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Objectives: Early diagnosis of infections is pivotal in critically ill patients. Innovative gene expression-based approaches promise to deliver precise, fast, and clinically practicable diagnostic tools to bedside. This study aimed to validate the SepsisMetaScore, an 11-gene signature previously reported by our study group, in a representative longitudinal cohort of trauma patients., Design: Prospective observational cohort study., Setting: Surgical ICUs of the University Medical Center Goettingen, Germany., Patients: Critically ill patients with severe traumatic injuries., Interventions: None., Measurements and Main Results: Paired box gene (PAXgene) RNA blood tubes were drawn at predefined time points over the course of disease. The performance of the SepsisMetaScore was tested using targeted polymerase chain reaction and compared with Procalcitonin using area under the receiver operating characteristics analyses. The SepsisMetaScore showed significant differences between infected and noninfected patients (n = 52). It was able to accurately discriminate infectious from noninfectious acute inflammation with an area under the receiver operating characteristics of 0.92 (95% CI, 0.85-0.99) and significantly outperformed Procalcitonin (area under the receiver operating characteristics curve = 0.53; 95% CI, 0.42-0.64) early in the course of infection (p = 0.014)., Conclusions: We demonstrated the clinical utility for diagnosis of infections with higher accuracy using the SepsisMetaScore compared with Procalcitonin in a prospective cohort of severe trauma patients. Future studies should assess whether the SepsisMetaScore may substantially improve clinical practice by accurate differentiation of infections from sterile inflammation and identification of patients at risk for sepsis. Our results support further investigation of the SepsisMetaScore for the development of tailored precision treatment of critically ill patients., Competing Interests: Drs. Thair and Sweeney are employees of, and shareholders in, Inflammatix, Inc. Drs. Thair, Sweeney, and Khatri received funding from Inflammatix, Inc, Burlingame, CA. Inflammatix is developing the SepsisMetaScore as part of a broader test for commercial use (HostDx-Sepsis; Inflammatix). Dr. Quintel also received funding from Xenies/Fresenius, B.Braun, and Baxter. Dr. Khatri is a shareholder in and a consultant to Inflammatix; he is funded, in part, by the Bill and Melinda Gates Foundation (OPP1113682); the National Institute of Allergy and Infectious Diseases grants 1U19AI109662, U19AI057229, and 5R01AI125197; Department of Defense contracts W81XWH-18-1-0253 and W81XWH1910235; and the Ralph & Marian Falk Medical Research Trust. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objectives: Early identification of sepsis is critical to improving patient outcomes. Impact of the new sepsis definition (Sepsis-3) on timing of recognition in the emergency department has not been evaluated. Our study objective was to compare time to meeting systemic inflammatory response syndrome (Sepsis-2) criteria, Sequential Organ Failure Assessment (Sepsis-3) criteria, and quick Sequential Organ Failure Assessment criteria using electronic health record data., Design: Retrospective, observational study., Setting: The emergency department at the University of California, San Francisco., Patients: Emergency department encounters between June 2012 and December 2016 for patients greater than or equal to 18 years old with blood cultures ordered, IV antibiotic receipt, and identification with sepsis via systemic inflammatory response syndrome or Sequential Organ Failure Assessment within 72 hours of emergency department presentation., Interventions: None., Measurements and Main Results: We analyzed timestamped electronic health record data from 16,612 encounters identified as sepsis by greater than or equal to 2 systemic inflammatory response syndrome criteria or a Sequential Organ Failure Assessment score greater than or equal to 2. The primary outcome was time from emergency department presentation to meeting greater than or equal to 2 systemic inflammatory response syndrome criteria, Sequential Organ Failure Assessment greater than or equal to 2, and/or greater than or equal to 2 quick Sequential Organ Failure Assessment criteria. There were 9,087 patients (54.7%) that met systemic inflammatory response syndrome-first a median of 26 minutes post-emergency department presentation (interquartile range, 0-109 min), with 83.1% meeting Sequential Organ Failure Assessment criteria a median of 118 minutes later (interquartile range, 44-401 min). There were 7,037 patients (42.3%) that met Sequential Organ Failure Assessment-first, a median of 113 minutes post-emergency department presentation (interquartile range, 60-251 min). Quick Sequential Organ Failure Assessment was met in 46.4% of patients a median of 351 minutes post-emergency department presentation (interquartile range, 67-1,165 min). Adjusted odds of in-hospital mortality were 39% greater in patients who met systemic inflammatory response syndrome-first compared with those who met Sequential Organ Failure Assessment-first (odds ratio, 1.39; 95% CI, 1.20-1.61)., Conclusions: Systemic inflammatory response syndrome and Sequential Organ Failure Assessment initially identified distinct populations. Using systemic inflammatory response syndrome resulted in earlier electronic health record sepsis identification in greater than 50% of patients. Using Sequential Organ Failure Assessment alone may delay identification. Using systemic inflammatory response syndrome alone may lead to missed sepsis presenting as acute organ dysfunction. Thus, a combination of inflammatory (systemic inflammatory response syndrome) and organ dysfunction (Sequential Organ Failure Assessment) criteria may enhance timely electronic health record-based sepsis identification.

Objectives: To derive and validate a predictive algorithm integrating a nomogram-based prediction of the pretest probability of infection with a panel of serum biomarkers, which could robustly differentiate sepsis/septic shock from noninfectious systemic inflammatory response syndrome., Design: Multicenter prospective study., Setting: At emergency department admission in five University hospitals., Patients: Nine-hundred forty-seven adults in inception cohort and 185 adults in validation cohort., Interventions: None., Measurements and Main Results: A nomogram, including age, Sequential Organ Failure Assessment score, recent antimicrobial therapy, hyperthermia, leukocytosis, and high C-reactive protein values, was built in order to take data from 716 infected patients and 120 patients with noninfectious systemic inflammatory response syndrome to predict pretest probability of infection. Then, the best combination of procalcitonin, soluble phospholipase A2 group IIA, presepsin, soluble interleukin-2 receptor α, and soluble triggering receptor expressed on myeloid cell-1 was applied in order to categorize patients as "likely" or "unlikely" to be infected. The predictive algorithm required only procalcitonin backed up with soluble phospholipase A2 group IIA determined in 29% of the patients to rule out sepsis/septic shock with a negative predictive value of 93%. In a validation cohort of 158 patients, predictive algorithm reached 100% of negative predictive value requiring biomarker measurements in 18% of the population., Conclusions: We have developed and validated a high-performing, reproducible, and parsimonious algorithm to assist emergency department physicians in distinguishing sepsis/septic shock from noninfectious systemic inflammatory response syndrome.

Objectives: The Sepsis III clinical criteria for the diagnosis of sepsis rely on scores derived to predict inhospital mortality. In this study, we introduce the novel outcome of "received critical care intervention" and investigate the related predictive performance of both the quick Sequential Organ Failure Assessment and the Systemic Inflammatory Response Syndrome criteria., Design: This was a single-center, retrospective analysis of electronic health records., Setting: Tertiary care hospital in the United States., Patients: Patients with suspected infection who presented to the emergency department and were admitted to the hospital between January 2010 and December 2014., Interventions: Systemic Inflammatory Response Syndrome and quick Sequential Organ Failure Assessment scores were calculated, and their relationships to the receipt of critical care intervention and inhospital mortality were determined., Measurement and Main Results: A total of 24,164 patients were included of whom 6,693 (27.7%) were admitted to an ICU within 48 hours; 4,453 (66.5%) patients admitted to the ICU received a critical care intervention. Among those with quick Sequential Organ Failure Assessment less than 2, 13.4% received a critical care intervention and 3.5% died compared with 48.2% and 13.4%, respectively, for quick Sequential Organ Failure Assessment greater than or equal to 2. The area under the receiver operating characteristic was similar whether quick Sequential Organ Failure Assessment was used to predict receipt of critical care intervention or inhospital mortality (0.74 [95% CI, 0.73-0.74] vs 0.71 [0.69-0.72]). The area under the receiver operating characteristic of Systemic Inflammatory Response Syndrome for critical care intervention (0.69) and mortality (0.66) was lower than that for quick Sequential Organ Failure Assessment (p < 0.001 for both outcomes). The sensitivity of quick Sequential Organ Failure Assessment for predicting critical care intervention was 38%., Conclusions: Emergency department patients with suspected infection and low quick Sequential Organ Failure Assessment scores frequently receive critical care interventions. The misclassification of these patients as "low risk," in combination with the low sensitivity of quick Sequential Organ Failure Assessment greater than or equal to 2, may diminish the clinical utility of the quick Sequential Organ Failure Assessment score for patients with suspected infection in the emergency department.

