Takumi Taniguchi

Change in the ratio of interleukin-6 to interleukin-10 predicts a poor outcome in patients with systemic inflammatory response syndrome.

OBJECTIVE To examine whether changes in interleukin (IL)-6 and IL-10 concentrations in patients with systemic inflammatory response syndrome (SIRS) can predict a poor outcome. DESIGN Prospective study. SETTING Emergency and intensive care unit of a medical school hospital. PATIENTS Twenty-five patients who fulfilled the criteria for SIRS. INTERVENTIONS Blood samples were collected for cytokine determinations. MEASUREMENTS AND MAIN RESULTS IL-6 and IL-10 concentrations were measured by enzyme-linked immunosorbent assay in plasma samples. Blood samples were obtained at 0, 1, 2, and 4 days from patients who fulfilled the criteria for SIRS. Of 25 patients, 19 survived and the other six patients died of multiple organ failure. Although IL-6 and IL-10 concentrations in survivors decreased gradually from 186.1 +/- 34.4 to 93.6 +/- 18.9 (SEM) pg/mL (p < .05) and from 77.4 +/- 21.2 to 32.0 +/- 11.8 pg/mL (p < .05), IL-6 concentrations in nonsurvivors did not. Although the ratio of IL-6 to IL-10 in survivors was almost stable, the ratio in nonsurvivors increased from 5.5 +/- 3.1 to 18.7 +/- 2.8 (p < .05). Multivariate analysis showed that when heart rate, mean arterial pressure, IL-6, IL-10, and the ratio of IL-6 to IL-10 were taken into account, there only remained a relationship between the ratio of IL-6 to IL-10 and outcome. CONCLUSIONS In nonsurvivors, IL-6 concentrations did not decrease, IL-10 concentration decreased, and the ratio of IL-6 to IL-10 increased. An increase in the ratio of IL-6 to IL-10 indicated a correlation with a poor outcome.

Effects of propofol on hemodynamic and inflammatory responses to endotoxemia in rats.

Objective: To document the effects of propofol on the hemodynamic and inflammatory responses to endotoxemia in an animal model. Design: Randomized, prospective laboratory study. Setting: University experimental laboratory. Subjects: Thirty‐two male rats. Interventions: The animals were randomly assigned to one of four groups: a) endotoxemia group (n = 8), which received intravenous Escherichia coli endotoxin (15 mg/kg over 2 mins); b) control group (n = 8), which was treated identically to the endotoxemia group except for the substitution of 0.9% saline for endotoxin; c) propofol group (n = 8), which was treated identically to the control group but also received propofol (10 mg/kg bolus, followed by infusion at 10 mg/kg/hr) immediately after the injection of 0.9% saline; and d) propofol‐endotoxemia group (n = 8), which was treated identically to the endotoxemia group with the additional administration of propofol (10 mg/kg bolus, followed by infusion at 10 mg/kg/hr) immediately after endotoxin injection. Measurements and Main Results: Hemodynamics, arterial blood gases, and acid‐base status were recorded and the blood propofol concentrations and plasma cytokine concentrations were measured during the 5‐hr observation. Microscopic findings of lung tissue for each group were obtained at necropsy. The systolic arterial pressure and heart rate of the propofol‐endotoxemia group were similar to those of the endotoxemia group. The increases in the plasma cytokine (tumor necrosis factor, interleukin‐6, and interleukin‐10) concentrations, in the base deficit, and in the infiltration of neutrophils in the air space or vessel walls of the lungs were attenuated in the propofol‐endotoxemia group compared with the endotoxemia group. Conclusions: Propofol attenuated cytokine responses, base deficit, and activation of neutrophils to endotoxemia. These findings suggest that propofol may inhibit inflammatory response and prevent the development of metabolic acidosis during endotoxemia.

Dose- and time-related effects of dexmedetomidine on mortality and inflammatory responses to endotoxin-induced shock in rats.

