Toyokazu Yoshioka

Treatment of septic shock with a protease inhibitor in a canine model: A prospective, randomized, controlled trial

Objectives.To evaluate the efficacy and mechanism of action of a protease inhibitor (ulinastatin) in septic shock. Design.Prospective, randomized, controlled trial. Setting.A university laboratory. Subjects.Twelve mongrel dogs. Interventions.One of the protease inhibitors, ulinastatin, a glycoprotein (molecular weight 67,000 daltons) detected in human urine was estimated. We used Escherichia coli to obtain a model of septic shock in dogs in vivo study. Human neutrophils were used as an activating target in vitro. Measurements and Main Results.The final concentration ofE. coli was 1.9×106 colony-forming units/mL. There was no significant difference in E. coli concentration between ulinas-tatin-treated and control groups. Human neutrophils treated with 100 U/mL of ulinastatin showed 70.5% to 78.7% of the superoxide production or untreated neutrophils. Phagocytic activity was enhanced in a dose-dependently manner by ulinastatin. At a ulinastatin concentration of 100 U/mL, an approximate two-fold increase in activation was found. In the ulinastatin-treated group, cardiac index, blood pressure, lactic acid, blood glucose, and blood base values significantly improved 60 mins after ulinastatin administration, and the bacterial count was significantly decreased, while the endotoxin concentration in the control group showed a continuous increase of endotoxin concentration. The improvement in the monitored factors observed 60 mins after initiation of treatment persisted after the end of treatment. The survival rate after 1 wk in the ulinastatin-treated group was 84% (five of six dogs survived), while it was 16% (one of six dogs survived) in the control group (p = .04). Conclusions.Ulinastatin does not have antimicrobial activity, and it does not sufficiently activate phagocytes. It is suggested that the efficacy of this agent in experimental septic shock is due to a mechanism that activates the reticuloendothelial system and septic reactions. (Crit Care Med 1993; 21:925–930)

Spontaneous hematoma of the lateral abdominal wall caused by a rupture of a deep circumflex iliac artery: report of two cases.

Expanding hematoma of the abdominal wall is a rare example of acute abdominal disease. We report two cases of lateral abdominal wall hematoma caused by the rupture of a deep circumflex iliac artery, which is a rare cause of an abdominal wall hematoma. Both patients experienced severe abdominal pain after sneezing or coughing. In both cases, computed tomography (CT) findings suggested that active bleeding was continuing. Emergent angiography was therefore performed, and the hematoma was embolized using Spongel or Microcoils. Ultrasound examinations were repeatedly used to monitor the size of the hematoma. The size of the hematoma and patients pain gradually decreased after embolization. Ultrasound and CT examinations provided useful information for the differential diagnosis of this disease. We conclude that emergent angiography should be performed to control bleeding and avoid any unnecessary surgical procedures in patients with hematoma of the abdominal wall.

Multicenter Study of Plasma Diafiltration in Patients With Acute Liver Failure

Plasma diafiltration (PDF) is a blood purification therapy in which simple plasma exchange (PE) is performed using a selective membrane plasma separator while the dialysate flows outside the hollow fibers. A prospective, multicenter study was undertaken to evaluate the changes in bilirubin, IL‐18, and cystatin C, as well as the 28‐day and 90‐day survival rates, with the use of PDF according to the level of severity as measured by the Model for End‐Stage Liver Disease (MELD) score. Twenty‐one patients with liver failure were studied: 10 patients had fulminant hepatitis and PDF therapies were performed 28 times; 11 had acute liver failure with the therapy performed 96 times. Levels of total bilirubin, IL‐18, and cystatin C decreased significantly after treatment. The 28‐day survival rate was 70.0% and that at 90 days was 16.7%. According to the severity of the MELD score, each of the results compared well with the use of Molecular Adsorbent Recirculating System or Prometheus therapy. In conclusion, PDF appears to be one of the most useful blood purification therapies for use in cases of acute liver failure in terms of medical economics and the removal of water‐soluble and albumin‐bound toxins.

Novel mechanical assistance in the treatment of endotoxic and septicemic shock

Systemic sepsis is a frequent and fatal complication of postoperative patients. More recently, therapeutic trials of plasma or blood exchange are performed in septic patients for the purpose of reducing both endotoxins and albumin-bound toxins. As an alternate approach such as this for the removal of endotoxin directly from the blood, the authors recently developed polymyxin B immobilized fiber (PMX-F) as a biomaterial for selectively detoxifying endotoxin. That this newly invented PMX-F neutralizes a sufficient amount of endotoxin in vitro was reported previously. In ex vivo experiments, direct hemoperfusion by PMX-F was performed on purified endotoxin injected canine and on live Escherichia coli induced septic dogs. Only 5% (1/20) survived in the control group, but 75% (30/40) survived in the treated group. Septic dogs died within 18 hours after bacteria infusion in the control group. But all in the treated group survived 3 days. Forty percent of them survived permanently. These observations indicate that PMX-F treatment, namely selective removal of endotoxin in the endotoxic and septicaemic dogs prolongs or increases the chances of survival. Blood compatibility of PMX-F was also evaluated both in vitro and in vivo. With platelets it was shown to be fairly good and with red blood cells, white blood cells, and proteins, extremely good. A preclinical study on the efficacy and safety of PMX-F throughout widespread experiments has just ended.

