Search

Background: Tumor necrosis factor (TNF) antagonists [e.g., TNF soluble receptor (TNFsr)] improved survival in preclinical but not clinical sepsis trials. However fluid support-itself beneficial-is standard clinically but rarely employed in preclinical sepsis models. We hypothesized that these therapies may not have additive benefit. Methods and results: Antibiotic-treated rats ( n = 156) were randomized to intratracheal or intravenous Escherichia coli challenges (>LD50) and either placebo or TNFsr and 24 h fluid treatments alone or together. The survival effects of these therapies did not differ significantly comparing challenge routes. When averaged across route, while TNFsr or fluid alone decreased the hazard ratio of death significantly [ln ± standard error (SE): −0.65 ± 0.30 and −0.62 ± 0.30, respectively, p ≤ 0.05], together they did not ( p = 0.16). Furthermore, the observed effect of TNFsr and fluid together on reducing the hazard ratio was significantly less than estimated (−0.37 ± 0.29 versus −1.27 ± 0.43, respectively, p = 0.027) based on TNFsr and fluid alone. While each treatment increased central venous pressure at 6 and 24 h, the observed effects of the combination were also less than estimated ones ( p ≤ 0.0005). Conclusions: The individual survival benefits of TNFsr and fluids were not additive in this rat sepsis model. Investigating new sepsis therapies together with conventional ones during preclinical testing may be informative. [ABSTRACT FROM AUTHOR]

To assess left ventricular (LV) contractile function and adrenergic responsiveness in septic patients. We used echocardiographically defined fractional area of contraction (FAC), and LV area to end-systolic arterial pressure estimates of end-systolic elastance (E'es) and its change in response to dobutamine (5 μg/kg/min) in 10 subjects in septic shock admitted to an intensive care unit of an academic medical center. Subjects were studied on admission and again at both 5 days and 8–10 days after admission. Three of the 10 subjects died as a result of their acute process, while the others were discharged from hospital. Nine out of 10 subjects required intravenous vasopressor therapy on day 1, while only 1 of 9 subjects required vasopressor support at day 5. LV end-diastolic area (EDA) increased from day 1 to day 5 and days 8–10 ( p < 0.05), but neither FAC nor E'es was altered by time (EDA 15.7 ± 5.8, 21.4 ± 5.1, and 19.4 ± 5.6 cm2; FAC 0.46 ± 0.19, 0.50 ± 0.20, and 0.48 ± 0.15%; E'es 21.6 ± 12.6, 23.2 ± 8.5, and 19.2 ± 6.3 mmHg/cm2, mean ± SD, for days 1, 5 and 8–10 respectively). Although dobutamine did not alter E'es on day 1 or day 5, E'es increased in all of the 5 subjects studied on days 8–10 ( p < 0.05). Adrenergic hyporesponsiveness is present in septic shock and persists for at least 5 days into recovery, resolving by days 8–10 in survivors. [ABSTRACT FROM AUTHOR]

Objective: To clarify the dose-related effects of direct hemoperfusion using a cytokine adsorbent column (CTR) on the mortality and inflammatory responses to endotoxin-induced shock in rats.Design: Prospective and randomized study.Setting: University research laboratory.Subjects: Male Wistar rats.Interventions: Forty-eight rats were injected intravenously with Escherichia coli endotoxin (15 mg/kg over 2 min), and then were randomly allocated to one of the following four groups (n = 12 per group): control group, treated without CTR for 120 min; quarter-dose treatment group, treated with CTR 0.25 ml for 120 min; half-dose treatment group, treated with CTR 0.50 ml; and full-dose treatment group, treated with CTR 1.0 ml.Measurements and Results: Hemodynamics and arterial blood gases were recorded, and mortality and plasma cytokine concentrations were calculated for the 8-h observation period. The mortality rates 8 h after endotoxin injection were 92%, 58%, 42% and 17% for the control column, quarter-dose, half-dose, and full-dose CTR groups, respectively. The increases in plasma cytokine concentrations were smaller in the half-dose and full-dose CTR treatment groups than in the endotoxemic group.Conclusions: The present study showed that CTR treatment dose-dependently decreased the mortality rate and inhibited inflammatory responses in vivo. [ABSTRACT FROM AUTHOR]

The article reports on the study in intensive care which describes several mechanisms probably involved in sepsis-induced intrinsic cardiomyopathy. Carbon monoxide is kept during septic shock where cardiac contractility is depressed. These changes detected in heart may be broadened to other organs and may be involved in the pathophysiology of multiple organ failure. The succeeding studies should evaluate whether therapies like activated protein C have affect to prevent myocardial function.

