Endotoxin, also referred to as lipopolysaccharide (LPS), is a potent stimulator of the inflammatory cascade which may progress to sepsis and septic shock. The term endotoxic septic shock has been ...used for patients who have a clinical phenotype that is characterized by high endotoxin activity in addition to a high burden of organ failure; especially a pattern of organ failure including hepatic dysfunction, acute kidney injury, and various forms of endothelial dysfunction. Endotoxic septic shock has been a target for drug therapy for decades with no success. A likely barrier to their success was the inability to quantify endotoxin in the bloodstream. The Endotoxin Activity Assay (EAA) is positioned to change this landscape. In addition, medical devices using adsorptive technology in an extra-corporeal circulation has been shown to remove large quantities of endotoxin from the bloodstream. Focusing on the use of EAA to determine high concentrations of endotoxin will allow patients with endotoxic septic shock to be identified quickly and these patients may benefit most from removal of endotoxin using extracorporeal methods.
Polymyxin B hemoperfusion reduces blood endotoxin levels in sepsis. Endotoxin activity can be measured in blood with a rapid assay. Treating patients with septic shock and elevated endotoxin activity ...using polymyxin B hemoperfusion may improve clinical outcomes.
To test whether adding polymyxin B hemoperfusion to conventional medical therapy improves survival compared with conventional therapy alone among patients with septic shock and high endotoxin activity.
Multicenter, randomized clinical trial involving 450 adult critically ill patients with septic shock and an endotoxin activity assay level of 0.60 or higher enrolled between September 2010 and June 2016 at 55 tertiary hospitals in North America. Last follow-up was June 2017.
Two polymyxin B hemoperfusion treatments (90-120 minutes) plus standard therapy completed within 24 hours of enrollment (n = 224 patients) or sham hemoperfusion plus standard therapy (n = 226 patients).
The primary outcome was mortality at 28 days among all patients randomized (all participants) and among patients randomized with a multiple organ dysfunction score (MODS) of more than 9.
Among 450 eligible enrolled patients (mean age, 59.8 years; 177 39.3% women; mean APACHE II score 29.4 range, 0-71 with higher scores indicating greater severity), 449 (99.8%) completed the study. Polymyxin B hemoperfusion was not associated with a significant difference in mortality at 28 days among all participants (treatment group, 84 of 223 37.7% vs sham group 78 of 226 34.5%; risk difference RD, 3.2%; 95% CI, -5.7% to 12.0%; relative risk RR, 1.09; 95% CI, 0.85-1.39; P = .49) or in the population with a MODS of more than 9 (treatment group, 65 of 146 44.5% vs sham, 65 of 148 43.9%; RD, 0.6%; 95% CI, -10.8% to 11.9%; RR, 1.01; 95% CI, 0.78-1.31; P = .92). Overall, 264 serious adverse events were reported (65.1% treatment group vs 57.3% sham group). The most frequent serious adverse events were worsening of sepsis (10.8% treatment group vs 9.1% sham group) and worsening of septic shock (6.6% treatment group vs 7.7% sham group).
Among patients with septic shock and high endotoxin activity, polymyxin B hemoperfusion treatment plus conventional medical therapy compared with sham treatment plus conventional medical therapy did not reduce mortality at 28 days.
ClinicalTrials.gov Identifier: NCT01046669.
Polymyxin B hemadsorption (PMX-HA) reduces blood endotoxin levels, but characteristics of patients with sepsis likely to benefit from PMX-HA are not well known. We sought to identify patient ...subgroups likely to benefit from PMX-HA.
We retrospectively identified 1911 patients with sepsis from a retrospective observational study in Japan (the JSEPTIC-DIC study) and 286 patients with endotoxemic septic shock from a randomized controlled trial in North America that restricted patients to those with high endotoxin activity (the EUPHRATES trial). We applied the machine learning-based causal forest model to the JSEPTIC-DIC cohort to investigate heterogeneity in treatment effects of PMX-HA on 28-day survival after adjusting for potential confounders and ascertain the best criteria for PMX-HA use. The derived criteria for targeted therapy by PMX-HA were validated using the EUPHRATES trial cohort.
