OBJECTIVE - To evaluate new treatments directed against
endotoxin,
tumor necrosis factor alpha, and
interleukin 1 for use in
sepsis and related disorders (
sepsis syndrome and
septic shock). DATA SOURCES - Investigations of these treatments in animal models, healthy human volunteers, and patients with
sepsis and related disorders. STUDY SELECTION - Particular attention was paid to studies of patients with
sepsis and related disorders, especially randomized, double-blind, controlled trials. DATA EXTRACTION - Animal studies and investigations with human volunteers were judged by how closely the experimental model replicated the clinical disorder (
sepsis). Patient trials were assessed by sample size and design. Results of all studies were used to evaluate the likelihood that a given treatment would reduce mortality. DATA SYNTHESIS - Direct comparison of E5 and HA-1A antibody studies is difficult because of differences in their design, definitions of
shock, and methods of subgroup analysis. However, both
antibodies improve outcome in some subgroups: E5 benefits patients with gram-negative
infection (bacteremic or focal) who do not have refractory
shock, and HA-1A benefits those with gram-negative
bacteremia (regardless of whether
shock is present) but not those with focal gram-negative
infection. Two agents that may be beneficial in gram-positive and gram-negative
infection are
monoclonal antibodies to
tumor necrosis factor alpha and receptor antagonists to
interleukin 1. Preliminary results with both are reviewed. CONCLUSIONS - All three types of treatment may improve outcome in
sepsis. The best results will probably be obtained with combination
therapy that interrupts multiple points of the inflammatory cascade underlying
sepsis.