Mark Tidswell

Effect of Eritoran, an Antagonist of MD2-TLR4, on Mortality in Patients With Severe Sepsis: The ACCESS Randomized Trial

IMPORTANCE Eritoran is a synthetic lipid A antagonist that blocks lipopolysaccharide (LPS) from binding at the cell surface MD2-TLR4 receptor. LPS is a major component of the outer membrane of gram-negative bacteria and is a potent activator of the acute inflammatory response. OBJECTIVE To determine if eritoran, a TLR4 antagonist, would significantly reduce sepsis-induced mortality. DESIGN, SETTING, AND PARTICIPANTS We performed a randomized, double-blind, placebo-controlled, multinational phase 3 trial in 197 intensive care units. Patients were enrolled from June 2006 to September 2010 and final follow-up was completed in September 2011. INTERVENTIONS Patients with severe sepsis (n = 1961) were randomized and treated within 12 hours of onset of first organ dysfunction in a 2:1 ratio with a 6-day course of either eritoran tetrasodium (105 mg total) or placebo, with n = 1304 and n = 657 patients, respectively. MAIN OUTCOME MEASURES The primary end point was 28-day all-cause mortality. The secondary end points were all-cause mortality at 3, 6, and 12 months after beginning treatment. RESULTS Baseline characteristics of the 2 study groups were similar. In the modified intent-to-treat analysis (randomized patients who received at least 1 dose) there was no significant difference in the primary end point of 28-day all-cause mortality with 28.1% (366/1304) in the eritoran group vs 26.9% (177/657) in the placebo group (P = .59; hazard ratio, 1.05; 95% CI, 0.88-1.26; difference in mortality rate, -1.1; 95% CI, -5.3 to 3.1) or in the key secondary end point of 1-year all-cause mortality with 44.1% (290/657) in the eritoran group vs 43.3% (565/1304) in the placebo group, Kaplan-Meier analysis of time to death by 1 year, P = .79 (hazard ratio, 0.98; 0.85-1.13). No significant differences were observed in any of the prespecified subgroups. Adverse events, including secondary infection rates, did not differ between study groups. CONCLUSIONS AND RELEVANCE Among patients with severe sepsis, the use of eritoran, compared with placebo, did not result in reduced 28-day mortality. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00334828.

Phase 2 trial of eritoran tetrasodium (E5564), a Toll-like receptor 4 antagonist, in patients with severe sepsis*

Objectives:Endotoxin is a potent stimulus of proinflammatory response and systemic coagulation in patients with severe sepsis. Endotoxin is a component of Gram-negative bacteria that triggers an innate immune response through Toll-like receptor 4 signaling pathways in myeloid cells. We evaluated safety and tolerability of two dose regimens of eritoran tetrasodium (E5564), a synthetic Toll-like receptor 4 antagonist, and explored whether it decreases 28-day mortality rate in subjects with severe sepsis. Design:Prospective, randomized, double-blind, placebo-controlled, multicenter, ascending-dose phase II trial. Setting:Adult intensive care units in the United States and Canada. Patients:Three hundred adults within 12 hrs of recognition of severe sepsis, with Acute Physiology and Chronic Health Evaluation (APACHE) II-predicted risk of mortality between 20% and 80%. Interventions:Intravenous eritoran tetrasodium (total dose of either 45 mg or 105 mg) or placebo administered every 12 hrs for 6 days. Measurements and Main Results:Prevalence of adverse events was similar among subjects treated with 45 mg or 105 mg of eritoran tetrasodium or with placebo. For modified intent-to-treat subjects, 28-day all-cause mortality rates were 26.6% (eritoran tetrasodium 105 mg), 32.0% (eritoran tetrasodium 45 mg), and 33.3% in the placebo group. Mortality rate in the eritoran tetrasodium 105-mg group was not significantly different from placebo (p = .335). In prespecified subgroups, subjects at highest risk of mortality by APACHE II score quartile had a trend toward lower mortality rate in the eritoran tetrasodium 105-mg group (33.3% vs. 56.3% placebo group, p = .105). A trend toward a higher mortality rate was observed in subjects in the lowest APACHE II score quartile for the eritoran 105-mg group (12.0% vs. 0.0% placebo group, p = .083). Conclusions:Eritoran tetrasodium treatment appears well tolerated. The observed trend toward a lower mortality rate at the 105-mg dose, in subjects with severe sepsis and high predicted risk of mortality, should be further investigated.

