AE-ILD patients.

PH after the first session of direct hemoperfusion with polymyxin B-immobilized fibers predicts mortality in patients with sepsis and septic shock.

The definition of sepsis was updated to sepsis-3 in February 2016. Currently, direct hemoperfusion therapy using the polymyxin B-immobilized fiber cartridge (PMX-DHP) is widely performed to treat sepsis and septic shock. However, the prognostic factors of PMX-DHPs in patients with sepsis using the new definition are unclear. We retrospectively assessed prognostic factors in patients who had received PMX-DHP therapy for sepsis and septic shock. We included 71 patients with severe infection who underwent PMX-DHP treatment from January 2006 to August 2015 in this study. Participants were re-evaluated according to the criteria of sepsis-3. The patients were divided into two groups based on having survived (n = 59) or not survived (n = 12) for 28 days after PMX-DHP treatment. Clinical data before and after PMX-DHP treatment were compared between the two groups. Non-survivors showed a lower Glasgow Coma Scale (GCS) score before PMX-DHP treatment compared with 28-day survivors [12 (6-14) vs 14 (12-15), P < 0.01]. Furthermore, pH after the first PMX-DHP session was significantly lower in non-survivors than in survivors (7.28 ± 0.23 vs 7.39 ± 0.06, P = 0.03). Multivariate logistic regression analysis showed that only lower pH after the first PMX-DHP session was a predictor of 28-day mortality independent of age, sex, GCS score, and mean arterial pressure (odds ratio per pH of 0.01, 0.93; 95% confidence interval, 0.83-0.99; P = 0.02). The pH after the first PMX-DHP session is an independent risk factor for mortality in patients receiving PMX-DHP for sepsis and septic shock.

Direct hemoperfusion with polymyxin B-immobilized fibre treatment for acute exacerbation of interstitial pneumonia.

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is recognized as an important cause of mortality. AE has also been reported in patients with other interstitial lung diseases such as idiopathic non-specific interstitial pneumonia (NSIP) and interstitial pneumonia associated with collagen vascular disease (CVD). Current therapies such as high-dose corticosteroid with immunosuppressive agents have provided little benefit for AE. Direct hemoperfusion (DHP) with a polymyxin B-immobilized fibre column (PMX) was originally developed for the treatment of endotoxaemia. Recent clinical reports have suggested beneficial effects of PMX-DHP treatment on patients with AE. In this study, we evaluated the effectiveness and safety of PMX-DHP treatment for patients with AE. The clinical records of patients with AE admitted to our intensive care unit between 2006 and 2015 were retrospectively reviewed. Of 54 patients with AE identified from clinical records, 24 were treated with PMX-DHP and 30 were treated without PMX-DHP. The peripheral white blood cell count was significantly decreased (P < 0.001) and the PaO2 /FiO2 (P/F) ratio was significantly improved after PMX-DHP (P = 0.032). While no significant difference was found in the survival proportion between patients treated with and without PMX-DHP, the prognosis of patients with dermatomyositis was significantly improved with the treatment (P = 0.045). Among the PMX-DHP-treated patients, those who received the treatment within 3 days of AE onset tended to have a better prognosis (P = 0.026). The early induction of PMX-DHP treatment may improve the prognosis of patients with AE, especially those with dermatomyositis.

Measurements of procalcitonin facilitate targeting of endotoxin adsorption treatment in febrile neutropenic patients suffering from shock

Immediate initiation of hemoperfusion treatment with polymixin B immobilized fiber (PMX-DHP) is a potent strategy to improve hemodynamics in septic patients with critical circulatory failure. However, it is often difficult to accurately and rapidly differentiate between bacterial infections and non-infectious causes of shock in acutely critically-ill patients. Procalcitonin (PCT) measurements may assist in the early identification of bacterial infection/sepsis and determination of severity in such patients. We present two febrile neutropenic (FN) patients who developed severe shock after chemotherapy for hematological malignancies. PCT levels were markedly elevated in both patients (≥ 10 ng/ml), suggesting a high likelihood of bacterial infectious etiology as the cause of their shock, and thus they were promptly treated with PMX-DHP. Measurements of PCT may facilitate targeting of PMX-DHP treatment among FN patients suffering from shock, which may lead to better prognosis.

