Endotoxemia Correlates with Kidney Function and Length of Stay in Critically Ill Patients.

INTRODUCTION: Endotoxin is a key driver of sepsis, which frequently causes acute kidney injury (AKI). However, endotoxins may also be found in non-bacteremic critically ill patients, likely from intestinal translocation. Preclinical models show that endotoxins can directly injure the kidneys, and in COVID-19 patients, endotoxemia correlated with AKI. We sought to determine correlations between endotoxemia and kidney and hospital outcomes in a broad group of critically ill patients. METHODS: In this single-center, serial prospective study, 124 predominantly Caucasian adult patients were recruited within 48 h of admission to Stony Brook University Hospital Intensive Care Unit (ICU). Demographics, vital signs, laboratory data, and outcomes were collected. Circulating endotoxin was measured on days 1, 4, and 8 using the endotoxin activity assay (EAA). The association of EAA with outcomes was examined with EAA: (1) categorized as <0.6, ≥0.6, and nonresponders (NRs); and (2) used as a continuous variable. RESULTS: Patients with EAA ≥0.6 had a higher prevalence of proteinuria, and lower arterial oxygen saturation (SaO2) to fraction of inspired oxygen (FiO2) (SaO2/FiO2) ratio versus patients with EAA <0.6. EAA levels positively correlated with serum creatinine (sCr) levels on day 1. Patients whose EAA level stayed ≥0.6 had a slower decline in sCr compared to those whose EAA started at ≥0.6 and subsequently declined. Patients with AKI stage 1 and EAA ≥0.6 on day 1 showed slower decline in sCr compared to patients with stage 1 AKI and EAA <0.6. EAA ≥0.6 and NR patients had longer hospital stay and delayed ICU discharge versus EAA <0.6. CONCLUSIONS: High EAA levels correlated with worse kidney function and outcomes. Patients whose EAA levels fell, and those with AKI stage I and day 1 EAA <0.6 recovered more quickly compared to those with EAA ≥0.6, suggesting that removal of circulating endotoxins may be beneficial in critically ill patients.

Targeted therapy using polymyxin B hemadsorption in patients with sepsis: a post-hoc analysis of the JSEPTIC-DIC study and the EUPHRATES trial.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Bayesian methods: a potential path forward for sepsis trials.

BACKGROUND: 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. 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. RESULTS: 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. CONCLUSIONS: 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.

Endotoxic Septic Shock: Diagnosis and Treatment.

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.

Endotoxemia in Critically Ill Patients with COVID-19.

INTRODUCTION: Mechanism(s) mediating critical illness in coronavirus disease 2019 (COVID-19) remain unclear. Previous reports demonstrate the existence of endotoxemia in viral infections without superimposed gram-negative bacteremia, but the rate and severity of endotoxemia in critically ill patients with COVID-19 requires further exploration. MATERIALS AND METHODS: This is a single-center cross-sectional study of 92 intensive care unit patients diagnosed with COVID-19 pneumonia. Endotoxin activity (EA) was measured in patients that met the following criteria: (1) age ≥18 years and (2) multi-organ dysfunction score >9 from March 24, 2020, to June 20, 2020. RESULTS: A total of 32 patients met the inclusion/exclusion criteria for measurement of EA. The median age of the study cohort was 60 years with a majority male (21/32, 65%) with hypertension (50%). A significant proportion of the patients exhibited either elevated EA in the intermediate range (0.40-0.59 EA units) (10/32, 31%) or high range (≥0.60 EA units) (14/32, 44%) or were nonresponders (NRs, low neutrophil response) to EA (6/32, 19%), with the presence of gram-negative bacteremia only in 2/32 (6%) patients. Low EA was reported in 2/32 patients. NRs (5/6, 83%) and patients with high EA (7/14, 50%) exhibited higher acute kidney injury (AKI) as compared to patients with low/intermediate EA level (1/12, 8.3%). DISCUSSION/CONCLUSION: Elevated EA was observed in a large majority of critically ill patients with COVID-19 and multi-organ dysfunction despite a low incidence of concurrent gram-negative bacteremia. While we observed that elevated EA and nonresponsiveness to EA were associated with AKI in critically ill patients with COVID-19, these findings require further validation in larger longitudinal cohorts.

