Mechanistic
research in patients with established sepsis has failed
to overcome several key methodological limitations.
Eliminating confounding factors from case–control
study design in established sepsis is challenging, if
not impossible. Age,6 gender,7,8 ethnicity9 and comorbidity
10,11 all profoundly alter normal physiological
function. Therapeutic agents commonly used to
treat sepsis, including antibiotics,12,13 sedatives14 and
steroids,15 all exert off-target immunologic and metabolic
effects. These factors alter multi-organ function
and therefore confound the biological and clinical
interpretation of experimental readouts being attributed
to sepsis syndrome per se. However, the default
control population for critical illness studies using
case–control methodology has typically been healthy
volunteers. By contrast, elucidating mechanisms