Polymyxin-B固定化ファイバーを用いた直接血液灌流療法(PMX-DHP)施行時における利尿機序の検討

In the present study, we applied direct hemoperfusion with polymyxin B-immobilized fiber(PMX-DHP) to patients who developed endotoxin shock after laparotomy, and examined the influence of PMX-DHP on the kidney function. Seven patients were enrolled in this study, whose conditions were matched to the following criteria: 1) endotoxin shock was highly suspected, 2) blood pressure became stable before PMX-DHP was indicated, 3) renal function(demonstrated with creatinine clearance(CCr) and fractional excretion of sodium (FENa)) was proven before the surgery. All patients underwent emergency surgery in Fuji City General Hospital because of perforative peritonitis. A 2-hour session of PMX-DHP was performed on the day of the laparotomy and the second 2-hour treatment was performed the following day. Urine was collected at 2 hours before starting PMX, during the treatment, and 2 hours after PMX-DHP, and urine volume(U-Vol), sodium and creatinine levels of urine were monitored. Sodium and creatinine levels in the serum were measured at the start and end of the PMX-DHP session. Average atrial natriuretic polypeptide (ANP) was obtained using a total of 8 samples from the 14 treatment sessions. Parameters of hemodynamics such as pulmonary capillary wedge pressure(PCWP) were monitored at the start and end of PMX-DHP session. Urine volume increased significantly during and after PMX-DHP. The change in urine volume correlated significantly with the change in CCr during PMX-DHP, and with the change in FENa after PMX-DHP. The change in FENa was significantly correlated with the changes in hemodynamic factors such as PCWP and with the change in serum ANP, but no significant correlation was observed between the change of CCr and the other parameters. In conclusion, the early increase in urine volume with PMX-DHP treatment might be attributable to the increase in glomerular filtration independently of systemic hemodynamic factors.

A Case of Successful Treatment with Polymyxin B-immobilized Fiber Column Direct Hemoperfusion in Acute Respiratory Distress Syndrome after Influenza A Infection

We report a case of acute respiratory distress syndrome (ARDS) after influenza A infection who was successfully treated with combined treatment including direct hemoperfusion with polymyxin B-immobilized fiber (PMX-DHP) column. A 56-year-old Japanese man was admitted to our hospital in January 2010 because of progressive dyspnea, hypoxemia, fever and bilateral diffuse infiltration on chest radiograph after pandemic influenza A infection. His chest computed tomography showed diffuse and patchy bilateral ground-glass opacities, and we diagnosed ARDS after influenza A infection. The patient was successfully treated with PMX-DHP in addition to the treatment with oseltamivir, corticosteroid, sivelestat and antibiotics with mechanical ventilation, and the patient recovered with only minor pulmonary fibrotic change. Although the efficacy of PMX-DHP treatment in patients with acute lung injury (ALI)/ARDS after influenza virus infection is not well established, this treatment could be a possible therapeutic modality in treating the patients with this disease.

Polymyxin B-immobilized Fiber Column Hemoperfusion Treatment for Drug-Induced Severe Respiratory Failure: Report of Three Cases

The effects of direct hemoperfusion with polymyxin B-immobilized fiber (PMX-DHP) treatment for acute exacerbation of interstitial pneumonia have been reported. Here, we report 3 severe cases of drug-induced interstitial lung disease (DI-ILD) that were treated with PMX-DHP. Two DI-ILD cases were caused by methotrexate, and the third case was caused by the herbal medicine sanmotsu-ogon-to. The arterial oxygen tension/inspiratory oxygen fraction ratio improved during PMX-DHP treatment in all 3 patients. Finally, 2 patients survived and 1 died. The study findings indicate that PMX-DHP treatment is a viable option for the management of acute respiratory failure in patients with DI-ILD.

