The author of this review article delivered the special lecture entitled “Pathophysiology of Severe Sepsis/Septic Shock and Therapeutic Approach with Acute Blood Purification” at the 20th annual meeting of the Japan Society of Blood Purification in Critical Care (JSBPCC) in 2009 and the lecture was published as a review article in this journal. Then in 2010, the author again delivered the lecture entitled “Pathophysiology of Sepsis- up-to date” at the 21st annual meeting of the JSBPCC. The latter lecture aimed to cover some aspects of pathophysiology of sepsis which were not referred much in the previous lecture. The main topics in the latter lecture include new aspect in pathophysiology such as pattern recognition receptors，significance of autophagy, immunoparalysis and inflammatory reflex. Some new aspects in the treatment of sepsis referred in the latter lecture include importance of lactate clearance as an endpoint of circulatory support for the patients with septic shock, some serious concerns on the efficacy of PMX-DHP as a therapeutic approach to septic shock, and long-term survival of severe sepsis and septic shock. The present article is the record of the latter lecture. This author would like to ask the readers to read both reviews and wish that those two review articles would be somewhat interesting to the readers of the journal.

In order to clarify the present status of blood purification therapy (BPT) in critical care in Japan, questionnaires investigating the patients treated with BPT in hospitals with both more than 200 beds and the facility of ICU in a year of 2009 were distributed. The number of patients who received BPT was 2,010, and the number of BPT performed was 2,561. 50.3% of all BPT was CRRT, followed by PMX-DHP and plasma-exchange. The worst survival rate of patients treated with BPT was 55.4% in multiple organ failure, followed by 66.0% in sepsis, 67.7% in acute disorders of electrolyte, water and acid-base of blood, 68.9% in severe acute pancreatitis and 69.3% in acute hepatic failure. Since survival rate of patients with multiple organ failure and sepsis were very low, more studies are needed from now on.

Histological findings from lung specimens obtained from patients with acute lung injury, including acute exacerbation of idiopathic pulmonary fibrosis, show diffuse alveolar damage (DAD). The prognosis of DAD is extremely poor and no effective treatment has been established. Direct hemoperfusion with polymyxin B-immobilized fiber (PMX-DHP) was originally developed for the removal of endotoxin and used for the treatment of endotoxemia. Recent clinical studies have suggested the beneficial effects of PMX treatment in DAD. We showed that the cells adsorbed by PMX were neutrophils that highly expressed HLA-DR, CD14, CD62L and CD114 in interstitial pneumonia (IP) patients with acute exacerbation (AE). Activated metalloproteinase (MMP)-9 was detected in washing medium from PMX fibers. PMX-DHP significantly reduced the serum MMP-9 level, indicating that PMX-DHP may be beneficial for acute exacerbations of IP. We also demonstrated that the serum HMGB-1 level in IP patients with AE was significantly elevated compared with that in stable IP patients. PMX-DHP significantly reduced the serum high mobility group box (HMGB)-1 level and improved oxygenation in IP patients with AE. HMGB-1 was detected in washing medium with PMX, suggesting that PMX may directly absorb HMGB-1. These results suggest that PMX-DHP may be an efficacious therapeutic option for DAD.

Acute kidney injury (AKI) is a new concept describing a common clinical syndrome involving the sudden onset of reduced kidney function manifested by increased serum creatinine or a reduction in urine output. More than 30 different definitions have been presented in the literature, causing difficulties in comparing clinical study results. The recent consensus definition proposed by the Acute Dialysis Quality Initiative (ADQI) group in 2002 and expanded by the Acute Kidney Injury Network (AKIN) in 2005 has brought the RIFLE criteria and staging into position as the standard definition and diagnostic criteria for this syndrome. AKIN defined AKI as an abrupt (within 48 hours) reduction in kidney function currently defined as an absolute increase in serum creatinine by 0.3mg/dL or more. In this article, the RIFLE criteria, AKIN criteria and problematical issues that need to be solved were discussed. Furthermore, a brief overview of the AKIN Summit Meeting 2010 and 2011 held in San Diego is presented.

Early diagnosis of acute kidney injury (AKI) in intensive care units is crucial because critically ill patients complicated with AKI show unacceptably high mortality. Recently developed AKI biomarkers for detection of renal tubular epithelial cell injury are expected to enable detection of AKI earlier than either serum creatinine or urine output, which are not sufficiently sensitive for AKI detection. We evaluated the performance of new AKI biomarkers including urinary L-FABP, NGAL, IL-18, NAG, and albumin in a mixed adult ICU with heterogeneous patients. These biomarkers were able to detect AKI at ICU admission and were able to predict later onset AKI with moderate but significant prognostic power. Moreover, urinary L-FABP and NGAL predicted mortality better than serum creatinine did. Improvement of new AKI biomarkers is necessary for clinical use to contribute to new diagnostic tools for AKI, and for dialysis indication and mortality prediction in critical care.

