Yoshihiro Yagi

Alterations in coagulation and fibrinolysis during sepsis.

Circulating levels of thrombin-antithrombin III complex (TAT) and plasmin-α2 plasmin inhibitor complex (PIC) in 49 septic patients (23 patients with organ dysfunction (OD), 26 without OD) and 11 postgastrectomy patients were measured to determine the significance of the coagulation-fibrinolytic systems in the development of OD. Tissue plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1), and thrombomodulin were also measured. The mean level of TAT on the day when OD occurred was significantly higher compared with the maximum level of TAT in septic patients without OD (P < .01) or postoperative patients (P < .01). There was no difference in PIC levels between the three groups. The TAT/PIC ratio was significantly higher in septic patients with OD compared with the other groups (P < .001). Septic patients with OD showed higher levels of PAI-1 (P < .001) but not of t-PA. Thrombomodulin levels were significantly higher in the septic patients with OD compared with the others (P < .001). We conclude that suppression of the fibrinolytic system contributes to the imbalance between coagulation and fibrinolysis, and that this hypercoagulabe millieu on the endothelial surface leads to the onset of OD.

Increased Plasma Levels of Soluble Thrombomodulin in Patients with Sepsis and Organ Failure

The fact that thrombomodulin (TM) is released into the bloodstream from damaged vascular endothelial cells led us to hypothesize that plasma levels of soluble TM could be an indicator of the development of organ failure. In this study, we examined the changes in plasma levels of TM in 60 septic patients and 13 postsurgical patients, and investigated the circulating levels of interleukin 6 (IL-6) and polymorphonuclear leukocyte elastase (PMN-E) to determine the mechanism causing the excess liberation of TM. The arterial ketone body ratio (AKBR) was also measured as an indicator of the hepatocyte energy state. Of the 60 septic patients, 26 developed organ failure, 10 of whom died. In contrast, none of the postsurgical patients developed organ failure. The mean plasma level of TM was significantly higher in the septic patients who developed organ failure compared to those without organ failure (P<0.001) or the postsurgical patients (P<0.001). Furthermore, those patients whose plasma TM values became elevated over 6.0ng/ml frequently developed complications. A positive correlation was also observed between the plasma TM levels and the IL-6 (P<0.01) and PMNE levels (P<0.01). In contrast, a negative correlation was seen between the plasma TM levels and the AKBR (P<0.01). These findings show that plasma TM could be a useful indicator of impending organ failure during sepsis.

Total parenteral nutrition supplemented with medium-chain triacylglycerols prevents atrophy of the intestinal mucosa in septic rats

Total parenteral nutrition (TPN) is associated with an increased incidence of bacterial translocation (BT) compared with enteral nutrition because of the disuse atrophy of the intestine. In this study, we assessed the effect of adding medium-chain triacylglycerols (MCT) to TPN for the prevention of mucosal atrophy in the intestine. Rats were subjected to either fat-free TPN, TPN with long-chain triacylglycerols (LCT), or TPN with MCT for 5 d and nutrition parameters were evaluated. In another set of rats receiving the same TPN regimen, 0.8 or 0.05 mg/kg endotoxin was administered on day 4. Survival was evaluated and BT to the mesenteric lymph nodes, liver, and systemic blood was measured 24 h later. The mucosal heights of the jejunum and ileum were evaluated concurrently. The survival rate was significantly improved in the MCT group (P < 0.05) at the endotoxin dose of 0.8 mg/kg. The nutrition condition presented by phospholipid, total cholesterol, and total ketone body levels was the best in the MCT group compared to the other groups. The intestinal villous height in the ileum was significantly greater in the MCT group. However, the improvement of BT in MCT group was not statistically significant. In this endotoxin-challenged rat model, survival rate was improved by the supplementation of MCT. This effect may be presented in some part by the improvement in nutrition condition and by the prevention of mucosal atrophy in the intestine.

Intermittent low-dose cisplatin infusion as a possible modulator of 5-fluorouracil

BackgroundThis study was designed to determine whether 5-fluorouracil combined with intermittent low-dose cisplatin (cis-diaminedichloroplatinum, CDDP), a 5-fluorouracil modulator, would be an effective antitumor regimen.MethodsSarcoma 180 tumor (mouse sarcoma) was implanted in mice, and intravenous CDDP injections (0.5 mg/kg) were given at intervals of 12 hours. Tumors were removed on days 1, 3, and 5 of treatment for quantification of the tumor tetrahydrofolate and blood platinum levels. One group of mice was treated with a combination of CDDP and 5-fluorouracil (10 mg/kg), and another group was treated with 5-fluorouracil alone. Tumor thymidylate synthetase levels and tumor weights were compared between these 2 groups.ResultsBlood total platinum levels rose as the number of doses increased, while the tumor tetrahydrofolate levels did not change. Neither the levels of thymidylate synthetase, nor tumor reduction, differed between the CDDP/5-fluorouracil and the 5-fluorouracil treatment groups.ConclusionNo significant effect of intermittent low-dose CDDP therapy was seen on folic acid or thymidylate synthetase levels, or on tumor growth. The results of this study do not endorse the efficacy of intermittent low-dose CDDP as a modulator of 5-fluorouracil.