Abstract:

INTRODUCTION Why Have Clinical Trials of Sepsis Been Unsuccessful? It is disconcerting that entering the third millennium, severe microbial infections and their sequelae e.g., sep- sis, septic shock, ARDS, “flesh-eating syndromes,” still claim the lives of numerous patients annually. Further- more, it is of great interest that while immunomodu- lating agents have proved beneficial in the treatment of inflammatory conditions such as rheumatoid arthri- tis, a large series of clinical trials which have been con- ducted in the last decade and which have mainly tested only single immunomodulating agents as therapies for septic shock, have been mostly unsuccessful. In 1996, Verhoef et al. (1) have stated that reviewing the liter- ature on sepsis therapies “the area of immunomodula- tion has now become an area of more realism and the results of early trials have forced investigators to go back to the drawing board to re-investigate the whole con- cept of immunotherapy and immunoprophylaxis. In a more recent Point of View in Critical Care Medicine, entitled “Sepsis research: We must change course,” Dr. Nasraway has hit the nail on its head (2). Reviewing the disappointing results of no less than 29 prospec- tive controlled studies of human sepsis performed in the last decade, he has questioned whether “it is rational to attempt to alter the inflammatory responses by admin- istering a single immunomodulating agent while simul- taneously failing to control for the many interventions that also alter cytokine expression?” He has also raised serious doubts about the morality of any future trials of sepsis if conducted in the present manner. Baue (3), Opal and Yu (4), Cross et al. (5), Teplick and Ruben (6) and Abraham (7), have recently assessed the state of the art in sepsis research prevention and treatment, the reasons why the trials of sepsis have invariably failed to prolong the lives of septic patients, the hazards involved in the future use of multidrug strategies in sepsis, and the con- tributions of animal models to the development effec- tive therapeutic regimens in humans. Reading through the extensive literature on sepsis research and treatment, it was surprising to realize that no less than 35 different anti-inflammatory agents and strategies have been rec- ommended, usually singly, to cope with post-infectious sequelae (in 1–13). It is however important to stress that, at the bedside, anti-inflammatory agents are too often administered to patients when the deleterious pathophys- iological cascades leading to septic shock and organ fail- ure have already been irreversibly initiated. Therefore, one cannot avoid assuming that the recommendations to test only one antagonist, at time, to suppress the patho- physiological cascades in sepsis and septic shock, might have been unrealistic to begin with and also erroneous. Presumably, these have been based on the concept that there might exist a single “omnipotent” pro-inflamma- tory agonist generated following microbial invasions of the blood stream, which is efficiently neutralized, on time, might inhibit the multiple pathophysiological cas- cades responsible for the sepsis syndrome. Also, the use of multidrug strategies (4, 5, 8, 13) has been ham- pered by reports warning against the hazards of combi- nation therapies in sepsis (4, 5, 16). Is it possible that, today, sepsis research has reached a dead end because of “flawed concept or faulty implementation?” (5). Results from animal models have clearly indicated that the inhibition of septic shock induced either by endotoxin (LPS), lipoteichoic acid (LTA), peptidogly- can (PPG) or by viable microbial cells, has been mostly successful only if the anti-inflammatory agent has been administered prior to microbial challenge. This strongly suggests that the main obstacle facing clinicians at the bedside is that once sepsis symptoms have appeared, it might already be too late to effectively prevent the pathophysiological cascades leading to tissue damage and organ failure. Therefore, strategies to prevent sep- tic shock and of additional post-infectious sequelae in humans should inonvolve distinct preventive measures especially in defined groups of high-risk patients (3–13).