Masaki Fukunaga

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.

Activated protein C improves the visceral microcirculation by attenuating the leukocyte-endothelial interaction in a rat lipopolysaccharide model

Objective:Abnormalities in the vascular endothelial function play an important role in the development of septic organ dysfunction. The aim of the study was to examine the effect of recombinant human activated protein C on leukocyte-endothelial interaction in endotoxemia. Design:Experimental animal model of sepsis. Setting:University research laboratory. Subjects:Normal Wistar rats. Each animal was infused with 4.5 mg/kg lipopolysaccharide to simulate severe sepsis. Interventions:Rats were injected with endotoxin simultaneously with either a low or a high dose of recombinant human activated protein C (n = 7). One, 2, and 3 hrs after injection, mesenteric microcirculation was observed under intravital microscopy. In another series, tumor necrosis factor, interleukin-6, alanine transaminase, and blood urea nitrogen levels were evaluated (n = 5). Measurements and Main Results:The adhesive leukocyte count on the endothelium was significantly suppressed in both high-dose and low-dose groups (p < .01 and .05, respectively). The bleeding events decreased in the low-dose treatment group compared with both the control (p < .05) and high-dose group (p < .05). Microcirculatory flow as expressed by red blood cell velocity was maintained better in the low-dose group. Comparison of cytokine levels showed a significant decrease in the treatment groups. Organ damage markers were also suppressed in the treatment groups (p < .05) Conclusions:Recombinant human activated protein C demonstrated a protective effect on microcirculation through the inhibition of leukocyte-endothelial interaction and suppression of inflammatory cytokine production.

Single-incision laparoscopic colectomy for colon cancer: early experience with 31 cases.

BACKGROUND: Transumbilical single-port surgery has been developed with the aim to further reduce the invasiveness of conventional laparoscopy. OBJECTIVE: This study aimed to report our experience with 31 patients who were treated with transumbilical single-incision laparoscopic colectomy for colon cancer. DESIGN: This is a retrospective review of prospectively gathered data. SETTINGS: This study was conducted at the Department of Surgery of Juntendo University Urayasu Hospital between April 2009 and April 2010. Data were obtained from a prospectively maintained single-institution laparoscopic colon cancer database. PATIENTS: Thirty-one consecutively selected patients (mean BMI, 22.5 ± 2.3) were evaluated. INTERVENTIONS: All patients underwent single-incision laparoscopic colectomy for colon cancer. Two different approaches were used for single-incision laparoscopic colectomy: the trocar insertion method and the SILS port method. The trocar insertion method was adopted in 22 of 31 patients, and the SILS port method was used in 9 patients. MAIN OUTCOME MEASURES: The main measures of outcomes were intraoperative findings, postoperative course, and oncological outcomes. RESULTS: The most common procedure was sigmoid colon resection performed in 12 of 31 (39%) patients. The mean skin incision was 2.72 ± 0.79 (range, 3–5) cm. The operating time ranged from 101 to 263 (mean, 156 ± 45) minutes. The volume of bleeding ranged from 5 to 60 (mean, 27 ± 19) mL. No intraoperative complications were observed in this series. Postoperatively, there was no mortality. Wound infection was observed in 1 patient. The number of harvested lymph nodes was 18 ± 2.1, and the mean tumor-free resection margin was 11 ± 4.8 cm. CONCLUSION: Our experience indicates that single-incision laparoscopic colectomy is feasible for selected patients with colon cancer.