Objective: Studies in sepsis are limited by heterogeneity regarding what constitutes suspicion of infection. We sought to compare potential suspicion criteria using antibiotic and culture order combinations in terms of patient characteristics and outcomes. We further sought to determine the impact of differing criteria on the accuracy of sepsis screening tools and early warning scores., Design: Observational cohort study., Setting: Academic center from November 2008 to January 2016., Patients: Hospitalized patients outside the ICU., Interventions: None., Measurements and Main Results: Six criteria were investigated: 1) any culture, 2) blood culture, 3) any culture plus IV antibiotics, 4) blood culture plus IV antibiotics, 5) any culture plus IV antibiotics for at least 4 of 7 days, and 6) blood culture plus IV antibiotics for at least 4 of 7 days. Accuracy of the quick Sepsis-related Organ Failure Assessment score, Sepsis-related Organ Failure Assessment score, systemic inflammatory response syndrome criteria, the National and Modified Early Warning Score, and the electronic Cardiac Arrest Risk Triage score were calculated for predicting ICU transfer or death within 48 hours of meeting suspicion criteria. A total of 53,849 patients met at least one infection criteria. Mortality increased from 3% for group 1 to 9% for group 6 and percentage meeting Angus sepsis criteria increased from 20% to 40%. Across all criteria, score discrimination was lowest for systemic inflammatory response syndrome (median area under the receiver operating characteristic curve, 0.60) and Sepsis-related Organ Failure Assessment score (median area under the receiver operating characteristic curve, 0.62), intermediate for quick Sepsis-related Organ Failure Assessment (median area under the receiver operating characteristic curve, 0.65) and Modified Early Warning Score (median area under the receiver operating characteristic curve 0.67), and highest for National Early Warning Score (median area under the receiver operating characteristic curve 0.71) and electronic Cardiac Arrest Risk Triage (median area under the receiver operating characteristic curve 0.73)., Conclusions: The choice of criteria to define a potentially infected population significantly impacts prevalence of mortality but has little impact on accuracy. Systemic inflammatory response syndrome was the least predictive and electronic Cardiac Arrest Risk Triage the most predictive regardless of how infection was defined.

Objective: The Third International Consensus Definitions Task Force (Sepsis-3) recently recommended changes to the definitions of sepsis. The impact of these changes remains unclear. Our objective was to determine the outcomes of patients meeting Sepsis-3 septic shock criteria versus patients meeting the "old" (1991) criteria of septic shock only., Design: Secondary analysis of two clinical trials of early septic shock resuscitation., Setting: Large academic emergency departments in the United States., Patients: Patients with suspected infection, more than or equal to two systemic inflammatory response syndrome criteria, and systolic blood pressure less than 90 mm Hg after fluid resuscitation., Interventions: Patients were further categorized as Sepsis-3 septic shock if they demonstrated hypotension, received vasopressors, and exhibited a lactate greater than 2 mmol/L. We compared in-hospital mortality in patients who met the old definition only with those who met the Sepsis-3 criteria., Measurements and Main Results: Four hundred seventy patients were included in the present analysis. Two hundred (42.5%) met Sepsis-3 criteria, whereas 270 (57.4%) met only the old definition. Patients meeting Sepsis-3 criteria demonstrated higher severity of illness by Sequential Organ Failure Assessment score (9 vs 5; p < 0.001) and mortality (29% vs 14%; p < 0.001). Subgroup analysis of 127 patients meeting only the old definition demonstrated significant mortality benefit following implementation of a quantitative resuscitation protocol (35% vs 10%; p = 0.006)., Conclusion: In this analysis, 57% of patients meeting old definition for septic shock did not meet Sepsis-3 criteria. Although Sepsis-3 criteria identified a group of patients with increased organ failure and higher mortality, those patients who met the old criteria and not Sepsis-3 criteria still demonstrated significant organ failure and 14% mortality rate.

Objectives: SeptiCyte Lab (Immunexpress, Seattle, WA), a molecular signature measuring the relative expression levels of four host messenger RNAs, was developed to discriminate critically ill adults with infection-positive versus infection-negative systemic inflammation. The objective was to assess the performance of Septicyte Lab in critically ill pediatric patients., Design: Prospective observational study., Setting: Pediatric and Cardiac ICUs, Seattle Children's Hospital, Seattle, WA., Patients: A cohort of 40 children with clinically overt severe sepsis syndrome and 30 children immediately postcardiopulmonary bypass surgery was recruited. The clinically overt severe sepsis syndrome children had confirmed or highly suspected infection (microbial culture orders, antimicrobial prescription), two or more systemic inflammatory response syndrome criteria (including temperature and leukocyte criteria), and at least cardiovascular ± pulmonary organ dysfunction., Interventions: None (observational study only)., Measurements and Main Results: Next-generation RNA sequencing was conducted on PAXgene blood RNA samples, successfully for 35 of 40 (87.5%) of the clinically overt severe sepsis syndrome patients and 29 of 30 (96.7%) of the postcardiopulmonary bypass patients. Forty patient samples (~ 60% of cohort) were reanalyzed by reverse transcription-quantitative polymerase chain reaction, to check for concordance with next-generation sequencing results. Postcardiopulmonary bypass versus clinically overt severe sepsis syndrome descriptors included the following: age, 7.3 ± 5.5 versus 9.0 ± 6.6 years; gender, 41% versus 49% male; Pediatric Risk of Mortality, version III, 7.0 ± 4.6 versus 8.7 ± 6.4; Pediatric Logistic Organ Dysfunction, version II, 5.1 ± 2.2 versus 4.8 ± 2.8. SeptiCyte Lab strongly differentiated postcardiopulmonary bypass and clinically overt severe sepsis syndrome patients by receiver operating characteristic curve analysis, with an area-under-curve value of 0.99 (95% CI, 0.96-1.00). Equivalent performance was found using reverse transcription-quantitative polymerase chain reaction. There was no significant correlation between the score produced by the SeptiCyte Lab test and measures of illness severity, immune compromise, or microbial culture status., Conclusions: SeptiCyte Lab is able to discriminate clearly between clinically well-defined and homogeneous postcardiopulmonary bypass and clinically overt severe sepsis syndrome groups in children. A broader investigation among children with more heterogeneous inflammation-associated diagnoses and care settings is warranted.

Objective: In response to a need for better sepsis diagnostics, several new gene expression classifiers have been recently published, including the 11-gene "Sepsis MetaScore," the "FAIM3-to-PLAC8" ratio, and the Septicyte Lab. We performed a systematic search for publicly available gene expression data in sepsis and tested each gene expression classifier in all included datasets. We also created a public repository of sepsis gene expression data to encourage their future reuse., Data Sources: We searched National Institutes of Health Gene Expression Omnibus and EBI ArrayExpress for human gene expression microarray datasets. We also included the Glue Grant trauma gene expression cohorts., Study Selection: We selected clinical, time-matched, whole blood studies of sepsis and acute infections as compared to healthy and/or noninfectious inflammation patients. We identified 39 datasets composed of 3,241 samples from 2,604 patients., Data Extraction: All data were renormalized from raw data, when available, using consistent methods., Data Synthesis: Mean validation areas under the receiver operating characteristic curve for discriminating septic patients from patients with noninfectious inflammation for the Sepsis MetaScore, the FAIM3-to-PLAC8 ratio, and the Septicyte Lab were 0.82 (range, 0.73-0.89), 0.78 (range, 0.49-0.96), and 0.73 (range, 0.44-0.90), respectively. Paired-sample t tests of validation datasets showed no significant differences in area under the receiver operating characteristic curves. Mean validation area under the receiver operating characteristic curves for discriminating infected patients from healthy controls for the Sepsis MetaScore, FAIM3-to-PLAC8 ratio, and Septicyte Lab were 0.97 (range, 0.85-1.0), 0.94 (range, 0.65-1.0), and 0.71 (range, 0.24-1.0), respectively. There were few significant differences in any diagnostics due to pathogen type., Conclusions: The three diagnostics do not show significant differences in overall ability to distinguish noninfectious systemic inflammatory response syndrome from sepsis, though the performance in some datasets was low (area under the receiver operating characteristic curve, < 0.7) for the FAIM3-to-PLAC8 ratio and Septicyte Lab. The Septicyte Lab also demonstrated significantly worse performance in discriminating infections as compared to healthy controls. Overall, public gene expression data are a useful tool for benchmarking gene expression diagnostics.

