EVERE SEPSIS, A SYNDROME OF acute infection complicated by organ dysfunction, is caused by a dysregulated systemic inflammatory response. Sepsis can progress to systemic hypotension (septic shock), 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, Ϫ1.1; 95% CI, Ϫ5.3 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.

ART-123 is a safe intervention in critically ill patients with sepsis and suspected disseminated intravascular coagulation. The study provided evidence suggestive of efficacy supporting further development of this drug in sepsis-associated coagulopathy including disseminated intravascular coagulation. Future study should focus on using ART-123 in the subgroup of patients most likely to respond to this agent.

Objective To describe quality of life (QoL) among sepsis survivors. Design Secondary analyses of 2 international, randomized clinical trials (ACCESS [derivation cohort] and PROWESS-SHOCK [validation cohort]). Patients Adults with severe sepsis admitted to the intensive care unit. We analyzed only patients who were functional and living at home without help before sepsis hospitalization (n=1,143 and 987 from ACCESS and PROWESS-SHOCK). Measurements and Main Results In ACCESS and PROWESS-SHOCK, the average age of patients living at home independently was 63 and 61 years; 400 (34.9%) and 298 (30.2%) died by 6 months. In ACCESS, 580 patients had a QoL measured using EQ-5D at 6 months. Of these, 41.6% could not live independently (22.7% were home but required help, 5.1% were in nursing home or rehabilitation facilities, and 5.3% were in acute care hospitals). Poor QoL at 6 months, as evidenced by problems in mobility, usual activities, and self-care domains were reported in 37.4%, 43.7%, and 20.5%, respectively, and the high incidence of poor QoL was also seen in patients in PROWESS-SHOCK. Over 45%of patients with mobility and self-care problems at 6 months in ACCESS died or reported persistent problems at 1 year. Conclusions Among individuals enrolled in a clinical trial who lived independently prior to severe sepsis, one third had died and of those who survived, a further one third had not returned to independent living by 6 months. Both mortality and QoL should be considered when designing new interventions and considering endpoints for sepsis trials.

Solid organ transplant recipients are at risk for Pneumocystis carinii pneumonia (PCP), but the risk of PCP beyond 1 year is poorly defined. We identified 25 cases of PCP in 1,299 patients undergoing solid organ transplantation between 1987 and 1996 at The Cleveland Clinic Foundation (4.8 cases per 1,000 person transplant-years [PTY]). Ten (36%) of 28 PCP cases (transplantation was performed before 1987 in three cases) occurred > or = 1 year after transplantation, and no patient developed PCP while receiving prophylaxis for PCP. The incidence of PCP during the first year following transplantation was eight times higher than that during subsequent years. The highest rate occurred among lung transplant recipients (22 cases per 1,000 PTY), for whom the incidence did not decline beyond the first year of transplantation. We conclude that the incidence of PCP is highest during the first year after transplantation and differs by type of solid organ transplant. Extending the duration of PCP prophylaxis beyond 1 year may be warranted for lung transplant recipients.

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.