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Combined Biomarkers Predict Acute Mortality Among Critically Ill Patients With Suspected Sepsis*

Kelly, Brendan J., MD, MSCE1; Lautenbach, Ebbing, MD, MPH, MSCE1,2,3; Nachamkin, Irving, DrPH, MPH4; Coffin, Susan E., MD, MPH5,6; Gerber, Jeffrey S., MD, PhD, MSCE2,3,5,6; Fuchs, Barry D., MD, MS7; Garrigan, Charles, MB4; Han, Xiaoyan, MS1,2; Bilker, Warren B., PhD2,3; Wise, Jacqueleen, BS2; Tolomeo, Pam, MPH2; Han, Jennifer H., MD, MSCE1,2,3 for the Centers for Disease Control and Prevention (CDC) Prevention Epicenters Program

doi: 10.1097/CCM.0000000000003137
Clinical Investigations

Objectives: Sepsis is associated with high early and total in-hospital mortality. Despite recent revisions in the diagnostic criteria for sepsis that sought to improve predictive validity for mortality, it remains difficult to identify patients at greatest risk of death. We compared the utility of nine biomarkers to predict mortality in subjects with clinically suspected bacterial sepsis.

Design: Cohort study.

Setting: The medical and surgical ICUs at an academic medical center.

Subjects: We enrolled 139 subjects who met two or more systemic inflammatory response syndrome (systemic inflammatory response syndrome) criteria and received new broad-spectrum antibacterial therapy.

Interventions: We assayed nine biomarkers (α-2 macroglobulin, C-reactive protein, ferritin, fibrinogen, haptoglobin, procalcitonin, serum amyloid A, serum amyloid P, and tissue plasminogen activator) at onset of suspected sepsis and 24, 48, and 72 hours thereafter. We compared biomarkers between groups based on both 14-day and total in-hospital mortality and evaluated the predictive validity of single and paired biomarkers via area under the receiver operating characteristic curve.

Measurements and Main Results: Fourteen-day mortality was 12.9%, and total in-hospital mortality was 29.5%. Serum amyloid P was significantly lower (4/4 timepoints) and tissue plasminogen activator significantly higher (3/4 timepoints) in the 14-day mortality group, and the same pattern held for total in-hospital mortality (Wilcoxon p ≤ 0.046 for all timepoints). Serum amyloid P and tissue plasminogen activator demonstrated the best individual predictive performance for mortality, and combinations of biomarkers including serum amyloid P and tissue plasminogen activator achieved greater predictive performance (area under the receiver operating characteristic curve > 0.76 for 14-d and 0.74 for total mortality).

Conclusions: Combined biomarkers predict risk for 14-day and total mortality among subjects with suspected sepsis. Serum amyloid P and tissue plasminogen activator demonstrated the best discriminatory ability in this cohort.

1Division of Infectious Diseases, Department of Medicine, University of Pennsylvania, Philadelphia, PA

2Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA

3Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

4Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA

5Division of Infectious Diseases, Children’s Hospital of Philadelphia, Philadelphia, PA

6Center for Pediatric Clinical Effectiveness, Children’s Hospital of Philadelphia, Philadelphia, PA.

7Division of Pulmonary and Critical Care Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

*See also p. 1194.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Supported, in part, by the Centers for Disease Control and Prevention Healthcare-Associated Infection Prevention Epicenters Program (U54 CK000485), of which Dr. Lautenbach is the principal investigator. In addition, Drs. Kelly and Han were supported by career development awards from the National Institute of Allergy and Infectious Diseases (K23 AI121485 and K01 AI103028, respectively).

Drs. Kelly, X. Han, and J. H. Han received support for article research from the National Institutes of Health (NIH). Drs. Lautenbach and Nachamkin received support for article research from the Centers for Disease Control and Prevention (CDC). Dr. Coffin’s institution received funding from the CDC, NIH, and Agency for Healthcare Research and Quality, and she received funding from the Society for Healthcare Epidemiology of America/Infectious Diseases Society of America (participation on working group and medical legal consulting). Dr. Bilker’s institution received funding from the NIH, and he disclosed government work. The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: brendank@mail.med.upenn.edu

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