Direct Hemoperfusion Using Polymyxin-B Immobilized Fiber for Septic Shock After Cardiac Surgery

The factors contributing to the efficacy and outcome of direct hemoperfusion using polymyxin-B immobilized fiber (PMX-DHP) after cardiac surgery were investigated. In 23 patients who received PMX-DHP for shock related to infection after cardiac surgery, there were no differences in the pre- and intraoperative clinical data of survivors (n=14) and non-survivors (n=9). Before the PMX-DHP treatment, the clinical assessment values of the survivors and non-survivors, respectively, showed the following significant differences: sepsis-related organ failure assessment score, 9.46+/-2.84 vs 12.89+/-3.37 (P<0.05); number of failed organs, 1.8+/-0.9 vs 3.1+/-1.1 (P<0.05); partial pressure of oxygen in arterial blood/fraction of inspired oxygen ratio, 194+/-118 vs 102+/-29 (P<0.05); and total bilirubin, 2.7+/-2.8 vs 8.7+/-6.5 mg/dl (P<0.05). The systolic blood pressure and catecholamine index in the survivors improved significantly 12 h after PMX-DHP treatment, from 83+/-19 mmHg to 118+/-14 mmHg (P<0.01), and from 20.7+/-11.5 to 14.9+/-8.0 (P<0.05). Conversely, in the non-survivors, only the systolic blood pressure improved significantly, from 74+/-17 mmHg to 118+/-33 mmHg (P<0.001). Prompt initiation of PMX-DHP with drug treatment during the postoperative course of patients with septic shock caused by systemic inflammatory response syndrome related to infection and who are refractory to vasopressor treatment, can improve the disease state before multiple organ failure develops.

Removal of 2‐Arachidonylglycerol by Direct Hemoperfusion Therapy With Polymyxin B Immobilized Fibers Benefits Patients With Septic Shock

Arachidonylethanolamide (AEA) and 2-arachidonylglycerol (2-AG) are endocannabinoids involved in septic shock, and 8-epi prostaglandin F2alpha (F2-isoprostane) is a biomarker of oxidative stress in biological systems. Because the antibiotic polymyxin B absorbs endocannabinoids as well as endotoxins, direct hemoperfusion therapy with polymyxin B-immobilized fibers (PMX-DHP) decreases serum levels of endocannabinoids. To investigate the features of sepsis and determine the proper use of PMX-DHP, we measured the changes in levels of endocannabinoids and F2-isoprostane in patients with septic shock. Twenty-six patients with septic shock, including those with septic shock induced by peritonitis, underwent laparotomy for drainage. Endocannabinoids absorption with PMX-DHP was examined in two groups of patients: patients whose mean arterial blood pressure (mABP) had increased more than 20 mm Hg (responder group; N = 13); and patients iwhose mABP did not increase or had increased no more than 20 mm Hg (non-responder group; N = 13). Levels of AEA did not change after PMX-DHP in either the non-responder or responder groups, whereas levels of 2-AG decreased significantly after PMX-DHP in the responder group, but not in the non-responder group. F2-isoprostane gradually increased after PMX-DHP treatment; on the other hand, levels of F2-isoprostane remained constant in the responder group. Patients with septic shock are under considerable oxidative stress, and 2-AG plays an important role in the cardiovascular status of these patients. The removal of 2-AG by PMX-DHP benefits patients with septic shock by stabilizing cardiovascular status and decreasing long-term oxidative stress.

The Effect of Continuous Veno‐Venous Hemofiltration or Direct Hemoperfusion With Polymyxin B‐Immobilized Fiber on Neutrophil Respiratory Oxidative Burst in Patients With Sepsis and Septic Shock

