Mediator modulation therapy of severe sepsis and septic shock: does it work?

F or years, pivotal multiplecenter clinical trials in sepsis have attempted to demonstrate that various innovative therapies, new products, or products that are not currently used for that purpose could improve outcome in severe sepsis. Most of these products have been mediators, modulators, or inhibitors. What is a pivotal trial? For industry, it is a trial that is designed such that if it is positive, it will exert favorable influence toward federal agency approval. Nonindustry pivotal trials are designed such that a positive outcome would influence physicians to use the drug in that clinical situation. Table 1 lists 23 clinical trials ( 17,000 patients) that have studied innovative therapy in severe sepsis and septic shock and which we would classify as pivotal. The table ends with the trial of the nonselective nitric oxide (NO) inhibitor Nmethyl-L-arginine hydrochloride (LNMMA), which is published in this issue of Critical Care Medicine (1). Publication of these important trials provides an opportunity to look back and evaluate both the substance and the process of conducting pivotal trials. We will attempt to address the issue of whether the methodology has been effective and what lessons have been learned. It all began with steroids. Some earlier trials addressed the issue of steroids in sepsis, but these were small, singlecenter, or not classically randomized. The first pivotal multiple-center trials in severe sepsis (sepsis syndrome) were published in 1987 and tested steroid therapy (2, 3). Since that time, although target population selection and terminology have varied somewhat (sepsis, sepsis syndrome, or more recently, severe sepsis), the overwhelming majority of the trials have targeted infection-induced organ/ system dysfunction, tissue hypoperfusion, or shock that puts the patient at significant risk for morbidity and mortality. The first studies published included from 200 to 400 patients and were considered large at the time. What a difference 16 yrs makes, with many current trials designed for agency approval targeting 2,000 or more patients. Although the 1987 high-dose, short-duration, steroid trials were not successful, more recently, lower-dose, stress-range steroids seem to be beneficial in septic shock (4). After the steroid trials and as investigation moved into the early 1990s, excitement was generated around endotoxin blockade, with trials of both mouse monoclonal antibody and humanized antibody against endotoxin (5–8). In the end, the two compounds tested were judged not to be effective. Although the humanized antibody suggested benefit in a multiple-center prospective study of Gram-negative bacteremic patients, a second larger trial showed no benefit (5, 6). A post hoc analysis in this second trial for the first time raised questions of harm of an innovative therapy, in this case, use of an antibody against Gram-negative endotoxin in the Gram-positive–infected patients. Interest in anti-endotoxin therapy has continued, with additional negative trials (9, 10), and today, activity continues, with two compounds, one a neutralizing lipid emulsion and the other a competitive receptor blocker, in the clinical study pipeline (11, 12). Why this continued interest? Because it is accepted that endotoxemia predicts a poor prognosis, and endotoxemia is clearly linked to organ dysfunction and mortality. The next era of innovative therapy featured compounds directed at neutralization of tumor necrosis factor (TNF), with these studies persisting to the turn of the century and beyond. TNF continues to be regarded as the single most potent proinflammatory cytokine. Both monoclonal antibody against TNF and soluble TNF receptors have been studied (13–18). Trials were getting bigger and the concept of post hoc analysis of large studies to identify subgroups for subsequent large studies was born. Unfortunately, this method did not lead to successful trials (15, 19). P75 TNF receptor fusion protein became the first compound to clearly demonstrate harm to septic patients in a clinical trial (16). Interestingly, this anti-TNF compound has now been shown to be clinically beneficial and is approved by the Food and Drug Administration (FDA) for treating rheumatoid arthritis (20, 21). The 2003 Physicians Desk Reference does, however, state, “not to be administered in patients with sepsis. ” A second anti-TNF compound, infliximab (antiTNF antibody), abandoned in phase II sepsis trials, is also approved for treating chronic inflammation in both rheumatoid arthritis and Crohn’s disease (22, 23). A “risk of infection” warning is listed in the prescribing information for this compound. In addition, despite two large negative trials in severe sepsis, interleukin-1 receptor antagonist, when delivered by an alternative delivery route (subcutaneous), is now FDA approved for treatment of rheumatoid arthritis (19, 24, 25). Therefore, of all the innovative therapy drugs that were initially studied in severe sepsis, three have become FDA approved for rheumatoid arthritis but only one for severe sepsis (26). Despite the failure of individual studies, a meta-analysis of anti-TNF therapy in severe sepsis (excluding the P75 receptor study) suggests a small but consistent reduction in mortality of approximately 3% (27). Throughout this period, other trials targeting various inflammatory mediators such as bradykinin, platelet activating factor, and prostaglandins were also unsuccessful (28–30). The most recent trials have targeted antithrombotic therapy, with antithrombin and tissue factor pathway inhibitor trials being unsuccessful (31, 32). However, the first large multiple-center trial *See also pp. 1, 13, and 21.