Background: The efficacy of therapy with drotrecogin alfa (activated) (DrotAA) (recombinant
human activated protein C) for surgical patients with severe sepsis has been questioned, and
there is concern that patients who have undergone surgery recently may be at increased risk
of bleeding complications from the drug. This review was performed to analyze recent data
and clinical trends in the management of surgical patients with severe sepsis with respect to
the efficacy and safety of therapy with DrotAA.
Methods: Review and synthesis of the pertinent English-language literature.
Results: Source control is the mainstay of therapy for surgical infections, including intraabdominal
infections, whereas antibiotics, fluid resuscitation, and support of visceral organ
function are necessary adjuncts. Therapy with DrotAA can be given to surgical patients, albeit
with some delay (most protocols specify a 12-h wait after major surgery to mitigate the
perceived increased risk of bleeding), but efficacy as well as safety have been questioned. In
the pivotal PROWESS clinical trial, DrotAA therapy did not appear to be efficacious for surgical
sepsis, but rigorous scrutiny of surgical indications and adequacy of source control by
blinded reappraisal of the PROWESS database suggested that DrotAA therapy may be effective
for surgical patients at high risk of death (Acute Physiology and Chronic Health Evaluation
[APACHE] II score ≥25 points). Several comparable studies have now been aggregated
in the INDEPTH database, which shows a significant reduction in mortality (OR 0.66; 95%
CI 0.45–0.97) for therapy with DrotAA of surgical patients with severe sepsis and a high risk
of death. The risk of bleeding is higher in surgical patients compared with DrotAA-treated
non-surgical patients, but there is a substantial improvement in survival with DrotAA treatment.
In contrast, surgical patients at a lower risk of death do not benefit from therapy with
DrotAA but are placed at risk for bleeding.
Conclusion: Accumulating experience indicates that surgical patients with severe sepsis and
a high risk of death (APACHE II ≥25 points) have a significantly lower mortality rate if treated
with DrotAA. The increased risk of bleeding associated with therapy is acceptable given the
clear improvement in survival. Surgical patients with sepsis who are at lower risk of death
do not appear to benefit from therapy with DrotAA, which should be withheld in most circumstances
because of the increased risk of bleeding.
