LY315920NA/S-5920, a selective inhibitor of group IIA secretory phospholipase A2, fails to improve clinical outcome for patients with severe sepsis

OBJECTIVE: Group IIA secretory phospholipase A2 (sPLA2-IIA), released during inflammation, is increased in severe sepsis, and plasma levels are inversely related to survival. In a previous study, a selective inhibitor of sPLA2-IIA (LY315920NA/S-5920) was well tolerated and appeared to improve survival in a subgroup of patients who received the drug within 24 hrs of first sepsis-induced organ failure. This study was designed to determine whether improvement in survival could be confirmed in a larger patient population meeting the characteristics of that subgroup. DESIGN: Multicenter, double-blind, placebo-controlled, parallel-group clinical trial of LY315920NA/S-5920 in patients with severe sepsis. SETTING: Seventy-five institutions worldwide. PATIENTS: A total of 373 patients with at least two sepsis-induced organ failures. INTERVENTIONS: Patients were randomized 1:1 to receive LY315920NA/S-5920 (target plasma concentration of 800 ng/mL; n = 188) or placebo (n = 185). Study medication was administered as a continuous intravenous infusion for 168 hrs. MEASUREMENTS AND MAIN RESULTS: The study was terminated after data on 250 patients suggested a significant improvement in 28-day all-cause mortality would not be found if the trial continued as planned. The mortality rate was 39.4% in the LY315920NA/S-5920 group, compared with 31.9% in the placebo group (p = .092). The negative trend in mortality was most pronounced among patients with cardiovascular failure at baseline (41.6% vs. 28.7%; p = .008) and patients whose culture data at baseline were negative (42.9% vs. 22.7%; p = .045). The negative trend in mortality is not explained by adverse events, microbiology, or laboratory data. CONCLUSIONS: Continuous 7-day infusion of an inhibitor of sPLA2-IIA had no beneficial effect on 28-day all-cause mortality among severe sepsis patients with at least two organ failures. This study did not confirm earlier promising subgroup results with LY315920NA/S-5920, which provides a reminder that subgroup effects should be viewed cautiously, especially when primary effects are not significant.     

Therapeutic time-window of a group IIA phospholipase A2 inhibitor in rabbit acute lung injury: correlation with lung surfactant protection

OBJECTIVE: We attempted to determine whether group IIA secretory phospholipase A2 (sPLA2-IIA) blockade after the onset of lung injury exerted therapeutic efficacy in the treatment of oleic acid (OA)-induced acute lung injury by using S-5920/LY315920Na, a novel specific inhibitor of sPLA2-IIA, with special interest in the changes of lung surfactant. DESIGN: Prospective animal study. SETTING: University laboratory. SUBJECTS: Forty Japanese white rabbits. INTERVENTIONS: The rabbits, under anesthesia, were endotracheally intubated and mechanically ventilated and then were divided into the following groups: OA + vehicle groups, intravenous infusion of OA for the first 2 hrs (0.1 mL x kg(-1) x hr(-1)) with the addition of vehicle (1 or 2 hrs after OA administration, each n = 9, total 18 rabbits); OA + S-5920/LY315920Na groups, treated identically to the OA control with the addition of S-5920/LY315920Na (1 mg/kg bolus followed by infusion at 0.5 mg x kg(-1) x hr(-1)) after OA (1 or 2 hrs after OA administration, each n = 9, total 18 rabbits); saline control groups, treated with saline instead of OA with the addition of vehicle (1 hr after OA administration, 4 rabbits). Arterial blood gas, lung mechanics, lung inflammation, lung surfactant phospholipids, and production of inflammatory mediators in the lung were measured. MEASUREMENTS AND MAIN RESULTS: Treatment with S-5920/LY315920Na 1 hr after OA infusion, but not 2 hrs after infusion, significantly attenuated the lung injury, as estimated by hypoxemia, decreased lung compliance, pulmonary edema, and vascular permeability. The therapeutic efficacy was similar to that found in our previous pretreatment study. The treatment after 1 hr dramatically inhibited OA-induced surfactant degradation in the bronchoalveolar lavage fluid (BALF), without affecting the concentrations of thromboxane A2, leukotriene B4, and interleukin-8 in BALF. The degree of surfactant degradation in BALF paralleled well with the severity of the lung injury. Furthermore, recombinant human sPLA2-IIA reproduced the similar hydrolysis pattern of isolated surfactant in vitro, which was inhibited by S-5920/LY315920Na. CONCLUSIONS: Our results indicate that therapeutic blockade of sPLA2-IIA ameliorated lung dysfunction via protection of surfactant degradation in an animal model of acute lung injury, and they suggest a new strategy in treating clinical acute lung injury.     

Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial

OBJECTIVE: Platelet-activating factor (PAF) and structurally-related oxidized phospholipids are proinflammatory mediators in systemic inflammatory states such as severe sepsis. The enzyme platelet-activating factor acetylhydrolase (PAF-AH) rapidly degrades PAF and oxidized phospholipids into inactive metabolites. Reduced PAF-AH activity has been observed in patients with severe sepsis and may contribute to their systemic inflammatory response and organ dysfunction. A previous clinical trial with recombinant human PAF-AH (rPAF-AH, Pafase) suggested that this treatment may decrease 28-day all-cause mortality in patients with severe sepsis. The current study was undertaken to confirm this result. DESIGN: A prospective, randomized, double-blind, placebo-controlled, multicenter, international trial. SETTING: One hundred forty-six intensive care units from nine countries. PATIENTS: Approximately 2,522 patients were planned to be enrolled < or =12 hrs after the onset of severe sepsis. Eligible patients were randomized to receive either rPAF-AH 1.0 mg/kg or placebo administered intravenously once daily for five consecutive days. MEASUREMENTS AND MAIN RESULTS: The study was terminated based on the recommendation of an independent data and safety monitoring committee after the second of three planned interim analyses, and the enrollment of 1,425 patients. rPAF-AH treatment was well tolerated among the 1,261 patients included in the interim analysis (643 rPAF-AH and 618 placebo), but did not decrease 28-day all-cause mortality compared with placebo (25% for rPAF-AH vs. 24% for placebo; relative risk, 1.03; 95% confidence interval, 0.85-1.25; p =.80). There were no statistically significant differences between treatment groups in any of the secondary efficacy end points. The overall incidence of adverse events was similar among rPAF-AH and placebo-treated patients, and no rPAF-AH-treated patients developed antibodies to PAF-AH. CONCLUSIONS: rPAF-AH was well tolerated and not antigenic, but did not decrease 28-day all-cause mortality in patients with severe sepsis.     

Score-based immunoglobulin G therapy of patients with sepsis: the SBITS study

OBJECTIVE: Intravenous immunoglobulin as an adjunctive treatment in sepsis was regarded as promising by a Cochrane meta-analysis of smaller trials. In this phase III multicenter trial, we assessed whether intravenous immunoglobulin G (ivIgG) reduced 28-day mortality and improved morbidity in patients with score-defined severe sepsis. DESIGN: Randomized, double-blind, placebo-controlled, multicenter trial. SETTING: Twenty-three medical and surgical intensive care units in university centers and large teaching hospitals. PATIENTS: Patients (n = 653) with score-defined sepsis (sepsis score 12-27) and score-defined sepsis-induced severity of disease (Acute Physiology and Chronic Health Evaluation II score 20-35). INTERVENTIONS: Patients were assigned to receive either placebo or ivIgG (day 0, 0.6 g/kg body weight; day 1, 0.3 g/kg body weight). MEASUREMENTS AND MAIN RESULTS: The prospectively defined primary end point was death from any cause after 28 days. Prospectively defined secondary end points were 7-day all-cause mortality, short-term change in morbidity, and pulmonary function at day 4. Six hundred fifty-three patients from 23 active centers formed the intention-to-treat group, 624 patients the per-protocol group (placebo group, n = 303; ivIgG group, n = 321). The 28-day mortality rate was 37.3% in the placebo group and 39.3% in the ivIgG group and thus not significantly different (p = .6695). Seven-day mortality was not reduced, and 4-day pulmonary function was not improved. Drug-related adverse events were rare in both groups. Exploratory findings revealed a 3-day shortening of mechanical ventilation in the surviving patients and no effect of ivIgG on plasma levels of interleukin-6 and tumor necrosis factor receptors I and II. CONCLUSIONS: In patients with score-defined severe sepsis, ivIgG with a total dose of 0.9 g/kg body weight does not reduce mortality.     

Recombinant platelet-activating factor acetylhydrolase to prevent acute respiratory distress syndrome and mortality in severe sepsis: Phase IIb,multicenter, randomized,placebo-controlled,clinical trial

OBJECTIVE: Platelet-activating factor (PAF) is a potent proinflammatory mediator implicated in the pathogenesis of both severe sepsis and acute respiratory distress syndrome. One of the regulatory pathways for PAF involves degradation to the inactive metabolite lyso-PAF by the enzyme PAF acetylhydrolase (PAF-AH). Because reduced concentrations of the natural form of PAF-AH have been reported in septic patients, the present study was conducted to determine whether treatment with recombinant human PAF-AH (rPAF-AH, Pafase) was safe when administered after the onset of severe sepsis and whether it decreases the prevalence of acute respiratory distress syndrome and 28-day all-cause mortality. DESIGN: A prospective, randomized, double-blind, placebo-controlled, multicenter trial. SETTING: Thirty-three medical and surgical intensive care units located in the United States. PATIENTS: A total of 127 patients with severe sepsis, but without established acute respiratory distress syndrome, were enrolled in the study. Randomization occurred within 12 hrs of the onset of severe sepsis. Patients then received 1.0 mg/kg rPAF-AH (n = 45), 5.0 mg/kg rPAF-AH (n = 39), or placebo (n = 43) administered intravenously, once daily, for five consecutive days. MEASUREMENTS AND MAIN RESULTS: Demographic and baseline clinical characteristics of the three treatment groups were similar, except for a significantly higher prevalence of respiratory tract infections as the cause of severe sepsis in patients treated with 1.0 mg/kg rPAF-AH. There were no treatment-related deaths, and the overall prevalence of adverse events was similar among rPAF-AH-treated and placebo-treated patients. There were no significant differences in the prevalence of acute respiratory distress syndrome among the three treatment groups. However, 28-day all-cause mortality was 21% in the 1.0 mg/kg rPAF-AH group, 28% in the 5.0 mg/kg rPAF-AH group, and 44% in the placebo group (overall chi-square p =.07; 1.0 mg/kg rPAF-AH vs. placebo, p =.03). A trend toward reduced multiple organ dysfunction also was observed in the 1.0 mg/kg rPAF-AH group compared with the placebo group (p =.11). CONCLUSION: The results from this study indicate that rPAF-AH was well tolerated and should be pursued as a potential new treatment to decrease mortality in patients with severe sepsis.     