PurposeOur previous study demonstrated that dexmedetomidine drastically reduced mortality and inhibited the inflammatory response during endotoxemia in rats. The aim of this study was to clarify the dose- and time-related effects of dexmedetomidine on mortality and inflammatory responses to endotoxemia in rats.MethodsMale Wistar rats (n = 96) were anesthetized intraperitoneally with pentobarbital sodium and assigned to one of two protocols: one representing the dose-related effects of dexmedetomidine, and the other, the time-related effects of dexmedetomidine. To evaluate the dose-related effects, the animals were randomly assigned to one of four groups (n = 15 each): endotoxemic group (group E), receiving intravenous Escherichia coli endotoxin (15 mg·kg−1 over 2 min); small-dose group (group S), treated with a small dose of dexmedetomidine (2.5 μg·kg−1·h−1, IV); medium-dose group (group M), treated with a medium dose (5 μg·kg−1·h−1, IV); and large-dose group (group L), treated with a large dose (10 μg·kg−1·h−1, IV). To evaluate the time-related effects, the animals were randomly assigned to one of three groups (n = 12 per group): endotoxemic group; early posttreatment group, treated with 10 μg·kg−1·h−1 dexmedetomidine at 1 h after endotoxin injection; and late posttreatment group, treated with 10 μg·kg−1·h−1 at 2 h after endotoxin injection. Hemodynamics and arterial blood gases were recorded and plasma cytokine concentrations were measured throughout the observation period. The mortality rate was assessed up to 8 h after endotoxin injection.ResultsIn the dose-related study, the mortality rates at 8 h after endotoxin injection were 81%, 26%, 32%, and 20% for groups E, S, M, and L, respectively. Plasma tumor necrosis factor-alpha (TNF) concentrations were lower in groups M and L than in group E at 2 h after endotoxin injection. Plasma interleukin-6 (IL-6) concentrations were lower in groups M and L than in group E at 4 and 5 h after endotoxin injection. In the time-related study, the mortality rates at 8 h after the endotoxin injection were 83%, 33%, and 58% for the endotoxemic, early posttreatment, and late posttreatment groups, respectively. The TNF concentration was lower in the early posttreatment group than in the endotoxemic group at 2 h after endotoxin injection, and the IL-6 concentration was lower in the early posttreatment group than in the endotoxemic group at 5 h after endotoxin injection.ConclusionDexmedetomidine dose-dependently attenuated extremely high mortality rates and increases in plasma cytokine concentrations after endotoxin injection. Moreover, the early administration of dexmedetomidine drastically reduced the high mortality rate and inhibited cytokine responses in endotoxin-exposed rats. These findings suggest that dexmedetomidine administration may be effective during sepsis.

Ketamine inhibits endotoxin-induced shock in rats

BackgroundCytokines and nitric oxide are believed to participate importantly in the pathogenesis of endotoxin-induced shock. Several investigators have documented that ketamine attenuates production of cytokines and nitric oxide in endotoxemia, but little is known concerning hemodynamic effects of the drug in this state. The objective of the current study was to assess the potential modifying effects of ketamine in endotoxemia. MethodsThe authors randomly assigned 40 rats to one of four equal groups: endotoxin alone, receiving Escherichia coli endotoxin (15 mg/kg, administered intravenously); saline control, receiving saline only; ketamine alone, receiving ketamine (10 mg · kg−1 · h−1, administered intravenously); pretreatment, with ketamine administration initiated before the endotoxin exposure; and posttreatment, with ketamine initiated 2 h after endotoxin. During the 5 h after endotoxin injection, hemodynamics, acid-base status, and plasma concentrations of tumor necrosis factor &agr; and interleukin 6 were assessed in each group. ResultsEndotoxin injection produced progressive hypotension, metabolic acidosis, and a large increase in the plasma cytokine concentrations. This hemodynamic and cytokine responses to endotoxin were completely abolished in the pretreatment group and modestly suppressed in the posttreatment group. In the absence of endotoxin, ketamine did not modify these responses. ConclusionKetamine administration inhibited hypotension, metabolic acidosis, and cytokine responses in rats injected with endotoxin. The results suggest that judicious use of ketamine as an anesthetic agent may offer advantages in endotoxemia.

Effects of posttreatment with propofol on mortality and cytokine responses to endotoxin-induced shock in rats

