CLINICAL PROGRESS

The roles of tissue hypoxia, blood sugar control, corticosteroid administration, and the use
of aPC in clinical outcomes have been recently subjected to clinical trials. A recent study
by Rivers et al. (!" demonstrated improved survival #ith early restoration of oxygen
transport in septic patients. $trategies for increasing oxygen delivery are discussed in
Chapters % and &'. (an den )erghe et al. (%" studied the benefit of intensive control of
blood sugar in critically ill patients. *ith intensive control of blood sugar in a group of
primarily post+operative cardiac surgery patients, mortality #as improved. The mechanism
producing benefit is not clear. ,o#+dose corticosteroids #ere sho#n to reduce mortality
in highly selected patients. These findings suggest that adrenal insufficiency may
be a part of the organ failure syndrome. Perhaps, corticosteroids are vital for the
counter+inflammatory response ('". The importance of the coagulation cascade in producing
-$./ is suggested by the aPC trial. 0n a randomi1ed controlled trial, a survival
benefit #as observed in patients #ith sepsis #ho received aPC ('2".
FUTURE CONSIDERATIONS
)asic science research has made remar3able strides in determining the path#ays at
the cellular, protein, and gene levels, #hich regulate both the initial and the secondary
inflammatory responses to infection, toxin, or ischemia. $everal lines of investigation
are #or3ing their #ay to#ard clinical trials. 4o#ever, none of the organi1ing hypotheses
alone ade5uately explains the clinical phenomena observed in critically ill patients.
Rather, they are conceptual frame#or3s that serve #ell to organi1e research data at a
reductionist level, but, #hen applied to complex clinical situations, the shortcomings of
a single unifying hypothesis are stri3ingly apparent. .ne difficulty is the concept of
sepsis and -./ as a single disease entity. )y the !66!7!66% Consensus Conference criteria,
both an 89+year+old #ith fecal peritonitis and an 8+month+old #ith otitis media can
be said to have :sepsis; (<". $hould both be entered in the same clinical trial= >et clinical
trials in :sepsis; patients are by nature beset #ith extreme selection bias problems. 0dentification
of a statistically identifiable benefit hidden in a sea of patients #ho #ill get #ell
#ithout the intervention, and patients #ho #ill sic3en and die #ith or #ithout the intervention,
poses formidable difficulties. Clearly, identifying the appropriate patient population
for trials, as #ell as for each of the therapies #e already possess, #ill be essential to
improving care. A %99! conference re+examined the definitions of sepsis, and proposed
a model of categori1ing response to infectious challenge modeled on the T?- staging
system used by oncologists (<" and designated as the P0R. model. 0n this formulation,
P is patient disposition and reflects genetic susceptibility to infection and inflammation@
0 is infection and includes site, extent, and organism(s" responsible@ R is response and
5uantifies the characteristics of the patient response to infection (by measurement of
mediators and mar3ers of inflammation" both #ith regard to an expected time course
and extent based on population studies@ and . represents organ dysfunction. The hope
is to produce a hypothesis+generating schema by staging each patient #ith sepsis/-./
in a #ay that reflects the clinical picture seen daily in 0CAs, leads to more focused use
of current therapies, and produces better designed clinical trials. The difficulties #ith restaging
patients as they progress clinically and 3eeping the model from becoming too cumbersome
for useful application #ill be challenging, but as a first step in clearly defining
patient populations for clinical trials, the model is #orthy of a strong effort.