Objectives: Sepsis generates significant global acute illness burden. The international variations in sepsis epidemiology (illness burden) have implications for region specific health policy. We hypothesised that there have been changes over time in the sepsis definitional elements (infection and organ dysfunction), and these may have impacted on hospital mortality., Design: Cohort study., Setting: We evaluated a high quality, nationally representative, clinical ICU database including data from 181 adult ICUs in England., Patients: Nine hundred sixty-seven thousand five hundred thirty-two consecutive adult ICU admissions from January 2000 to December 2012., Interventions: None., Measurements and Main Results: To address the proposed hypothesis, we evaluated a high quality, nationally representative, clinical, ICU database of 967,532 consecutive admissions to 181 adult ICUs in England, from January 2000 to December 2012, to identify sepsis cases in a robust and reproducible way. Multinomial logistic regression was used to report unadjusted trends in sepsis definitional elements and in mortality risk categories based on organ dysfunction combinations. We generated logistic regression models and assessed statistical interactions with acute hospital mortality as outcome and cohort characteristics, sepsis definitional elements, and mortality risk categories as covariates. Finally, we calculated postestimation statistics to illustrate the magnitude of clinically meaningful improvements in sepsis outcomes over the study period. Over the study period, there were 248,864 sepsis admissions (25.7%). Sepsis mortality varied by infection sources (19.1% for genitourinary to 43.0% for respiratory; p < 0.001), by number of organ dysfunctions (18.5% for 1 to 69.9% for 5; p < 0.001), and organ dysfunction combinations (18.5% for risk category 1 to 58.0% for risk category 4). The rate of improvement in adjusted hospital mortality was significant (odds ratio, 0.939 [0.934-0.945] per year; p < 0.001), but showed different secular trends in improvement between infection sources., Conclusions: Within a sepsis cohort, we illustrate case-mix heterogeneity using definitional elements (infection source and organ dysfunction). In the context of improving outcomes, we illustrate differential secular trends in impact of these variables on adjusted mortality and propose this as a valid reason for international variations in sepsis epidemiology. Our article highlights the need to determine standardized reporting elements for optimal comparisons of international sepsis epidemiology.

Objectives: Lifesaving early distinction of infectious systemic inflammatory response syndrome, known as "sepsis," from noninfectious systemic inflammatory response syndrome is challenging in the ICU because of high systemic inflammatory response syndrome prevalence and lack of specific biomarkers. The purpose of this study was to use an automatic algorithm to detect systemic inflammatory response syndrome criteria (tachycardia, tachypnea, leukocytosis, and fever) in surgical ICU patients for ICU-wide systemic inflammatory response syndrome prevalence determination and evaluation of algorithm-derived systemic inflammatory response syndrome descriptors for sepsis prediction and diagnosis in a polytrauma cohort., Design: Cross-sectional descriptive study and retrospective cohort study., Setting: Electronic medical records of a tertiary care center's surgical ICU, 2006-2011., Patients: All ICU admissions and consecutive polytrauma admissions., Interventions: None., Measurements and Main Results: Average prevalence of conventional systemic inflammatory response syndrome (≥ 2 criteria met concomitantly) from cross-sectional application of the algorithm to all ICU patients and each minute of the study period was 43.3%. Of 256 validated polytrauma patients, 85 developed sepsis (33.2%). Three systemic inflammatory response syndrome descriptors summarized the 24 hours after admission and before therapy initiation: 1) systemic inflammatory response syndrome criteria average for systemic inflammatory response syndrome quantification over time, 2) first-to-last minute difference for trend detection, and 3) change count reflecting systemic inflammatory response syndrome criteria fluctuation. Conventional systemic inflammatory response syndrome for greater than or equal to 1 minute had 91% sensitivity and 19% specificity, whereas a systemic inflammatory response syndrome criteria average cutoff value of 1.72 had 51% sensitivity and 77% specificity for sepsis prediction. For sepsis diagnosis, systemic inflammatory response syndrome criteria average and first-to-last minute difference combined yielded 82% sensitivity and 71% specificity compared with 99% sensitivity and only 31% specificity of conventional systemic inflammatory response syndrome from a nested case-control analysis., Conclusions: Dynamic systemic inflammatory response syndrome descriptors improved specificity of sepsis prediction and particularly diagnosis, rivaling established biomarkers, in a polytrauma cohort. They may enhance electronic sepsis surveillance once evaluated in other patient populations.

Objectives: To determine the effect of two doses of intramuscular cholecalciferol on serial serum 25-hydroxy-vitamin-D levels and on pharmacodynamics endpoints: calcium, phosphate, parathyroid hormone, C-reactive protein, interleukin-6, and cathelicidin in critically ill adults., Design: Prospective randomized interventional study., Setting: Tertiary, academic adult ICU., Patients: Fifty critically ill adults with the systemic inflammatory response syndrome., Intervention: Patients were randomly allocated to receive a single intramuscular dose of either 150,000 IU (0.15 mU) or 300,000 IU (0.3 mU) cholecalciferol., Measurements and Main Results: Pharmacokinetic, pharmacodynamic parameters, and outcome measures were collected over a 14-day period or until ICU discharge, whichever was earlier. Prior to randomization, 28 of 50 patients (56%) were classified as vitamin D deficient. By day 7 after randomization, 15 of 23 (65%) and 14 of 21 patients (67%) normalized vitamin D levels with 0.15 and 0.3 mU, respectively (p=0.01) and by day 14, 8 of 10 (80%) and 10 of 12 patients (83%) (p=0.004), respectively. Secondary hyperparathyroidism was manifested in 28% of patients at baseline. Parathyroid hormone levels decreased over the study period with patients achieving vitamin D sufficiency at day 7 having significantly lower parathyroid hormone levels (p<0.01). Inflammatory markers (C-reactive protein and interleukin-6) fell significantly over the study period. Greater increments in 25-hydroxy-vitamin-D were significantly associated with greater increments in cathelicidin at days 1 and 3 (p=0.04 and 0.004, respectively). Although in-hospital mortality rate did not differ between the groups, patients who did not mount a parathyroid hormone response to vitamin D deficiency had a higher mortality (35% vs 12%; p=0.05). No significant adverse effects were observed., Conclusions: A single dose of either dose of intramuscular cholecalciferol corrected vitamin D deficiency in the majority of critically ill patients. Greater vitamin D increments were associated with early greater cathelicidin increases, suggesting a possible mechanism of vitamin D supplementation in inducing bactericidal pleiotropic effects.

Objective: Early detection and start of appropriate treatment are highly correlated with survival of sepsis and septic shock, but the currently available predictive tools are not sensitive enough to identify patients at risk., Design: Linear (time and frequency domain) and nonlinear (unifractal and multiscale complexity dynamics) measures of beat-to-beat interval variability were analyzed in two mouse models of inflammatory shock to determine if they are sensitive enough to predict outcome., Setting: University research laboratory., Subjects: Blood pressure transmitter-implanted female C57BL/6J mice., Interventions: IV administration of tumor necrosis factor (n = 11) or lipopolysaccharide (n = 14)., Measurements and Main Results: Contrary to linear indices of variability, unifractal dynamics, and absolute heart rate or blood pressure, quantification of complex beat-to-beat dynamics using multiscale entropy was able to predict survival outcome starting as early as 40 minutes after induction of inflammatory shock. Based on these results, a new and clinically relevant index of multiscale entropy was developed that scores the key features of a multiscale entropy profile. Contrary to multiscale entropy, multiscale entropy scoring can be followed as a function of time to monitor disease progression with limited loss of information., Conclusions: Analysis of multiscale complexity of beat-to-beat dynamics at high temporal resolution has potential as a sensitive prognostic tool with translational power that can predict survival outcome in systemic inflammatory conditions such as sepsis and septic shock.

