New Targets for Extracorporeal Blood Purification Therapies in Sepsis.

As highlighted by the last international consensus definition for sepsis and septic shock (sepsis-3), sepsis comes from a complex relationship between a pathogen and a dysregulated host response. To date, the treatment of sepsis is based on antimicrobial treatment, source control, and organ support. Extracorporeal blood purification therapies have been proposed as adjuvant therapies to modulate the dysregulated inflammatory response. These therapies aim mostly at removing inflammatory mediators (cytokines) and endotoxins from the blood. However, so far, they failed to clearly demonstrate an improvement in patient survival when evaluated in randomized trials. Recently, new devices directly targeting the primary determinants of sepsis, e.g., the pathogen itself and the host immune cells, have been developed. This short review aimed at presenting new blood purification devices that have recently been developed to target pathogens and immune cells. For each, we will present the mechanism of action of the therapy and discuss the related literature.

Application and Efficacy of Vitamin E-Bonded Polysulfone Membrane in Acute Blood Purification Therapy.

INTRODUCTION: Acute blood purification therapy (BPT) has been evaluated in the context of intensive care for serious conditions related to systemic inflammation, but its mechanism and efficacy are not fully understood. OBJECTIVE: This study examined the feasibility of using vitamin E-bonded polysulfone membranes (VEPS) for BPT in a LPS-induced rat model of systemic inflammation. METHODS: To evaluate the efficacy of BPT with a VEPS membrane, polysulfone (PS) membranes conventionally used in intensive care were bonded with the antioxidant vitamin E and used in a rat model of lipopolysaccharide (LPS)-induced systemic inflammation. BPT using a PS membrane (PS group) or a VEPS membrane (VEPS group) was performed 6 h after administration of LPS. Extracorporeal circulation was established in normal rats as a control (sham group). Survival rates, histology of lung specimens, and levels of myeloperoxidase (MPO) and high mobility group box-1 (HMGB-1) were examined in each group. RESULTS: Survival rates at 24 h after LPS administration were 100% in the VEPS group and 50% in the PS group. Pulmonary architecture was largely maintained and the level of infiltration of inflammatory cells remained moderate in the VEPS group. Levels of active MPO before and after BPT were significantly higher in the PS and VEPS groups than in the sham group, with no significant differences between the PS and VEPS groups. HMGB-1 levels were significantly elevated after BPT in the PS group. CONCLUSIONS: This study demonstrated that use of the VEPS membrane for BPT increased survival rate and reduced lung injury in a rat model of systemic inflammatory response syndrome (SIRS), suggesting the possible use of VEPS membranes in the treatment of serious conditions related to systemic inflammation.

Extracorporeal Blood Purification Therapies for Sepsis.

Extracorporeal blood purification is proposed as an adjuvant therapy for sepsis, aiming at controlling the associated dysregulation of the immune system, which is known to induce organ dysfunctions. Different therapies have been developed to address certain steps of the immune dysregulation. Most of the available blood purification devices focus on a single target, such as the endotoxin that triggers the immune cascade, or the cytokine storm that causes organ damages. However, the highly adsorptive membrane named oXiris® is a unique 4-in-1 device that combines cytokine and endotoxin removal properties, renal replacement function, and antithrombogenic properties. More recently, promising treatments that focus on the pathogen itself or the immune cells have been developed and are currently under investigation. In this review, we aim to summarize, according to their target, the different extracorporeal blood purification techniques that are already available for use. We will also briefly introduce the most recent techniques that are still under development. Because of its unique ability to remove both endotoxins and cytokines, we will particularly discuss the highly adsorptive preheparinized oXiris® membrane. We will present its properties, advantages, pitfalls, as well as therapeutic perspectives based on experimental and clinical data. Video Journal Club "Cappuccino with Claudio Ronco" at  https://www.karger.com/Journal/ArticleNews/223997?sponsor=52.

Efficacy of continuous plasma diafiltration therapy in critical patients with acute liver failure.