Objective To clarify the effects of posttreatment with propofol administration on mortality rate and cytokine responses to endotoxin-induced shock in rats. Design Randomized prospective laboratory study. Setting University laboratory. Subjects Thirty-three male rats. Interventions Animals were randomly assigned to one of three groups (n = 11 per group): a) endotoxemic group, receiving intravenous Escherichia coli endotoxin (20 mg/kg over 2 mins); b) early posttreatment group, treated identically to the endotoxemic group with the additional administration of propofol (10 mg/kg bolus, followed by infusion at 10 mg·kg−1·hr−1) 1 hr after the injection of endotoxin; and c) late posttreatment group, treated identically to the endotoxemic group with the additional administration of propofol (10 mg/kg bolus, followed by infusion at 10 mg·kg−1·hr−1) 2 hrs after the injection of endotoxin. Measurements and Main Results Hemodynamics and arterial blood gases were recorded, and mortality rate and plasma cytokine concentrations were calculated for the 5-hr observation. The mortality rate 5 hrs after endotoxin injection was 73% for the endotoxic, 9% for the early posttreatment, and 36% for the late posttreatment groups. The mortality rate for the early posttreatment group was significantly lower than that for the other groups. The increases in plasma cytokine (tumor necrosis factor-&agr; and interleukin-6 and -10) concentrations were less for the early posttreatment group than the other two groups. Conclusions The early posttreatment of propofol after endotoxin injection drastically reduced the mortality rate of rats and attenuated their cytokine responses. Moreover, propofol attenuated the production of tumor necrosis factor-&agr;. These findings suggest that propofol administration may be beneficial during sepsis.

Effects of lidocaine administration on hemodynamics and cytokine responses to endotoxemia in rabbits.

Objective: To investigate the effects of lidocaine administration on hemodynamics and cytokine concentrations in Escherichia coli endotoxemia in rabbits. Design: Randomized, prospective laboratory study. Setting: University laboratory. Subjects: Thirty‐two Japanese rabbits anesthetized with urethane and ventilated mechanically. Interventions: Animals were randomly assigned to one of four groups: endotoxemic controls (n = 8), receiving intravenous E. coli endotoxin (0.5 mg/kg bolus) via the mesenteric vein; laparotomy controls (n = 8), treated identically to the endotoxemic controls except for the substitution of 0.9% saline for endotoxin; lidocaine controls (n = 8), treated identically to the laparotomy controls with the addition of intravenous lidocaine (3 mg/kg bolus followed by infusion at 2 mg/kg/hr) administered immediately after the injection of 0.9% saline; and lidocaine‐treated rabbits (n = 8), treated identically to the endotoxemic controls with the addition of intravenous lidocaine (3 mg/kg bolus followed by infusion at 2 mg/kg/hr) administered immediately after the injection of endotoxin. Measurements and Main Results: We compared the cardiac output, systemic vascular resistance, blood gases, and plasma cytokine concentrations (tumor necrosis factor, interleukin [IL]‐6, and IL‐8) for each group. After endotoxin injection, the mean arterial pressure, cardiac output, and systemic vascular resistance decreased progressively in the endotoxemic controls. At 4 hrs after injection, all of the variables except the heart rate and central venous pressure were lower in the endotoxemic controls than in the other groups. At 4 hrs after endotoxin injection, both IL‐6 and IL‐8 concentrations increased in all groups. However, the mean concentrations of IL‐6 and IL‐8 in the endotoxemic controls significantly exceeded those in the other groups. No significant differences existed between the laparotomy controls and lidocaine‐treated rabbits. Conclusions: Lidocaine had a profound inhibitory effect on the hemodynamic and cytokine responses to endotoxemia when it was administered immediately after exposure to endotoxin. Our results demonstrate the potential usefulness of lidocaine as an anti‐inflammatory agent in endotoxemia.

The attitudes of Japanese high school students toward cardiopulmonary resuscitation

BACKGROUND AND OBJECTIVES It is essential to have a clear understanding of the present condition of cardiopulmonary resuscitation (CPR) training courses and the associated problems. The present study was performed to identify the current conditions of CPR training in Japanese high schools and the attitudes of students toward CPR. METHODS AND RESULTS We distributed a questionnaire study to the students of 12 cooperating high schools regarding their willingness to perform CPR in 5 hypothetical scenarios of cardiopulmonary arrest: a stranger, a trauma patient, a child, an elderly person, and a relative. Between February and March 2006, a total of 3316 questionnaires were completed. Across all scenarios, only 27% of respondents from general high schools reported willingness to perform chest compression (CC) plus mouth-to-mouth ventilation (MMV), and 31% reported willingness to perform CC alone. Fifty-nine percent of students had previous CPR training, and only 35% were willing to perform CC plus MMV. Most of the respondents who reported that they would decline to perform full CPR, stated that poor knowledge and/or fear of incomplete performance of CPR were deciding factors. CONCLUSIONS Japanese high school students are reluctant to perform CC plus MMV, despite having received training. The present educational system in Japan has limitations in encouraging high school students to perform CC plus MMV.

A novel adsorbent of circulating bacterial toxins and cytokines: the effect of direct hemoperfusion with CTR column for the treatment of experimental endotoxemia.