Randomized Clinical Trial of Activated Protein C for the Treatment of Acute Lung Injury

RATIONALE Microvascular injury, inflammation, and coagulation play critical roles in the pathogenesis of acute lung injury (ALI). Plasma protein C levels are decreased in patients with acute lung injury and are associated with higher mortality and fewer ventilator-free days. OBJECTIVES To test the efficacy of activated protein C (APC) as a therapy for patients with ALI. METHODS Eligible subjects were critically ill patients who met the American/European consensus criteria for ALI. Patients with severe sepsis and an APACHE II score of 25 or more were excluded. Participants were randomized to receive APC (24 microg/kg/h for 96 h) or placebo in a double-blind fashion within 72 hours of the onset of ALI. The primary endpoint was ventilator-free days. MEASUREMENTS AND MAIN RESULTS APC increased plasma protein C levels (P = 0.002) and decreased pulmonary dead space fraction (P = 0.02). However, there was no statistically significant difference between patients receiving placebo (n = 38) or APC (n = 37) in the number of ventilator-free days (median [25-75% interquartile range]: 19 [0-24] vs. 19 [14-22], respectively; P = 0.78) or in 60-day mortality (5/38 vs. 5/37 patients, respectively; P = 1.0). There were no differences in the number of bleeding events between the two groups. CONCLUSIONS APC did not improve outcomes from ALI. The results of this trial do not support a large clinical trial of APC for ALI in the absence of severe sepsis and high disease severity.

A replicable method for blood glucose control in critically Ill patients.

Context:To ensure interpretability and replicability of clinical experiments, methods must be adequately explicit and should elicit the same decision from different clinicians who comply with the study protocol. Objective:The objective of this study was to determine whether clinician compliance with protocol recommendations exceeds 90%. Design:We developed an adequately explicit computerized protocol (eProtocol-insulin) for managing critically ill adult patient blood glucose. We monitored clinician compliance with eProtocol-insulin recommendations in four intensive care units in four hospitals and compared blood glucose distributions with those of a simple clinical guideline at one hospital and a paper-based protocol at another. All protocols and the guideline used intravenous insulin and 80 to 110 mg/dL (4.4–6.1 mmol/L) blood glucose targets. Setting:The setting for this study was four academic hospital intensive care units. Patients:This study included critically ill adults requiring intravenous insulin. Intervention:Intervention used in this study was a bedside computerized protocol for managing blood glucose. Main Outcome Measure:The main outcome measure was clinician compliance with eProtocol-insulin recommendations. Results:The number of patients was 31 to 458 and the number of blood glucose measurements was 2,226 to 19,925 among the four intensive care units. Clinician compliance with eProtocol-insulin recommendations was 91% to 98%. Blood glucose distributions were similar in the four hospitals (generalized linear model p = .18). Compared with the simple guideline, eProtocol-insulin glucose measurements within target increased from 21% to 39%, and mean blood glucose decreased from 142 to 115 mg/dL (generalized linear model p < .001). Compared with the paper-based protocol, eProtocol-insulin glucose measurements within target increased from 28% to 42%, and mean blood glucose decreased from 134 to 116 mg/dL (generalized linear model p = .001). Conclusions:The 91% to 98% clinician compliance indicates eProtocol-insulin is an exportable instrument that can establish a replicable experimental method for clinical trials of blood glucose management in critically ill adults. Control of blood glucose was better with eProtocol-insulin than with a simple clinical guideline or a paper-based protocol.

Randomized, Double-Blind, Placebo-Controlled Trial of Thiamine as a Metabolic Resuscitator in Septic Shock: A Pilot Study.

