Static and dynamic assessment of biomarkers in surgical patients with severe sepsis.
BACKGROUND
Severe sepsis, defined as a systemic inflammatory response to infection associated with acute organ dysfunction, is common among surgical patients and is a major cause of morbidity and mortality. Severe sepsis has been associated with changes in inflammatory and hemostatic biomarkers. In patients undergoing surgical procedures there may be additional stimulation of cytokine release and activation of the coagulation system. The purpose of this study was to characterize the baseline differences in biomarkers between surgical and non-surgical patients. In addition, we assessed the dynamic changes in biomarkers and coagulation parameters in surgical patients with severe sepsis enrolled in PROWESS and treated with placebo or drotrecogin alfa (activated).


METHODS
A blinded PROWESS surgical evaluation committee (SEC) verified patients as having undergone a relevant operative procedure within 30 days of enrollment for inclusion in the surgical cohort of PROWESS. At baseline and on study days 1-7, biomarkers and coagulation parameters available for analysis were D-dimer, interleukin-6 (IL-6), protein C activity, protein S activity, anti-thrombin III (ATIII), activated partial thromboplastin time (aPTT), and prothrombin time (PT). Platelet count was determined at baseline only. Baseline values were compared between SEC-defined surgical and all other non-surgical patients, and between pre- and post-operative surgical patients from the PROWESS trial. Changes from baseline were compared between drotrecogin alfa (activated)-treated and placebo-treated surgical patients. Statistical analyses were performed using ANOVA on the ranked values.


RESULTS
The SEC verified 474 (28%) of the 1,690 PROWESS patients as surgical. Median D-dimer, IL-6, aPTT and PT values were significantly higher at baseline for surgical patients than non-surgical patients (p < 0.001). Surgical patients had significantly lower median protein C, protein S, and ATIII activity at baseline than non-surgical patients (p < 0.001). Surgical patients treated with drotrecogin alfa (activated) showed a significant decrease in D-dimer levels on study days 1-5 (p < 0.05), and a more rapid increase in Protein C levels on study days 1-4 (p < 0.05) compared to placebo.


CONCLUSIONS
Surgical patients with severe sepsis appear to have a higher severity of illness at baseline as demonstrated by derangements in biomarkers and coagulation markers compared to non-surgical patients. Surgical patients treated with drotrecogin alfa (activated)showed reduced D-dimer concentrations and a more rapid increase in protein C concentrations during the infusion period.
Lowry
Stephen F
SF
Robert Wood Johnson Medical Center, New Brunswick, New Jersey, USA.
Awad
Samir
S
Ford
Henri
H
Cheadle
William
W
Williams
Mark D
MD
Qualy
Rebecca L
RL
McCollam
Jill Shwed
JS
Bates
Becky M
BM
Fry
Donald E
DE
D018806:APACHE; D000704:Analysis of Variance; D015415:Biomarkers / Q000032:analysis*; D002097:C-Reactive Protein / Q000032:analysis; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D006801:Humans; D007378:Interleukins / Q000032:analysis; D008297:Male; D010314:Partial Thromboplastin Time; D011336:Probability; D011379:Prognosis; D011486:Protein C / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000627:therapeutic use; D012016:Reference Values; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D018805:Sepsis / Q000175:diagnosis* / Q000188:drug therapy / Q000401:mortality*; D012720:Severity of Illness Index; D013514:Surgical Procedures, Operative / Q000009:adverse effects* / Q000379:methods; D013530:Surgical Wound Infection / Q000175:diagnosis* / Q000401:mortality; D016019:Survival Analysis
D015415:Biomarkers; D005338:Fibrin Fibrinogen Degradation Products; D007378:Interleukins; D011486:Protein C; D011994:Recombinant Proteins; C036309:fibrin fragment D; D002097:C-Reactive Protein; C421124:drotrecogin alfa activated