Impact of Conversion on Surgical Outcomes after Laparoscopic Operation for Rectal Carcinoma: A Retrospective Study of 1,073 Patients

BACKGROUND In laparoscopic operations for rectal carcinoma, only a few multicenter studies of a large number of patients have examined the impact of conversion on outcomes and determined risk factors for conversion. This study was designed to evaluate short-term outcomes and risk factors for conversion to open operation in laparoscopic operations for rectal carcinoma. STUDY DESIGN A total of 1,073 patients with carcinoma of the rectum and anus who underwent laparoscopic operations were reviewed retrospectively. Patients were collected from 28 institutions. Patients who required conversion during laparoscopic operation were compared with those with completed laparoscopic resection. RESULTS Conversion rate was 7.3% (n = 78), and patients requiring conversion were considerably heavier (mean body mass index 24.6 versus 22.7) and had a substantially higher rate of low anterior resection (94.9% versus 83.5%). Conversion was also associated with longer operation time (median 295 minutes versus 270 minutes), greater blood loss (median 265 mL versus 80 mL), longer median postoperative hospital stay (20 days versus 14 days), and higher rates of intraoperative (32.1% versus 3.5%) and postoperative (43.6% versus 21.1%) complications. In multivariate analysis, body mass index and rate of low anterior resection were predictive of conversion. CONCLUSIONS Conversion to open operation is associated with greater morbidity than completed laparoscopic resection. Body mass index and the particular laparoscopic procedure are risk factors for conversion, indicating that appropriate patient selection is essential in laparoscopic operations for rectal carcinoma.

Results of a multicenter study of 1,057 cases of rectal cancer treated by laparoscopic surgery

BackgroundThe aim of this study was to clarify the feasibility of laparoscopic surgery for rectal cancer retrospectively in 28 centers throughout Japan.MethodsBetween May 1994 and February 2006, 1,057 selected patients with rectal cancer underwent laparoscopic surgery. All the data regarding the patient details, and operative and postoperative outcome were collected retrospectively.ResultsMean follow-up was 30 months. Procedures included anterior resection in 938, abdominoperineal resection in 107, Hartmann’s procedure in 10, and others in two patients. Conversion to open procedures occurred in 77 patients (7.3%). Postoperative surgical complications developed in 235 patients (22.2%), including anastomotic leakage in 84 (9.1%). Median length of postoperative hospital stay was 15 days (7–271 days). Patients with upper rectal cancer had shorter hospital stay than those with lower rectal cancer (14 versus 18 days, p < 0.01). Tumor–node–metastases (TNM) stage included 83(7.9%) stage 0, 495 (46.8%) stage I, 197 (18.6%) stage II, 230 (21.8%) stage III, and 52 (4.9%) stage IV. Recurrence was developed in 67 patients (6.6%) of the 1,011 curatively treated patients. Local recurrence occurred in 11 patients (1.0%). There was no port-site metastasis. Of the 1,011 curatively treated patients, the 3-year disease-free survival rate was 100% in stage 0, 94.6% in stage I, 82.1% in stage II, and 79.7% in stage III.ConclusionsLaparoscopic surgery is feasible and safe in selected patients with rectal cancer, with favorable short-term and mid-term outcome.

Association Between The Severity Of Sepsis And The Changes In Hemostatic Molecular Markers And Vascular Endothelial Damage Markers

It is well known that disorders of coagulation and fibrinolysis play a major role in the development of organ dysfunction during sepsis. Furthermore, the importance of the early initiation of anticoagulation therapy for severe cases has been emphasized based on the success of recent clinical trials. The purpose of this study is to search for useful markers for predicting organ dysfunction. Plasma samples were prospectively collected from 78 patients within 48 h after the onset of sepsis. Hemostatic markers and endothelial damage markers were compared between the patients with and without organ dysfunction. The WBC and platelet counts were not different between the groups. In contrast, fibrin/fibrinogen degradation products, D-dimer, thrombin-antithrombin complex, plasmin α2-antiplasmin complex, soluble fibrin, and total plasminogen activator inhibitor-1 were significantly higher, and the antithrombin activity and protein C levels were lower in the patients with organ dysfunction. Thus, the changes in the hemostatic molecular markers were associated with organ dysfunction from an early stage of sepsis, and antithrombin and protein C activities were found to be the most reliable markers.

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.