The causal forest model revealed heterogeneity in treatment effects of PMX-HA. Since patients having higher treatment effects were more likely to have severe coagulopathy and hyperlactatemia, we identified the potential treatment targets of PMX-HA as patients with PT-INR > 1.4 or lactate > 3 mmol/L. In the EUPHRATES trial cohort, PMX-HA use on the targeted subpopulation (75% of all patients) was significantly associated with higher 28-day survival (PMX-HA vs. control, 68% vs. 52%; treatment effect of PMX-HA, + 16% 95% CI + 2.2% to + 30%, p = 0.02).
Abnormal coagulation and hyperlactatemia in septic patients with high endotoxin activity appear to be helpful to identify patients who may benefit most from PMX-HA. Our findings will inform enrollment criteria for future interventional trials targeting patients with coagulopathy and hyperlactatemia.
In the fields of sepsis and systemic inflammation, endotoxin might be the most studied molecule since the term was coined by Richard Pfeiffer in 1892. Paradoxically measuring endotoxin in humans and ...finding an effective treatment for endotoxemia have remained challenging. While advances have been made in understanding the mechanisms of how this simple molecule can trigger an intense immune cascade, there is an ever growing need to develop better treatments. Studies measuring endotoxin levels in patients with septic shock have consistently demonstrated that there is a dose-response relationship between endotoxin levels and adverse outcomes. A rapid assay to measure endotoxin activity has been available for more than a decade, but few studies have synergized the assay with a therapeutic. Polymyxin B hemoperfusion (PMX-HP) leverages a molecule with high affinity for endotoxin with a technique to eliminate exposure. Polymyxin is bound and immobilized to fibers within a cartridge and administered as an extracorporeal therapy via veno-venous hemoperfusion. Clinical evidence of its use is plentiful yet inconsistent in studies based on an outcome for mortality at 28 days. Herein, we describe targeted patient selection using the endotoxin activity assay and clinical phenotyping followed by adsorption of endotoxin using the PMX-HP for endotoxemic sepsis.
Given the success of recent platform trials for COVID-19, Bayesian statistical methods have become an option for complex, heterogenous syndromes like sepsis. However, study design will require ...careful consideration of how statistical power varies using Bayesian methods across different choices for how historical data are incorporated through a prior distribution and how the analysis is ultimately conducted. Our objective with the current analysis is to assess how different uses of historical data through a prior distribution, and type of analysis influence results of a proposed trial that will be analyzed using Bayesian statistical methods.
We conducted a simulation study incorporating historical data from a published multicenter, randomized clinical trial in the US and Canada of polymyxin B hemadsorption for treatment of endotoxemic septic shock. Historical data come from a 179-patient subgroup of the previous trial of adult critically ill patients with septic shock, multiple organ failure and an endotoxin activity of 0.60-0.89. The trial intervention consisted of two polymyxin B hemoadsorption treatments (2 h each) completed within 24 h of enrollment.
In our simulations for a new trial of 150 patients, a range of hypothetical results were observed. Across a range of baseline risks and treatment effects and four ways of including historical data, we demonstrate an increase in power with the use of clinically defensible incorporation of historical data. In one possible trial result, for example, with an observed reduction in risk of mortality from 44 to 37%, the probability of benefit is 96% with a fixed weight of 75% on prior data and 90% with a commensurate (adaptive-weighting) prior; the same data give an 80% probability of benefit if historical data are ignored.
Using Bayesian methods and a biologically justifiable use of historical data in a prior distribution yields a study design with higher power than a conventional design that ignores relevant historical data. Bayesian methods may be a viable option for trials in critical care medicine where beneficial treatments have been elusive.