Drotrecogin alfa (activated) treatment in severe sepsis from the global open-label trial ENHANCE: further evidence for survival and safety and implications for early treatment

OBJECTIVE: To provide further evidence for the efficacy and safety of drotrecogin alfa (activated) treatment in severe sepsis. DESIGN: Single-arm, open-label, trial of drotrecogin alfa (activated) treatment in severe sepsis patients. Enrollment began in March 2001 and day-28 follow-up completed in January 2003. SETTING: ENHANCE took place in 25 countries at 361 sites. PATIENTS: Patients with known or suspected infection, three or four systemic inflammatory response syndrome criteria, and one or more sepsis-induced organ dysfunctions. Of 2,434 adults entered, 2,378 received drotrecogin alfa (activated), and of these, 2,375 completed the protocol. INTERVENTIONS: Drotrecogin alfa (activated) was infused at a dose of 24 mug/kg/hr for 96 hrs. MEASUREMENTS AND MAIN RESULTS: The 28-day all-cause mortality approximated that observed in PROWESS (25.3% vs. 24.7%). Although patients in ENHANCE had increased serious bleeding rates compared with patients in the drotrecogin alfa (activated) arm of PROWESS (during infusion, 3.6% vs. 2.4%; postinfusion, 3.2% vs. 1.2%; 28-day, 6.5% vs. 3.5%), increased postinfusion bleeding suggested a higher background bleeding rate. Intracranial hemorrhage was more common in ENHANCE than PROWESS (during infusion, 0.6% vs. 0.2%; 28-day, 1.5% vs. 0.2%). The incidence of fatal intracranial hemorrhage was the same during infusion (0.2%) and higher at 28 days (0.5% vs. 0.2%). ENHANCE patients treated within 0-24 hrs from their first sepsis-induced organ dysfunction had lower observed mortality rate than those treated after 24 hrs (22.9% vs. 27.4%, p = .01). CONCLUSIONS: ENHANCE provides supportive evidence for the favorable benefit/risk ratio observed in PROWESS and suggests that more effective use of drotrecogin alfa (activated) might be obtained by initiating therapy earlier.     

Influence of severity of illness on the effects of eritoran tetrasodium (E5564) and on other therapies for severe sepsis

Disease severity varies widely in patients with severe sepsis. Eritoran tetrasodium (E5564), a TLR4 antagonist, blocks the binding of endotoxin and is being evaluated as a novel therapy for severe sepsis. This analysis aimed to assess the efficacy of eritoran based on severity of illness and similar effects in other recent sepsis trials. Prospective covariates from a randomized, double-blind, placebo-controlled, phase 2 trial were analyzed for treatment interaction measured by 28-day mortality. Five statistical interaction methodologies were used. The modified intent-to-treat population (n = 292), all-cause 28-day mortality was as follows: placebo, 33.3% (32/96); eritoran 45 mg/105 mg, 29.6% (58/196). Logistic regression analysis identified Acute Physiology and Chronic Health Evaluation II scores, predicted-risk-of-mortality scores, IL-6, age, sex, race, and eritoran use as associated with survival. Significant treatment interactions were observed (eritoran vs. placebo) for baseline covariates: Acute Physiology and Chronic Health Evaluation II (P = 0.035), predicted-risk-of-mortality scores (P = 0.008), number of organ failures (P = 0.079), international normalized ratio (P = 0.05), and acute physiology score (P = 0.039). I analysis showed that 38% of the total eritoran treatment variance was explained by the severity-of-illness heterogeneity rather than by chance. No interactions observed with other variables. Consistent with the finding in this eritoran trial, other sepsis trials (IL-1 receptor antagonist, TNFsr-p55, antithrombin, drotrecogin alfa-activated) also demonstrated significant treatment by severity interaction. Potential survival benefits of eritoran in severe sepsis patients were associated with high severity of illness. These findings were used to design a phase 3 trial. Similar treatment by severity-of-illness interaction was found in most recent sepsis trials.     

Assessment of the safety of recombinant tissue factor pathway inhibitor in patients with severe sepsis: a multicenter, randomized, placebo-controlled, single-blind, dose escalation study.