Objectives: Systemic inflammatory response syndrome and sepsis frequently occur after cardiac surgery with cardiopulmonary bypass. The aim of the present study was to investigate whether preoperative cholesterol levels can predict sepsis onset and postoperative complications in patients undergoing cardiac surgery with cardiopulmonary bypass., Design: Prospective observational study., Setting: Surgical ICU of a French university hospital., Patients: Two hundred and seventeen consecutive patients older than 18 years admitted for planned cardiac surgery with cardiopulmonary bypass., Interventions: Measurements of plasma blood lipids and inflammation markers before anesthesia induction (baseline), at cardiopulmonary bypass start, at cardiopulmonary bypass end, and 3 and 24 hours after cardiac surgery. Outcomes were compared in systemic inflammatory response syndrome patients with sepsis (n = 15), systemic inflammatory response syndrome patients without sepsis (n = 95), and non-systemic inflammatory response syndrome patients (n = 107)., Measurements and Main Results: A gradual decrease in plasma cholesterol concentration occurred during surgery with cardiopulmonary bypass but was no longer present after correction for hemodilution. Corrected cholesterol levels were significantly lower at baseline in sepsis patients than in other subgroups, and it remained lower in the sepsis group during and after cardiopulmonary bypass. With regard to sepsis, the discriminatory power of baseline cholesterol was fairly good as indicated by receiver operating characteristic curve analysis (area under the curve, 0.78; 95% CI, 0.72-0.84). The frequency of sepsis progressively decreased with increasing baseline cholesterol level quintiles (18.6% and 0% in the bottom and top quintiles, respectively, p = 0.005). In multivariate analysis, baseline cholesterol levels and cardiopulmonary bypass duration were significant and independent determinants of the 3-hour postcardiopulmonary bypass increase in concentrations of procalcitonin and interleukin-8, but not of interleukin-6., Conclusions: Low cholesterol levels before elective cardiac surgery with cardiopulmonary bypass may be a simple biomarker for the early identification of patients with a high risk of sepsis.

Objectives: To assess whether systemic inflammatory response syndrome is associated with morbidity and mortality in ST-elevation myocardial infarction., Design and Setting: Secondary analysis of multicenter randomized controlled trials., Patients: Complement and reduction of infarct size after angioplasty or lytics project patients (n=1,903) with ST-elevation myocardial infarction undergoing fibrinolysis or mechanical reperfusion., Interventions: None., Measurements and Main Results: The prevalence of systemic inflammatory response syndrome was described in the 1,186 patients (64.4%) with data available for all systemic inflammatory response syndrome criteria. Using multiple imputations for the 1,843 patients (96.8%) with available endpoints, we compared the 90-day prevalence of death, shock, heart failure, or stroke between patients with and without systemic inflammatory response syndrome at presentation and at 24 hours post admission. Systemic inflammatory response syndrome was defined as ≥2 of 1) heart rate>90 beats/min, 2) respiratory rate>20 breaths/min, 3) body temperature>38 or <36°C, or 4) leukocyte count>12 or<4×10/L. At presentation, 25.0% of patients met systemic inflammatory response syndrome criteria; at 24 hours, 8.1% of patients met systemic inflammatory response syndrome criteria. The primary outcome was more frequent among patients with systemic inflammatory response syndrome at presentation (31.0% vs 16.7%; adjusted hazard ratio, 1.78 [95% CI, 1.35-2.34]; p<0.001) and at 24 hours (36.7% vs 11.1%; adjusted hazard ratio, 2.84 [95% CI, 2.03-3.97]; p<0.001). Mortality at 90 days was also higher among patients with systemic inflammatory response syndrome at either time point. Each additional systemic inflammatory response syndrome criterion was independently associated with 90-day outcomes at the time of presentation (adjusted hazard ratio, 1.41 per systemic inflammatory response syndrome criteria [95% CI, 1.24-1.61]; p<0.001) and at 24 hours (adjusted hazard ratio, 1.72 per systemic inflammatory response syndrome criteria [95% CI, 1.47-2.01]; p<0.001)., Conclusion: The diagnosis of systemic inflammatory response syndrome and the cumulative number of systemic inflammatory response syndrome criteria were independently associated with 90-day clinical outcomes in a population of patients with ST-elevation myocardial infarction. The independent association of this simple composite measure of the inflammatory response with outcomes underscores the importance of the clinical inflammatory response in ST-elevation myocardial infarction.

Introduction: Adrenal insufficiency may be common in adults and children with vasopressor-resistant shock. We developed a protocolized approach to low-dose adrenocorticotropin testing and empirical low-dose glucocorticoid/mineralocorticoid supplementation in children with systemic inflammatory response syndrome and persistent hypotension following fluid resuscitation and vasopressor infusion., Hypothesis: We hypothesized that absolute and relative adrenal insufficiency was common in children with systemic inflammatory response syndrome requiring vasopressor support and that steroid administration would be associated with decreased vasopressor need., Methods: Retrospective review of pediatric patients with systemic inflammatory response syndrome and vasopressor-dependent shock receiving protocol-based adrenocorticotropin testing and low-dose steroid supplementation. The incidence of absolute and relative adrenal insufficiency was determined using several definitions. Vasopressor dose requirements were evaluated before, and following, initiation of corticosteroids., Results: Seventy-eight patients met inclusion criteria for systemic inflammatory response syndrome and shock; 40 had septic shock. Median age was 84 months (range, 0.5-295). By adrenocorticotropin testing, 44 (56%) had absolute adrenal insufficiency, 39 (50%) had relative adrenal insufficiency, and 69 (88%) had either form of adrenal insufficiency. Adrenal insufficiency incidence was significantly higher in children >2 yrs (p = .0209). Therapeutic interventions included median 80-mL/kg fluid resuscitation; 65% of patients required dopamine, 58% norepinephrine, and 49% dopamine plus norepinephrine. With steroid supplementation, median dopamine dose decreased from 10 to 4 μg/kg/min at 4 hrs (p = .0001), and median dose of norepinephrine decreased from 0.175 μg/kg/min to 0.05 μg/kg/min at 4 hrs (p = .039)., Conclusions: Absolute and relative adrenal insufficiency was prevalent in this cohort of children with systemic inflammatory response syndrome and vasopressor-dependent shock and increased with age. Introduction of steroids produced a significant reduction in vasopressor duration and dosage. Use of low-dose adrenocorticotropin testing may help further delineate populations who require steroid supplementation.

Objective: To describe the composition of metabolic acidosis in patients with severe sepsis and septic shock at intensive care unit admission and throughout the first 5 days of intensive care unit stay., Design: Prospective, observational study., Setting: Twelve-bed intensive care unit., Patients: Sixty patients with either severe sepsis or septic shock., Interventions: None., Measurements and Main Results: Data were collected until 5 days after intensive care unit admission. We studied the contribution of inorganic ion difference, lactate, albumin, phosphate, and strong ion gap to metabolic acidosis. At admission, standard base excess was -6.69 +/- 4.19 mEq/L in survivors vs. -11.63 +/- 4.87 mEq/L in nonsurvivors (p < .05); inorganic ion difference (mainly resulting from hyperchloremia) was responsible for a decrease in standard base excess by 5.64 +/- 4.96 mEq/L in survivors vs. 8.94 +/- 7.06 mEq/L in nonsurvivors (p < .05); strong ion gap was responsible for a decrease in standard base excess by 4.07 +/- 3.57 mEq/L in survivors vs. 4.92 +/- 5.55 mEq/L in nonsurvivors with a nonsignificant probability value; and lactate was responsible for a decrease in standard base excess to 1.34 +/- 2.07 mEq/L in survivors vs. 1.61 +/- 2.25 mEq/L in nonsurvivors with a nonsignificant probability value. Albumin had an important alkalinizing effect in both groups; phosphate had a minimal acid-base effect. Acidosis in survivors was corrected during the study period as a result of a decrease in lactate and strong ion gap levels, whereas nonsurvivors did not correct their metabolic acidosis. In addition to Acute Physiology and Chronic Health Evaluation II score and serum creatinine level,inorganic ion difference acidosis magnitude at intensive care unit admission was independently associated with a worse outcome., Conclusions: Patients with severe sepsis and septic shock exhibit a complex metabolic acidosis at intensive care unit admission, caused predominantly by hyperchloremic acidosis,which was more pronounced in nonsurvivors. Acidosis resolution in survivors was attributable to a decrease in strong ion gap and lactate levels.