The National Institute of Health has made it a priority to identify, develop, and refine strategies to disseminate and implement effective interventions (National Institute of Health, 2015). This ...study examined qualitative reports of the strategies therapists used to manage common implementation problems they encountered during midtreatment in Multisystemic Therapy® (MST) and Functional Family Therapy (FFT), two widely disseminated evidence‐ and family‐based treatments for substance abusing and delinquent adolescents. Experienced therapists from dissemination sites across the U.S. described cases in which they encountered midtreatment problems they perceived as serious threats to treatment success. They indicated why each case terminated and rated the outcome of the case. Qualitative analyses examined 16 treatment failures and then 16 treatment successes to identify contextual obstacles that accompanied the problems therapists identified, along with strategies they reported using with families that ultimately succeeded or failed. Therapists reported that midtreatment problems were often embedded in additional related difficulties and that they employed multiple relationship techniques and process‐focused strategies to try to resolve these problems. For the most part, therapists described obstacles and strategies for successful and unsuccessful families in similar ways. Patterns of themes and subthemes suggested, however, that therapists in successful cases may be more likely to report “on‐script” strategies and therapists in unsuccessful cases may describe more “off‐script” strategies as well as more generic relationship building and advice‐giving strategies.
Resumen
Los Institutos Nacionales de Salud (NIH, por sus siglas en inglés) han priorizado la detección, el desarrollo y la perfección de estrategias para difundir e implementar intervenciones eficaces (National Institute of Health, 2015). Este estudio analizó los informes cualitativos de las estrategias que usaron los terapeutas para manejar los problemas comunes de implementación que encontraron durante la mitad del tratamiento en la terapia multisistémica (Multisystemic Therapy®, MST) y en la terapia familiar funcional (Functional Family Therapy, FFT), dos tratamientos factuales y basados en la familia ampliamente difundidos para adolescentes con problemas de delincuencia y de abuso de sustancias. Un grupo de terapeutas experimentados de centros de difusión de todo Estados Unidos describió casos en los cuales encontraron problemas en la mitad del tratamiento que ellos percibieron como amenazas graves para el éxito del tratamiento. Estos terapeutas indicaron por qué cada caso terminó y calificaron el resultado del caso. Los análisis cualitativos analizaron 16 fallas del tratamiento y luego 16 aciertos del tratamiento para detectar obstáculos contextuales que acompañaban a los problemas mencionados por los terapeutas, junto con estrategias que informaron haber usado con familias y que finalmente fueron satisfactorias o fallaron. Los terapeutas informaron que los problemas en la mitad del tratamiento generalmente formaban parte de otras dificultades relacionadas y que ellos emplearon varias técnicas relacionales y estrategias centradas en los procesos para intentar resolver estos problemas. En su mayoría, los terapeutas describieron los obstáculos y las estrategias utilizadas con las familias favorables y con las desfavorables de maneras similares. Sin embargo, los patrones de temas y subtemas indicaron que los terapeutas de los casos favorables pueden ser más propensos a informar estrategias “dentro del libreto” y que los terapeutas de los casos desfavorables pueden describir más estrategias “fuera del libreto”, así como estrategias más genéricas de construcción de relaciones y de asesoramiento.