Plasma Diafiltration Therapy in Patients With Postoperative Liver Failure

Plasma diafiltration (PDF) is a blood purification therapy in which simple plasma exchange (PE) is performed using a selective membrane plasma separator while the dialysate flows outside of the hollow fibers. A prospective, multicenter study was undertaken to evaluate the changes in biochemical examination of blood and the 28‐day and 90‐day survival rates of patients with postoperative liver failure (PLF). Eleven patients with PLF were studied with the therapy performed 98 times. The Model for End‐Stage Liver Disease (MELD) score was categorized into three grades: 20–29, 30–39, and 40 or higher. The survival rate was assessed by the severity of MELD score. The 28‐day survival rate was 45.5% and that at 90 days was 27.3%. The levels of total bilirubin, BUN, and creatinine decreased significantly after treatment. On the other hand, the levels of total protein increased after treatment and those of albumin did not change significantly. PDF may be the useful blood purification therapies for use in cases of PLF in terms of medical economics and the removal of water‐soluble and albumin‐bound toxins.

A Case Report of Pulmonary‐Renal Syndrome Treated With Continuous Hemodiafiltration and Hemodialysis

Abstract:  This case describes a 40‐year‐old man complaining of general malaise, dyspnea with hemoptysis and anuria. Laboratory data indicated renal failure and the presence of systemic inflammation. His chest radiograph and computed tomography showed bilateral diffuse interstitial alveolar infiltration. These findings indicated acute deterioration of chronic renal dysfunction complicated by interstitial pneumonitis. He initially received daily conventional hemodialysis (HD), an antibiotic and oxygen therapy. However, his renal and pulmonary function continued to deteriorate. Antineutrophil cytoplasm antibodies against myeloperoxidase (MPO‐ANCA) and antibodies against proteinase 3 (PR3‐ANCA) were negative. We suspected that his pulmonary‐renal syndrome was caused by ANCA‐negative vasculitis. We applied mechanical ventilation, pulsed methylprednisolone therapy and continuous hemodiafiltration (CHDF) combined with HD. PaO2/FiO2 ratio and mean pulmonary arterial pressure gradually improved after initiation of CHDF. He was finally separated from mechanical ventilation after 44 days in the hospital. He is currently alive with the support of conventional HD.

Endotoxin concentration by Limulus assay correlates with biological activity in mice and human peripheral blood mononuclear cells

Endotoxin is thought to play a major role in septic shock and multiple systemic organ failure (MOF). However, endotoxin is not always detected in the plasma during Gram-negative sepsis by current Limulus lysate assays. Additionally, it is unknown to what extent the biological activity of endotoxin is truly reflected in endotoxemia. This paper assesses quantitatively a comparison of three types of Limulus assays for the detection of the biological activity of endotoxin in plasma. Mouse lethal activity and TNF production were used for assessment of the biological activity of endotoxin both before and after potential modification of LPS activity by plasma constituents. We have concluded that the dilution and heating method coupled with a toxinometer provides the most accurate correlation with other biological activities of endotoxin in plasma. The fact that the biological activity of endotoxin decreased to 17% of initial dose after incubation at 37ºC for 90 min in normal plasma suggests further a temporal dependence of time in plasma upon the manifestation of biological activities normally attributable to this biologically active microbial constituent found in the plasma of septic patients.

The new therapy for septic multiple organs failure.

Forty-two patients with severe infection were treated with direct hemoperfusion (DHP) using polymyxin B immobilized fiber column (PMX) . Thirty-eights out of 42 suffered MOF. DHP was performed for 2 hours via femoral vein with double lumen catheter.Blood endotoxin level was high in 35 patients, and in these patients were cured 19/35 (54%), but 3/8 (38%) in the patients with normal endotoxin level. The patients with pathogenic bacteria were cured 20/31 (61%), but patients without cultured bacteria showed significantly lower survival rate (23%) .Blood endotoxin levels significantly decreased between the inlet and the outlet of column.Cardiovascular parameter (blood pressure, C.I SVR, VO2I) and body temperature were significantly improved after DHP in the patients with abnormal values.PMX therapy on the MOF patients with systemic inflammatory response syndrome due to infection was demonstrated to be effective.

The efficiency of new leukocyte removal filters : CF-1 and CF-2

Two new leukocyte removal filters, Nipro CF-1 and CF-2 (Nipo Medical Industries, Osaka, Japan), were evaluated. These non-woven polyester filters, which are gravity flow devices that require no priming and no rinsing after use, were developed for preparing 400 ml of whole blood or red cell concentrates from 400 ml of whole blood. A flow cytometric technique was developed to measure extremely low white blood cell (WBC) counts. To evaluate the efficiency of these filters, leukocyte counts were measured by three techniques: 1) electronic, 2) visual, and 3) flow cytometry. Flow cytometric counting was done using a Coulter EPICS-C cytometer (Coulter Corp., Hialeah, FL). Nipro CF-1 removed 99.97 +/- 0.01% (mean +/- SD, n = 14) of leukocytes measured by flow cytometry, and CF-1 recovered 90.7 +/- 4.47% (n = 21) of red blood cells. After filtration through CF-2, more than a 6 log10 (> 99.9999%) depletion of WBCs was detected in six samples, a 6 log10 (99.9999%) depletion of WBCs was detected in two samples, a 5 log10 (99.999%) depletion was detected in five samples, and a 4 log10 (99.99%) depletion was detected in one sample. CF-1, in which size and priming volume was smaller than other commercial leukocyte removal filters, accomplished a 3 log10 reduction in WBC count, compared with other commercial filters. CF-2 achieved a 4-6 log10 depletion of WBCs assayed by flow cytometry.