Comparison of the protective effects of type III phosphodiesterase (PDE3) inhibitor (cilostazol) and acetylsalicylic acid on intestinal microcirculation after ischemia reperfusion injury in mice

ABSTRACT Antiplatelet therapy has been proposed as the treatment of choice for ischemia/reperfusion injury. The aim of this study is to elucidate the difference in effect between cilostazol (CZ) and acetylsalicylic acid (ASA) on microcirculatory disturbance in ischemia/reperfusion injury. Either 10 mg/kg of CZ (n = 14) or 100 mg/kg of ASA (n = 14) was administered orally to mice. Thereafter, 20 min of intestinal ischemia, followed by 60-min reperfusion, was applied; then, the status of submucosal microcirculation was observed under intravital microscopy. The blood cell counts and organ damage markers were examined in the portal blood. Next, 5 mm of the ileum was excised and was then histologically examined. Platelet-leukocyte aggregates were often observed in the postcapillary venules, and this formation was significantly reduced by both CZ and ASA. The number of adherent leukocytes was significantly lesser in the CZ-treated mice than in the ASA-treated mice (P < 0.01). The leukocyte number, lactate dehydrogenase, and lactate levels were best maintained in the CZ-treated mice (P < 0.05). The villus height was best preserved in the CZ-treated mice. Cilostazol inhibited not only the platelet aggregation but also the leukocyte adhesion to the endothelium, thereby inducing organ protection.

Factor Xa-inhibitor (DX-9065a) modulates the leukocyte-endothelial cell interaction in endotoxemic rat.

Abnormalities of vascular endothelial function and coagulation play important roles in the development of septic organ dysfunction. DX-9065a is a novel Factor Xa inhibitor that is expected to modulate both coagulation and endothelial function. The purpose of this study is to examine the effect of DX-9065a on leukocyte-endothelial interaction. Rats were injected with 1.0 mg/kg of endotoxin simultaneously with saline, (placebo group), 0.3 mg/kg DX-9065a (low-dose group), or 3.0 mg/kg DX-9065a (high-dose group;n = 6 in each group). At 1 and 3 h after injection, the mesenteric microcirculation was observed under intravital microscopy. In addition, TNF, IL-6, alanine aminotransferase (ALT), blood urea nitrogen (BUN), and lactate levels were measured. The number of leukocytes adhering to the endothelium was significantly reduced in both the high-dose and low-dose groups (P < 0.05 for both, compared to the control group). A comparison of the cytokine levels showed that the peak levels in the treatment groups tended to be lower. Markers of organ damage also showed less increase in the treatment groups (P < 0.05 for both treatment groups compared to the control group). In summary, the Factor Xa inhibitor DX-9065a showed a protective effect on the microcirculation of endotoxemic rats by attenuating leukocyte-endothelial interaction. Although the mechanism for this effect could not be fully elucidated, suppression of both excessive coagulation and cytokine production appear to play a role.

Pretreatment of sivelestat sodium hydrate improves the lung microcirculation and alveolar damage in lipopolysaccharide-induced acute lung inflammation in hamsters

ABSTRACT Damage to the lung microcirculation and alveoli caused by activated leukocytes is known to play an important role in the development of acute lung injury (ALI). The aim of this study is to evaluate the difference in the effect of pretreatment and posttreatment of a synthetic neutrophil elastase inhibitor sivelestat on ALI. Hamsters were instilled with 10.0 mg/kg of lipopolysaccharide (LPS) intratrachealy for 1 h to simulate ALI. Two milligrams per kilogram of sivelestat was injected intraperitoneally either previously or after LPS infusion. One and 24 hours after the infusion of LPS, pulmonary microcirculation was observed under the intravital microscopy. In another series, the blood cell counts were evaluated. The adhesive leukocyte count on the endothelium was significantly lower in pretreatment group compared with control group (P < 0.01), whereas the difference was not significant in the posttreatment group. Similarly, the number of obstructed capillary was significantly lower in the pretreatment group (P < 0.01). The width of interstitum was significantly lower in the pretreatment and posttreatment group (P < 0.01 and 0.05, respectively). A comparison of white blood cell counts showed a better maintenance in pretreatment group (P < 0.05). Pretreatment of sivelestat demonstrated a protective effect on both intravascular and extravascular damage in the lung, whereas posttreatment only suppressed the latter damage.