BACKGROUND AND AIMS: Acute liver failure (ALF) is a critical illness with high mortality. Plasma diafiltration (PDF) is a blood purification therapy that is useful for ALF patients, but it is difficult to use when those patients have multiple organ failure or unstable hemodynamics. In these patients, symptoms are also likely to exacerbate immediately after PDF therapy. We developed continuous PDF (CPDF) as a new concept in PDF therapy, and assessed its efficacy and safety in ALF patients. METHODS: Ten ALF patients (gender: M/F 6/4, Age: 47 ± 14) were employed CPDF therapy. The primary outcomes were altered liver function, measured by the model for end-stage liver disease (MELD) score, and total bilirubin and prothrombin time international normalized ratios (PT-INR), 5 days after CPDF therapy. Secondary outcomes included sequential organ failure assessment (SOFA) scores, 5 days after CPDF therapy, and the survival rate 14 days after this therapy. RESULTS: The MELD score (34.5-28.0; P = 0.005), total bilirubin (10.9-7.25 mg/dL; P = 0.048), PT-INR (1.89-1.31; P = 0.084), and SOFA score (10.0-7.5; P < 0.039) were improved 5 days after CPDF therapy. Nine patients were alive, and one patient died because of acute pancreatitis, complicated by ALF. There were no major adverse events related to this therapy under hemodynamic stability. CONCLUSION: In the present study, CPDF therapy safely supported liver function and generally improved the condition of critically ill patients with ALF.

A case of multiorgan failure due to carbamazepine intoxication successfully treated with multimodal blood purification therapy.

Carbamazepine (CBZ) intoxication can occur due to various factors, including drug interactions and over-ingestion. Extracorporeal elimination, particularly through hemodialysis and hemoperfusion, is effective in treating severe carbamazepine intoxication. However, as the effectiveness of various modalities can differ, method selection may be based on a specific clinical situation. A 47-year-old woman who took CBZ for schizophrenia presented to our hospital with episodes of vomiting and consciousness disorder. As the CBZ concentration was > 20 µg/mL, she was admitted to the intensive care unit with a diagnosis of acute CBZ poisoning. She underwent one session of hemoperfusion for 2 h, and her CBZ level decreased from > 20 µg/mL to 6.4 µg/mL. However, she developed acute kidney and liver injuries 2 days after admission and underwent intermittent hemodialysis, plasma exchange, continuous hemodiafiltration (CHDF), and online HDF, depending on her condition. Her general condition improved, and she was transferred to the psychiatric department. To our knowledge, no case reports have described severe acute CBZ poisoning in a patient who developed multiorgan failure to date, which was successfully treated with multimodal blood purification therapy. When treating severe CBZ intoxication, blood purification therapy should be tailored to the changing pathophysiology of the condition.

Use of the Superficialized Brachial Artery as Vascular Access for a Patient with Myasthenia Gravis with a Frequent Need for Plasmapheresis: A Case Report.

A 41-year-old woman diagnosed with seronegative myasthenia gravis struggled to maintain remission for a decade, facing crises every 3 months for several years. After repeated apheresis using a non-tunneled non-cuffed central venous dialysis catheter (NTNCC), complications such as catheter-related thrombus in the internal jugular veins and morbid obesity from steroids made the insertion of NTNCC increasingly difficult, leading to consideration of an alternative permanent vascular access (VA) approach. Thus, we created a subcutaneously superficialized brachial artery as the VA, which allowed the patient to undergo safe and uninterrupted apheresis therapy.

Capnocytophaga canimorsus Meningitis Complicated by Septic Shock: The Use of Extracorporeal Blood Purification Techniques.

Capnocytophaga canimorsus is a Gram-negative bacterium, commonly found as a commensal germ in the oral cavity of dogs and cats. It is an opportunistic pathogen, but, in specific situations, it can cause very severe diseases, including arthritis, pleuritis, endocarditis, sepsis, and, in extremely rare cases, meningoencephalitis. The predisposing situations include immunosuppression, liver cirrhosis, splenectomy, hemochromatosis, beta thalassemia major (Cooley's anemia), and alcohol abuse. In this report, we describe the case of a 48-year-old male patient, with a medical history of several predisposing conditions, who developed a severe case of meningoencephalitis caused by C. canimorsus, following a dog bite on his hand. The patient was successfully treated for his meningitis, but subsequently he developed a hospital-acquired septic shock from Acinetobacter baumannii, which was treated with targeted antibiotic therapy and sequential extracorporeal blood purification therapies using Oxiris™ and Toraymyxin™ hemofilters.

Hepatic failure in pregnancy successfully treated by online hemodiafiltration: Chronic hepatitis B virus infection without viral genome mutation.