摘要
美国国家健康研究院把识别、发展和改进有关传播和实施有效干预措施的战略作为优先考虑的重要事项(国家健康研究院, 2015年)。本研究考察了治疗师在多系统治疗® (MST) 和功能家庭治疗 (FFT) 的中期治疗中遇到的常见实施问题所使用策略的定性研究报告, 这是两种广泛传播的基于证据和基于家庭的药物滥用和青少年罪犯的治疗方法。来自美国各地传播场所的经验丰富的治疗师描述了他们在治疗过程中遇到的问题, 他们认为这些问题严重威胁到治疗是否取得成功。他们指出了每个案例终止的原因, 并对案例的结果进行了评估。定性分析研究了16个治疗失败和16个治疗成功的案例, 以确定伴随着治疗师发现的问题的背景障碍, 以及他们报告的最终成功或失败的家庭使用的策略。治疗师报告说, 在治疗过程中出现的问题常常和其他相关的困难交织在一起, 他们使用了多种关系技巧和过程聚焦策略来试图解决这些问题。然而, 主题和次主题的模式表明, 成功案例中的治疗师可能更有可能报告 "按常规办事 "的策略, 而不成功案例中的治疗师可能会描述更多 "不照常规办事 "的策略以及更通用的建立关系和提供建议的策略。
Multisystemic Therapy® (MST) and Functional Family Therapy (FFT) are two widely disseminated evidence‐based family‐based treatments for substance abusing and delinquent adolescents. This mixed‐method ...study examined common implementation problems in midtreatment in MST and FFT. A convenience sample of experienced therapists (20 MST, 20 FFT) and supervisors (10 MST, 10 FFT) from dissemination sites across the United States participated in semistructured telephone interviews. Participants identified retrospectively serious midtreatment process problems they perceived as threats to treatment success. Coders extracted descriptions of problems from interview transcripts and coded them into 12 categories that fell into five major themes: engaging families in treatment; difficulties implementing strategies; family relational and communication problems; complications external to therapy; and youth problem behavior. Analyses examined caregiver, therapist, and youth variables as predictors of these common midtreatment problems and whether treatment outcomes varied depending on the type of problem, therapy model, and race/ethnic match of therapist and family. MST and FFT therapists and supervisors identified many similar problems. There were, however, model‐specific differences consistent with differing features of the models (e.g., FFT participants identified more family relational problems and fewer follow‐through problems than their MST counterparts). Results underscore the need to consider both common and specific factors in treatment process.
La terapia multisistémica (Multisystemic Therapy®, MST) y la terapia familiar funcional (Functional Family Therapy, FFT) son dos tratamientos factuales familiares ampliamente difundidos para adolescentes con problemas de abuso de sustancias y delincuencia. Este estudio de métodos combinados analizó los problemas de implementación comunes a mediados del tratamiento en la MST y la FFT. Una muestra de conveniencia de terapeutas experimentados (20 MST, 20 FFT) y supervisores (10 MST, 10 FFT) de centros de difusión de todo EE. UU. participaron en entrevistas telefónicas semiestructuradas. Los participantes reconocieron retrospectivamente graves problemas en el proceso a mediados del tratamiento que percibieron como amenazas para el éxito del tratamiento. Los codificadores extrajeron las descripciones de problemas de las transcripciones de las entrevistas y los codificaron en 12 categorías que comprendían cinco temas principales: interés de las familias por el tratamiento; dificultades para implementar estrategias; problemas de comunicación y relacionales con la familia; complicaciones ajenas a la terapia; y comportamiento problemático de los jóvenes. Los análisis examinaron las variables de cuidador, terapeuta y joven como predictores de estos problemas comunes a mediados del tratamiento y si los resultados del tratamiento variaron según el tipo de problema, el modelo de terapia y la coincidencia étnica/racial entre el terapeuta y la familia. Los terapeutas y los supervisores de la MST y la FFT detectaron varios problemas similares. Sin embargo, hubo diferencias específicas de los modelos que coincidieron con las distintas características de los modelos (p. ej.: los participantes de la FFT reconocieron más problemas de relaciones familiares y menos problemas para terminar el tratamiento que sus homólogos de la MST). Los resultados subrayan las necesidad de tener en cuenta tanto los factores comunes como específicos del proceso de tratamiento.