Effect of Targeted Polymyxin B Hemoperfusion on 28-Day Mortality in Patients With Septic Shock and Elevated Endotoxin Level: The EUPHRATES Randomized Clinical Trial.

Importance: 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. Objective: 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. Design, Setting, and Participants: 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. Interventions: 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). Main Outcomes and Measures: 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. Results: 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). Conclusions and Relevance: 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. Trial Registration: ClinicalTrials.gov Identifier: NCT01046669.

Endotoxin removal: bringing the mission to North America.

The EUPHRATES trial (Evaluating Use of Polymyxin B Hemoperfusion in a Randomized Controlled Trial of Adults Treated for Endotoxemia and Septic Shock) is the first biomarker-driven trial in sepsis. This unique trial is being run in a blinded manner, further contributing to the robustness of its design. This paper will describe the implementation of the EUPHRATES trial focusing on 3 pertinent features: (1) managing (and maintaining) the blinding of a medical device trial; (2) impact of the use of a diagnostic test where eligible subjects with septic shock must also have high levels of endotoxin (≥ 0.60 EAA units), and (3) managing enrolment in a complicated trial design where two medical teams are involved (the intensivist as the blinded caregiver and nephrologists as the unblinded performers of the intervention). The study is nearing the halfway mark and is currently experiencing excellent recruitment success.

Endotoxemic Shock: A Molecular Phenotype in Sepsis.

BACKGROUND: Marked heterogeneity exists among patients with sepsis, both in terms of distribution of organ dysfunction and its severity. Such heterogeneity could be explained by the presence of multiple subtypes of sepsis that may have important implications for treatment. METHODS: Narrative review of published literature involving endotoxin from 1970 to 2022. RESULTS: In humans, endotoxemia is most consistently associated with a specific pattern of organ failure including shock, endothelial dysfunction, acute kidney injury, and hepatic dysfunction. This pattern is consistent with complement activation and uncontrolled inflammation, two features of endotoxemia. Unbiased discovery using artificial intelligence also identifies a subtype of sepsis which features these same organ failures. CONCLUSION: Endotoxin appears to represent an important molecular phenotype of sepsis with unique clinical features and high mortality.

Adsorption of Endotoxin and Mitigation of Sepsis.

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.

Importance of Endotoxin Clearance in Endotoxemic Septic Shock: An Analysis From the Evaluating Use of PolymyxinB Hemoperfusion in a Randomized Controlled Trial of Adults Treated for Endotoxemic Septic Shock (EUPHRATES) Trial.

To investigate the relationship between survival and treatment-related reduction in endotoxin activity for patients in the Evaluating Use of PolymyxinB Hemoperfusion in a Randomized controlled trial of Adults Treated for Endotoxemia and Septic shock trial with baseline endotoxin activity assay greater than or equal to 0.60 to less than 0.90 units. DESIGN: Post hoc analysis of a multicenter randomized controlled clinical trial. SETTING: Fifty-five tertiary hospitals in North America. PATIENTS: Patients with septic shock and endotoxin activity assay level greater than or equal to 0.60 to less than 0.90 and multiple organ dysfunction syndrome greater than 9. INTERVENTIONS: Two polymyxin B hemoperfusion treatments or Sham. MEASUREMENTS AND MAIN RESULTS: One-hundred ninety-four patients were included (88 polymyxin B and 106 Sham). We evaluated the impact of changes in endotoxin activity assay based on comparison to the median reduction from baseline to day 3 and a second method where a target post-treatment endotoxin activity assay level (day 3) was established. The population median reduction in endotoxin activity assay level was 10.4%. In patients with a greater than median reduction, there was trend toward lower mortality with polymyxin B (17.1% vs 33.3%; p = 0.07) and a significant increase in mechanical ventilation-free days (20 vs 13.5; p = 0.04). The pressure adjusted heart rate showed a significant improvement in the polymyxin B group (p = 0.02). For patients who achieved an endotoxin activity assay of less than 0.65 at day 3, the polymyxin B treated group had a trend toward a mortality reduction compared to Sham (16% vs 33%;p = 0.06) and a significant increase in ventilation-free day (20 vs 16; p = 0.05). Kaplan-Meier analysis showed a 17% reduction in mortality with polymyxin B (p = 0.04). CONCLUSIONS: These findings suggest that reducing endotoxin activity assay levels with polymyxin B as measured by comparison to a median reduction or when a treatment target is established, may result in improvements in mortality and organ function outcomes. This article is the first to report endotoxin activity assay measurements in response to polymyxin B use versus Sham in patients with septic shock and elevated endotoxin activity assay. These findings are considered to be hypothesis generating and will need to be prospectively validated.

