Anti-cytokine and anti-inflammatory therapies for the treatment of severe sepsis: progress and pitfalls

Abstract

The medical care of patients with sepsis or severe inflammatory response syndromes has seen tremendous technological advancements in recent years; yet, several clinical studies with anti-cytokine therapies targetted to this population have met with disappointing results. Four primary factors have been identified that represent potential pitfalls involving the use of biological response modifiers in critically-ill patients. First, the physiological response in the stressed patient is complex. Redundancy within this system may not allow a single intervention to produce a clinical response. Second, the critically-ill patient population is heterogenous and important factors including the age of the patient, associated co-morbidities, the nature of the original injury and the presence or absence of an ongoing injury can modulate the effectiveness of a specific therapy. Third, the timing of the therapeutic intervention can be difficult to standardize among patients and can often produce differing results. A greater understanding of the physiological response to injury has shown that there are both proinflammatory and anti-inflammatory processes ongoing simultaneously. Determining the optimal time to intervene within this framework can be problematic. Fourth, the presence of genetic polymorphisms within the general population has identified subsets of individuals who may have different physiological responses to similar stresses. The relative proportions of patients with these polymorphisms within clinical trials may affect outcome and data analysis. Thus, a better understanding of these issues will result in improvement of the experimental design of clinical trials involving anti-cytokine therapies and critically-ill patients. Avoidance of these pitfalls will enhance the quality and utility of outcomes research in this subset of patients.