Masahiro Kojika

Endotoxin Adsorption Therapy for Septic Shock Using Polymyxin B‐Immobilized Fibers (PMX): Evaluation by High‐sensitivity Endotoxin Assay and Measurement of the Cytokine Production Capacity

Abstract:  Because of its low sensitivity, the conventional measurement method for endotoxin (ET) is not the most appropriate for monitoring the effect of ET adsorption therapy. Thus, the efficacy of ET adsorption therapy was investigated using a newly developed high‐sensitivity ET assay method. The changes in the cytokine production capacity of whole blood were also examined. We treated 24 peritonitis patients who had developed postoperative septic shock with ET adsorption therapy using a column of polymyxin B‐immobilized fibers (PMX) and their serum ET levels were measured using the high‐sensitivity ET assay based on the kinetic turbidimetric Limulus assay. In addition, the changes in the tumor necrosis factor‐(TNF‐α) production capacity of whole blood following lipopolysaccharide (LPS) stimulation and clinical outcome in the study patients were also examined. The 28‐day mortality rate was 12%. PMX‐direct hemoperfusion (PMX‐DHP) was associated with elevation of the mean arterial pressure and urine output, reduction in the mean dose requirement of vasopressor agents, and recovery from the shock state in all the patients. The PaO2/FIO2 ratio also showed significant improvement. Using the high‐sensitivity ET assay, ET was detected in the blood of 20 out of the 24 patients (80%) before the PMX‐DHP, and a significant reduction in the ET level was noted after the PMX‐DHP. The TNF‐α production capacity of whole blood, which was found to be lower in the septic shock patients than in healthy subjects, was significantly increased after PMX‐DHP. Elimination of ET by PMX‐DHP in septic shock patients was confirmed by the high‐sensitivity ET assay. PMX‐DHP is thus considered to be a useful adjuvant therapeutic technique in the treatment of septic shock. Also, PMX‐DHP might alleviate the immunosuppression associated with severe sepsis.

Significance of Measuring S100A12 and sRAGE in the Serum of Sepsis Patients with Postoperative Acute Lung Injury

Background: There is a report that S100A12 is useful as an early marker of acute lung injury (ALI). The purpose of this study was to determine whether S100A12 or sRAGE is useful as a marker during the development of ALI in postoperative sepsis patients. Methods: The subjects were patients who underwent emergency surgery because of sepsis secondary to perforation of the lower gastrointestinal tract. We conducted a retrospective study comparing 2 groups of patients: a group of 9 patients who developed postoperative ALI, the ALI(+) group, and a group of 8 patients who did not develop postoperative ALI, the ALI(–) group. Their blood S100A12, sRAGE, IFN-γ, WBC count, and CRP values were measured immediately after surgery and on postoperative day 1 (D1). Results: The changes in S100A12 showed significantly higher values immediately postoperatively in the ALI(+) group (p < 0.05). The sRAGE values immediately postoperatively were similar, but on D1, they were significantly higher in the ALI(–) group (p < 0.05). Conclusions: S100A12 increases in the early stage of development of ALI. sRAGE production increases in patients who do not develop ALI.

Serum Procalcitonin Levels Are Elevated in Esophageal Cancer Patients with Postoperative Infectious Complications

Background: The normal systemic inflammatory response to surgical stimuli often makes early diagnosis of postoperative infections difficult. Purpose: We investigated whether serum procalcitonin (PCT) levels may be a useful marker of bacterial infections in patients after invasive surgery. Subjects and Methods: The subjects were 40 patients who had undergone radical surgery for esophageal carcinoma by a right thoracoabdominal approach. Nine patients were diagnosed to have a postoperative infection during the first 7 days after surgery. Changes in serum PCT levels were compared between the group diagnosed to have postoperative infection (infection group) and the group without infection (noninfection group). Results: The postoperative serum PCT levels were significantly higher in the infection group than in the noninfection group (ANOVA: p < 0.01). Serum PCT peaked on postoperative day (POD) 5 in the infection group (8.7 ± 8.2 ng/ml, mean ± SD) and on POD 1 in the noninfection group (0.5 ± 0.5 ng/ml). No significant differences were found between the two groups in leukocyte count, serum CRP or cytokine levels. The receiver operating characteristics (ROC) curve was constructed for infection identification. The area under the ROC curve for peak postoperative PCT was 0.968, and at a cutoff value of 2.0 ng/ml, the sensitivity was 89% and the specificity was 93%. Conclusions: Serum PCT levels may be useful for the early diagnosis of postoperative infectious complications.

Preliminary study on glucose control with an artificial pancreas in postoperative sepsis patients.

