Satoshi Ikei

Elevation of circulating interleukin 6 after surgery: Factors influencing the serum level

To investigate the effect of surgical trauma and other factors on the postoperative elevation of serum interleukin 6 (IL-6), we examined changes in IL-6 concentration after major thoracoabdominal surgery. Serum IL-6 levels reached the maximum concentration on the first postoperative day in all 38 patients, with peak ranging from 1400.8 +/- 383.4 pg/ml (mean +/- SEM) to 29.8 +/- 3.8 among six groups who underwent surgery at different sites. The IL-6 peak was significantly correlated with surgical trauma as defined by the operation length and the volume of blood loss during surgery (r = 0.554, P < 0.01 and r = 0.427, P < 0.01, respectively). The peak concentration of serum IL-6 in patients undergoing esophagectomy was significantly higher than in those undergoing pancreaticoduodenectomy (P < 0.05), despite a similar degree of surgical trauma defined by the operation length and volume of blood loss during surgery. Peak IL-6 concentration observed in a patient who underwent esophagectomy was about 100-fold greater in fluid drained from the thorax than in the peripheral blood. IL-6 mRNA was demonstrated in leukocytes from thoracic and abdominal exudate at 6, 24 and 48 h after surgery. In contrast, IL-6 mRNA could not be detected in leukocytes from the peripheral blood. Similar findings were also observed for interleukin 8 (IL-8). However, interleukin 1 beta (IL-1 beta) and tumour necrosis factor-alpha (TNF-alpha) were detected only once after surgery in the drainage fluid.(ABSTRACT TRUNCATED AT 250 WORDS)

Estimation of Physiologic Ability and Surgical Stress (E-PASS) as a new prediction scoring system for postoperative morbidity and mortality following elective gastrointestinal surgery.

Overwhelming surgical stress exceeding a patient’s reserve capacity causes a disruption of homeostasis, leading to various postoperative complications. This study was under-taken to develop a new scoring system, “E-PASS”, standing for the Estimation of Physiologic Ability and Surgical Stress, that predicts the postsurgical risk by quantification of the patient’s reserve and surgical stress. E-PASS comprises the preoperative risk score (PRS), the surgical stress score (SSS), and the comprehensive risk score (CRS) that is determined by both scores. These scores were computed by a multiple regression analysis conducted on 292 consecutive patients who underwent elective common gastrointestinal operations at one hospital between 1992 and 1995 (internal group). The usefulness of the scores was evaluated in 989 consecutive patients who underwent the same surgical procedures during the same period at another hospital (external group). The morbidity and mortality rates increased similarly in both groups as the CRS increased. A marked step-up of both rates was observed at a CRS>1.0, reaching mortality rates of 20% in the internal subjects and 28.5% in the external subjects. These results suggest that the E-PASS scoring system is reproducible, and that it may be useful for surgical decision making. This system requires no special examinations and can be used in every hospital.

Systemic inflammatory response syndrome and organ dysfunction following gastrointestinal surgery.

OBJECTIVES Progression from systemic inflammatory response syndrome (SIRS) to sepsis, severe sepsis, and septic shock has been demonstrated in a variety of patients. However, the presence of SIRS alone was not helpful in predicting the development of multiple organ dysfunction syndrome (MODS) since SIRS includes many nonprogressive conditions. This study was conducted to investigate the clinical significance of SIRS in postoperative patients. DESIGN Retrospective study. SETTING The surgical department of a university hospital. PATIENTS Two hundred ninety-two consecutive patients who received elective common gastrointestinal surgery (esophagectomy, pancreatoduodenectomy, hepatectomy, gastrectomy, colorectal resection, and laparoscopic cholecystectomy) between 1992 and 1995. INTERVENTIONS Patients were analyzed for preoperative physiologic status, surgical stress parameters, and postoperative status of SIRS, complications, and end-organ dysfunction. MEASUREMENTS AND MAIN RESULTS Duration of SIRS or positive criterias number of SIRS after surgery significantly correlated with surgical stress parameters (blood loss/body weight and operation time) and peak serum C-reactive protein concentrations. SIRS that continued or reappeared after postoperative day 3 was an early sign of postoperative complications. SIRS continuing consecutively for 2 days after postoperative day 3 had a 70.6% positive predictive value and a 92.5% negative predictive value for postoperative complications. Septic complications and prolongation of SIRS were associated with MODS. Five of six patients who met the SIRS criteria for >30 days developed severe MODS, and three of them died. CONCLUSIONS SIRS is a useful criterion for the recognition of postoperative complications and end-organ dysfunctions. Early recovery from SIRS may arrest the progression of organ dysfunction.

Relationship between plasma cytokine concentration and multiple organ failure in patients with acute pancreatitis.

