Endotoxin Elimination in Patients with Septic Shock: An Observation Study (original) (raw)
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Trials, 2016
Background: Severe sepsis and septic shock are common in intensive care and carry high mortality rates. In patients with Gram-negative infections, early and extensive removal of endotoxin may limit the inflammatory response that characterizes septic shock. The Alteco® LPS Adsorber (hereafter referred to cited as the lipopolysaccharide (LPS) Adsorber) can be used for endotoxin removal and attenuate the deleterious inflammatory and clinical responses seen in septic shock. Methods/design: The Abdominal Septic Shock-Endotoxin Adsorption Treatment (ASSET) trial is a pilot study investigating the feasibility and safety of LPS Adsorber therapy. This pilot, multicenter, stratified, parallel, double-blinded, randomized, phase IIa, feasibility clinical investigation will be performed in five Scandinavian intensive care units. Thirty-two subjects with early septic shock and organ failure, following adequate resuscitation, will be randomized to receive either: extracorporeal veno-venous hemoperfusion therapy with the LPS Adsorber or veno-venous hemoperfusion therapy with a placebo adsorber (without active LPS-binding peptide). Patients will be stratified by infection focus such that 20 subjects with an abdominal focus (stratum A) and 12 subjects with a urogenital focus (stratum B) will be included in a parallel design. Thereafter, an interim analysis will be performed and an additional 12 patients may be included in the study. The study is designed as adaptive a priori: the patients from this study can be included in a later phase IIb study. The aim of the study is to investigate the feasibility of LPS Adsorber therapy commenced early in the time-course of septic shock. The primary endpoint will be a characterization of all reported unanticipated serious adverse device effects and anticipated serious adverse device effects. Secondary outcomes are decrease in endotoxin plasma concentration, impact on clinical outcome measures and impact on inflammatory response by LPS Adsorber therapy, as well as detailed description of the relevant mediators bound to the LPS Adsorber. Recruitment of patients will start in September 2015.
Journal of Endotoxin Research, 2004
The pathogenesis of sepsis begins with the proliferation of microorganisms at a site of infection, followed by invasion of the bloodstream and other organs. Gram-negative bacteria account for a large part of sepsis cases. The structural component of Gram-negative bacteria, endotoxin or lipopolysaccharide (LPS), induces the synthesis and release of endogenous mediators of sepsis. A growing number of investigations of the molecular mechanisms occurring in sepsis, point to endotoxin as a central mediator leading to multi-organ failure and death. In numerous clinical trials, attempts to target molecules downstream of endotoxin have been made, but have not been associated with improved survival. We describe an affinity-based system for the selective removal of endotoxin from plasma. The small-scale device, a 1.5 ml cartridge, contains beads that bind endotoxin with high specificity and efficiency. In addition, evidence is presented that this device does not affect plasma hemostasis, nor does it activate the complement system. Taken together, these results represent a proof of principle for endotoxin removal from plasma, which may be of clinical value to treat sepsis by extracorporeal circulation of the blood through a scaled-up version of this endotoxin-removing device.
Endotoxin elimination in sepsis: physiology and therapeutic application
Langenbeck's Archives of Surgery, 2010
Purpose The present review summarizes key papers on the elimination of endotoxin in human. Results Lipopolysaccharides (LPS) are extremely strong stimulators of inflammatory reactions, act at very low concentrations, and are involved in the pathogenesis of sepsis and septic shock. Elimination of LPS is vital; therefore, therapeutic detoxification of LPS may offer new perspectives. Multiple mechanisms eliminate LPS in human comprising molecules that bind LPS and prevent it from signaling, enzymes that degrade and detoxify LPS, processes that inactivate LPS following uptake into the reticulo-endothelial system, and mechanisms of adaptation that modify target cells responding to LPS. These mechanisms are powerful and detoxification capacity adapts as required. Results of therapeutic interventions aiming at the removal of LPS by medication (immunoglobulins) or extracorporeal means are controversial. At least in part, animal experiments revealed increased survival. Human trials confirmed the positive effects on parameters of secondary importance, but not on morbidity or survival which was attributed to the heterogeneity of patients suffering from consequences of severe infectious diseases and sepsis. Conclusion The hypothesis of LPS-driven inflammatory processes remains very attractive. However, few therapeutic yet immature options have been developed to date.
Circulating endotoxin and antiendotoxin antibodies during severe sepsis and septic shock
Journal of Critical Care, 2003
The presence of circulating endotoxin is common during sepsis but its prognostic value is poor. We hypothesized that this lack of correlation with outcome could be related in part to the presence of circulating antiendotoxin antibodies. In a 14-bed medical intensive care unit, in an 821-bed tertiary teaching hospital, we prospectively assessed endotoxin and antiendotoxin antibodies in patients with severe sepsis or septic shock. Blood samples for the determination of circulating endotoxin and antiendotoxin antibodies were drawn when severe sepsis or septic shock were diagnosed (day 0) and then on day 1, day 2, and day 4. Daily measurements of antiendotoxin antibodies did not discriminate survivors from nonsurvivors. No an-tibody depletion was observed. However, during follow-up, the antiendotoxin immunoglobulin (Ig)M antibody level increased among survivors but decreased among nonsurvivors (51.2 vs ؊44.8 MU/mL, P ؍ .007). Circulating endotoxin was detectable among 9 of 17 patients on inclusion but neither the basal value nor sequential measurements correlated with outcome. These results suggest that during severe sepsis and septic shock, circulating endotoxin is a poor prognostic marker whereas the detection of an increase in IgM antiendotoxin antibody levels could identify survivors. This increase in IgM antibody levels could be attributed to a reactivation of the immune system.
Blood Purification, 2008
Background: Mortality of severe sepsis and septic shock is unacceptably high. Adsorptive removal of endotoxin may interrupt the inflammatory cascade triggered by lipopolysaccharide. Methods: Prospective feasibility study with plasma separation and adsorption (PSA) treatment using a novel arginine-coated adsorber column was performed in a tertiary care gastroenterological intensive care unit. Results: 10 patients with severe sepsis/septic shock (median APACHE II score: 27, hospital mortality 40%) were treated with PSA on 5 consecutive days. There were no serious adverse events. No patient died during the treatment period. During treatment sessions, mean arterial pressure and cardiac power index increased while vasopressors could be reduced. Advanced oxidation protein products and in vitro pro- apoptotic activity of plasma decreased. We could not demonstrate any changes in endotoxin levels. Conclusions: PSA resulted in a reduction of indicators of oxidative stress and pro-apoptotic ac...
The importance of early detection of endotoxemia
Innate Immunity, 2016
Endotoxin is considered a key signaling molecule in the pathogenesis of sepsis and septic shock. Anti-endotoxin therapies may result in the improvement of a patient’s clinical condition and lower mortality. The pressing clinical challenge is to identify patients for whom endotoxin elimination would be the most beneficial. An endotoxin activity assay (EAA) has been available for detection of endotoxins, allowing selection of patients at high risk of endotoxemia in intensive care units (ICUs). We studied a cohort of 172 consecutive patients who had septic shock on admission to the ICU. Endotoxin activity (EA) was measured with a rapid chemiluminescent EAA, regarded as point-of-care testing. Endotoxemia with a mean EA of 0.59 ± 0.14 EAU was present in 104 patients (60%) and absent in 68 patients (EA = 0.25 ± 0.11 EAU). The risk of endotoxemia increased with the presence of a Gram-negative infection [odds ratio (OR) 3.1, 95% confidence interval (CI) 1.6–5.9; P = 0.001] and bacteremia (O...