OBJECTIVE: To identify a safe and potentially effective recombinant tissue factor pathway inhibitor (rTFPI) dose for further clinical evaluation in patients with severe sepsis. DESIGN: Prospective, randomized, single-blind, placebo-controlled, dose escalation, multicenter, multinational phase II clinical trial. SETTING: Thirty-eight intensive care units in the United States and Europe. PATIENTS: Two hundred and ten subjects with severe sepsis who received standard supportive care and antimicrobial therapy. INTERVENTIONS: Subjects received a continuous intravenous infusion of placebo or rTFPI at 0.025 or 0.05 mg/kg/hr for 4 days (96 hrs). MEASUREMENTS AND MAIN RESULTS: There were no significant imbalances in demographics, severity of illness, or source of infection in patients randomized to placebo or either dose of rTFPI. A 20% relative reduction in 28-day all-cause mortality was observed when all rTFPI-treated patients were compared with all placebo patients. An improvement in pulmonary organ dysfunction score and in a composite intensive care unit score (pulmonary, cardiovascular, and coagulation) were also noted in the rTFPI-treated patients. Logistic regression modeling indicated a substantial treatment by baseline laboratory international normalized ratio (INR) interaction effect when only treatment and INR were in the model (p =.037) and when baseline Acute Physiology and Chronic Health Evaluation (APACHE II) and log10 interleukin 6 were adjusted for (p =.026). This interaction effect indicates that higher baseline INR is associated with a more pronounced beneficial rTFPI effect. There was no increase in mortality in subjects treated with either dose of rTFPI compared with placebo. Biological activity, as detected by a statistically significant reduction in thrombin-antithrombin complexes (TATc), was noted in the all rTFPI-treated patients compared with those receiving placebo. There were no major imbalances across all treatment groups with respect to safety. The frequency of adverse events (AEs) and severe adverse events (SAEs) was similar among the treatment groups, with a slight increase in SAEs and SAEs involving bleeding in the 0.05 mg/kg/hr rTFPI group. The overall incidence of AEs involving bleeding was 28% of patients in the all placebo group and 23% of patients in the all rTFPI-treated group; a slight but statistically insignificant increase in incidence of SAEs involving bleeding was observed in the all rTFPI group (9%) as compared with the all placebo group (6%; p =.39). CONCLUSIONS: Although the trial was not powered to show efficacy, a trend toward reduction in 28-day all-cause mortality was observed in the all rTFPI group compared with all placebo. This study demonstrates that rTFPI doses of 0.025 and 0.05 mg/kg/hr could be safely administered to severe sepsis patients. Additionally, rTFPI demonstrated bioactivity, as shown by reduction in TATc complexes and interleukin-6 levels. These findings warrant further evaluation of rTFPI in an adequately powered, placebo controlled, randomized trial for the treatment of severe sepsis.     

Lenercept (p55 tumor necrosis factor receptor fusion protein) in severe sepsis and early septic shock: a randomized, double-blind, placebo-controlled, multicenter phase III trial with 1,342 patients

OBJECTIVE: Phase III study to confirm a trend observed in a previous phase II study showing that a single dose of lenercept, human recombinant p55 tumor necrosis factor receptor-immunoglobulin G1 (TNFR55-IgG1) fusion protein, decreased mortality in patients with severe sepsis or early septic shock. DESIGN: Multicenter, double-blind, phase III, placebo-controlled, randomized study. SETTING: A total of 108 community and university-affiliated hospitals in the United States (60), Canada (6) and Europe (42). PATIENTS: A total of 1,342 patients were recruited who fulfilled the entry criteria within the 12-hr period preceding the study drug administration. INTERVENTION: After randomization, an intravenous dose of 0.125 mg/kg lenercept or placebo was given. The patient was monitored for up to 28 days, during which standard diagnostic, supportive, and therapeutic care was provided. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was 28-day all-cause mortality. Baseline characteristics were as follows: a total of 1,342 patients were randomized; 662 received lenercept and 680 received placebo. The mean age was 60.5 yrs (range, 17-96 yrs); 39% were female; 65% had medical admissions, 8% had scheduled surgical admissions, and 27% had unscheduled surgical admissions; 73% had severe sepsis without shock, and 27% had severe sepsis with early septic shock. Lenercept and placebo groups were similar at baseline with respect to demographic characteristics, simplified acute physiology score II-predicted mortality, profiles of clinical site of infection and microbiological documentation, number of dysfunctioning organs, and interleukin-6 (IL-6) plasma concentration. Lenercept pharmacokinetics were similar in severe sepsis and early septic shock patients. Tumor necrosis factor was bound in a stable manner to lenercept as reflected by the accumulation of total serum tumor necrosis factor alpha concentrations. There were 369 deaths, 177 on lenercept (27% mortality) and 192 on placebo (28% mortality). A one-sided Cochran-Armitage test, stratified by geographic region and baseline, predicted 28-day all-cause mortality (simplified acute physiology score II), gave a p value of .141 (one-sided). Lenercept treatment had no effect on incidence or resolution of organ dysfunctions. There was no evidence that lenercept was detrimental in the overall population. CONCLUSION: Lenercept had no significant effect on mortality in the study population.     