The dynamic aspects of circulating cytokines and cytokine modulators and their relationship with development of multiple organ failure (MOF) in patients with acute pancreatitis were analyzed. All cytokine and C-reactive protein levels in the circulation were higher than those in the MOF group. In particular, plasma concentrations of soluble tumor necrosis factor receptors (sTNF-RI and sTNF-RII) were significantly higher in patients with MOF than in those without even at admission. Furthermore, plasma concentrations of sTNF-Rs and interleukin-1 (IL-1) receptor antagonist (IL-1ra) were much higher than those of their counterparts, TNF-&agr; and IL-1&bgr;, respectively. These results suggest that the plasma concentrations of sTNF-Rs are useful predictors for the development of MOF, and actions of TNF-&agr; and IL-1&bgr; could be regulated by their modulators (soluble receptor and receptor antagonist, respectively) in the pathologic condition of severe acute pancreatitis.

Evaluation of an Estimation of Physiologic Ability and Surgical Stress (E-PASS) Scoring System to Predict Postoperative Risk : A Multicenter Prospective Study

Abstract We previously reported generating a scoring system termed E-PASS that predicted postsurgical risk. This study was undertaken to evaluate the usefulness of this system. A consecutive series of 902 patients who underwent elective gastrointestinal operations in six national hospitals in Japan were prospectively assessed for a comprehensive risk score (CRS) of the E-PASS, which was compared with their postoperative course. The postoperative morbidity rates linearly increased as the CRS increased. The postoperative mortality rate was only 0.13%, when the CRS was below 0.5; however, it increased to 9.7% when the CRS ranged from 0.5 to <1.0, and to 26.9% when the CRS was ≥1.0. The CRS correlated significantly with the severity of postoperative complications (rs = 0.527, P < 0.0001) and the costs of hospital stay (rs = 0.810, P < 0.0001). When the CRS-adjusted mortality rate at the CRS of ≥0.5 was compared among the hospitals, it was related to the hospital volume of operations, being 44.2% at the volume of <100 cases per year, 20.6% at the range of 100–199 cases, and 8.6% at the volume of ≥200 cases. These results suggest that E-PASS may be useful for predicting postsurgical risk, estimating medical expense, and comparing surgical quality.

Blood concentrations of polymorphonuclear leucocyte elastase and interleukin‐6 are indicators for the occurrence of multiple organ failures at the early stage of acute pancreatitis

We studied potential indicators of severe acute pancreatitis by measuring the blood concentrations of various cytokines, polymorphonuclear leucocyte elastase (PMN‐E), acute phase reactants, pancreatic amylase (P‐AMY), pancreatic elastase‐1 (E‐1) and white blood cell (WBC) counts in patients with acute pancreatitis. In addition, the presence of multiple organ damage was assessed. Subjects consisted of 22 patients with acute pancreatitis including severe (n= 11), moderate (n= 4) and mild (n= 7) cases. A significant positive correlation was observed between the number of organs damaged and the peak concentrations of interleukin (IL)‐6, PMN‐E, C‐reactive protein (CRP) and pancreatic secretory trypsin inhibitor (PSTI). Among these markers, blood concentrations of PMN‐E and IL‐6 rapidly increased and peaked at the early phase of acute pancreatitis whereas CRP and PSTI did not. The elevation of PMN‐E and IL‐6 was greater the more severe the symptoms. However, no significant correlation was observed between the number of organs damaged and the maximum serum concentrations of P‐AMY and E‐1, or the WBC count, which have been considered to be markers of pancreatitis. These results suggest that PMN‐E and IL‐6 concentrations are useful indicators of severity and prognosis and their determination facilitates the selection of appropriate treatment in the early stages of disease to prevent the aggressive progression of acute pancreatitis.

The role of tumor necrosis factor-α in the aggravation of cerulein-induced pancreatitis in rats.

SummarySevere acute pancreatitis is often complicated by intraperitoneal infection, resulting in multiple organ failure (MOF). It is known to elevate serum tumor necrosis factor (TNF-α) in patients with sepsis and/or MOF. In order to study the role of TNF-α in the aggravation of acute pancreatitis, we investigated TNF-α production by peritoneal macrophages in acute pancreatitis rat using the cerulein-induced pancreatitis model. TNF-α production by isolated peritoneal macrophages following lipopolysaccharide (LPS) stimulation was significantly increased in pancreatitis rats as compared with nonpancreatitis control rats (p<0.001). Serum TNF-α activity was elevated following intraperitoneal administration of LPS as the septic challenge both in pancreatitis rats and in control rats, being significantly higher in the former (p<0.05). Histological findings and liver function tests revealed that LPS induced more severe liver damage in pancreatitis rats than in control rats within 24 h after LPS administration. These results indicate that increased TNF-α production by peritoneal macrophages in acute pancreatitis augmented LPS-induced liver injury and suggest the possibility that TNF-α may play a role in the development of MOF during acute pancreatitis complicated by intraabdominal sepsis.