A 23-year-old nulliparous woman, a hepatitis B virus (HBV) carrier with stable liver functions, presented with exacerbation of viral replication (HBV DNA level >9.0 log copies/mL) in gestational week 26. During the subsequent follow up without antiviral therapy, she was hospitalized with progression to hepatic failure in gestational week 35. Following initiation of antiviral therapy with lamivudine, emergent cesarean delivery was conducted for fetal safety. Liver atrophy and persistent hepatic encephalopathy (stage 2) necessitated artificial liver support (ALS) involving online hemodiafiltration (HDF) and plasma exchange. She regained full consciousness after the sixth online HDF session. ALS was terminated after the seventh online HDF session. On day 33 of hospitalization, she was discharged home without sequelae. Genetic analysis of the HBV strain isolated from her serum showed that this strain had genotype C. Direct full-length sequencing identified no known mutations associated with fulminant hepatitis B. HBV-related hepatic failure observed in the present case might have been related to perinatal changes in the host immune response.

A Case of Refractory Heel Ulcer Complicated by Moderate Osteomyelitis and Cellulitis Successfully Treated with Rheocarna.

Revascularization surgery was first considered for the treatment of ulcers in patients with critical limb ischemia (CLI). However, it may not be indicated for patients with severe infections or peripheral vascular occlusions. Although blood purification therapy is adjuvant therapy for such patients, it is not yet widely used due to insurance coverage. We report a case of a refractory heel ulcer with moderate osteomyelitis and cellulitis that was not amenable to revascularization. Treatment with the adsorptive blood purifier rheocarna® (Kaneka Corporation; Osaka, Japan) resulted in complete epithelialization of the ulcer and control of inflammation. Although this case required careful follow-up, we believe rheocarna might be a promising treatment option for patients with CLI who do not respond to revascularization. Rheocarna could improve peripheral blood flow and control inflammation by improving antibiotic drug delivery.

Rheocarna® as an alternative therapeutic option for patients with chronic limb-threatening ischemia: A case report.

Recently, a new low-density lipoprotein apheresis device (Rheocarna®; Kaneka Corporation, Osaka, Japan), a blood purification therapy, was approved in Japan for managing chronic limb-threatening ischemia with refractory ulcers. Here, we describe a case of chronic limb-threatening ischemia that was treated with the Rheocarna. A 65-year-old Asian man with an ulcer on the right heel was admitted to our hospital. Angiography revealed chronic total occlusion with severe calcification of the anterior tibial, peroneal, and posterior tibial arteries. The patient underwent distal bypass of the saphenous vein; however, the bypass was occluded in the early postoperative period. The Rheocarna was used, and the ulcers improved significantly postoperatively. Although endovascular treatment was eventually performed on the occluded bypass graft to completely heal the ulcer, the Rheocarna could be an alternative treatment option in challenging cases of chronic limb-threatening ischemia.

Severe Clozapine Poisoning Treated by Extracorporeal Blood Purification Therapy.

Clozapine is a frequently used antipsychotic that, in case of overdose, can cause severe adverse side effects, such as hematological, cardiovascular, and neurological complications. As there is no specific antidote or reversal agent available, extracorporeal techniques such as CytoSorb hemoadsorption might represent a viable option, having already been used in a variety of intoxication scenarios with favorable rates of success. A 56-year-old male was admitted with generalized epileptic seizures and arrhythmias following ingestion of clozapine in a suicide attempt (5,000 mg). Subsequently, conventional supportive care was initiated. To accelerate drug removal, continuous veno-venous hemodiafiltration including the application of CytoSorb hemoadsorption therapy was started. Serial measurements confirmed rapid reduction of clozapine plasma levels. The patient remained hemodynamically stable throughout this period. Furthermore, there were no cardiac arrhythmias detected and liver values were normal. The patient improved and was successfully extubated 3 days after admission with good vigilance and no residual neurological abnormalities. This is the first clinical case report on the use of CytoSorb hemoadsorption in severe clozapine intoxication which helped quickly and efficiently reduce clozapine levels to nontoxic serum levels while preserving organ function. Therefore, CytoSorb might represent an alternative treatment modality to be considered for potentially lethal clozapine intoxications.

Antimicrobial Exposure in Critically Ill Patients with Sepsis-Associated Multi-Organ Dysfunction Requiring Extracorporeal Organ Support: A Narrative Review.

Sepsis is a leading cause of disability and mortality worldwide. The pathophysiology of sepsis relies on the maladaptive host response to pathogens that fosters unbalanced organ crosstalk and induces multi-organ dysfunction, whose severity was directly associated with mortality. In septic patients, etiologic interventions aiming to reduce the pathogen load via appropriate antimicrobial therapy and the effective control of the source infection were demonstrated to improve clinical outcomes. Nonetheless, extracorporeal organ support represents a complementary intervention that may play a role in mitigating life-threatening complications caused by sepsis-associated multi-organ dysfunction. In this setting, an increasing amount of research raised concerns about the risk of suboptimal antimicrobial exposure in critically ill patients with sepsis, which may be worsened by the concomitant delivery of extracorporeal organ support. Accordingly, several strategies have been implemented to overcome this issue. In this narrative review, we discussed the pharmacokinetic features of antimicrobials and mechanisms that may favor drug removal during renal replacement therapy, coupled plasma filtration and absorption, therapeutic plasma exchange, hemoperfusion, extracorporeal CO2 removal and extracorporeal membrane oxygenation. We also provided an overview of evidence-based strategies that may help the physician to safely prescribe effective antimicrobial doses in critically ill patients with sepsis-associated multi-organ dysfunction who receive extracorporeal organ support.