Neutrophil activates and injures tissues and organs during sepsis or septic shock. Blood purification therapies such as continuous veno-venous hemofiltration (CVVH) and direct hemoperfusion with polymyxin-immobilized fiber (PMX-DHP) have been used for the treatment of sepsis and septic shock, however, the effects of such therapies on neutrophil activation have previously been poorly understood. We sought to evaluate neutrophil reactive oxygen species (ROS), especially H2O2 production, in the pathophysiology of sepsis or septic shock and the effect of CVVH or PMX-DHP on neutrophil ROS. Seven critically ill septic patients requiring CVVH (and 12 matched septic patients who did not require CVVH as control) and seven septic shock patients treated with PMX-DHP were studied. We found that patients with sepsis or septic shock had significantly higher levels of neutrophil ROS compared with normal volunteers (183 +/- 42, 292 +/- 90, and 103 +/- 30) (P < 0.05, and < 0.005). Neutrophil ROS did not change over time in patients treated either with CVVH or without CVVH. In contrast, neutrophil ROS significantly inhibited PMX-DHP treatment in patients with septic shock (pretreatment; 292 +/- 88 vs. post-treatment; 205 +/- 93, P < 0.05). In conclusion, neutrophil ROS was significantly enhanced in the sepsis or septic shock affected patients. CVVH did not affect neutrophil ROS while PMX-DHP significant inhibited neutrophil ROS.

Anandamide absorption by direct hemoperfusion with polymixin B-immobilized fiber improves the prognosis and organ failure assessment score in patients with sepsis

Direct hemoperfusion (DHP) with polymixin B-immobilized fiber (PMX) has been reported to be effective for patients with septic shock. The aim of this study was to clarify the mechanism of PMX-DHP effect on septic shock. The following parameters were measured in septic shock patients who were treated with PMX-DHP: survival rate, sepsis-related organ failure assessment (SOFA) score, acute physiology and chronic health evaluation II (APACHE-II) score, and plasma concentrations of cannabinoids [anandamide (ANA) and 2-arachidonyl glyceride (2-AG)], cytokines [interleukin (IL)-6, IL-8, IL-10], transforming growth factor beta (TGF-beta), and calcitonin gene-related peptide (CGRP)]. The primary end point was mortality from all causes at day 28 after intensive care unit (ICU) admission or discharge. The survival rate of all patients at 28 days after ICU admission was 37.5% (9/24). The survival group showed significantly lower SOFA and APACHE-II scores than the nonsurvival group after PMX-DHP treatment (P = 0.008 and 0.028, respectively). The improved SOFA score group showed a better survival rate than the nonimproved SOFA score group (71.4% versus 23.5%, P = 0.028). Plasma ANA level significantly decreased after PMX-DHP treatment both in the improved SOFA score group and in the survival group. The level of 2-AG, however, showed no significant change in either group. ANA, an intrinsic cannabinoid that induces hypotension in septic shock, is inferred to be the main mechanism of the PMX-DHP effect. Removal of ANA by PMX-DHP could be key to successful septic shock treatment.

Is it true that PMX-DHP can improve lung oxygenation?

Polymyxin B immobilized fiber (PMX-R; Toray industries, Inc) has been developed in Japan for direct removal of endotoxin (PMX-DHP). PMX-DHP is used for treatment of patients with sepsis and septic shock primarily caused by Gram-negative infections, and its effectiveness of hemodynamic changes has been evaluated. In 119 cases (62 ± 16 years old, 82 men and 37 women) treated with PMX-DHP, changes in pulmonary oxygenation before and after PMX-DHP were examined, using PaO2/FiO2 as an oxygenation indicator, separately according to the outcome (80 survivors and 39 who died). Improvement of PaO2/FiO2 was identified in 64% of all cases. In the survival group, there appeared to be a trend for PaO2/FiO2 improvement as blood pressure increased. In the non-survival group, however, no improvement of PaO2/FiO2 was obtained, regardless of an increase of blood pressure. There was no significant correlation between PaO2/FiO2 and the rate of change in endotoxin levels, TNF-α, and IL-6. Granulocyte elastase increased significantly after PMX-DHP treatment in both groups. In the survival group, PaO2/FiO2 appeared to increase as macrophage inflammatory protein (MIP-1) 1-α decreased, suggesting the possibility that changes in MIP-1-α influenced PaO2/FiO2. As the mechanism for the improvement of pulmonary oxygenation by PMX-DHP has been shown clearly, it remains to be examined further.