What if there was a rapid, inexpensive, and accurate blood diagnostic that could determine which patients were infected, identify the organism(s) responsible, and identify patients who were not responding to therapy? We hypothesized that systems analysis of the transcriptional activity of circulating immune effector cells could be used to identify conserved elements in the host response to systemic inflammation, and furthermore, to discriminate between sterile and infectious etiologies. We review herein a validated, systems biology approach demonstrating that 1) abdominal and pulmonary sepsis diagnoses can be made in mouse models using microarray (RNA) data from circulating blood, 2) blood microarray data can be used to differentiate between the host response to Gram-negative and Gram-positive pneumonia, 3) the endotoxin response of normal human volunteers can be mapped at the level of gene expression, and 4) a similar strategy can be used in the critically ill to follow septic patients and quantitatively determine immune recovery. These findings provide the foundation of immune cartography and demonstrate the potential of this approach for rapidly diagnosing sepsis and identifying pathogens. Further, our data suggest a new approach to determine how specific pathogens perturb the physiology of circulating leukocytes in a cell-specific manner. Large, prospective clinical trails are needed to validate the clinical utility of leukocyte RNA diagnostics (e.g., the riboleukogram).

Objective: To develop consensus statements for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients., Participants: A multidisciplinary, multispecialty task force of experts in critical care medicine was convened from the membership of the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. In addition, international experts in endocrinology were invited to participate., Design/methods: The task force members reviewed published literature and provided expert opinion from which the consensus was derived. The consensus statements were developed using a modified Delphi methodology. The strength of each recommendation was quantified using the Modified GRADE system, which classifies recommendations as strong (grade 1) or weak (grade 2) and the quality of evidence as high (grade A), moderate (grade B), or low (grade C) based on factors that include the study design, the consistency of the results, and the directness of the evidence., Results: The task force coined the term critical illness-related corticosteroid insufficiency to describe the dysfunction of the hypothalamic-pituitary-adrenal axis that occurs during critical illness. Critical illness-related corticosteroid insufficiency is caused by adrenal insufficiency together with tissue corticosteroid resistance and is characterized by an exaggerated and protracted proinflammatory response. Critical illness-related corticosteroid insufficiency should be suspected in hypotensive patients who have responded poorly to fluids and vasopressor agents, particularly in the setting of sepsis. At this time, the diagnosis of tissue corticosteroid resistance remains problematic. Adrenal insufficiency in critically ill patients is best made by a delta total serum cortisol of < 9 microg/dL after adrenocorticotrophic hormone (250 microg) administration or a random total cortisol of < 10 microg/dL. The benefit of treatment with glucocorticoids at this time seems to be limited to patients with vasopressor-dependent septic shock and patients with early severe acute respiratory distress syndrome (PaO2/FiO2 of < 200 and within 14 days of onset). The adrenocorticotrophic hormone stimulation test should not be used to identify those patients with septic shock or acute respiratory distress syndrome who should receive glucocorticoids. Hydrocortisone in a dose of 200 mg/day in four divided doses or as a continuous infusion in a dose of 240 mg/day (10 mg/hr) for > or = 7 days is recommended for septic shock. Methylprednisolone in a dose of 1 mg x kg(-1) x day(-1) for > or = 14 days is recommended in patients with severe early acute respiratory distress syndrome. Glucocorticoids should be weaned and not stopped abruptly. Reinstitution of treatment should be considered with recurrence of signs of sepsis, hypotension, or worsening oxygenation. Dexamethasone is not recommended to treat critical illness-related corticosteroid insufficiency. The role of glucocorticoids in the management of patients with community-acquired pneumonia, liver failure, pancreatitis, those undergoing cardiac surgery, and other groups of critically ill patients requires further investigation., Conclusion: Evidence-linked consensus statements with regard to the diagnosis and management of corticosteroid deficiency in critically ill patients have been developed by a multidisciplinary, multispecialty task force.

Objectives: To validate scoring algorithm criteria established by the Japanese Association for Acute Medicine (JAAM) for disseminated intravascular coagulation (DIC) and to evaluate its diagnostic property by comparing the two leading scoring systems for DIC, from the Japanese Ministry of Health and Welfare (JMHW) and International Society on Thrombosis and Haemostasis (ISTH)., Design: Prospective, multicenter study during a 3-month period., Setting: General critical care center in a tertiary care hospital., Patients: Two hundred seventy-three patients with platelet counts<150x109/L were enrolled., Intervention: None., Measurements and Main Results: The JAAM, JMHW, and ISTH DIC scoring algorithms were prospectively applied within 12 hrs of patients meeting the inclusion criteria (day 0) to days 1-3, by global coagulation tests. The numbers of systemic inflammatory response syndrome (SIRS) criteria and Sequential Organ Failure Assessment (SOFA) scores were determined simultaneously. Mortality associated with any cause was also assessed 28 days after the enrollment. All global coagulation tests and SIRS criteria adopted in the JAAM criteria and their cutoff points were validated with use of SOFA scores and mortality rate. DIC diagnostic rate of the JAAM DIC scoring system was significantly higher than that of the other two criteria (p<.001). The JAAM DIC algorithm was the most sensitive for early diagnosis of DIC (p<.001). PATIENTS who fulfilled the JAAM DIC criteria included almost all those whose DIC was diagnosed by the JMHW and ISTH scoring systems. The JAAM DIC scores showed significant correlation with SOFA scores ([rho]=0.499; p<.001). SOFA score and mortality rate worsened in accordance with an increase in the JAAM DIC score. Fibrinogen criteria had little effect in predicting outcome for the DIC patients, and a total score of 4 points in the JAAM scoring system without fibrinogen was closely related to poor prognosis. According to the results, we revised the JAAM criteria by excluding fibrinogen and confirmed that the DIC diagnostic properties of original criteria remained unchanged in the revised JAAM criteria., Conclusions: The JAAM scoring system has an acceptable property for the diagnosis of DIC. The scoring system identified most of the patients diagnosed by the JMHW and ISTH criteria. Revised JAAM DIC criteria preserved all properties of the original criteria for DIC diagnosis. The revised scoring system can be useful for selecting DIC patients for early treatment in a critical care setting.

Objective: To assess whether different diagnostic and prognostic cutoff values of procalcitonin should be considered in surgical and in medical patients with septic shock., Design: Prospective observational study., Setting: Intensive care unit of the Avicenne teaching hospital, France., Patients: All patients with septic shock or noninfectious systemic inflammatory response syndrome within 48 hrs after admission., Interventions: None., Measurements and Main Results: Patients were allocated to one of the following groups: group 1 (surgical patients with septic shock), group 2 (surgical patients with noninfectious systemic inflammatory response syndrome), group 3 (medical patients with septic shock), and group 4 (medical patients with noninfectious systemic inflammatory response syndrome). Procalcitonin at study entry was compared between group 1 and group 2 and between group 3 and group 4 to determine the diagnostic cutoff value in surgical and in medical patients, respectively. Procalcitonin was compared between survivors and nonsurvivors from group 1 and group 3 to determine its prognostic cutoff value. One hundred forty-three patients were included: 31 in group 1, 36 in group 2, 36 in group 3, and 40 in group 4. Median procalcitonin levels (ng/mL [interquartile range]) were higher in group 1 than in group 3 (34.00 [7.10-76.00] vs. 8.40 [3.63-24.70], p = .01). In surgical patients, the best diagnostic cutoff value was 9.70 ng/mL, with 91.7% sensitivity and 74.2% specificity. In medical patients, the best diagnostic cutoff value was 1.00 ng/mL, with 80% sensitivity and 94% specificity. Procalcitonin was a reliable early prognostic marker in medical but not in surgical patients with septic shock. A cutoff value of 6.00 ng/mL had 76% sensitivity and 72.7% specificity for separating survivors from nonsurvivors., Conclusions: The diagnostic cutoff value of procalcitonin was higher in surgical than in medical patients. Early procalcitonin was of prognostic interest in medical patients.