Neutrophil elastase inhibitor (ONO-5046) prevents lung hemorrhage induced by lipopolysaccharide in rat model of cerulein pancreatitis

The protective effects of a neutrophil elastase inhibitor (ONO-5046) on cerulein-induced pancreatitis followed by a septic challenge with intraperitoneal lipopolysaccharide (LPS) were studied in a rat model. Pancreatitis was induced by four intramuscular injections of cerulein (50 μg/kg at 1-hr intervals). ONO-5046 was administered by continuous intravenous infusion via the right jugular vein (50 mg/kg/hr, 30 min prior to the first cerulein injection to 20 hr following the last cerulein injection). Significant differences in serum amylase and pancreatic wet weight ratio were not observed between the animals with pancreatitis treated with or without ONO-5046. There was no significant difference in thein vitro tumor necrosis factor-alpha (TNF-α) production by peritoneal macrophages from rats with pancreatitis treated with or without ONO-5046. In a second experiment, LPS (10 mg/kg) was administered intraperitoneally as the septic challenge 6 hr following the first cerulein injection. Lung hemorrhage was seen in the animals with pancreatitis untreated with ONO-5046 24 hr following the first cerulein injection. No significant lung hemorrhage was observed in the animals with pancreatitis treated with ONO-5046 administering 30 min prior to the first cerulein injection. These results suggest that lung hemorrhage in cerulein-induced pancreatitis that follows a septic challenge with LPS can be prevented by the intravenous administration of ONO-5046. Thus there is a significant role for neutrophil elastase in pancreatitisassociated lung injury.

Enhanced expression of cytokine-induced neutrophil chemoattractant (CINC) by bronchoalveolar macrophages in cerulein-induced pancreatitis rats.

The role of bronchoalveolar macrophages (BAMs)in the aggravation of cerulein-induced pancreatitis wasstudied by measuring expression of cytokine-inducedneutrophil chemoattractant (CINC) in vitro. Pancreatitis was induced by four intramuscular injections ofcerulein (50 μg/kg at 1-hr intervals). Pancreatitisrats were injected intraperitoneally with 30 mg/kglipopolysaccharide (LPS) 6 hr following the first cerulein injection as a septic challenge. Ratswere divided into four groups: group I, nonpancreatitiswithout LPS; group II, pancreatitis without LPS; groupIII, nonpancreatitis with LPS; and group IV, pancreatitis with LPS. Hyperactivity of BAMs inresponse to LPS was assessed as a function of in vitroCINC production. CINC concentrations of the serum andbronchoalveolar lavage fluid in group IV were significantly higher than those in groups I,II, and III. BAMs in group II harvested 6 hr followingthe first cerulein injection had significantly greaterCINC production than those in group I. Northern blot analysis revealed abundant CINC mRNAtranscripts in BAMs from groups III and IV.Additionally, myeloperoxidase activity in the lung ofgroup IV rats 8 and 12 hr following the first ceruleininjection was significantly higher than that in group I,II, and III rats. Significant differences in static lungcompliance in group IV were found compared with groupsI, II, and III. These results indicate that BAMs from rats with cerulein-inducedpancreatitis were primed and had enhanced release ofCINC following LPS exposure. Enhanced expression of CINCmay modulate the pathogenesis of pancreatitis-associated lung injury complicated with sepsis.

A new approach to chemoembolization for unresectable hepatocellular carcinoma using aclarubicin microspheres in combination with cisplatin suspended in iodized oil

Sixty‐six consecutive patients with unresectable hepatocellular carcinoma (HCC) were treated with transcatheter arterial chemoembolization (TACE) using aclarubicin microspheres (ACRms) in combination with cisplatin suspended in iodized oil (Lipiodol, Laboratoire Guerbert, Paris, France) (CSL). The stages of the disease were as follows: Stage I (n = 1), Stage II (n = 10), Stage III (n = 26), and Stage IV (n = 29). The effectiveness of TACE was assessed by comparing ACRms with CSL with ACRms without CSL. Of 66 patients treated with ACRms and CSL, 62 (93.9%) could be examined for response. According to response criteria, there were 31 (50.0%) partial responses and 17 (27.4%) minor responses. In 13 cases (21.0%) there was no change and in 1 case (1.6%) there was progressive disease. The cumulative survival rate was 80.7% at 1 year, 64.2% at 2 years, and 50.6% at 3 years. The rates were significantly higher than those of the group treated with ACRms. Eleven patients in the ACRms and CSL group experienced clinical complications: cholecystitis (4.5%), pancreatitis (3.0%), liver abscess (3.0%), hepatic failure (3.0%), gastrointestinal bleeding (1.5%), and renal failure (1.5%). No lethal side effects related to the therapy were observed. TACE using ACRms in combination with CSL prolongs the survival of patients with unresectable HCC. Cancer 68:2555–2560, 1991.