Sepsis: A New Hypothesis for Pathogenesis of the Disease Process

The history of therapeutic interventions in clinical trials for sepsis has been referred to as the "graveyard for pharmaceutical companies." That is now set to change, as research provides hope for new approaches that will be therapeutically effective in humans with sepsis.

Novel strategies for the treatment of sepsis

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Acute lung injury and the acute respiratory distress syndrome: a clinical review

Our current understanding of sepsis and multiple organ dysfunction needs to be revised, as the uniformly negative results of new therapies for these disorders suggest. Previous theories for the pathogenesis of these conditions are incomplete; reasons for this include the following. First, the surrogate models that have been used to study these disorders are not analogous to the clinical situation. Second, patients who have less severe manifestations of these diseases are often overlooked. And third, patients' preexisting conditions have not been taken into account. Considerable new evidence indicates that, in addition to a massive proinflammatory reaction, a compensatory anti-inflammatory response contributes to the onset of these disorders. At a local site of injury or infection and during the initial appearance of pro- and anti-inflammatory mediators in the circulation, the beneficial effects of these mediators outweigh their harmful effects. Only when the balance between these two forces is lost do these mediators become harmful. Sequelae of an unbalanced systemic proinflammatory reaction include shock, transudation into organs, and defects in coagulation. An unbalanced systemic compensatory anti-inflammatory response can result in anergy and immunosuppression. The proinflammatory and anti-inflammatory forces may ultimately reinforce each other, creating a state of increasingly destructive immunologic dissonance.

Immunologic dissonance: a continuing evolution in our understanding of the systemic inflammatory response syndrome (SIRS) and the multiple organ dysfunction syndrome (MODS)

Rationale: It is commonly stated that mortality from acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) is decreasing.Objectives: To systematically review the literature assessing ARDS mortality over time and to determine patient- and study-level factors independently associated with mortality.Methods: We searched multiple databases (MEDLINE, EMBASE, CINAHL, Cochrane CENTRAL) for prospective observational studies or randomized controlled trials (RCTs) published during the period 1984 to 2006 that enrolled 50 or more patients with ALI/ARDS and reported mortality. We pooled mortality estimates using random-effects meta-analysis and examined mortality trends before and after 1994 (when a consensus definition of ALI/ARDS was published) and factors associated with mortality using meta-regression models.Measurements and Main Results: Of 4,966 studies, 89 met inclusion criteria (53 observational, 36 RCTs). There was a total of 18,900 patients (mean age 51.6 years; 39% female). Overall pooled ...

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Has mortality from acute respiratory distress syndrome decreased over time?: A systematic review.

ObjectiveTo evaluate the safety and efficacy of E5, a murine, monoclonal antibody directed against endotoxin, in the treatment of patients with Gram-negative sepsis.DesignA multicenter, randomized, double-blind, placebo-controlled trial.SettingFifty-three hospitals across the United States, includin

A second large controlled clinical study of E5, a monoclonal antibody to endotoxin: Results of a prospective, multicenter, randomized, controlled trial

Objective. —To evaluate the safety and potential efficacy of aerosolized surfactant in intubated patients with adult respiratory distress syndrome (ARDS). Design. —A prospective, double-blind, placebo-controlled, randomized, parallel, mutlicenter pilot clinical trial. Patients. —A total of 51 patients with sepsis-induced ARDS were entered into the study within 18 hours of developing sepsis or sepsis syndrome. Intervention. —Patients were randomized into four treatment groups in a 2:1:2:1 ratio, as follows: 12 hours of surfactant per day, 12 hours of 0.6% saline per day, 24 hours of surfactant per day, and 24 hours of 0.6% saline per day. Surfactant or saline was aerosolized continuously for up to 5 days using an in-line nebulizer that aerosolized only during inspiration. Main Outcome Measures. —Ventilatory data, arterial blood gases, and hemodynamic parameters were measured at baseline, every 4 or 8 hours during the 5 days of treatment, 24 hours after treatment, and 30 days after treatment, at which time mortality was also assessed. Safety was evaluated throughout the 30 days of the study. Results. —Surfactant was administered safely in ventilated patients when given continuously throughout the 5 days using the nebulizer system. Although there were no differences in any physiological parameter between the treatment groups, there was a dose-dependent trend in reduction of mortality from 47% in the combined placebo group to 41% and 35% in the groups treated with 12 hours and 24 hours of surfactant per day, respectively. Conclusions. —Aerosolized surfactant was well tolerated when administered on a continuous basis for up to 5 days; however, at the doses given, it did not result in significant improvements in patients with sepsis-induced ARDS. (JAMA. 1994;272:1433-1438)

H. David Reines

Papers

A second large controlled clinical study of E5, a monoclonal antibody to endotoxin: Results of a prospective, multicenter, randomized, controlled trial

Safety and potential efficacy of an aerosolized surfactant in human sepsis-induced adult respiratory distress syndrome.