Atypical drug-induced hypersensitivity syndrome with multiple organ failure rescued by combined acute blood purification therapy: a case report.

BACKGROUND: Drug-induced hypersensitivity syndrome (DIHS), including Stevens-Johnson syndrome (SJS), is a severe rash that often develops 2-6 weeks after the intake of the causative drug; however, its diagnosis is sometimes difficult. This article describes a case in which a patient with DIHS-induced multiple organ failure was successfully treated with blood purification therapy. CASE PRESENTATION: A male patient in his 60s was admitted to our hospital with autoimmune encephalitis. The patient was treated with steroid pulse therapy, acyclovir, levetiracetam, and phenytoin. From the 25th day, he presented with fever (≥ 38 °C) as well as miliary-sized erythema on the extremities and trunk, followed by erosions. DIHS and SJS were suspected; accordingly, levetiracetam, phenytoin, and acyclovir were discontinued. On the 30th day, his condition further deteriorated, and he was admitted to the intensive care unit for ventilatory management. The next day, he developed multi-organ failure and was started on hemodiafiltration (HDF) for acute kidney injury. Although he presented with hepatic dysfunction and the appearance of atypical lymphocytes, he did not meet the diagnostic criteria for DIHS or SJS/toxic epidermal necrolysis. Therefore, he was diagnosed with multi-organ failure caused by severe drug eruption and underwent a 3-day treatment with plasma exchange (PE) in addition to HDF. Accordingly, the patient was diagnosed with atypical DIHS. After being started on blood purification therapy, the skin rash began to disappear; moreover, the organ damage improved, with a gradual increase in urine output. Eventually, the patient was weaned off the ventilator and transferred to the hospital on the 101st day. CONCLUSIONS: HDF + PE could effectively treat multi-organ failure caused by atypical DIHS, which is difficult to diagnose.

Continuous blood purification in patients with pheochromocytoma crisis: A case report.

Key Clinical Message: Pheochromocytoma crisis accompanied by multi-organ failure necessitates prompt and comprehensive interventions, including VA-ECMO, CRRT, and others. Successful laparoscopic tumor resection promotes favorable outcomes and recovery. Abstract: Pheochromocytoma crisis is commonly associated with high mortality, high surgical risk, and rapidly fatal complications. This article presented successful treatments and nursing experiences in a patient with pheochromocytoma who developed cardiogenic shock and multiple organ failure. We report a case study of a 32-year-old female patient who experienced pheochromocytoma crisis accompanied by multiple organ failure. Initial assessment of bedside echocardiography revealed an extremely low left ventricular ejection fraction of 8%. The patient was promptly resuscitated though tracheal intubation and venoarterial extracorporeal membrane oxygenation (VA-ECMO), in conjunction with continuous renal replacement therapy (CRRT), alpha-blockers, beta-blockers, and other pharmacological interventions to manage blood pressure and heart rate. These interventions resulted in a remarkable increase in the left ventricular ejection fraction of 67%. However, the patient subsequently developed severe sepsis, which may have been caused by the intubation procedure, necessitating the discontinuation of VA-ECMO while maintaining CRRT. Close monitoring of plasma catecholamine metabolite level, hemodynamic index, inflammatory marker, liver and kidney functions, and electrolytes during CRRT support allows for evaluating the efficacy of these measures and assessing the impact of CRRT on pheochromocytoma crisis. Eventually, the patient successfully underwent laparoscopic resection of a large pheochromocytoma, leading to favorable prognosis and a successful recovery. Continuous blood purification therapy can effectively eliminate catecholamines and their byproducts from the plasma, stabilize hemodynamics, improve heart, liver, and kidney functions, significantly reduce inflammatory cytokine levels significantly, and extend the surgical window for patients.

Therapeutic apheresis in sepsis.

