Combined biomarkers discriminate a low likelihood of bacterial infection among surgical intensive care unit patients with suspected sepsis

Abstract

Among surgical intensive care unit (SICU) patients, it is difficult to distinguish bacterial sepsis from other causes of systemic inflammatory response syndrome (SIRS). Biomarkers have proven useful to identify the presence of bacterial infection. We enrolled a prospective cohort of 69 SICU patients with suspected sepsis and assayed the concentrations of 9 biomarkers (α-2 macroglobulin [A2M], C-reactive protein, ferritin, fibrinogen, haptoglobin, procalcitonin [PCT], serum amyloid A, serum amyloid P, and tissue plasminogen activator) at baseline, 24, 48, and 72 hours. Forty-two patients (61%) had bacterial sepsis by chart review. A2M concentrations were significantly lower, and PCT concentrations were significantly higher in subjects with bacterial sepsis at 3 of 4 time points. Using optimal cutoff values, the combination of baseline A2M and 72-hour PCT achieved a negative predictive value of 75% (95% confidence interval, 54–96%). The combination of A2M and PCT discriminated bacterial sepsis from other SIRS among SICU patients with suspected sepsis.

Introduction

It is difficult to distinguish bacterial sepsis from other causes of systemic inflammatory response syndrome (SIRS) in critically ill patients. The presence of 2 or more SIRS criteria with suspected infection has become the standard for sepsis diagnosis (ARISE Investigators et al., 2014, COIITSS Study Investigators et al., 2010, Holst et al., 2014, Mouncey et al., 1992, Opal et al., 2013, Perner et al., 2012, Ranieri et al., 2012, Sprung et al., 2008). However, the SIRS criteria have been criticized for lacking specificity for infection (Levy et al., 2003, Liao et al., 2014, Sprung et al., 2006, Vincent, 1997, Vincent et al., 2013). Given the morbidity and mortality associated with bacterial sepsis as well as evidence that early antibiotic therapy improves mortality in severe sepsis, guidelines recommend that empiric, broad-spectrum antibacterial agents be administered to patients who meet the 2-SIRS-criteria standard (Kaukonen et al., 2015, Brun-Buisson et al., 2004, Gaieski et al., 2010, Gaieski et al., 2013, Dellinger et al., 2013, Ferrer et al., 2014). The poor specificity of the SIRS criteria may thus contribute to excess use of broad, empiric antibiotics.

Surgical intensive care unit (SICU) patients, in particular, represent a population in whom SIRS criteria may demonstrate poor specificity for bacterial infection. The incidence of SIRS in the SICU exceeds the incidence in medical and cardiovascular intensive care units (ICUs). Prior studies have shown that greater than 90% of SICU patients meet SIRS criteria during their ICU stay (Pittet et al., 1995, Sigfrido Rangel-Frausto et al., 1995). The SICU has a higher proportion of culture-negative SIRS and sepsis than do medical or cardiovascular ICUs (Sigfrido Rangel-Frausto et al., 1995, Andersson and Tracey, 2011, Vincent et al., 2013).

Biomarkers have proven to be useful tools to distinguish the presence or absence of bacterial infection in specific patient populations. Procalcitonin (PCT) in particular has shown promise as a component of diagnostic and antibiotic stewardship strategies for respiratory tract infection and sepsis (Assicot et al., 1993, Schuetz et al., 2009, Schuetz et al., 2012a, Schuetz et al., 2012b, Schuetz et al., 2013, Christ-Crain et al., 2004, Simon et al., 2004, Uzzan et al., 2006, Tang et al., 2007, Nobre et al., 2008). A combination of biomarkers may be even more useful than a single biomarker by increasing specificity for infection and improving the ability to discriminate true bacterial sepsis from other causes of SIRS (Meisner et al., 1999, Harbarth et al., 2001, Castelli et al., 2004). To date, studies of biomarkers in sepsis have been limited in the number of biomarker combinations evaluated, and few studies have restricted analysis to SICU patients, a population in whom bacterial sepsis may be more difficult to discriminate (Hensel et al., 1998, Meisner et al., 1998, Uzzan et al., 2006, Castelli et al., 2009, Prkno et al., 2013, Wacker et al., 2013). The identification of SICU patients in whom antibacterial therapy can be safely stopped has the potential to aid antibiotic stewardship efforts, avoid adverse drug effects, and combat the evolution of drug-resistant pathogens (Fishman, 2006, Dellit et al., 2007, Roberts et al., 2009, Luyt et al., 2014). We designed this study in companion with a study of biomarker performance in medical ICU (MICU) patients with suspected sepsis (Han et al., 2015), with the hypothesis that optimal biomarker combinations and cutoffs may be specific to the SICU population.

We sought to systematically evaluate the ability of 9 biomarkers, individually and in combination, to distinguish bacterial sepsis from other causes of SIRS in SICU patients. We further sought to define optimal biomarker cutoffs and sampling times to identify SICU patients with a low likelihood of bacterial infection.