The Japanese have the greatest longevity in the world. Therefore, the provision of welfare and medical services for older people in Japan, is of great interest to many countries. What kind of policy for medical services and welfare should we have as the birthrate declines and the population ages? Firstly, we need primary care in the medical service. In terms of well-being, I think that we need to develop welfare products by using highly advanced technology and make them available so people can enjoy their older years. Of course the role of the sensory organs is of great significance for people to live happily throughout their lives. We need to think carefully about this aspect of the well-being of older people.

This review outlines the recent advances in acute blood purification in children. Advances in acute blood purification in children have occurred as a result of more-adaptable equipments and better techniques. At present, the extracorporeal blood purification would be applied to small pediatric patients with several kinds of critically ill conditions. To improve the prognosis of these children, more sophisticated blood purification techniques based on the better understanding of the pathophisioloy of ill conditions will be required. Also, a clinical manual for the technique of acute blood purification in children is essential to prepare for standardization.

In critical care medicine, renal replacement therapy is certainly needed. Of the available renal replacement therapies, continuous renal replacement therapy (CRRT) is frequently used for critically ill patients. However, there are few decisive studies of CRRT in the intensive care unit. It is important to establish whether CRRT really has advantages over other possibilities because it is expensive and requires many medical engineers. Here, examples of typical cases are presented and several meta-analyses from the literature are examined. From these data, it is concluded that CRRT is indeed efficient for patients suffering from either cardiogenic or septic shock.

Acute care is accompanied by its own characteristics, different from chronic care. Acute care demands prompt decisions from the medical staff and in most cases, it is necessary to perform treatment immediately with limited resources and people. Because of this, it is not always possible to perform the fundamental process of “explanation and consent”, which is the basis of modern medicine, in an emergency situation. This can be accepted as an “emergency rule”, but efforts should be made not to rely on this. The situation should be explained to the patient and/or family without delay and it is vital to discuss the content of the treatment to be performed. Especially in the case where developing medicine has been chosen, it becomes necessary to completely express one’s intentions. After careful consideration with the patient and/or the patient’s family regarding the patient’s QOL, the situation may arise where a decision must be made not to start treatment (withholding) or treatment once started may be cancelled (withdrawing). Here, the medical care giver is asked to make an “interpretation of life”.

These 10 years, Japanese hospitals have made efforts to prevent adverse events for patient safety, and some results have been carried out. JCQHC (Japan Council for Quality Health Care) that has been accredited hospitals also receives information on adverse events from hospitals which are mandated legally to report serious events. According to this reporting system of JCQHC, during 2009, 1895 cases of serious adverse events were reported from 273 hospitals. Among them, 788 cases were from tertiary care hospitals. 8.2％ patients were died and 40％ were injured. Accumulated cases have been applied not to repeat these accidents in other hospitals.

There is no clinical evidence for the effectiveness of blood purification for treatment of ALI/ARDS. It has been demonstrated that removal of inflammatory mediators that cause lung parenchymal injury and appreciate management of lung water by continuous renal replacement therapy (CRRT) result in improvement of impaired oxygenation in ALI/ARDS patients. Therefore, a large number of studies have been performed to clarify the precise mechanisms of the validity of blood purification for treatment of ALI/ARDS. In addition, for further utilization of CRRT for ALI/ARDS, conditions in which CRRT is performed, including the method used (hemodialysis/hemodiafiltration/hemofiltration), replacement volume, duration and fiber materials of the column, have been investigated. Moreover, direct hemoperfusion with a polymyxin B-immobilized fiber column (PMX-DHP) has been reported to improve oxygenation in ALI/ARDS patients. Therefore blood purification has a possible role in the treatment of ALI/ARDS. Further examination must be carried out to elucidate the effectiveness of blood purification for treatment of ALI/ARDS with due consideration of effects of medications and settings of mechanical ventilation.

Combination of plasma exchange (PE) and hemodiafiltration (HDF) was performed as an artificial liver support (ALS) for fulminant hepatic failure. The indication of PE according to national health insurance was limited to 10 times for fulminant hepatitis（FH）and 7 times for acute liver failure (ALF). Although the simple PE was not enough to recovery from hepatic coma, HDF was combined to purify the middle molecules included causal substances of hepatic coma. Extended daily HDF was performed with high volume filtrate (2～3L/hr) and high flow dialysate (500mL/min). When the ALF was complicated to post operative/traumatic or septic patients, the simple HDF during transfusion of fresh frozen plasma was started before PE. The indication of HDF according to national health insurance was limited to 10 times in month for 3 months. The mortality rates in our hospital were 54％ in 68 cases of FH and 68％ in 38 cases of ALF. While the ALS for FH was started from severe type of acute hepatitis, it should be started early for ALF in cases with thrombocytopenia.