Objective: Growth-arrest-specific protein 6 (Gas6), an intracellular protein released by apoptotic cells, has been detected in normal plasma. As the Gas6 system has been implicated in mouse susceptibility to sepsis, and as leukocyte apoptosis is thought to play a major role in the physiopathology of human severe sepsis, we studied Gas6 plasma levels and possibly related variables in patients with severe sepsis., Design: Matched case-control study., Setting: Adult intensive care unit in a university hospital., Patients: Thirty patients with severe sepsis, 30 patients with organ failure not related to infection, and 30 healthy subjects matched for age and gender., Interventions: Blood draw., Measurements and Main Results: Gas6 plasma levels were quantified using enzyme-linked immunosorbent assay. Whole-blood gas6 messenger RNA levels were measured by quantitative real-time polymerase chain reaction. Gas6 plasma levels were elevated (110 ng/mL [75, 139]; median values [interquartile range]) in severe sepsis patients compared with organ failure patients (85 ng/mL [56, 101]) and healthy subjects (54 ng/mL [49, 68]). In patients with severe sepsis, this increase correlated with the Acute Physiology and Chronic Health Evaluation II severity score, the organ failure Organ Dysfunction and Infection (ODIN) score, and the existence of a septic shock. Gas6 messenger RNA levels were increased in patients with severe sepsis and correlated specifically with the monocyte count., Conclusions: In severe sepsis, the recently described anti-apoptotic protein Gas6 was found at high levels in plasma and correlated well with the degree of organ dysfunction.

Objective: To assess the pressor response to phenylephrine infusion before and after hydrocortisone in severe trauma patients and to correlate this response with their adrenal reserve., Design: Prospective clinical study., Setting: Surgical intensive care unit in a university teaching hospital., Patients: Twenty-three young trauma patients (Injury Severity Score, 38 +/- 14) were studied at the end of the resuscitative period (27 +/- 15 hrs after trauma)., Interventions: Total cortisol response to intravenous corticotropin bolus (250 microg) was obtained. Total cortisol response <9 microg/dL defined an impaired adrenal function and the patient was called a nonresponder. Twelve to 24 hrs following this stimulation, phenylephrine was infused in a stepwise manner to establish the phenylephrine-mean arterial pressure dose-response curve before and after intravenous hydrocortisone administration (50 mg). An Emax model was used to describe the curve; the influence of the group (responder/nonresponder), the sequence (before/after hydrocortisone), and three covariates (Injury Severity Score, shock, and interleukin-6) were thereafter tested., Measurements and Main Results: Forty-three percent of patients were nonresponders. Total cortisol response was not correlated with serum albumin concentration and was negatively correlated with the interleukin-6 concentration. A trend for a higher incidence of nonresponders (53% vs. 36%) and a lesser total cortisol response (7.9 +/- 5.1 vs. 12.5 +/- 5.1 microg/dL) was observed in the shock patients. A phenylephrine dose-response structure (E0, ED50, and Emax) was described without influence of the group and the sequence. However, hydrocortisone induced a 37% decrease in ED50 without change in Emax in the shock patients., Conclusion: An acute administration of hydrocortisone increases the sensitivity to alpha1-adrenoceptor stimulation in fully resuscitated severe trauma patients following hemorrhagic shock. This effect is independent of the adrenal reserve of the patients and different from that previously reported in septic patients.

Objective: To develop definitions of infection that can be used in clinical trials in patients with sepsis., Context: Infection is a key component of the definition of sepsis, yet there is currently no agreement on the definitions that should be used to identify specific infections in patients with sepsis. Agreeing on a set of valid definitions that can be easily implemented as part of a clinical trial protocol would facilitate patient selection, help classify patients into prospectively defined infection categories, and therefore greatly reduce variability between treatment groups., Design and Methods: Experts in infectious diseases, clinical microbiology, and critical care medicine were recruited and allocated specific infection sites. They carried out a systematic literature review and used this, and their own experience, to prepare a draft definition. At a subsequent consensus conference, rapporteurs presented the draft definitions, and these were then refined and improved during discussion. Modifications were circulated electronically and subsequently agreed upon as part of an iterative process until consensus was reached., Result: Consensus definitions of infection were developed for the six most frequent causes of infections in septic patients: pneumonia, bloodstream infections (including infective endocarditis), intravascular catheter-related sepsis, intra-abdominal infections, urosepsis, and surgical wound infections., Conclusions: We have described standardized definitions of the common sites of infection associated with sepsis in critically ill patients. Use of these definitions in clinical trials should help improve the quality of clinical research in this field.

Objective: To determine the clinical and epidemiologic characteristics of patients with sepsis admitted to hospitals in Victoria, Australia, including the incidence of sepsis and severe sepsis, utilization of intensive care unit (ICU) resources, and hospital mortality., Design: A population-based hospital morbidity database generated from hospital discharge coding., Setting: State of Victoria, Australia (population, 4.5 million), the 4-yr period from July 1, 1999, to June 30, 2003., Patients: A total of 3,122,515 overnight hospitalizations., Interventions: None., Measurements and Main Results: The overall hospital incidence of sepsis was 1.1%, with a mortality of 18.4%. Of septic patients, 23.8% received some care in an ICU. For these patients, hospital mortality was 28.9%. Severe sepsis, defined by sepsis and at least one organ dysfunction, occurred in 39% of sepsis patients and was accompanied by a hospital mortality of 31.1%. Fifty percent of patients with severe sepsis received at least some care in an ICU., Conclusions: Australian state hospital administrative data reveal epidemiologic features of sepsis and severe sepsis that are strikingly similar to those recently reported from comparable populations in North American and Europe. This suggests that lessons learned in this area may be directly applicable internationally.

Objective: To investigate whether an inflammatory response occurs in patients undergoing infrarenal aortic abdominal aneurysm repair, the localization and timing (ischemia and/or reperfusion) of this activation, and finally whether it affects postoperative pulmonary function., Design: Prospective, observational study., Setting: Academic referral center in Italy., Patients: We included 12 patients undergoing infrarenal aortic abdominal aneurysm repair and 12 patients undergoing major abdominal surgery., Interventions: Timed measurement of gene activation (angiotensinogen, angiotensin type 1 receptor, angiotensin-converting enzyme, and interleukin-6 genes) in muscle biopsies by reverse transcriptase-polymerase chain reaction (RT-PCR), and prospective assessment of interleukin-6 plasma concentration and pulmonary function (Pao2/FIO2 and Pao2/PAO2 ratios)., Measurements and Main Results: After 30 mins of aortic clamping, angiotensinogen, angiotensin type 1 receptor, angiotensin-converting enzyme, and interleukin-6 genes were all overexpressed at RT-PCR studies in quadriceps muscle of patients undergoing aortic abdominal aneurysm repair, and the overexpression persisted after reperfusion. In situ hybridization and immunohistochemistry revealed that the inflammatory response was localized in endothelial cells. A significant increase in plasma interleukin-6 concentrations was then detectable at 6 and 12 hrs after reperfusion in aortic abdominal aneurysm surgery compared with patients undergoing abdominal surgery (p < .05). The increase in interleukin-6 plasma concentration was then followed (12 and 24 hrs after surgery) by a significant reduction of Pao2/ FIO2 and Pao2/PAO2 ratios (p < .05 vs. abdominal surgery)., Conclusions: The present study shows that a) during aortic surgery, the genes for interleukin-6 and for the components of the local renin-angiotensin system (angiotensinogen, angiotensin-converting enzyme, and angiotensin type 1 receptor subtype) are activated early in the ischemic muscle, and activation persists during reperfusion; b) interleukin-6 plasma concentration increases only in patients with tissue ischemia (aortic abdominal aneurysm), whereas no changes are detectable in patients with abdominal surgery; and finally c) the occurrence of systemic inflammatory reaction with increased interleukin-6 plasma concentrations is followed by impaired pulmonary function.