Background: Glucose control is essential to avoid hypoglycemia in postoperative patients. Aim: To conduct a preliminary examination to evaluate the feasibility of the use of an artificial pancreas for glucose control as well as the accuracy of assessment by the artificial pancreas of the insulin dose required. Subjects and Methods: Glucose control using an artificial pancreas was undertaken in 8 postoperative sepsis patients. The blood glucose level was set at 80–150 mg/dl. Blood glucose levels over time, insulin dose requirements, and occurrence of hypoglycemia (≤40 mg/dl) were recorded for each patient. The patients were divided into 2 groups based on the total insulin dose they received over the 7 days (HG, n = 4: consisting of patients who required a higher insulin dose; LG, n = 4: patients who required a lower insulin dose). The data of the 2 groups were analyzed retrospectively. Results: The blood glucose level before glucose control was 203.3 ± 9.9 mg/dl and could be controlled in all patients to within the target range. No hypoglycemia events were recorded for any of the patients. The insulin dose in the HG and LG groups was 21,824.8 ± 6,030.4 and 6,254.5 ± 3,402.3 mU/kg (p < 0.05). Conclusions: Accurate glucose control could be achieved with the artificial pancreas.

Changes in Serum S100A12 and sRAGE Associated with Improvement of the PaO2/FiO2 Ratio following PMX-DHP Therapy for Postoperative Septic Shock

Background: Endotoxin (Et) adsorption therapy with a column of polymyxin B-immobilized fibers (PMX) is effective in improving the partial pressure of arterial oxygen/fraction of inspired oxygen ratio (PaO2/FiO2 ratio) and increasing mean arterial blood pressure (MAP) in sepsis. S100A12 and soluble receptor for advanced glycation end product (sRAGE) are useful as early markers of acute lung injury. Purpose: To investigate the effect of improving the PaO2/FiO2 ratio by PMX-direct hemoperfusion (PMX-DHP) on production of S100A12 and sRAGE. Subjects and Methods: Sepsis patients after surgery for perforation of the lower gastrointestinal tract were adopted as the subjects. We retrospectively reviewed the cases of 20 patients on mechanical ventilation and continuous administration of norepinephrine. We recorded PaO2/FiO2 ratio, MAP, and norepinephrine doses. S100A12, sRAGE, and Et levels were measured before and after PMX-DHP. Results: The PaO2/FiO2 ratio and MAP improved significantly after PMX-DHP (p < 0.05). S100A12 and Et decreased significantly after PMX-DHP (p < 0.05). No differences were observed in sRAGE. Conclusion: S100A12 is useful as a marker that reflected improvement in the PaO2/FiO2 ratio after PMX-DHP. We consider PMX-DHP to be useful as adjunctive therapy for sepsis that reduces the Et and corrects the pathology in the early stage.

A newly developed kit for the measurement of urinary liver-type fatty acid-binding protein as a biomarker for acute kidney injury in patients with critical care.

In recent years, it has been reported that the urinary level of Liver-type fatty acid-binding protein (L-FABP) serves as a useful biomarker for diagnosing acute kidney injury (AKI) or sepsis complicated by AKI. However, because the urinary level of L-FABP is currently measured by enzyme-linked immunosorbent assay (ELISA), several days may elapse before the results of the measurement become available. We have newly developed a simplified kit, the Dip-test, for measuring the urinary level of L-FABP. The Dip-test was measured at 80 measurement points (22 points in noninfectious disease, 13 points in SIRS, 20 points in infectious disease, and 25 points in sepsis) in 20 patients. The urinary L-FABP levels as determined by ELISA in relation to the results of the Dip-test were as follows: 10.10 ± 12.85 ng/ml in patients with a negative Dip-test ([-] group), 41.93 ± 50.51 ng/ml in patients with a ± test ([±] group), 70.36 ± 73.70 ng/ml in patients with a positive test ([+] group), 1048.96 ± 2117.68 ng/ml in patients with a 2 + test ([2+] group), and 23,571.55 ± 21,737.45 ng/ml in patients with a 3 + test ([3+] group). The following tendency was noted: the stronger the positive Dip-test reaction, the higher the urinary L-FABP level. Multigroup comparison revealed a significant differences in the urinary L-FABP levels between the Dip-test (-) group and each of the other groups. In this study, the usefulness of the Dip-test, our newly developed simplified kit for measuring the urinary L-FABP level, is suggested.