Cytokines play a pivotal role in severe sepsis and can lead to the development of tissue damage, metabolic acidosis, hypotension and even death. Uuseful convective removal for mediators from the human circulation has not been achieved to date, although many cytokines have a molecular weight of 20-30kD which is below the theoretical cut-off point of the commercial membranes currently used. On the other hand, adsorption has been identified as a major mechanism for cytokine removal both in vitro and in vivo；nevertheless the membranes used are not specifically designed. Recently new high cut-off membranes or new adsorbing-membranes have developed for septic acute kidney injury；however, there is no clinical-protocol design of taking the choice of the membrane into account. The ability of HMGB1 adsorption for AN69ST was extremely high according to the report of the HMGB1 removal by Dr. Yumoto et al. The removal of the substance such as HMGB1 which is very well adsorbed to the AN69ST membrane could be maximized to blood flow rate when using adsorption membrane, but when using high cut-off membrane the removal would be limited within the filtration flow rate. As to adsorption mechanism, there is the report that the adsorption reaches saturation in a short time outside Japan. However, a quantity of adsorption or adsorption time will depends on the degree of fitting the mediator to membrane together well. In this review, we reconsidered the effective removal of the causative mediators based on the principle of the hemofiltration taking the in vitro experiment for the removal of HMGB1 as an example.

Sepsis is the major cause of acute kidney injury (AKI) in one-third of AKI patients requiring renal replacement therapy (RRT). Septic AKI has high morbidity and high mortality, with the latter being 60％. The annual incidence of AKI requiring RRT is 13.3 per 100,000 people in Japan. Thus, septic AKI is now considered as one of the most important clinical problems especially in intensive care units. Early goal-directed therapy, studies of new biomarkers, and refinement of RRT have been conducted as an attempt to prevent and/or alleviate septic AKI. The pathophysiology of septic AKI is complex and multifactorial. Recent studies have demonstrated strategies targeting vascular permeability, oxidative stress, and inducible nitric oxide synthase (iNOS) that can alleviate septic AKI. In addition, the regulation of Toll-like receptor (TLR) 9, one of TLRs starting innate immunity, has been reported to improve septic AKI and mortality through avoidance of immune suppression. This review provides an update on the pathophysiology of septic AKI with focus on 3 categories: renal hemodynamics, substantial renal injury, and innate immunity.

As a specific character for a continuous blood purification therapy (: CBP) in the pediatric category, it is a treatment under the low volume of blood flow and it occurs with the amount of blood circulation for extracorporeal circulatory volume more frequently in comparison. Hence, this CBP should be executed under the easier environment of circuit coagulation. In this thesis, we identified the prerequisites for CBP with the viewpoint of safety assurance and the measures to help prevent circuit coagulation by reviewing the factors for circuit coagulation and analyzing the structure of the currently used circuits that are designed for children. Based on our results, we have made some suggestions concerning this matter. These suggestions include omitting a pillow, installing an injection site for anticoagulation drug ahead of the blood pump and closer to the blood removal portion, and omitting the drip chamber for arterial side selectively.

Nurses play a particularly important role in continuous hemodiafiltration (CHDF) of acute blood purification therapies because it is continuously conducted for severe patients. Thus, we examined what nurses working in the ICU thought about the use of CHDF at this time. The results included both positive and negative thoughts, including 6 items, respectively, as a background of each thought. The positive thoughts of CHDF were contributed by sufficient medical safety measures such as education, manual preparation, information sharing, and the promotion of team health care. Meanwhile, negative thoughts were caused by considering troubleshooting as one’s weak point and marked anxiety. In order to resolve such anxiety, it is necessary to reinforce medical safety measures, and provide bedside education in coordination with experienced nurses, physicians, and MEs for nurses to realize team health care.