Objective: To determine serum concentrations of macrophage migration inhibitory factor and other cytokines in severe blunt trauma patients in critical settings and to evaluate their association with patient outcome., Design: Prospective, observational study., Setting: Emergency department and surgical intensive care unit of a university hospital., Patients: Fifty-four severe blunt trauma patients with systemic inflammatory response syndrome requiring intensive care, emergency surgical intervention, or both were enrolled in the study. Forty-four patients with minor injuries were the controls., Interventions: Serum macrophage migration inhibitory factor concentrations were measured in the emergency department <4 hrs postinjury (day 1) and the surgical intensive care unit 24 hrs later (day 2). Blood samples for determination of tumor necrosis factor-alpha, interleukin-6, interleukin-8, and interleukin-10 were measured both in patients with severe blunt trauma and in controls. The Acute Physiology and Chronic Health Evaluation II, Injury Severity Score, Revised Trauma Score, and Trauma Revised Injury Severity Score were used for clinical evaluation of trauma severity., Measurements and Main Results: Serum macrophage migration inhibitory factor concentrations were higher in severe blunt trauma patients than in controls; were significantly correlated with Acute Physiology and Chronic Health Evaluation II, Revised Trauma Score, and Trauma Revised Injury Severity Score scores in severe blunt trauma patients but not in controls; and were higher in nonsurvivors than in survivors., Conclusions: Our data suggest that the serum macrophage migration inhibitory factor concentration is higher in severe blunt trauma and that it reflects the severity of trauma. The serum macrophage migration inhibitory factor concentration might be a valuable predictor for the outcome of severe blunt trauma.

Objective: To determine the effect that acute physiologic derangements have on outcome after subarachnoid hemorrhage (SAH) and to design a composite score summarizing these abnormalities., Design: Prospective observational study., Setting: Neuroscience intensive care unit in a tertiary care academic center., Patients: Consecutive cohort of 413 patients with SAH admitted within 3 days of SAH onset with 3-month modified Rankin Scale scores., Interventions: None., Results: Among 20 physiologic variables assessed within 24 hrs of admission, four were independently associated with death or severe disability (modified Rankin Scale score, 4-6) at 3 months in a multivariate analysis: arterio-alveolar gradient of >125 mm Hg (odds ratio [OR], 4.5; 95% confidence interval [CI], 2.7-7.6), serum bicarbonate of <20 mmol/L (OR, 2.9; 95% CI, 1.6-5.6), serum glucose of >180 mg/dL (OR, 2.8; 95% CI, 1.6-4.8), and mean arterial pressure of <70 or >130 mm Hg (OR, 1.7; 95% CI, 1.0-2.9). Based on their proportional contribution to outcome, we constructed the SAH Physiologic Derangement Score (SAH-PDS; range, 0-8) by assigning the following weights for abnormal findings: arterio-alveolar gradient, 3 points; bicarbonate, 2 points; glucose, 2 points; and mean arterial pressure, 1 point. After controlling for known predictors of death or severe disability (age, admission neurologic status, loss of consciousness, aneurysm size, intraventricular hemorrhage, and rebleeding), the SAH Physiologic Derangement Score was independently associated with poor outcome (OR, 1.3 for each point increase; 95% CI, 1.1-1.6). By contrast, the systemic inflammatory response syndrome score and the Acute Physiology and Chronic Health Evaluation II physiologic subscore did not add predictive value to the model., Conclusion: Acute interventions specifically targeting hypoxemia, metabolic acidosis, hyperglycemia, and cardiovascular instability may improve the outcome of SAH patients. The SAH Physiologic Derangement Score may prove useful for rapidly quantifying the severity of important physiologic derangements in acute SAH.

Objective: To identify potential future means of monitoring injury and repair in critical illness., Design: Review of the literature., Results: Critically ill patients are monitored extensively and intensively by such means as hemodynamics, laboratory values, and radiologic studies. In general, however, the goal of monitoring has been to measure the degree of injury and to prevent further injury, rather than to measure repair. Measures of repair have been limited to phenotypic end points such as return of organ function, as measured by blood chemistry. In this article, I examine how it may be possible in the future to monitor the progress of repair using genomic and proteomic biomarkers. These types of monitors would enable clinicians to control the healing environment using real time, rapid biomarkers, and sophisticated techniques to target therapy to the patient's current inflammatory state, taking into account the genetic makeup of the patient and his or her likely response to a given drug., Conclusions: The rapidly evolving sciences of genomics, proteomics, computational biology, and complex system theory can be used a) to model critical illness; b) to model adaptive and maladaptive responses to critical illness; c) to tailor treatments to create an ideal inflammatory environment for repair and regeneration, taking into account the individual genetic contribution; and d) to monitor the progress of repair. The major obstacles to reaching these goals are technological, and experience suggests that they will be overcome.

Objective: Multiple organ dysfunction syndrome is a frequent complication of severe sepsis and septic shock and has a high mortality. We hypothesized that extensive apoptosis of cells might constitute the cellular basis for this complication., Design: Retrospective study., Setting: Medical and surgical wards or intensive care units of two university hospitals., Patients: Fourteen patients with fever, 15 with systemic inflammatory response syndrome, 32 with severe sepsis, and eight with septic shock., Interventions: None., Measurements and Main Results: We assessed circulating levels of nucleosomes, specific markers released by cells during the later stages of apoptosis, with a previously described enzyme-linked immunosorbent assay in these 69 patients with fever, systemic inflammatory response syndrome, severe sepsis, or septic shock. Severity of multiple organ dysfunction syndrome was assessed with sepsis scores, and clinical and laboratory variables. Elevated nucleosome levels were found in 64%, 60%, 94%, and 100% of patients with fever, systemic inflammatory response syndrome, severe sepsis, or septic shock, respectively. These levels were significantly higher in patients with septic shock as compared with patients with severe sepsis, systemic inflammatory response syndrome, or fever, and in nonsurvivors as compared with survivors. In patients with advanced multiple organ dysfunction syndrome, nucleosome levels correlated with cytokine plasma levels as well as with variables predictive for outcome., Conclusions: Patients with severe sepsis and septic shock have elevated plasma levels of nucleosomes. We suggest that apoptosis, probably resulting from exposure of cells to excessive amounts of inflammatory mediators, might by involved in the pathogenesis of multiple organ dysfunction syndrome.

Objective: To compare the clinical informative value of procalcitonin (PCT) and C-reactive protein (CRP) plasma concentrations in the detection of infection and sepsis and in the assessment of severity of sepsis., Design: Prospective study., Setting: Medicosurgical intensive care unit., Patients: Seventy consecutive adult patients who were admitted to the intensive care unit for an expected stay >24 hrs., Interventions: None., Measurements: PCT and CRP plasma concentrations were measured daily during the intensive care unit stay. Each patient was examined daily for signs and symptoms of infection and was classified daily in one of the following four categories according to the American College of Chest Physicians/Society of Critical Care Medicine criteria: negative, systemic inflammatory response syndrome, localized infection, and sepsis group (sepsis, severe sepsis, or septic shock). The severity of sepsis-related organ failure was assessed by the sepsis-related organ failure assessment score., Main Results: A total of 800 patient days were classified into the four categories. The median plasma PCT concentrations in noninfected (systemic inflammatory response syndrome) and localized-infection patient days were 0.4 and 1.4 ng/mL (p <.0001), respectively; the median CRP plasma concentrations were 79.9 and 85.3 mg/L (p =.08), respectively. The area under the receiver operating characteristic curve was 0.756 for PCT (95% confidence interval [CI], 0.675-0.836), compared with 0.580 for CRP (95% CI, 0.488-0.672) (p <.01). The median plasma PCT concentrations in nonseptic (systemic inflammatory response syndrome) and septic (sepsis, severe sepsis, or septic shock) patient days were 0.4 and 3.65 ng/mL (p <.0001), respectively, whereas those for CRP were 79.9 and 115.6 mg/L (p <.0001), respectively. The area under the receiver operating characteristic curve was 0.925 for PCT (95% CI, 0.899-0.952), compared with 0.677 for CRP (95% CI, 0.622-0.733) (p <.0001). The linear correlation between PCT plasma concentrations and the four categories was much stronger than in the case of CRP (Spearman's rho, 0.73 vs. 0.41; p <.05). A rise in sepsis-related organ failure assessment score was related to a higher median value of PCT but not CRP., Conclusion: PCT is a better marker of sepsis than CRP. The course of PCT shows a closer correlation than that of CRP with the severity of infection and organ dysfunction.