Daily variation in endotoxin levels is associated with increased organ failure in critically ill patients.

High blood levels of endotoxin on admission to the intensive care unit are predictive of adverse outcomes, including organ failure and death. However, the significance of changes in endotoxin levels over time has not been evaluated. We examined whether dynamic daily changes in endotoxin levels resulted in the development of greater organ dysfunction over time in critically ill patients. The study was a retrospective analysis of data from the longitudinal phase of a prospective observational multicenter cohort study of endotoxin levels in patients admitted to the intensive care unit. We analyzed 345 patients. Daily variation in endotoxin levels was assessed by calculating the number of inflections in the curve generated by plotting endotoxin levels against time. The degree of organ dysfunction over time was analyzed using a calculation of the total area under the curve generated by plotting the Multi Organ Dysfunction Score against time. From 1,301 endotoxin activity assay results, patients with dynamic daily variation in endotoxin levels as measured by a greater number of inflections had a greater degree of total organ dysfunction as measured by Multi Organ Dysfunction Score against time (P < 0.05). The arithmetic mean standard deviation of endotoxin activity assay results increased stepwise in the zero, one, and two inflection groups supporting the association between inflections and variability. Endotoxin activity assay variability was found to be independent of infection status (P = 0.52). Daily dynamic variation in endotoxin levels is a marker of increased severity of illness as measured by burden of total organ dysfunction over time. Further studies are warranted to assess the role of daily variation in endotoxin levels in the pathogenesis and potential therapy of organ failure in the critically ill.

Evidence-based clinical practice guideline for the prevention of ventilator-associated pneumonia.

BACKGROUND: Ventilator-associated pneumonia (VAP) is an important patient safety issue in critically ill patients. PURPOSE: To develop an evidence-based guideline for the prevention of VAP. DATA SOURCES: MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews. STUDY SELECTION: The authors systematically searched for relevant randomized, controlled trials and systematic reviews that involved mechanically ventilated adults and were published before 1 April 2003. DATA EXTRACTION: Physical, positional, and pharmacologic interventions that may influence the development of VAP were considered. Independently and in duplicate, the authors scored the validity of trials; the effect size and confidence intervals; the homogeneity of results; and safety, feasibility, and economic issues. DATA SYNTHESIS: Recommended: The orotracheal route of intubation, changes of ventilator circuits only for each new patient and if the circuits are soiled, use of closed endotracheal suction systems that are changed for each new patient and as clinically indicated, heat and moisture exchangers in the absence of contraindications, weekly changes of heat and moisture exchangers, and semi-recumbent positioning in the absence of contraindications. Consider subglottic secretion drainage and kinetic beds. Not recommended: Sucralfate to prevent VAP in patients at high risk for gastrointestinal bleeding and topical antibiotics to prevent VAP. Because of insufficient or conflicting evidence, no recommendations were made about systematically searching for maxillary sinusitis, chest physiotherapy, the timing of tracheostomy, prone positioning, prophylactic intravenous antibiotics, or intravenous plus topical antibiotics. LIMITATIONS: No formal economic analysis was performed, and patient perspectives were not considered. CONCLUSION: If effectively implemented, this guideline may decrease the morbidity, mortality, and costs of VAP in mechanically ventilated patients.

Influence of perceived functional and employment status on cardiopulmonary resuscitation directives.