Objective: To investigate the pharmacokinetics and safety of afelimomab, a murine antibody fragment against human tumor necrosis factor (TNF)-alpha in patients with sepsis.Design: Multicenter, randomized, open-label, placebo-controlled phase I/II clinical trial.Setting: Intensive care units of six academic medical centers in the United States.Patients: Forty-eight patients with a clinical diagnosis of sepsis who received standard supportive care and antimicrobial therapy.Interventions: Patients received 0.3, 1.0, or 3.0 mg/kg afelimomab or placebo intravenously over 20 min. Three patients in each dose group received single doses; the remaining nine patients in each group received multiple (nine) doses at 8-h intervals over 72 h.Measurements and Main Results: Afelimomab appeared safe and well tolerated. Single- and multiple-dose kinetics were predictable and dose related. The elimination half-life was 44.7 h. Afelimomab treatment resulted in increased serum concentrations of TNF (includes TNF-antibody complexes) and decreased serum interleukin-6 concentrations, whereas no discernible trends were observed in placebo-treated patients. There was no significant treatment effect on 28-day mortality as was expected given the small number of patients. However, overall mortality was significantly (p = 0.001) associated with baseline interleukin-6 concentration. All patients experienced adverse events, but the vast majority were considered unrelated to the study drug and demonstrated no apparent relationship to afelimomab dose. Although 41% of patients developed human anti-murine antibodies, there were no clinical sequelae.Conclusions: Multidose therapy with afelimomab was safe, well tolerated, and had predictable linear kinetics. A large randomized trial comparing afelimomab to placebo in patients with well defined sepsis has recently been completed. [ABSTRACT FROM AUTHOR]

Objective: To examine the incidence and the bacteriological and clinical significance of endotoxaemia in ICU patients with severe sepsis or septic shock.Design: Prospective review.Setting: A 15-bed general ICU in a university hospital.Patients: One hundred sixteen patients hospitalised in our ICU fulfilling Bone's criteria for severe sepsis or septic shock and with an available early endotoxin assay (chromogenic limulus assay).Interventions: None.Measurements and Results: The clinical characteristics of the population were: age 63.6 +/- 11.4 years; SAPS II: 45.4 +/- 15.6; mechanical ventilation: 72.4%; septic shock: 51.7% (n = 60); bacteraemia: 28.4% (n = 33); gram-negative bacteria (GNB) infection 47.4% (n = 55); ICU mortality: 39.6% (n = 46). Detectable endotoxin occurred in 61 patients (51.2%; mean level: 310 +/- 810 pg/ml). There was no relationship between detectable endotoxin and severity of infection at the moment of the assay. Endotoxaemia was associated with a higher incidence of bacteraemia (39.3% vs 16.3%; p = 0.01). There was a trend (p = 0.09) towards an association between positive endotoxin and gram-negative bacteraemia or GNB infection but this was non-significant. This relationship became significant only in the case of bacteraemia associated with GNB infection irrespective of the site of infection.Conclusion: Early detection of endotoxaemia appeared to be associated with GNB infection only in cases of bacteraemic GNB infection. Early endotoxaemia correlated neither to occurrence of organ dysfunction nor mortality in patients with severe sepsis or septic shock. This study suggests that the use of endotoxaemia as a diagnostic or a prognostic marker in daily practice remains difficult. [ABSTRACT FROM AUTHOR]