Acute blood purification (ABP) therapy is one of the most important therapies in pediatric and intensive care. The use of ABP therapy has been increasing in our hospital since 2007. Priming, circuit exchange, and other ABP-related procedures were successfully supported by the clinical engineers at our hospital. In this study, we reviewed the role of clinical engineers with respect to ABP therapy at our hospital and discussed the improvement in the teamwork between intensive care unit (ICU) nurses and doctors at our hospital, on the basis of a questionnaire administered to the ICU nurses. The survey results showed that the nurses felt uneasy while attending to patients undergoing ABP therapy because they lacked knowledge about the details of this therapy. We believe that their anxieties can be alleviated by increasing the frequency of seminars aimed at increasing their level of understanding regarding this therapy. An ideal level of cooperation that results in a good relationship develops when nurses actively consult doctors about the therapy, while maintaining a positive attitude toward it. This close liaison between health care providers that is orchestrated by clinical engineers is linked to obtaining successful outcomes and alleviating anxiety in pediatric patients and their parents. In conclusion, clinical engineers play a role in ensuring that ICU nurses are sufficiently educated to be confident about attending to patients undergoing ABP therapy.

【Background】Heparin-grafted AN69ST membrane hemofilter (oXiris^®) is a newly developed hemofilter, characterized by an increase in the surface treatment agent, polyethyleneimine, on the membrane surface and over-coating the agent with heparin. This process not only shows excellent anti-thrombotic properties, but can also be expected to remove HMGB1 (high mobility group box 1 protein), which has a specific binding site to heparin. This study investigated whether oXiris^® has an ability to remove HMGB1 that is specifically attributable to its own surface processing. 【Methods】Inflammatory mediators including HMGB1 were produced by continuous infusion of LPS into pooled swine blood. Utilizing the treated swine blood, CHDF (continuous hemodiafiltration) with an oXiris^® hemofilter was performed under the conditions of Qb=80mL/min, Qf=300mL/h and Qd=1,000mL/h. Serial samples were collected initially, after 30 minutes, 1, 3, 6, 12, 18 and 24 hours from the inlet, outlet and the filtrate sites of the hemofilter. Then, the HMGB1 level was measured in each sample. Further, HMGB1 clearance (CL) and sieving coefficient (SC) were calculated over time. 【Results】HMGB1 CL was 30.0±9.9 (mL/min) at 30 min after the start of CHDF, 23.5±9.5 after 1h, 34.6±5.4 after 3h, 24.5±14.8 after 6h, 26.9±14.7 after 12h, 13.3±11.0 after 18h, and 11.8±1.2 after 24h. In addition, the HMGB1 SC was 0.003 at 30 min after the start of CHDF, 0.003 after 1h, 0.006 after 3h, 0.003 after 6h, 0.002 after 12h, 0.001 after 18h, and 0.002 after 24h.【Conclusion】These findings suggest that oXiris^® has a high ability to remove HMGB1, probably due to the mechanisms of both binding to the heparin layer and adsorption in the bulk layer.

When implementing hemocatharsis by extracorporeal circulation in newborns and nursing infants with low circulating blood volume, blood products are generally replenished for reasons such as dilution rate. If blood products are employed in extracorporeal circuits during the preparation stage, determination of the extent of prewashing and the amount of concentrated RBC and protein products required to compensate for the low pH and hyperkalemia may be difficult. Therefore, using Microsoft Excel, we created a prototype spreadsheet to determine automatic fluid replenishment compensation. we measured these values ten times in an infant patient weighing approx. 3kg, who had undergone continuous hemodiafiltration (CHDF) because of anuria. Presuming that the hemoglobin and potassium values of the concentrated red blood cell products were fixed, we hypothesized that the concentration of fluids within the circuit were even when making the calculations, and were able to use the spreadsheet without any differences occurring. Thus, the results indicated that the automatic spreadsheet could be used for the implementation of safer hemocatharsis.