Direct hemoperfusion with polymyxin-B immobilized fiber (PMX-DHP) developed and currently in use in Japan, has not yet been evaluated abroad. We performed a retrospective study to reevaluate PMX-DHP for severe sepsis or septic shock patients in our intensive care unit. Objective and Method: Sepsis was diagnosed according to the criteria of American College of Chest Physicians and Society for Critical Care Medicine Consensus Conference Committee. We enrolled 301 patients in whom PMX-DHP has been performed for severe sepsis and septic shock from 1994 to 2010. These patients were allocated into 2 groups: those who survived for at least 28 days after the start of PMX-DHP therapy (S group: 201) and those who did not (NS group: 100). Background factors (age, gender, acute physiology and chronic health evaluationⅡscore, sepsis-related organ failure assessment score, Goris MOF score), hemodynamics (blood pressure, PaO2/FIO2 ratio, catecholamine requirement), inflammatory mediators (IL-6, IL-1ra), endothelial related markers (PAI-1) and procalcitonin levels were examined in each group. Results: On the background factors, only Goris MOF score showed a statistically significant difference among the groups. Blood pressure and PaO2/FIO2 ratio both improved markedly immediately after PMX-DHP. Also, the average required amount of catecholamines decreased after PMX-DHP. IL-6, IL-1ra and PAI-1levels decreased immediately after PMX-DHP in both groups. Conclusions: We confirmed an improvement in pulmonary oxygenation and hemodynamic parameters using PMX-DHP for severe sepsis and septic shock patients. The levels of various inflammatory mediators decreased using PMX-DHP, but we did not find any correlation between these changes and outcome.

We conducted a prospective, randomized study to compare acetate-free dialysate with conventional acetate-containing dialysate for the treatment of acute kidney injury (AKI). Forty patients with AKI who required intermittent renal replacement therapy (IRRT) were treated with either acetate-free dialysate (acetate-free group; AF-group) or acetate-containing dialysate (acetate-containing group; AC-group). IRRT, including hemodialysis and hemodiafiltration, was performed with a dialysate flow rate of 500mL/min. Baseline characteristics of the patients in the two treatment groups were similar. The duration of renal recovery was significantly shorter in the AF-group than in the AC-group (19.0±5.8 vs. 14.6±9.4 days, respectively; p＜0.05). The total number of treatments per patient was significantly lower in the AF-group compared to the AC-group (6.9±3.1 vs. 8.9±3.2 sessions/patient, respectively；p＜0.05). Similarly, hospital stay length was significantly shorter in the AF-group than in the AC-group (28.2±8.3 vs. 36.8±12.1 days, respectively；p＜0.05). The pH and bicarbonate concentrations were significantly higher in the AF-group than in the AC-group during the study period. Our results suggest that compared with conventional acetate-containing dialysate, acetate-free dialysate may accelerate renal recovery in patients with AKI.

In the field of emergency and critical care, continuous hemodiafiltration (CHDF) becomes the very important blood purification therapy. However, currently, CHDF conditions including the type of blood purification device vary among hospitals. We established the Yamanashi CHDF Standardization Working Group (WG), and investigated methods to rinse circuits, including blood purification devices, the optimal activated clotting time (ACT) during anti-coagulant therapy, and operational conditions in a survey regarding CHDF conditions in each hospital located in Yamanashi Prefecture. We recommended that blood purification devices and circuits be rinsed in 2,000mL of fluid and 500mL of anti-coagulant-containing solution in reference to the package inserts, and that the target ACT be established as 140 to 200 seconds on the exsanguination side and 180 to 230 seconds on the return side. In addition, the water balance should be regulated with the substitution fluid volume. However, these should be inspected more. It is also possible to standardize other CHDF conditions through discussion. CHDF conditions should be promptly standardized.

Endotoxin activity assay (EAA) is an ex vivo diagnostic test utilizing the biological response of patient neutrophils. Neutrophil gelatinase-associated lipocalin (NGAL) is a new acute kidney injury (AKI) biomarker produced not only by renal tubular epithelial cells but also by neutrophils. To date, several investigations have elucidated the role of neutrophil activation in AKI. Nevertheless, it remains unclear whether these assays are influenced by the condition of AKI. We measured EA values and plasma NGAL in 36 severe AKI patients who needed renal replacement therapy. Results show that the degree of renal dysfunction did not significantly influence EA values. Nine patients who had severe gram-negative rod infections that eventually caused septic shock showed significantly higher EA values and plasma NGAL levels. The combination of EAA and plasma NGAL measurement was able to detect septic shock with high sensitivity and specificity.