IgMA-enriched immunoglobulin in neutropenic patients with sepsis syndrome and septic shock: a randomized, controlled, multiple-center trial

OBJECTIVE: To evaluate the effect of intravenous IgMA-enriched immunoglobulin (ivIGMA) therapy on mortality in neutropenic patients with hematologic malignancies and sepsis syndrome or septic shock. DESIGN: Multiple-center, prospective randomized, controlled study. SETTING: Six university hospitals in Germany. PATIENTS: Patients were 211 neutropenic patients with sepsis syndrome or septic shock after chemotherapy for severe hematologic disorders between 1992 and 1999. INTERVENTIONS: Patients received 1300 mL of ivIGMA (7.8 g IgM, 7.8 g IgA, and 49.4 g IgG) infused intravenously within a period of 72 hrs or human albumin according to the same schedule as ivIGMA. MEASUREMENTS AND MAIN RESULTS: All-cause mortality at 28 days, sepsis-related mortality at 28 days, all-cause mortality at 60 days, mortality from septic shock, and mortality from microbiologically proven Gram-negative sepsis and septic shock were recorded. Immunoglobulin had no benefit over human albumin. The 28-day mortality rate was 26.2% and 28.2% in the ivIGMA and control patients, respectively (difference, 2.0% [95% confidence interval, -10.2 to 14.2 percentage points]). Likewise, the 60-day mortality rate did not differ between both arms (29.6% vs. 34.7% in the ivIGMA and control patients, respectively). Mortality rates in patients with sepsis syndrome (17.1% vs. 16.7%) and septic shock (51.9% vs. 54.8%) were also found to be similar between both groups. CONCLUSIONS: Intravenous ivIGMA had no beneficial effects in neutropenic patients with hematologic malignancies and sepsis syndrome and septic shock.     

Neutrophil elastase inhibition in acute lung injury: results of the STRIVE study

OBJECTIVE: Neutrophil elastase is believed to be an important mediator of acute lung injury. Sivelestat (ONO-5046, Elaspol) is a small molecular weight inhibitor of neutrophil elastase. The primary objectives of this study were to determine whether sivelestat would reduce 28-day all-cause mortality or increase the number of ventilator-free days (days alive and free from mechanical ventilation from day 1 to day 28) compared with placebo in mechanically ventilated patients with acute lung injury. DESIGN: Multiple-center, double-blind, placebo-controlled trial administering a continuous infusion of sivelestat at a dose of 0.16 mg.kg(-1)hr(-1). SETTING: One hundred and five institutions in the United States, Canada, Belgium, Spain, Australia, and New Zealand. PATIENTS: A total of 492 mechanically ventilated patients with acute lung injury. INTERVENTIONS: Patients were randomized in a 1:1 fashion to sivelestat or placebo. Study drug was administered as a continuous infusion for the duration of mechanical ventilation plus 24 hrs for a maximum of 14 days. All patients were managed using low tidal volume mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: The study was stopped prematurely at the recommendation of an external Data and Safety Monitoring Board, which noted a negative trend in long-term mortality rate. Final analysis revealed no effect of sivelestat on the primary end points of ventilator-free days (day 1-day 28) or 28-day all-cause mortality. There were 64 deaths in each treatment group within the 28-day study period, and the mean number of ventilator-free days was 11.4 and 11.9 in the sivelestat and placebo treatment groups, respectively (p =.536). There was no evidence of effect on measures of pulmonary function, including Pao2/Fio2, static lung compliance, and time to meeting weaning criteria. There was no difference in adverse events or serious adverse events between treatment groups. A comparison of the Kaplan-Meier 180-day survival curves showed no difference between treatment groups (p =.102), but there was an increase in 180-day all-cause mortality in the sivelestat treatment group compared with the placebo group (p =.006). CONCLUSIONS: Intravenous sivelestat had no effect on 28-day all-cause mortality or ventilator-free days in a heterogeneous acute lung injury patient population managed with low tidal volume mechanical ventilation.     

Safety and dose relationship of recombinant human activated protein C for coagulopathy in severe sepsis.

OBJECTIVES: To assess the safety and effect on coagulopathy of a range of doses of recombinant human activated protein C (rhAPC). To determine an effective dose and duration of rhAPC for use in future clinical trials. DESIGN: Double-blind, randomized, placebo-controlled, multicenter, dose-ranging (sequential), phase II clinical trial. SETTING: Forty community or academic medical institutions in United States and Canada. PATIENTS: One hundred thirty-one adult patients with severe sepsis. INTERVENTIONS: Intravenous infusion of rhAPC (12, 18, 24, or 30 microg/kg/hr) or placebo for 48 or 96 hrs. MEASUREMENTS AND MAIN RESULTS: No significant differences in incidence of serious bleeding events (4% rhAPC, 5% placebo, p >.999) or incidence of serious adverse events (39% rhAPC, 46% placebo, p = 0.422) between rhAPC- and placebo-treated patients were observed. One of 53 rhAPC-treated patients with suitable immunogenicity samples had a low level, transient, non-neutralizing anti-APC antibody response not associated with any clinical adverse event. Significant dose-dependent decreases in both D-dimer (p <0.001) and end of infusion interleukin 6 levels (p =.021) were demonstrated. No statistically significant effects on fibrinogen or platelet counts were observed. A nonstatistically significant 15% relative risk reduction in 28-day all-cause mortality was observed between rhAPC- and placebo-treated patients. CONCLUSIONS: rhAPC was safe and well-tolerated and demonstrated a dose-dependent reduction in D-dimer and interleukin 6 levels relative to placebo. The dose of 24 microg/kg/hr for 96 hrs was selected for use in future clinical studies.     