A new type of continuous hemofilter, the “Hemofeel SHG” (SHG), was developed by Toray Industries, Inc., Tokyo, Japan. The SHG has a smoother inner surface of hollow fibers for blood flow than the existing “Hemofeel SH” (SH). In this study, we examined filter lifetime and solute removability using bovine blood. Both SHG and SH showed gradual increases in blood inlet pressure. The urea clearance of SHG did not differ significantly from that of SH at 20 min after starting the pump, but was significantly higher when the blood inlet pressure reached 250mmHg (a hemofiltor exchange criterion). In conclusion, based on urea clearance, the lifetime solute removability of SHG can be expected to be prolonged compared to that of SH.

Acute kidney injury (AKI), which is commonly encountered in critically ill patients, independently predicts a poor outcome. Although several recent reports have described that AKI requiring dialysis is associated with mortality and duration of stay in intensive care unit (ICU), some studies have examined discontinuation of continuous renal replacement therapy (CRRT). Therefore we used a retrospective case-control study based on chart review to investigate the condition of discontinuation of CRRT for AKI patients in the ICU. We examined a Case Group and Control Group. The Case Group patients continued RRT after discharge, although CRRT was discontinued for the Control Group patients, who were matched for age and sex with Case Group patients. Finally, we enrolled 10 patients in each group. The Case Group had higher blood urea nitrogen (BUN) and systolic blood pressure (SBP) at the CRRT initiation. The higher levels of BUN and SBP were significantly associated with the need for maintenance of RRT by logistic regression analysis. Results suggest that patients who had either high BUN or SBP at the beginning of CRRT have higher risk of requiring RRT even after discharge.

Thyroid storm is a life-threatening condition caused by an inability to compensate against excessive thyroid hormone action, which leads to fatal complications and multiple organ failure. The mortality rate exceeds 20％. A 42-year-old woman without hospital consultation since her last delivery and without treatment for Basedow disease was referred to our hospital because of dyspnea, systemic edema, and abdominal distension. She had tachycardia, hyperhidrosis, exophthalmos, enlarged thyroid, systemic edema, massive pleural effusion and ascites, and abdominal distension. Her laboratory data showed low TSH and high FT₃ and FT₄ values. She was diagnosed with thyroid storm and admitted to the ICU. Although intensive care and drug therapy had been initiated, she suffered cardiopulmonary arrest on the day after admission. Fortunately, she was resuscitated promptly. The FT₃ and FT₄ values decreased, and the patient’s condition temporarily improved following continuous hemodiafiltration and double filtration plasmapheresis in combination with standard treatment for thyroid storm. However, during her hospital stay, duodenal perforation and panperitonitis complicated her condition, leading to sepsis and progressive multiple organ failure. Furthermore, cerebral infarction and brain hemorrhage occurred concurrently, and she eventually died on the 36th day after hospitalization. We concluded that plasmapheresis will be effective in reducing the FT₃ and FT₄ serum levels in patients with thyroid storm and may improve the condition of these patients.

An 80-year-old male who had undergone repeated leg artery bypass surgery for obstructive arteriosclerosis (ASO) at another hospital developed sharp pain in his left leg, an ulcer, and degenerating gangrene consulted our hospital. We diagnosed acute limb ischemia (ALI) based on palpation and a blood flow evaluation inspection, and performed endovascular treatment (EVT). However, the development of symptoms of ischemia reperfusion injury (myonephropathic metabolic syndrome: MNMS) after revascularization was expected because of the large size of the ischemic region. For this reason, we enforced CHDF (continuous hemodiafiltration) beginning immediately after the procedure as a preventive measure. Although amputation of the lower extremity was necessary due to poor wound healing and sharp pain in the ischemia limb below the Popliteal artery after revascularization, we were able to save the patient’s life without MNMS developing. MNMS is a serious condition that, once it develops, is very difficult to treat. When a large ischemic area with signs of infection is present, as was the case in this ALI patient, we believe that early blood purification therapy after revascularization can contribute to the stabilization of the general state of the patient, and can help prevent a reperfusion injury, which may save the patient’s life.

Closed systems for transfusions have been developed for prevention of infection. Closed system refers to one having relatively little interaction with other systems or the outside environment. In medical practice, it is well known that the adoption of a closed infusion system resulted in a marked reduction in the rate of central venous catheter-associated bloodstream infections. Recently this system has been applied for double lumen catheters used in continuous renal replacement therapy (CRRT). In the present study, we examined the moment of inertia and torque of the joints of 3 types of double lumen catheters available in Japan：Planect^® (JMS), Interlink^® (Baxter) and Safe Access^® (Nippon Sherwood). Safe Access showed the lowest values for moment of inertia (51.8+4.4 N) and torque (12.5+1.2N) due probably to the polypropylene material and two male components used for the joints. These experiments indicate that connections between the double lumen catheters and the circuit are important factors for selection of the closed system.