[Background] The high mobility group box 1 protein (HMGB1) is an alarmin of lethal systemic inflammation. Thus, HMGB1 has been recognized as a therapeutic target；however, no drugs or devices are currently in practical use. We hypothesized that hemofilters composed of porous or cytokine-adsorbing membranes could remove HMGB1 from the blood. [Methods] The test solution contained 100μg of HMGB1 and 35g of albumin in 1000mL of a substitution fluid. Experimental hemofiltration was conducted for 360min in a closed loop circulation system, and the sieving coefficient (SC) and ultrafiltrate and solution clearance rates of HMGB1 were calculated. We selected internationally available membranes：high cut-off (HCO), surface-treated polyacrylonitrile (AN69ST), three types of polymethylmethacrylate (PMMA), two types of polysulfone (PS) membranes and tubing were tested. [Results] AN69ST showed the highest capacity to adsorb HMGB1；it adsorbed nearly 100μg of HMGB1 in the initial 60min and showed a markedly high clearance rate of 60.8±5.0mL/min at 15 min. PMMA membranes, N, SX and BG, showed rates of 25.8±4.8, 23.3±8.3 and 24.0±8.9 mL/min, respectively. FX, SH and HCO showed rates of 7.0±9.1, 10.1±5.7 and 18.7±4.4mL/min, respectively. Although the highest sieving coefficient for HMGB1 was obtained with HCO, which correlated with a constant filtrate clearance rate, albumin loss was observed. [Conclusion] This is the first in vitro study to demonstrate that the adsorption mechanism of hemofiltration is the most important principle to remove HMGB1.

During continuous blood purification (CBP) therapy, the temperature of the blood fluctuates with changes in certain conditions between blood transmission and removal. In this context, we investigated the change in temperature of each circuit part of the CBP apparatus and the calorific loss with changes in the blood circulation rate (Qb), dialysate flow rate (Qd), replacement flow rate (Qs), and in the temperature of the dialysate and replacement fluids(warmer temperature setting of 37℃), under conditions where blood temperature was simulated as 37℃ and room temperature as 27℃. Among the circuit parts, heat loss was significantly high in the hemofilter, whereas no heat loss was observed in the air trap chamber. The heat loss increased in direct proportion to increased blood circulation under specific conditions. When the fluids and diasylate used in the CBP process are not heated, hyperthermia increases at 30-50cal/min with every increase of 0.5L/h in Qd or Qs. In contrast, when the fluids and dialysate are appropriately heated, hyperthermia decreases with approximately 30cal/min of heat loss with every increase of 0.5 L/h in Qd or Qs.

Continuous renal replacement therapy (CRRT) has emerged as the preferred dialysis modality for critically ill patients with acute kidney injury, particularly for those with hemodynamic instability. Anticoagulation is necessary for effective delivery of CRRT. However, it has been reported that CRRT filter and circuit survival are suddenly diminished due to unexplained coagulation. A retrospective study was conducted of CRRT cases using polysulfone synthetic hemofilters that suddenly had to be discontinued due to unexplained coagulation. In our center, three different types of polysulfone synthetic hemofilters are used: AEF-07, SH-0.8, and D-30NR. The reasons for discontinuation due to coagulation were different for each type of hemofilter. In AEF-07, arterial tube pressures were increased and in D-30R, venous tube pressures were increased. In all three types of hemofilters, decreases in filtration pressures were found. However, when one filter was replaced with a different type, no unexplained coagulation occurred. From this retrospective evaluation, it was concluded that when sudden unexplained coagulation occurred, replacement of one of the three types of polysulfone synthetic hemofilters with a different type would be the preferable solution.

A 78-year-old man was referred to our department with acute kidney insufficiency (AKI). He had undergone endoscopic retrograde cholangio pancreatography (ERCP) for obstructive jaundice. After ERCP, he developed severe acute pancreatitis. His renal function, respiratory condition, and level of consciousness gradually worsened. We started sustained low-efficiency dialysis with filtration (SLED-f), expecting improvement of his AKI and respiratory condition, and removal of middle molecular weight substances. Following were the parameters for SLED-f: time, 6h; dialyzer PMMA membrane, 2.1m²; QB (blood flow rate), 100mL/min; QD (dialysate flow rate), 300mL/min; QF (hemofiltration flow rate), 1.2L/h with post-dilution. After three sessions of SLED-f and four sessions of intermittent hemodialysis, his respiratory condition and level of consciousness gradually improved. Contrary to our expectations, there were no changes in interleukin-6 before and after hemodialysis. SLED-f was performed and hemodynamic stability was maintained. We allowed the patient to stay in the hospital ward not in the ICU, thus enabling diagnostic imaging examinations.