Group IIA-Soluble Phospholipase A2 Levels in Patients with Infections After Esophageal Cancer Surgery

PurposeTo examine the changes in blood-soluble phospholipase A2-IIA levels caused by surgical stress and postoperative infections.MethodsWe retrospectively analyzed a prospective database of 40 patients who underwent esophagectomy for esophageal cancer. Nine of these patients had a postoperative infection (E Inf(+) group), and 31 did not have a postoperative infection (E Inf(−) group). The blood sPLA2-IIA level was measured using a radioimmunoassay, and whole blood was stimulated with lipopolysaccharide (LPS) to examine the sPLA2-IIA production.ResultsIn the E Inf(−) group, the blood sPLA2-IIA levels peaked on postoperative day (POD) 3 then decreased gradually thereafter. Receiver-operator characteristic statistics based on the sPLA2-IIA values on POD 5, which are used to classify postoperative infectious complications, revealed an area under the curve of 0.789. However, stimulation of peripheral blood cells with LPS did not induce the production of sPLA2-IIA.ConclusionDuring the early postoperative phase, blood sPLA2-IIA levels increase according to the surgical stress. Soluble PLA2-IIA may be produced at the site of infection or in the liver, but not in the circulating blood. Sustained elevation of the serum sPLA2-IIA level, observed even after POD 3, seems to represent a response to postoperative infection.

G-Csf and Leukocytosis in Anaplastic Thyroid Carcinoma Associationbetween Granulocyte Colonies Stimulating Factor(G-Csf) Production andLeukocytosis in Anaplastic Thyroid Carcinoma

Background: Leukocytosis is an independent prognostic factor for anaplastic thyroid carcinoma (ATC). In the present study, the potential causes of leukocytosis in ATC were analyzed. Methods: This study involved 22 patients with histologic or cytologic evidence of ATC, as well as papillary thyroid carcinoma (PTC), between June 2000 and October 2009. Samples were obtained from ATC patients before treatment. The xMAP serum assay for 17 cytokines [IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, and IL-17, TNF-α, IFN-γ, GM-CSF, G-CSF, MIP-1β, and MCP-1] and IHC from surgical specimens were performed. Results: WBC was ≥ 10000/mm3 in 9 (41%) and G-CSF was ≥ 100 pg/ml in 4 (18%) ATC cases. The G-CSF level showed a positive correlation with the WBC count in ATC cases (r=0.78). Both G-CSF and G-CSFR protein expressions were seen on immunohistochemical staining in 50% (5/10) and 70% (7/10) of ATC cases, respectively. Serum IL-6, IL-7, IL-8, IL-12, IL-17, MCP-1, TNF-α, and G-CSF concentrations were significantly higher in ATC than in PTC. WBC and G-CSF (r=0.61) had a positive correlation (>0.6). Patients with leukocytosis (n=9) had a poorer survival rate than those with WBC<10000/mm3 (p=0.0002). Similarly, patients with G-CSF ≥ 100 pg/ml had a poorer survival rate than those with G-CSF <100 pg/ml (p=0.0107). Conclusion: Leukocytosis and a high G-CSF level before treatment are linked to poor prognosis in ATC patients.

Multiple Transverse Colonic Perforations Associated with Slow-Release Nonsteroidal Anti-Inflammatory Drugs and Corticosteroids: A Case Report

The patient was a 36-year-old woman with sarcoidosis and Sjogrens syndrome, and had been prescribed slow-release diclofenac sodium and prednisolone for the treatment of pain associated with uveitis and erythema nodosum. She was admitted to our emergency center with abdominal pain and distention. A chest X-ray showed free air under the diaphragm on both sides, and an emergency laparotomy was performed for suspected panperitonitis associated with intestinal perforation. Laparotomy revealed several perforations on the antimesenteric aspect of the transverse colon. The resected specimen showed 11 punched-out ulcerations, many of which were up to 10 mm in diameter. The microscopic findings were non-specific, with leukocytic infiltration around the perforations. She showed good postoperative recovery, as evaluated on day 42. The present case highlights the need for exercising caution while prescribing slow-release nonsteroidal anti-inflammatory drugs with corticosteroids to patients with autoimmune diseases, as such treatment may exacerbate intestinal epithelial abnormalities.

Regulating migration of esophageal stents - management using a Sengstaken-Blakemore tube: A case report and review of literature

Stent migration, which causes issues in stent therapy for esophageal perforations, can counteract the therapeutic effects and lead to complications. Therefore, techniques to regulate stent migration are important and lead to effective stent therapy. Here, in these cases, we placed a removable fully covered self-expandable metallic stent (FSEMS) in a 52-year-old man with suture failure after surgery to treat Boerhaave syndrome, and in a 53-year-old man with a perforation in the lower esophagus due to acute esophageal necrosis. At the same time, we nasally inserted a Sengstaken-Blakemore tube (SBT), passing it through the stent lumen. By inflating a gastric balloon, the lower end of the stent was supported. When the stent migration was confirmed, the gastric balloon was lifted slightly toward the oral side to correct the stent migration. In this manner, the therapy was completed for these two patients. Using a FSEMS and SBT is a therapeutic method for correcting stent migration and regulating the complete migration of the stent into the stomach without the patient undergoing endoscopic rearrangement of the stent. It was effective for positioning a stent crossing the esophagogastric junction.