BACKGROUND: Perceptions about functional and employment status before admission to the intensive care unit (ICU) may influence how patients and clinicians make decisions about cardiopulmonary resuscitation. OBJECTIVE: To examine the relationship between cardiopulmonary resuscitation directives established within 24 hours of admission to the ICU and clinical perceptions of premorbid functional and employment status. DESIGN: Prospective observational study in 15 university-affiliated centers in Canada, the United States, Australia, and Sweden. PATIENTS: A total of 1,008 ICU patients aged 18 years or older expected to stay in the ICU at least 72 hours. MEASUREMENTS: By using multinomial logistic regression, we examined the relationship between functional status and employment status perceived by the ICU team 1 month before ICU admission (the independent variables) and resuscitation status (the dependent variable). Each patient had either an explicit resuscitation directive (to resuscitate or not to resuscitate), or an implicit resuscitation directive to resuscitate. RESULTS: On average, patients were 61.7 years (+/-17.4 y) old with an Acute Physiology and Chronic Health Evaluation (APACHE) II score of 21.5 (+/-8.7); 846 (83.9%) were ventilated mechanically within 48 hours and 345 (34.2%) died in the ICU. Most patients (793, 78.7%) had no explicit resuscitation directive; 98 (9.7%) had an explicit plan to resuscitate, whereas 117 (11.6%) had an explicit plan of do-not-resuscitate. Of 1,008 patients, 98 (9.7%) were severely functionally limited, 217 (21.5%) were somewhat limited, 628 (62.3%) were totally independent, and 65 (6.4%) had unknown functional status 1 month before ICU admission. Severe functional status impairment was associated moderately with an explicit plan to resuscitate (odds ratio, 2.2 relative to no explicit directive) and associated strongly with an explicit do-not-resuscitate plan (odds ratio, 6.2 relative to no explicit directive, P value on the difference =.011). This relationship was not influenced by age, sex, APACHE II score, medical or surgical status, admission diagnosis, employment status, or city. However, severe functional status was associated strongly and significantly with an explicit do-not-resuscitate directive among those who could not participate in decision making (odds ratio, 8.2; 95% confidence interval, 4.5-15.0), and more weakly associated in those who could participate (odds ratio, 1.7; 95% confidence interval, 0.3-8.6). Being unemployed was associated with an increased odds of an explicit resuscitation directive versus no explicit directive (odds ratio, 5.5; 95% confidence interval, 2.2-13.4). CONCLUSIONS: Functional status impairment perceived by the ICU team is associated clearly with do-not-resuscitate directives in patients unable to participate in decision making. However, the association appears much weaker in patients able to participate in decision making. PATIENTS' perceived employment status also may influence resuscitation decisions. Our results emphasize the challenges of ensuring that crucial resuscitation decisions are not affected adversely by patients' inability to participate in decisions, and by their functional and employment status.

The EUPHRATES trial (Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized controlled trial of Adults Treated for Endotoxemia and Septic shock): study protocol for a randomized controlled trial.

BACKGROUND: Septic shock is common and has unacceptably high morbidity, mortality, and associated cost with numerous failed attempts at developing effective therapies. Endotoxin, one of the most potent mediators of sepsis, is found in high levels in approximately 50% of patients with septic shock. Polymyxin B (PMX) hemoperfusion has been shown in numerous studies to successfully remove endotoxin and potentially improve outcomes. EUPHRATES (Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized controlled trial of Adults Treated for Endotoxemia and Septic shock) is a theragnostic trial (matching blood measurement to treatment capability) of PMX hemoperfusion in patients with septic shock and confirmed endotoxemia as measured by the endotoxin activity assay (EAA). METHODS: EUPHRATES is a pivotal regulatory trial that is multi-centered, placebo-controlled and blinded. The trial is being conducted in fifty ICUs in the United States and Canada and is powered to enroll 360 patients. Patients with persistent septic shock despite adequate fluid resuscitation on vasopressors for more than 2 and less than 30 hours are eligible for measurement of the EAA. Those with EAA ≥0.60 are eligible to be randomized to treatment with two sessions of PMX hemoperfusion 24 hours apart. The primary endpoint for the trial is 28-day all-cause mortality. DISCUSSION: Unique features of the trial include absence of systemic inflammatory response (SIRS) criteria as a requirement for inclusion, use of the EAA to confirm endotoxemia as a requisite for treatment, and use of a detailed "façade" hemoperfusion event as a blinding mechanism. The outcomes of the second interim analysis included a resizing of the trial to 650 patients and the addition of an exclusion criterion of subjects with multiple organ dysfunction score (MODS) ≤ 9. Results are anticipated in 2016. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01046669. Registered: January 8, 2010.