A 79 year-old man was admitted to our hospital and diagnosed with a low rectal adenocarcinoma. He was underwent a low anterior resection but subsequently developed pan-peritonitis due to an anastomotic leak. He was operated again but developed sepsis and acute kidney injury. Blood purification therapy was chosen against acute kidney injury, sepsis and extreme hypercytokinemia. Continuous hemodiafiltration (CHDF) using polymethyl methacrylate (PMMA) hemofilter was carried out, but he fell shock immediately and responded transiently to rapid transfusion and catecholamines. On the next day, started PMMA-CHDF, he fell shock again with decline in systemic vascular resistance. Blood pressure doesn’t respond to escalating dose of catecholamine but recover from shock by retransfuion. Laboratory data showed that number of monocytes was upregulated, but number of eosinophils nor IgE was not increased. After changed the hemofilter to Polysulfone menbrane, CHDF was performed without any problem. PMMA hemofilter is thought to have high biocompatibilities and to be safe. In the present case, hyper-reaction against PMMA hemofilter was thought to be the cause of refractory shock. Monocyte might play key role of hyper-reaction against PMMA hemofilter.

The oxazolidinone linezolid is an antibacterial drug used for treating infections caused by methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus spp. Linezolid clearance is known to occur via non-enzymatic reactions and non-renal elimination and can also be achieved by renal replacement therapy involving the metabolites of linezolid. Therefore, the adjustment of linezolid dosage is not needed in patients with renal dysfunction and in those undergoing renal replacement therapy. However, information on linezolid clearance in patients undergoing continuous renal replacement therapy is limited. Hence, we measured linezolid clearance in patients undergoing continuous venovenous hemodiafiltration (CVVH). We found that the plasma concentration of linezolid was high in 3 patients. The elimination half-life and total clearance of linezolid were 13.0h, 11.0h, and 11.0h and 4.2L/h, 3.6L/h, and 4.5L/h, respectively, in the 3 patients. These results suggested that linezolid was not always removed by CVVH. Furthermore, 2 patients developed thrombocytopenia as a frequent side effect of linezolid. The high plasma concentration of linezolid might have induced the thrombocytopenia. Hence, clinicians should be aware of the side effect of linezolid in patients undergoing CVVH.

Fulminant myocarditis is a potentially fatal disease characterized by sudden onset of severe hemodynamic compromise and marked myocardial inflammation. Here we report the successful management of a patient with fulminant myocarditis using percutaneous cardiopulmonary support (PCPS) with plasma exchange (PE) and continuous hemodiafiltration (CHDF). A 9-year-old girl presented with severe fatigue, abdominal pain, and sustained vomiting following fever. Despite fluid replacement therapy under a provisional diagnosis of acute gastroenteritis, her condition worsened and echocardiography on day 2 demonstrated severe hypokinesia. Therefore, she was diagnosed as having acute myocarditis and transferred to the ICU. She then developed clouding of consciousness, with sudden onset of circulatory collapse. She was immediately intubated and PCPS was instituted, along with intensive administration of catecholamines, methylprednisolone pulse therapy, and high-dose gamma-globulin. In addition, PE and CHDF were started for removal of humoral mediators such as cytokines, and for management of hepatic failure. PCPS was removed on day 6, PE on day 5 and CHDF on day 13. She was weaned from mechanical ventilation on day 11, and finally discharged with no sequelae on day 61. Our experience with this case shows that circulatory support with PCPS combined with PE and CHDF is an effective approach for management of children with fulminant myocarditis.

We present a case of septic shock complicated by acute kidney injury in a patient with a left ventricular assist system (LVAS) that was successfully treated with high flow-volume continuous hemodiafiltration (CHDF). The patient was a 62-year-old man with a LVAS installed to treat low output syndrome following an acute myocardial infarction. During hospitalization, an infection developed near the inlet/outlet conduits. We controlled the infection with open drainage, but he was transferred to the intensive care unit (ICU) for septic shock upon fever onset and rapid deterioration of general conditions. Hemodynamics did not improve with early goal-directed therapy (EGDT). The patient’s condition was also complicated by acute kidney injury；therefore, we quickly introduced high flow-volume CHDF at three times the normal volume, which improved the hemodynamics. Six hours later, hemodynamics were stable and catecholamine reduction became possible；therefore, the patient was transitioned to standard CHDF. Subsequently, progress was satisfactory, and on the sixth day the patient left the ICU. Our findings suggest that high flow-volume CHDF may improve hemodynamics for septic shock that is complicated by acute kidney injury and is unresponsive to EGDT.