Objectives:The current study examined the ability of a new adsorbent, CTR, to remove enterotoxins, toxic shock syndrome toxin-1 (TSST-1), and cytokines from blood and/or serum in vitro and the effects of the extracorporeal treatment with CTR column on mortality rate and inflammatory responses to endotoxic shock in vivo. Design:Laboratory investigation. Setting:University and company experimental laboratory. Materials:CTR is composed of porous cellulose beads to which a hydrophobic organic compound with a hexadecyl alkyl chain has been covalently bound to the surface as a ligand. Human/bovine serum and human blood samples in vitro and Male Wistar rats were used. Interventions:CTR’s ability to adsorb bacterial toxins and cytokines related to sepsis in serum and/or blood was examined with an in vitro batch adsorption protocol. In vivo, male Wistar rats were anesthetized and assigned to one of three groups (n = 14 per group): Escherichia coli endotoxin (15 mg/kg intravenously) alone (endotoxemic), apheresis with control column without CTR for 120 mins (control column), or extracorporeal treatment with CTR column for 120 mins (CTR treatment). Measurements and Main Results:With use of the CTR adsorbent, the adsorption rates were 50% to 90% for enterotoxins, TSST-1, and cytokines such as TNF-&agr; and interleukin (IL)-6 in the batch tests. In vivo, the mortality rates at 8 hrs after endotoxin injection were 92%, 92%, and 14% for the endotoxemic, control column, and CTR treatment groups, respectively. Hypotension and elevated plasma cytokine concentrations and the infiltration of neutrophils of the lungs were less conspicuous in the CTR treatment group than in the other two groups. Conclusions:CTR, a novel adsorbent, effectively adsorbed small- to middle-sized proteins, such as cytokines, enterotoxins, and TSST-1 in vitro. Direct hemoperfusion apheresis with CTR column reduced mortality and had inhibitory effects on the inflammatory responses during endotoxemia in vivo. These findings suggest that extracorporeal blood purification with CTR column may be available to use for patients with sepsis and/or endotoxemia.

Anti-inflammatory effects of intravenous anesthetics on endotoxemia.

Endotoxemia and endotoxin shock are common problems in the intensive care unit and carry a very high mortality rate. Endotoxemia increases production of endogenous cytokines, including tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), IL-6, and IL-8. Not only endotoxin but also cytokines have been implicated as important factors in the pathophysiology of endotoxic shock and the development of cardiovascular dysfunction in endotoxemia. Recently, it has been shown both in vitro and in vivo that several intravenous anesthetics have anti-inflammatory effects. Thiopental and ketamine inhibit the endotoxin-induced TNF-alpha, IL-1 and IL-8 responses and increase IL-10 release in vitro. Ketamine prevent the pro-inflammatory cytokine (TNF-alpha, IL-1, and IL-6) responses to endotoxemia in vivo. Moreover, thiopental and ketamine suppress the activation of nuclear factor-kappa B induced by endotoxin. Propofol have been proven its anti-inflammatory effects on endotoxemia both in vitro and in vivo, but several studies have shown that propofol does not have any anti-inflammatory effects and deteriorates the inflammatory response to endotoxemia. This article reviews the anti-inflammatory effects of intravenous anesthetics on endotoxemia and endotoxic shock.

Cytokine Adsorbing Columns

Sepsis induces the activation of complement and the release of inflammatory cytokines such as TNF-alpha and IL-1beta. The inflammatory cytokines and nitric oxide induced by sepsis can decrease systemic vascular resistance, resulting in profound hypotension. The combination of hypotension and microvascular occlusion results in tissue ischemia and ultimately leads to multiple organ failure. Recently, several experimental and clinical studies have reported that treatment for adsorption of cytokines is beneficial during endotoxemia and sepsis. Therefore, the present article discusses cytokine adsorbing columns. These columns, such as CytoSorb, CYT-860-DHP, Lixelle, CTR-001 and MPCF-X, the structures of which vary significantly, have excellent adsorption rates for inflammatory cytokines such as TNF-alpha, IL-1beta, IL-6 and IL8. Many studies have demonstrated that treatment with cytokine adsorbing columns has beneficial effects on the survival rate and inflammatory responses in animal septic models. Moreover, several cases have been reported in which treatment with cytokine adsorbing columns is very effective in hemodynamics and organ failures in critically ill patients. Although further investigations and clinical trials are needed, in the future treatment with cytokine adsorbing columns may play a major role in the treatment of hypercytokinemia such as multiple organ failure and acute respiratory distress syndrome.