Pharmacology of LY315920/S-5920, [[3-(aminooxoacetyl)-2-ethyl-1- (phenylmethyl)-1H-indol-4-yl]oxy] acetate, a potent and selective secretory phospholipase A2 inhibitor: A new class of anti-inflammatory drugs, SPI

LY315920 is a potent, selective inhibitor of recombinant human, group IIA, nonpancreatic secretory PLA2 (sPLA2). In a chromogenic isolated enzyme assay, LY315920 inhibited sPLA2 activity with an IC50 of 9 +/- 1 nM or 7.3 x 10(-6) mole fraction, which approached the stiochiometric limit of this assay. The true potency of LY315920 was defined using a deoxycholate/phosphatidylcholine assay with a mole fraction of 1.5 x 10(-6). LY315920 was 40-fold less active against human, group IB, pancreatic sPLA2 and was inactive against cytosolic PLA2 and the constitutive and inducible forms of cyclooxygenase. Human sPLA2-induced release of thromboxane A2 (TXA2) from isolated guinea pig lung bronchoalveolar lavage cells was inhibited by LY315920 with an IC50 of 0.79 microM. The release of TXA2 from these cells by N-formyl-methionyl-leucyl-phenylalanine or arachidonic acid was not inhibited. The i.v. administration of LY315920, 5 min before harvesting the bronchoalveolar lavage cells, resulted in the inhibition of sPLA2-induced production of TXA2 with an ED50 of 16.1 mg/kg. Challenge of guinea pig lung pleural strips with sPLA2 produced contractile responses that were suppressed in a concentration-dependent manner by LY315920 with an apparent KB of 83 +/- 14 nM. Contractile responses induced by arachidonic acid were not altered. Intravenous or oral administration of LY315920 to transgenic mice expressing the human sPLA2 protein inhibited serum sPLA2 activity in a dose-related manner over a 4-h time course. LY315920 is a potent and selective sPLA2 inhibitor and represents a new class of anti-inflammatory agent designated SPI. This agent is currently undergoing clinical evaluation and should help to define the role of sPLA2 in various inflammatory disease states.     

Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab')2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels

OBJECTIVE: To evaluate whether administration of afelimomab, an anti-tumor necrosis factor F(ab')2 monoclonal antibody fragment, would reduce 28-day all-cause mortality in patients with severe sepsis and elevated serum levels of IL-6. DESIGN: Prospective, randomized, double-blind, placebo-controlled, multiple-center, phase III clinical trial. SETTING: One hundred fifty-seven intensive care units in the United States and Canada. PATIENTS: Subjects were 2,634 patients with severe sepsis secondary to documented infection, of whom 998 had elevated interleukin-6 levels. INTERVENTIONS: Patients were stratified into two groups by means of a rapid qualitative interleukin-6 test kit designed to identify patients with serum interleukin-6 levels above (test positive) or below (test negative) approximately 1000 pg/mL. Of the 2,634 patients, 998 were stratified into the test-positive group, 1,636 into the test-negative group. They were then randomly assigned 1:1 to receive afelimomab 1 mg/kg or placebo for 3 days and were followed for 28 days. The a priori population for efficacy analysis was the group of patients with elevated baseline interleukin-6 levels as defined by a positive rapid interleukin-6 test result. MEASUREMENTS AND MAIN RESULTS: In the group of patients with elevated interleukin-6 levels, the mortality rate was 243 of 510 (47.6%) in the placebo group and 213 of 488 (43.6%) in the afelimomab group. Using a logistic regression analysis, treatment with afelimomab was associated with an adjusted reduction in the risk of death of 5.8% (p = .041) and a corresponding reduction of relative risk of death of 11.9%. Mortality rates for the placebo and afelimomab groups in the interleukin-6 test negative population were 234 of 819 (28.6%) and 208 of 817 (25.5%), respectively. In the overall population of interleukin-6 test positive and negative patients, the placebo and afelimomab mortality rates were 477 of 1,329 (35.9%)and 421 of 1,305 (32.2%), respectively. Afelimomab resulted in a significant reduction in tumor necrosis factor and interleukin-6 levels and a more rapid improvement in organ failure scores compared with placebo. The safety profile of afelimomab was similar to that of placebo. CONCLUSIONS: Afelimomab is safe, biologically active, and well tolerated in patients with severe sepsis, reduces 28-day all-cause mortality, and attenuates the severity of organ dysfunction in patients with elevated interleukin-6 levels.     

Aspirin Therapy and 28-Day Mortality in ICU Patients: A Retrospective Observational Study From Two Large Databases

PurposeAspirin is widely used in patients in the intensive care unit (ICU); nonetheless, its effects on these patients remain controversial. This retrospective analysis of data from clinical practice investigated the effects of aspirin on 28-day mortality in ICU patients.MethodsThis retrospective study included data from patients in the Medical Information Mart for Intensive Care (MIMIC)-III database and the eICU–Collaborative Research Database (CRD). Patients aged 18 to 90 years and admitted to the ICU were eligible and were assigned to one of two groups according to whether they were given aspirin during their ICU stay. Multiple imputation was used for patients with >10% missing data. Multivariate Cox models and propensity score analysis were used to estimate the association of aspirin treatment with 28-day mortality among patients admitted to the ICU.FindingsIn total, 146,191 patients were enrolled in this study, and 27,424 (18.8%) used aspirin. Aspirin treatment in ICU patients, especially in nonseptic patients, was associated with a lower 28-day all-cause mortality on multivariate Cox analysis (eICU-CRD, hazard ratio [HR] = 0.81, [95% CI, 0.75–0.87]; MIMIC-III, HR = 0.72 [95% CI, 0.68–0.76]). Aspirin treatment was associated with lower 28-day all-cause mortality after propensity score matching (eICU-CRD, HR = 0.80 [95% CI, 0.72–0.88]; MIMIC-III, HR = 0.80 [95% CI, 0.76–0.85]). However, on subgroup analysis, aspirin therapy was not associated with a lower 28-day mortality in patients without systemic inflammatory response syndrome (SIRS) symptoms or with sepsis in either database.ImplicationsAspirin treatment during the ICU stay was associated with a significantly reduced 28-day all-cause mortality, particularly in patients with SIRS symptoms but without sepsis. In patients with sepsis and with/without SIRS symptoms, beneficial effects were not clear, or more careful patient selection is required.     