Objective: Of the animal models of human hemorrhagic shock, the volume-controlled hemorrhage model appears to come closer to the clinical situation than the commonly used pressure-controlled model, since the volume-controlled model allows regulatory adjustment of blood pressure. The effects of volume-controlled hemorrhage on local cerebral blood flow (LCBF) of conscious animals are not known. The present study investigates specific reaction patterns of LCBF in comparison to mean cerebral blood flow (CBF) during graded volume-controlled hemorrhagic shock in conscious rats.Methods: Conscious, spontaneously breathing, and minimally restrained rats were subjected to different degrees of volume-controlled hemorrhage (taking either 25, 30, 35, or 40 ml arterial blood/kg body weight (b.w.). Thirty minutes after the completion of blood taking, LCBF was determined during hemorrhagic hypovolemia using the autoradiographic iodo (14C) antipyrine method. A group of untreated rats (no hemorrhage) served as controls. LCBF was determined in 34 defined brain structures and mean CBF was calculated.Results: During less severe hemorrhage (25 and 30 ml/kg b.w.) mean CBF was significantly higher than in the control group (+19% and +25%). During severe hemorrhage (35 and 40 ml/kg b.w.) mean CBF remained unchanged compared to the control values, although significant increases in LCBF could be detected in many of the brain structures analyzed (maximum +44%). The mean coefficient of variation of CBF was increased, indicating a larger heterogeneity of LCBF values at shed blood volumes of 35 and 40 ml/kg b.w.Conclusions: A comprehensive and novel description of the local distribution of CBF during graded volume-controlled hemorrhage in conscious rats shows unexpected increases in LCBF and mean CBF. This "hypovolemic cerebral hyperemia" might be caused by endogenous hemodilution, thus maintaining the blood supply to the brain during hypovolemic shock. [ABSTRACT FROM AUTHOR]

Objective: To study post-operative plasma concentrations of tumor necrosis factor alpha (TNF), interleukin-1 beta (IL-1) and interleukin-6 (IL-6) in infected and non-infected patients.Design: Prospective controlled clinical study.Setting: The intensive care unit (ICU) of a university hospital.Patients and Participants: The study comprised 20 patients, 9 infected and 11 non-infected, consecutively admitted to the ICU after moderate or major surgery. Twelve healthy volunteers were used as controls.Measurements and Results: Leucocyte count, CRP and the plasma TNF, IL-1 and IL-6 concentrations were studied 24-48 h after the start of surgery. Axillary temperature, the duration of surgery, the number of packed red cells transfused, the APACHE II score and outcome were registered. Both infected and non-infected patients had higher plasma concentrations of IL-6 than the controls (p < 0.001 and p < 0.01 respectively). Patients with infection had a higher plasma IL-6 concentration than non-infected patients (p < 0.05). Similar analyses of plasma TNF concentrations revealed no differences between infected and non-infected patients. Plasma IL-1 was detected only occasionally. Non-survivors (n = 4) had higher plasma concentrations of TNF and IL-6 than survivors (p < 0.05 and p = 0.05 respectively). In non-infected patients a correlation between the number of units of packed red cells transfused and the plasma IL-6 concentration was observed (r = 0.73, p < 0.05).Conclusion: No specific plasma cytokine pattern for infected patients subjected to surgery was observed. The effect of surgery and infection on the plasma IL-6 concentration seemed to be additive. Transfusion of packed red cells appeared to elevate the post-operative plasma IL-6 concentration. [ABSTRACT FROM AUTHOR]

Author(s): Ping Qiu [sup.1], Yan Li [sup.1], Yi Ding [sup.1], Jia Weng [sup.1], Steven M. Banks [sup.1], Steven Kern [sup.1], Yvonne Fitz [sup.1], Anthony F. Suffredini [sup.1], Peter Q. Eichacker [...], Background Tumor necrosis factor (TNF) antagonists [e.g., TNF soluble receptor (TNFsr)] improved survival in preclinical but not clinical sepsis trials. However fluid support-itself beneficial-is standard clinically but rarely employed in preclinical sepsis models. We hypothesized that these therapies may not have additive benefit. Methods and results Antibiotic-treated rats (n = 156) were randomized to intratracheal or intravenous Escherichia coli challenges (>LD50) and either placebo or TNFsr and 24 h fluid treatments alone or together. The survival effects of these therapies did not differ significantly comparing challenge routes. When averaged across route, while TNFsr or fluid alone decreased the hazard ratio of death significantly [ln ± standard error (SE): -0.65 ± 0.30 and -0.62 ± 0.30, respectively, p [less than or equal to] 0.05], together they did not (p = 0.16). Furthermore, the observed effect of TNFsr and fluid together on reducing the hazard ratio was significantly less than estimated (-0.37 ± 0.29 versus -1.27 ± 0.43, respectively, p = 0.027) based on TNFsr and fluid alone. While each treatment increased central venous pressure at 6 and 24 h, the observed effects of the combination were also less than estimated ones (p [less than or equal to] 0.0005). Conclusions The individual survival benefits of TNFsr and fluids were not additive in this rat sepsis model. Investigating new sepsis therapies together with conventional ones during preclinical testing may be informative.