ª 2014 by the American College of Surgeon

Published by Elsevier Inc.

CRITICAL CARE II: CLINICAL STUDIES

Early Changes in Leukocyte Gene-Expression UnderlieIncreased Mortality Associated with Burn Size but NotAge or Inhalation InjuryRavi Sood, MD, Nicole S Gibran, MD, FACS,Brett D Arnoldo, MD, FACS, Richard L Gamelli, MD, FACS,Ronald G Tompkins, MD, FACS, David N Herndon, MD, FACSHarborview Medical Center/University of Washington,Seattle, WA

INTRODUCTION: Increased age, inhalation injury, and high

percent total-body-surface-area (TBSA) burned are established riskfactors for mortality after burn injury, which is known to induce amassive inflammatory response. We hypothesized that these factors

would be associated with early changes in peripheral-leukocytegene expression.

METHODS: Adults (age�18 years) with�20%TBSA burned wereprospectively enrolled at five US burn centers from 2003e2009.Blood was drawn within one week post-burn and RNAwas extractedfrom pooled leukocytes for hybridization onto Affymetrix HU133

Plus 2.0 GeneChips. A multivariate regression model was con-structed to determine risk factors for mortality. Differential geneexpression was measured between groups differing in one risk factor

and matched on the others.

RESULTS: Of 324 subjects (median age 41; median TBSA burned

36%), 242 (75%) were male, 127 (39%) had inhalation injury, and64 (20%) died; 112 (35%) provided samples for microarray anal-ysis. Age �60 y (RR 3.6), TBSA burned �40% (RR 3.8), and

inhalation injury (RR 2.1) were significantly associated with mor-tality (p < 0.01). No differentially expressed genes were associatedwith age �60 y or inhalation injury using a fold-change threshold

of 1.5 and false-discovery rate of 0.05. In contrast, 71 genes weredifferentially expressed in association with �40% TBSA. Thesegenes represent diverse functions including inflammation, cell-cellinteractions, immunity, and metabolism.

CONCLUSIONS: Burn size �40% TBSA is associated with analtered early peripheral-leukocyte gene-expression profile that is

associated with increased mortality. Understanding the functionalconsequences of this genomic response may lead to novel therapiesthat improve survival after large burns.

Gene Expression Can Robustly Separate Infectious andNon-Infectious InflammationTimothy E Sweeney, MD, PhD, Purvesh Khatri, PhDStanford University, Palo Alto, CA

INTRODUCTION: Sepsis is difficult to distinguish from non-infec-

tious inflammation such as trauma or SIRS. Gene expression hasbeen widely used to study SIRS, sepsis, and trauma, but largelywithout producing any useful clinical diagnostic tools.

METHODS: We carried out integratedmeta-analysis of 13 indepen-dent clinical gene expression cohorts (n¼1,206) from the NCBI

GEO andGlueGrant databases. After rank normalization, 6 datasets(531 samples) were used as the discovery cohort to identify

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differentially expressed genes in sepsis compared to non-infectedSIRS or trauma patients. We applied two meta-analysis methods;

one combines effect sizes using Hedges’ g; the other uses Fisher’ssum of logs method combining p values. We applied leave-one-study-out validation to minimize contribution from any single test

set. The geometric mean of ranks for the resulting differentiallyexpressed genes was then taken for each sample as its ‘infection score’.The gene signature was validated in 7 additional datasets (675 sam-

ples) and evaluated with area under the ROC curve (AUROC).

RESULTS: We identified 15 differentially expressed genes in(FDR �0.2), across multiple different patient populations and

clinical conditions. The score was effective in differentiating sepsisfrom SIRS or trauma in the discovery datasets (AUROC 0.63-0.95) but less effective in the validation datasets (AUROC 0.54-0.73). The infection score was not associated with sex, infection

source, or infecting pathogen type.

CONCLUSIONS: We have derived a small subset of genes that candifferentiate between sepsis and non-infectious inflammation such

as SIRS or trauma. The subset of sepsis patients with low infectionscores may represent the ‘CARS’ phenotype.

Performance Improvement with CurrentThromboprophylaxis Strategies Does Not ReducePulmonary Embolism in Trauma PatientsMatthew J Pommerening, MD, Hudson H Seidel, BS,Bryan A Cotton, MD, MPH, FACS, Charles E Wade, PhD,John B Holcomb, MD, FACSUniversity of Texas Medical School at Houston, Houston, TX

INTRODUCTION: Pulmonary embolism (PE) is a significant source

of morbidity and mortality after traumatic injury. In 01/2009, weimplemented a performance improvement (PI) process to improvethromboprophylaxis in our trauma population in an effort to reduce

PE. This included several sequential interventions, including auditsfor missed doses, earlier and more aggressive chemical prophylaxis,and placement of prophylactic IVC filters in high-risk patients.

METHODS: We retrospectively reviewed adult trauma patientsadmitted to a Level 1 trauma center over a 6-year period. Patientsadmitted in 2006-2008 (Pre-PI) were compared to those admittedin 2009-2011 (Post-PI) after implementation of the PI process.

Purposeful logistic regression was used to compare PE rates beforeand after PI implementation.

RESULTS: Of 23,863 trauma admissions during the study period,

12,571(53%) were Post-PI. After implementation of the PI process,time to first prophylaxis (47 vs 105 hours; p<0.001) and proportionof patients with missed doses (8% vs 46%; p<0.001) were signifi-

cantly reduced. On multivariate analysis, implementation of PI wasnot associated with a significant reduction in all PE (OR 1.04;95%CI 0.80-1.34) or central PE in the pulmonary artery (p>0.05).

CONCLUSIONS: Implementation of a PI process resulted in areduction in time to prophylaxis and number of missed doses,

http://dx.doi.org/10.1016/j.jamcollsurg.2014.07.095

ISSN 1072-7515/14