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Treating medical and surgical patients with activated protein C: a preliminary comparison

Sepsis is a significant cause of morbidity and mortality in the critically ill patient. Drotrecogin alfa (activated) (APC) has been shown to significantly decrease mortality in patients with severe sepsis, although surgical patients constituted the minority in the initial multicenter trial. In our initial experience with APC, we sought to determine whether surgical intensive care unit (ICU) patients have the same rate of bleeding complications as medical ICU patients. We hypothesized that surgical patients are more apt to bleed following APC administration, but have higher survival rates than medical patients.

Methods

We performed a retrospective analysis of all medical and surgical patients in a single academic medical center who received APC for the treatment of sepsis between January 2002 and November 2002. Primary outcome variables included incidence of clinically significant bleeding, defined as blood loss requiring transfusion of at least 4 units of packed red cells (PRBC) during APC treatment, and 28-day mortality. Secondary outcomes included ICU length of stay (ILOS), hospital length of stay (LOS), completion of treatment course, and units of blood products transfused. Demographic data such as sex, age, severity of illness at the time of APC administration (APACHE II score), and primary site of infection at the time of sepsis diagnosis were obtained. Coagulation parameters were compared at three time points: within 24 hours of APC administration, during APC infusion, and within 24 hours of stopping APC. Hospital mortality following APC treatment was compared with baseline mortality for historically similar patients in our ICU matched 2:1 by age within 12 years, APACHE II score within 10 points and same site of infection.

Results

A total of 29 patients were treated with APC, 59% in the surgical ICU. Demographics and severity of illness were similar (Table 1). Prior to APC infusion, surgical patients were more coagulopathic and anemic, and had already received on average four times as many PRBC units than medical patients. Surgical patients also received more PRBC after APC infusion was started. All bleeding events occurred in surgical patients at surgical sites and two of the bleeds occurred in patients who received therapeutic heparin infusions as well as APC. However, no difference was demonstrated in the number of patients who completed APC therapy, LOS or mortality. For all patients, the mean partial thromboplastin time during APC infusion was higher than has been previously reported (99.4 medical vs 94.3 surgical, P = 0.7408), and there was an 84% increase in the mean PTT (52.4 ± 4.9 before vs 96.4 ± 7.5 during, P < 0.0001), as well as a 32% decrease in the mean platelet count during the APC administration (189.9 ± 24 vs 130.0 ± 16, P = 0.008), both of which normalized in the 24 hour period following cessation of APC. Mean maximum INR during APC infusion was 1.9 ± 0.2; after treatment, there was a 21% decrease to 1.5 ± 0.1 (P = 0.0025). In the case–control analysis, APC recipients had a similar age (61 ± 3.1 vs 60 ± 1.9, P = 0.83) and APACHE II score (31 ± 1.4 vs 29 ± 0.9, P = 0.37), but significantly lower mortality than matched controls (35% vs 66%, P = 0.0119).

Table 1

Conclusions

In this preliminary comparison of the open-label use of activated protein C in patients with severe sepsis, we witnessed a 30% reduction in overall hospital mortality compared with historical controls, and a substantial, but reversible, coagulopathy during APC infusion. Although the severity of illness and degree of coagulopathy were similar between medical and surgical patients, the only clinically significant bleeding complications were observed in the surgical cohort. This may be due to the unique features of surgical sepsis, with increased incidence of tissue barrier violation and blood loss anemia, or perhaps a reflection of the burden of blood product transfusion and greater tendency towards coagulopathy than thrombosis. Further studies should endeavor to define risk factors for bleeding among surgical patients and to determine whether interventions such as repletion of other coagulation factors, intermittent infusion of APC, or restriction of other anticoagulant therapies may be beneficial.

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Evans, H., Milburn, M., Calloway, T. et al. Treating medical and surgical patients with activated protein C: a preliminary comparison. Crit Care 7, P022 (2003). https://doi.org/10.1186/cc1911

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Keywords

  • Intensive Care Unit
  • Severe Sepsis
  • Intermittent Infusion
  • Drotrecogin Alfa
  • Intensive Care Unit Length