Sepsis is a leading cause of morbidity and mortality worldwide. Dysregulated immune response to infection is a hallmark of sepsis, leading to life-threatening organ dysfunction or even death. Advancing knowledge of the complex pathophysiological mechanisms has been a strong impetus for the development of therapeutic strategies aimed at rebalancing the immune response by modulating the excess of both pro- and anti-inflammatory mediators. There is a wealth of preclinical data suggesting clinical benefits of various extracorporeal techniques in an attempt to modulate the exaggerated host inflammatory response. However, the evidence base is often weak. Owing to both an advancing comprehension of the pathophysiology and the increased quality of clinical trials, progress has been made in establishing extracorporeal therapies as part of the general therapeutic canon in sepsis. We aim for a comprehensive overview of the technical aspects and clinical applications in the context of the latest evidence concerning these techniques.

Hemodiafiltration combined with polymyxin B-immobilized fiber column direct hemoperfusion is effective for acute postoperative exacerbation of interstitial pneumonia: a case report.

BACKGROUND: Postoperative acute exacerbation of interstitial pneumonia has a high mortality rate; however, its treatment methods have not been standardized. CASE PRESENTATION: A 72-year-old man with rheumatoid arthritis developed acute respiratory failure about 3 weeks after lung cancer surgery. There were increased diffuse frosted shadows in both lung fields. His condition was diagnosed as an acute exacerbation of interstitial pneumonia associated with rheumatoid arthritis, and he was started on steroid pulse therapy; however, his respiratory condition deteriorated. He was urgently intubated and started on veno-venous extracorporeal membrane oxygenation. Further, intensive care, including blood purification therapy, was initiated. The blood purification therapy comprised a combination of hemodiafiltration and 6-h polymyxin B-immobilized fiber column direct hemoperfusion. The patient was weaned off veno-venous extracorporeal membrane oxygenation, extubated, and discharged from the intensive care unit on the ninth day. CONCLUSIONS: Blood purification therapy was effective for acute exacerbation of interstitial pneumonia.

Plasma filtration with dialysis for the treatment of capillary leak syndrome occurring secondary to surgery for colon cancer-related perforating peritonitis.

The use of plasma filtration with dialysis (PDF) may be considered when treating the acute phase of capillary leak syndrome (CLS). To the best of our knowledge, this is the first report using PDF for CLS.

A novel anticoagulant affinity membrane for enhanced hemocompatibility and bilirubin removal.

Affinity membrane is widely employed to promote specific adsorption of toxins and reduce the blood purification therapeutic time. However, it suffers from insufficient toxin binding and low hemocompatibility. Herein, a novel anticoagulant affinity membrane (AAM) was developed to clear bilirubin from human blood in a pore-flow-through way. Firstly, a nylon net membrane with a regularly arranged pore as the matrix was coated with poly(pyrrole-3-carboxylic acid) via chemical vapor deposition (CVD) method. Then, poly(L-arginine) (PLA) as a highly specific ligand of bilirubin, was immobilized onto the surface of the composited membrane after the modification of heparin. Owing to the 3-dimensional molecular architecture of PLA, up to 86.1 % of bilirubin was efficiently cleared. Besides, the AAM exhibited effective anticoagulant activity in the measurement of clotting time, with suppressed thrombus formation, low hemolysis ratio, minimized platelet and leukocyte adhesion, and excellent biosafety. Therefore, the AAM has enormous potential in blood purification therapy for enhancing hemocompatibility and bilirubin removal.

Nursing effect of continuous blood purification therapy in treatment of severe sepsis.

OBJECTIVE: To explore the nursing effect of continuous blood purification therapy in the treatment of severe sepsis patients. METHODS: A total of 142 patients with severe sepsis in our hospital were divided into two groups, 70 patients in the experimental group who received an optimize nursing plan, while 72 patients in the control group were given routine nursing intervention. The SF-36 questionnaire, nursing satisfaction and serious adverse events and complications were collected. RESULTS: The nursing intervention effect of the two groups after intervention were improved before intervention (P<0.05), and the patient's quality of life between the two groups (SF-36 questionnaire) in the experimental group was increased compared to that of the control group after nursing intervention. The nursing satisfaction scores of the experimental group were obviously improved after receiving optimize nursing intervention, and the scores in the experimental group were much higher than in the control group after receiving the intervention, namely (P<0.05). Moreover, the occurrence of serious adverse events and complications in the experimental group was decreased compared to that in the control group, especially the occurrence of acid base imbalance (P<0.05). CONCLUSION: The patients with severe sepsis who received continuous blood purification therapy and optimized nursing intervention had shortened ICU hospitalization time, reduced mortality and complication rates, and improved nursing satisfaction and quality of life.