Safety and efficacy of affinity-purified, anti-tumor necrosis factor-alpha, ovine fab for injection (CytoFab) in severe sepsis

OBJECTIVE: Tumor necrosis factor (TNF) is a critical inflammatory mediator in sepsis. This trial was designed to evaluate the safety and effectiveness of polyclonal ovine anti-TNF fragment antigen binding (Fab) fragments (CytoFab) on plasma TNF-alpha, interleukin-6 (IL-6), and interleukin-8 (IL-8) concentrations and the number of shock-free and ventilator-free days in severely septic patients. DESIGN: Phase II, randomized, blinded, placebo-controlled trial conducted from September 1997 to July 1998. SETTING: Nineteen intensive care units in the United States and Canada. PATIENTS: Eighty-one septic patients with either shock or two organ dysfunctions. INTERVENTIONS: Patients were randomized to receive CytoFab, infused as a 250-units/kg loading dose, followed by nine doses of 50 units/kg every 12 hrs, or 5 mg/kg human albumin as placebo. MEASUREMENTS AND MAIN RESULTS: CytoFab promptly reduced plasma TNF-alpha (p = .001) and IL-6 concentrations (p = .002) compared with placebo. CytoFab also significantly decreased TNF-alpha in bronchoalveolar lavage (BAL) fluid (p < .001). The number of shock-free days did not differ between CytoFab and placebo (10.7 vs. 9.4, respectively) (p = .270). CytoFab increased mean ventilator-free days (15.0 vs. 9.8 for placebo; p = .040) and ICU-free days (12.6 vs. 7.6 for placebo; p = .030) at day 28. All-cause, 28-day mortality rates were 37% (14/38) for placebo recipients, compared with 26% (11/43) for CytoFab recipients (p = .274). No differences in incidences of adverse events, laboratory, or vital sign abnormalities were observed between groups. Although 41% of CytoFab-treated patients developed detectable plasma levels of human anti-sheep antibodies, none demonstrated clinical manifestations during the 28-day study. CONCLUSIONS: CytoFab is well tolerated in patients with severe sepsis, effectively reducing serum and BAL TNF-alpha and serum IL-6 concentrations and increasing the number of ventilator-free and ICU-free days at day 28.     

Hospital mortality and resource use in subgroups of the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial

OBJECTIVE: To compare differences in hospital mortality and resource use in adult severe sepsis subjects randomized to receive drotrecogin alfa (activated) (DrotAA) or placebo in the PROWESS trial. DESIGN: Retrospective, cross-sectional, blinded follow-up of subjects enrolled in a previous randomized, controlled trial. SETTING: One hundred sixty-four tertiary care institutions in 11 countries. PARTICIPANTS: The 1,690 subjects with severe sepsis enrolled and treated with study drug in PROWESS, of whom 1,220 were alive at 28 days (the end of the original PROWESS follow-up). INTERVENTIONS: DrotAA (n = 850), 24 microg/kg/hr for 96 hrs, or placebo (n = 840). MEASUREMENTS AND MAIN RESULTS: New follow-up data through hospital discharge were merged with existing 28-day follow-up data. Hospital mortality was calculated for designated subgroups. Intensive care unit and hospital length of stay and Simplified Therapeutic Intervention Scoring System-28 (TISS-28) scores were calculated overall and in designated subgroups. Hospital discharge location was recorded. The 95% confidence interval of most subgroups contained the relative risk estimate for overall 28-day and hospital mortality. Median hospital length of stay and intensive care unit length of stay were similar in both treatment groups: 16 vs. 17 days (p = .22) and 9 vs. 9 days (p = .7) for placebo vs. DrotAA. No significant difference in TISS-28 scores was observed between treatment groups overall or in subgroups of disease severity. In subjects for whom discharge destination was reported, 42.8% of placebo subjects and 46.8% of DrotAA subjects (two thirds of survivors in each group) were discharged directly to home. CONCLUSIONS: Reduction in hospital mortality with DrotAA in most of the subgroups of PROWESS is consistent with the reduction in 28-day and hospital mortality observed in the overall PROWESS population. Additional survivors created with DrotAA treatment did not increase per-patient resource use or intensive care unit or hospital length of stay.     