Objective:To determine if intravenous thiamine would reduce lactate in patients with septic shock. Design:Randomized, double-blind, placebo-controlled trial. Setting:Two US hospitals. Patients:Adult patients with septic shock and elevated (> 3 mmol/L) lactate between 2010 and 2014. Interventions:Thiamine 200 mg or matching placebo twice daily for 7 days or until hospital discharge. Measurements and Main Results:The primary outcome was lactate levels 24 hours after the first study dose. Of 715 patients meeting the inclusion criteria, 88 patients were enrolled and received study drug. There was no difference in the primary outcome of lactate levels at 24 hours after study start between the thiamine and placebo groups (median: 2.5 mmol/L [1.5, 3.4] vs. 2.6 mmol/L [1.6, 5.1], p = 0.40). There was no difference in secondary outcomes including time to shock reversal, severity of illness and mortality. 35% of the patients were thiamine deficient at baseline. In this predefined subgroup, those in the thiamine treatment group had statistically significantly lower lactate levels at 24 hours (median 2.1 mmol/L [1.4, 2.5] vs. 3.1 [1.9, 8.3], p = 0.03). There was a statistically significant decrease in mortality over time in those receiving thiamine in this subgroup (p = 0.047). Conclusion:Administration of thiamine did not improve lactate levels or other outcomes in the overall group of patients with septic shock and elevated lactate. In those with baseline thiamine deficiency, patients in the thiamine group had significantly lower lactate levels at 24 hours and a possible decrease in mortality over time.

Hemodynamic consequences of heart-lung interactions.

The management of critically ill patients requires a fundamental understanding of cardiopulmonary interactions associated with mechanical ventilation. The hemodynamic changes due to ventilation are a result of changes in lung volume and intrathoracic pressure (ITP) and can occur during spontaneous or positive pressure ventilation despite constant tidal volumes. Pulmonary vascular resistance (PVR) and mechanical heart-lung interactions play prominent roles in determining the hemodynamic response to mechanical ventilation. Lung inflation alters PVR and right ventricular wall tension and, at high lung volume, mechanically limits cardiac volumes. The authors will consider the mechanisms of the effects of ITP on the pulmonary arterial and venous branches. These effects will aid in understanding the complex interactions between ventilation and right and left ventricular pressures and volumes, as well as the influence of lung inflation pressure on ventricular interdependence.

Toll-like receptor-4 antagonist eritoran tetrasodium for severe sepsis

The human innate immune system initiates inflammation in response to bacterial molecules, particularly Gram-negative bacterial endotoxin. The steps by which endotoxin exposure leads to systemic inflammation include binding to Toll-like receptor-4 that specifically recognizes endotoxin and subsequently triggers cellular and molecular inflammatory responses. Severe sepsis is a systemic inflammatory response to infection that induces organ dysfunction and threatens a person’s survival. Severe sepsis is frequently associated with increased blood levels of endotoxin. It is a significant medical problem that effects approximately 700,000 patients every year in the USA, resulting in 250,000 deaths. Eritoran tetrasodium is a nonpathogenic analog of bacterial endotoxin that antagonizes inflammatory signaling by the immune receptor Toll-like receptor-4. Eritoran is being evaluated for the treatment of patients with severe sepsis.

Drotrecogin alfa (activated) in sepsis: Initial experience with patient selection, cost, and clinical outcomes.

During a 1-year period, the authors examined clinical experience with drotrecogin alfa, activated for sepsis in a 24-bed medical-surgical intensive care unit. Drotrecogin alfa, activated was administered 46 times to 44 patients (3% of all intensive care unit admissions). Eighty-six percent of patients were on vasopressors; 95% were mechanically ventilated. Mean Acute Physiology and Chronic Health Evaluation II score was 22.0 at admission and 21.9 during the 24 hours before drug administration. The 28-day all-cause mortality was 36.4% and hospital mortality was 43.2%, trending higher ( P = .10) than in the PROWESS study, which can be attributed to clinical use in patients who would not have met PROWESS study inclusion criteria. Failure to complete a 96-hour infusion of drotrecogin alfa, activated and transfer from another hospital or nursing home before treatment were associated with poor outcome. Total cost of hospital care, including mean drotrecogin alfa, activated drug cost of

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Nonlinear imputation of pa o 2/F io 2 from Sp o 2/F io 2 among mechanically ventilated patients in the ICU: A prospective, observational study

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