Endotoxin removal: how far from the evidence? From EUPHAS to EUPHRATES.

There is a large amount of support for the safety of polymyxin-B (PMX-B) hemoperfusion in the treatment of septic shock from Japan and Europe. There is also support for potential efficacy, although randomized controlled trials are few and conflicting. PMX-B hemoperfusion represents a promising new treatment that could significantly improve survival. Previous clinical trials of PMX-B have been criticized for methodological issues, such as the absence of blinding, the use of surrogate outcomes and lack of longer term mortality outcomes. The variability in the number of treatment cartridges used, the selection of subjects based on likelihood of endotoxin presence without endotoxin measurement, and small sample sizes in mainly single-center trials have also been cited. The newly designed EUPHRATES trial (Evaluating Use of Polymyxin Hemoperfusion in a Randomized Controlled Trial of Adults treated for Endotoxemia and Septic Shock) addresses many of the methodological issues and represents a significant opportunity to test for clinical efficacy of endotoxin removal in the critically ill septic patient.

Measures, markers, and mediators: toward a staging system for clinical sepsis. A report of the Fifth Toronto Sepsis Roundtable, Toronto, Ontario, Canada, October 25-26, 2000.

BACKGROUND: Sepsis is not a single disease but a complex and heterogeneous process. Its expression is variable, and its severity is influenced by the nature of the infection, the genetic background of the patient, the time to clinical intervention, the supportive care provided by the clinician, and a number of factors as yet unknown. The evaluation of effective therapies has been hampered by limitations in our ability to characterize the process and to stratify patients into more homogeneous groups with respect to pathogenesis. OBJECTIVES: To develop a taxonomy of markers relevant to clinical research in sepsis and to propose a testable candidate system for stratifying patients into more therapeutically homogeneous groups. DATA SOURCE: An expert roundtable discussion and a MEDLINE review using search terms "marker" and "sepsis." RESULTS: Markers provide information in one or more of three domains: diagnosis, prognosis, and response to therapy. More than 80 putative markers of sepsis have been described. All correlate with the risk of mortality (prognosis), yet none has shown utility in stratifying patients with respect to therapy (diagnosis) or in titrating that therapy (response). Their limitations arise from the challenges of establishing causality in a complex disease process such as sepsis and of stratifying patients into more homogeneous populations. The former limitation may be addressed through a modification of Koch's postulates to differentiate causality from simple association. The latter suggests the need for a staging system analogous to those used in other complex disease processes such as cancer. A candidate framework for such a system, based on the infection, the host response, and the extent of organ dysfunction (the IRO system) is described. CONCLUSIONS: Advances in the understanding and management of patients with sepsis will necessitate more rigorous approaches to disease description and stratification. Models should be developed, tested, and modified through clinical studies rather than through consensus.

Measurement of endotoxin activity in critically ill patients using whole blood neutrophil dependent chemiluminescence.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Diagnostic and prognostic implications of endotoxemia in critical illness: results of the MEDIC study.

A novel assay for endotoxin, based on the ability of antigen-antibody complexes to prime neutrophils for an augmented respiratory burst response, was studied in a cohort study of 857 patients admitted to an intensive-care unit (ICU). On the day of ICU admission, 57.2% of patients had either intermediate (>or=0.40 endotoxin activity [EA] units) or high (>or=0.60 units) EA levels. Gram-negative infection was present in 1.4% of patients with low EA levels, 4.9% with intermediate levels, and 6.9% with high levels; EA had a sensitivity of 85.3% and a specificity of 44.0% for the diagnosis of gram-negative infection. Rates of severe sepsis were 4.9%, 9.2%, and 13.2%, and ICU mortality was 10.9%, 13.2%, and 16.8% for patients with low, intermediate, and high EA levels, respectively. Stepwise logistic regression analysis showed that elevated Acute Physiology and Chronic Health Evaluation II score, gram-negative infection, and emergency admission status were independent predictors of EA.