Treatment effects of high-dose antithrombin without concomitant heparin in patients with severe sepsis with or without disseminated intravascular coagulation

BACKGROUND: Disseminated intravascular coagulation (DIC) is a serious complication of sepsis that is associated with a high mortality. OBJECTIVES: Using the adapted International Society on Thrombosis and Haemostasis (ISTH) diagnostic scoring algorithm for DIC, we evaluated the treatment effects of high-dose antithrombin (AT) in patients with severe sepsis with or without DIC. PATIENTS AND METHODS: From the phase III clinical trial in severe sepsis (KyberSept), 563 patients were identified (placebo, 277; AT, 286) who did not receive concomitant heparin and had sufficient data for DIC determination. RESULTS: At baseline, 40.7% of patients (229 of 563) had DIC. DIC in the placebo-treated patients was associated with an excess risk of mortality (28-day mortality: 40.0% vs. 22.2%, P < 0.01). AT-treated patients with DIC had an absolute reduction in 28-day mortality of 14.6% compared with placebo (P = 0.02) whereas in patients without DIC no effect on 28-day mortality was seen (0.1% reduction in mortality; P = 1.0). Bleeding complications in AT-treated patients with and without DIC were higher compared with placebo (major bleeding rates: 7.0% vs. 5.2% for patients with DIC, P = 0.6; 9.8% vs. 3.1% for patients without DIC, P = 0.02). CONCLUSIONS: High-dose AT without concomitant heparin in septic patients with DIC may result in a significant mortality reduction. The adapted ISTH DIC score may identify patients with severe sepsis who potentially benefit from high-dose AT treatment.     

Dynamic evolution of coagulopathy in the first day of severe sepsis: relationship with mortality and organ failure

OBJECTIVE: To determine whether changes in coagulation biomarkers during the first day of severe sepsis correlate with progression from single to multiple organ failure and subsequent death. DESIGN: Analysis of secondary endpoints in a prospective, randomized, placebo-controlled, multinational clinical trial (PROWESS). SETTING: The study involved 164 medical centers. PATIENTS: A total of 840 patients who met criteria for severe sepsis and were randomized to receive placebo plus supportive care. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Coagulation biomarkers, prothrombin time, antithrombin activity, and D-dimer and protein C levels were measured, and Sequential Organ Failure Assessment was performed daily. Multiple logistic regression analysis identified baseline antithrombin activity <54% and changes in prothrombin time, D-dimer, and antithrombin activity during the first calendar day after the onset of the first sepsis-induced organ dysfunction (i.e., the first day of severe sepsis, day 1) as predictive of 28-day mortality (p < or = .01). A composite coagulopathy score was determined using points for predetermined levels of change from baseline to day 1. The composite coagulopathy score correlated with progression from single to multiple organ failure (p = .0007), time to resolution of organ failure (p = .0004), and 28-day mortality (p < .0001). Combining the composite coagulopathy score with the Acute Physiology and Chronic Health Evaluation (APACHE) II score improved ability to identify patients who would progress to multiple organ failure (area under receiver operating characteristic curve 0.61 APACHE II vs. 0.65 APACHE II + composite coagulopathy score) and who would die (area under receiver operating characteristic curve 0.69 APACHE II vs. 0.74 APACHE II + composite coagulopathy score). CONCLUSIONS: Continuation or worsening of coagulopathy during the first day of severe sepsis was associated with increased development of new organ failure and 28-day mortality. These results further suggest that coagulation abnormalities contribute to organ failure and death.     

Intravenous administration of ulinastatin (human urinary trypsin inhibitor) in severe sepsis: a multicenter randomized controlled study

Purpose

Ulinastatin, a serine protease inhibitor, inhibits several pro-inflammatory proteases and decreases inflammatory cytokine levels and mortality in experimental sepsis. We studied the effect of ulinastatin on 28-day all-cause mortality in a double-blind trial in patients with severe sepsis in seven Indian hospitals.

Methods

Patients with sepsis were randomized within 48 h of onset of one or more organ failures to receive intravenous administration of ulinastatin (200,000 IU) or placebo 12 hourly for 5 days.

Results

Of 122 randomized subjects, 114 completed the study (55 receiving ulinastatin, 59 receiving placebo). At baseline, the mean APACHE II score was 13.4 (SD = 4.4), 48 (42 %) patients were receiving mechanical ventilation, 58 (51 %) were on vasopressors, and 35 % had multiple organ failure. In the modified intention-to-treat analysis (patients receiving six or more doses of study drugs), 28-day all-cause mortality was 7.3 % with ulinastatin (4 deaths) versus 20.3 % (12 deaths) with placebo (p = 0.045). On multivariate analysis too, treatment with ulinastatin (odds ratio 0.26, 95 % CI 0.07–0.95; p = 0.042) independently decreased 28-day all-cause mortality. However, the mortality difference did not reach statistical significance in the intention-to-treat analysis [10.2 % (6/59 deaths) with ulinastatin versus 20.6 % (13/63 deaths) in the placebo group; p = 0.11]. The ulinastatin group had lower incidence of new-onset organ failure (10 vs. 26 patients, p = 0.003), more ventilator-free days (mean ± SD 19.4 ± 10.6 days vs. 10.2 ± 12.5 days, p = 0.019), and shorter hospital stay (11.8 ± 7.1 days vs. 24.2 ± 7.2 days, p < 0.001).

Conclusions

In this pilot study, intravenous administration of ulinastatin reduced mortality in patients with severe sepsis in the modified intention-to-treat analysis, but not in the intention-to-treat analysis.