多系统治疗 (MST)和功能家庭治疗(FFT)是两个广泛使用于针对药物滥用和犯罪青少年的以证据为基础的家庭心理治疗。该混合方法研究考察了MST和FFT中期治疗过程中通常的实行问题。一个由来自全美传播地点的经验丰富的治疗师(20 MST, 20 FFT)和监督者(10 MST, 10 FFT)组成的便利样本参与了半结构性的电话采访。参与者回顾了其面临的威胁治疗成功的严重治疗中期过程问题。编码人员从采访记录中找出对于问题的描述,并将其分为纳入5个主题的12门类:家庭参与到治疗中;实行措施困难;家庭关系和沟通问题;治疗以外复杂因素;青少年问题行为。分析考察了照料人,心理咨询师,以及青少年变量作为这些普遍中期治疗问题的预测因素。治疗成果是否有变化取决于问题类型,治疗模式,咨询师和家庭的族裔匹配。MST and FFT心理咨询师和监督者确认了很多相似问题。然而,不同模型特点有模型特定差异(例如,FFT参与者比MST参与者表现出更多的家庭关系问题和较少的贯彻始终问题)。结果强调了考虑治疗过程中普遍和特定因素的重要性。
Lipopolysaccharide (endotoxin) from the cell wall of Gram-negative bacteria is a potent trigger for the release of host-derived inflammatory mediators. The relationship between endotoxaemia, ...Gram-negative infection and the clinical syndrome of sepsis has been difficult to establish, in part because of the limitations of available endotoxin assays.
We performed an observational cohort study in critically ill patients in the medical/surgical intensive care unit (ICU) of a tertiary care hospital. Whole blood endotoxin levels on the day of ICU admission were measured using a novel chemiluminescent assay--the endotoxin activity assay (EAA)--and the chromogenic modification of the limulus amoebocyte lysate (LAL) assay.
We studied 74 consecutive admissions. Endotoxin levels were higher in patients with a diagnosis of sepsis (470 +/- 57 pg/ml) than in patients admitted with a diagnosis other than sepsis (157 +/- 140 pg/ml; P < 0.001). Endotoxaemia was significantly associated with Gram-negative infection (P < 0.05); no patient with a Gram-negative infection had an endotoxin level below 50 pg/ml. White blood cell counts of patients with EAA-detected endotoxaemia were significantly higher (15.7 +/- 9.1 x 10(9) cells/l for endotoxaemic patients versus 10.8 +/- 6.2 x 10(9) cells/l for patients without endotoxaemia; P < 0.05).
Endotoxaemia is associated with Gram-negative infection from any source, and with a diagnosis of sepsis and leukocytosis. These correlations were not apparent using the LAL method. The EAA may be a useful diagnostic tool for the investigation of invasive Gram-negative infection and incipient sepsis.
A rapid (30 min) whole blood assay for the detection of lipopolysaccharide (LPS) is described. This chemiluminescent (CL) assay utilizes the CR
1 and CR
3 receptor-induced oxidant production of ...polymorphonuclear leucocytes as a detection platform. The differential priming of neutrophils in whole blood by LPS-antibody complexes allows the specificity of the assay to be achieved. Oxidant released in response to complement opsonized zymosan results in luminol oxidation and subsequent light emission. This is dependent on heat labile putative complement proteins in the plasma. The assay consists of a
control which measures baseline whole blood neutrophil oxidant production. The
test assay contains murine monoclonal IgM antibody against the Lipid A epitope of LPS and measures the enhanced chemiluminescent response of the neutrophils in the presence of LPS-antibody complexes. Maximal sensitivity of the CL assay is dependent upon optimal antigen–antibody equivalence and duration of pre-incubation with the whole blood sample. The quantification of LPS is possible by inclusion of a positive control containing a maximally reactive LPS dose (800 pg/ml
Escherichia coli 055:B5 LPS at an antibody concentration of 0.8
μg/assay). The CL assay is insensitive to variations in patient neutrophil concentration over a minimum range of 0.5 to 20×10
9 cells/l. The CL assay is widely reactive with the LPS of many strains of gram negative bacteria but not with the cell wall products of gram positive bacteria or
Candida and
Aspergillus. In comparison to acid extraction chromogenic LAL, the CL assay demonstrates superior recovery precision and accuracy in in vitro studies. This was reproducible over a wide range of LPS concentrations (0.017–1.6 EU/ml or 20–2000 pg/ml). This assay may be a clinically useful tool for the diagnosis of infection or endotoxin in patients.
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