Goal 3: Advance Translational Research

TREATMENT OF SEPSIS-MULTIPLE ORGAN DYSFUNCTION SYNDROME (MODS) UTILIZING APHERESIS BASED STRATEGIES

Sepsis, a systemic inflammatory response to infection, is the most common cause of death in non-cardiac intensive care units. The incidence and severity of sepsis have increased over the last two decades. With advances in supportive care, sepsis carries a mortality that averages 17%, however, this figure increases to 50 - 80% in Multiple Organ Dysfunction Syndrome (MODS), defined as failure of 3 or more organ systems. Although apheresis based strategies have been studied in limited setting with some success (especially in the pediatric population) in sepsis/MODS,equipoise still remains in the application of this technology.

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Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Despite many attempts, therapeutic trials using pharmacologic agents to interrupt specific pathways of inflammation and coagulation have been unsuccessful. The failed targeted therapies include the administration of corticosteroids, monoclonal antibodies to TNF, soluble TNF receptor, antithrombin (AT), activated protein C, and tissue factor pathway inhibitor. Because it is non-selective, plasma exchange has the potential to remove deleterious mediators and restore anti-inflammatory/anticoagulant factors consumed in sepsis/MODS. There is evidence that some of the implicated mediators of sepsis can be effectively removed by plasma exchange, eg, TNF alpha and endotoxin. In addition, the normal regulatory molecules consumed during the systemic inflammatory process, such as AT, proteins C and S, and ADAMTS-13 would be replaced, which may influence the pathophysiology of MODS/sepsis. However, the mechanism of action of plasma exchange, whether removal of inflammatory mediators of sepsis or modulation of the later consequences of MODS such as sustained endothelial activation, remains unclear at the present time. Other apheresis based strategies also have been attempted but their results also require confirmation by well-designed clinical trials to answer the question of their value in treatment of sepsis.

Development of apheresis strategies which address the pathophysiology of sepsis and identify responsive patient populations would have a great societal value

Feasibility and challenges of addressing this CQ or CC :

Feasibility: the large number of patients who develop sepsis provides for significant number of potential patients who can be enrolled. More sophisticated methods of enrollment may help as many patients are not capable of providing informed consent. Establishing an apheresis consortium and collaboration with intensive care physicians will be an important step in assuring appropriate accrual of patients. The availability of apheresis devices is likely to be high in the tertiary/quaternary care medical centers where these studies can be performed. Animal models of sepsis are being investigated and are necessary for studies evaluating pathophysiology; though some apheresis strategies can be moved to clinical studies without additional preclinical developments.

 

Challenges: Identification of the patient population which responds optimally to apheresis based strategies is critical to the development of a randomized clinical trial. One study has indicated that it would be the critically ill pediatric population; however, the critically ill adult population is the largest affected group). Given the equipoise of using apheresis based strategies in the treatment of sepsis/MODS, finding patients to randomize is unlikely to be difficult. Other potential challenges include the cost of developing randomized clinical trials using apheresis, competition with other pharmacology based strategies, center bias, and the timing for initiation of the apheresis.

Name of idea submitter and other team members who worked on this idea : Zbigniew M. Szczepiorkowski; Joseph Kiss, Ed Wong on behalf of ASFA

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Idea No. 733