Objective: In 1991, the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) convened a "Consensus Conference," the goals of which were "to provide a conceptual and a practical framework to define the systemic inflammatory response to infection, which is a progressive injurious process that falls under the generalized term 'sepsis' and includes sepsis-associated organ dysfunction as well." The general definitions introduced as a result of that conference have been widely used in practice and have served as the foundation for inclusion criteria for numerous clinical trials of therapeutic interventions. Nevertheless, there has been an impetus from experts in the field to modify these definitions to reflect our current understanding of the pathophysiology of these syndromes., Design: Several North American and European intensive care societies agreed to revisit the definitions for sepsis and related conditions. This conference was sponsored by the SCCM, The European Society of Intensive Care Medicine (ESICM), The American College of Chest Physicians (ACCP), the American Thoracic Society (ATS), and the Surgical Infection Society (SIS)., Methods: The conference was attended by 29 participants from Europe and North America. In advance of the conference, five subgroups were formed to evaluate the following areas: signs and symptoms of sepsis, cell markers, cytokines, microbiologic data, and coagulation parameters. The subgroups corresponded electronically before the conference and met in person during the conference. A spokesperson for each group presented the deliberation of each group to all conference participants during a plenary session. A writing committee was formed at the conference and developed the current article based on executive summary documents generated by each group and the plenary group presentations. The present article serves as the final report of the 2001 International Sepsis Definitions Conference., Conclusion: This document reflects a process whereby a group of experts and opinion leaders revisited the 1992 sepsis guidelines and found that apart from expanding the list of signs and symptoms of sepsis to reflect clinical bedside experience, no evidence exists to support a change to the definitions. This lack of evidence serves to underscore the challenge still present in diagnosing sepsis in 2003 for clinicians and researchers and also provides the basis for introducing PIRO as a hypothesis-generating model for future research.

Objectives: To review the literature on direct and indirect markers of endothelial activation and damage in patients with sepsis and systemic inflammation and to assess their clinical usefulness for diagnosis and outcome. Various markers derived from or activated by endothelial cells are described, such as adhesion molecules, thrombomodulin, von Willebrand factor, parameters of the coagulation system, and interleukin-6. Furthermore, the association of these markers with the severity of sepsis, systemic inflammation, and outcome is evaluated., Data Extraction and Synthesis: Published research and review articles related to these parameters, with special emphasis on clinical studies., Conclusions: Endothelial activation and damage occur early during sepsis and play a major role in the pathophysiology of systemic inflammation. Various markers of endothelial activation are increased during sepsis and systemic inflammation, and in most studies, the level of markers such as soluble intercellular adhesion molecule, vascular cell adhesion molecule, and E selectin correlate well with the severity of inflammation and the course of the disease. However, to date, it remains unclear whether adhesion molecules and coagulation parameters are superior in this respect to interleukin-6 and procalcitonin, as direct comparisons are lacking. In addition, it is evident that markers of endothelial activation and coagulation parameters lack specificity for infection-induced endothelial damage and organ dysfunction.

Objective: Sepsis and systemic inflammatory response syndrome (SIRS) are major causes of morbidity and mortality after cardiopulmonary bypass. Attempts to suppress proinflammatory mediators have failed to improve outcomes in sepsis or in patients undergoing cardiopulmonary bypass. Recent work in adult patients has suggested that the balance between pro- and anti-inflammatory mediators is more important than the level of proinflammatory response alone. This balance may be reflected by the expression of monocyte human lymphocyte antigen (HLA)-DR, with low concentrations indicating an excess of anti-inflammatory stimuli and relative immunodeficiency. We investigated the relationship between monocyte HLA-DR expression and the subsequent development of sepsis/SIRS in children undergoing cardiopulmonary bypass., Design: A prospective, observational, clinical study., Setting: A tertiary pediatric cardiac center., Patients: Eighty-two infants and children undergoing elective cardiac surgery between March and December 1999., Measurements and Main Results: Monocyte HLA-DR expression was assessed before and after surgery and was found to be related to the length of hospital stay and the development of complications including sepsis/SIRS. The inflammatory insult of cardiopulmonary bypass decreased monocyte HLA-DR expression in all children. Lowest concentrations were seen within 72 hrs of surgery and were significantly lower in cases that subsequently required prolonged intensive care support (p <.0001, Mann-Whitney). HLA-DR expression on <60% of circulating monocytes was associated with a greatly increased risk of later (minimum 4 days) development of sepsis/SIRS (odds ratio, 12.9; 95% confidence interval, 3.4-47.5). Low HLA-DR was an independent predictor for the development of sepsis/SIRS after correction for age, bypass time, complexity of surgery, Paediatric Index of Mortality, and surgeon on multiple logistic regression analysis., Conclusions: Patients with decreased HLA-DR in the early postoperative period represent a subpopulation at greatly increased risk of later sepsis/SIRS. Such patients may benefit from strategies aimed to reduce this risk.

Objective: To evaluate at admission the performance of serum antithrombin III, serum C-reactive protein, white blood cell and platelet counts, and thromboplastin time values in prediction of hospital mortality rates in critically ill patients with suspected sepsis., Design: Prospective, cohort study., Setting: University hospital medical-surgical intensive care unit., Patients: One hundred eight consecutive critically ill patients with suspected sepsis., Interventions: None., Measurements and Main Results: The outcome measure was hospital mortality rate. Hospital survivors (n = 66) and nonsurvivors (n = 42) differed statistically significantly in admission antithrombin III activity (percentage of normal): survivors' median 66% (interquartile range, 48% to 82%) vs. nonsurvivors' median 46% (37% to 65%, p =.0002 by Mann-Whitney test). Analysis revealed similarly statistically significant differences between survivors and nonsurvivors in admission platelet count, admission thromboplastin time, day 1 Logistic Organ Dysfunction score, and Acute Physiology and Chronic Health Evaluation III score, but not in serum C-reactive protein concentrations or in white blood cells. However, the areas under the receiver operating curves (AUC) showed significantly worse discriminative power for admission antithrombin III concentration (AUC, 0.71; SE, 0.05), platelet count (AUC, 0.67; SE, 0.05), thromboplastin time (AUC, 0.65; SE, 0.05), C-reactive protein concentration (AUC, 0.60; SE, 0.05), and white blood cell count (AUC, 0.53; SE, 0.06) than did the day 1 Logistic Organ Dysfunction score (AUC, 0.82; SE, 0.04) and the Acute Physiology and Chronic Health Evaluation III score (AUC, 0.84; SE, 0.04). Multivariate logistic regression analysis revealed that only the Acute Physiology and Chronic Health Evaluation III score was independently associated with hospital mortality rate., Conclusions: Admission antithrombin III concentrations, but not C-reactive protein concentrations, differ significantly between hospital survivors and nonsurvivors among critically ill patients with septic infection. However, in prediction of hospital mortality rate, the discriminative power of admission antithrombin III concentration is poor, as judged by analysis of areas under the receiver operating curves, and is not independently associated with hospital mortality rate.

Objective: Shock in the course of fever is likely caused by septic shock. Because septic shock carries a high mortality rate, early recognition could benefit the patient. We tried to predict the development of shock in medical patients with fever and a clinical infection, on the basis of clinical and microbiological information, and to evaluate the role therein of systemic inflammatory response syndrome (SIRS) criteria: abnormal body temperature, tachycardia, tachypnea, and abnormal white blood cell counts., Design: Prospective observational study., Setting: Department of Internal Medicine at a university hospital., Patients: Patients were 212 consecutive medical patients with newly onset fever (temperature, >38.0 degrees C axillary or >38.3 degrees C rectally) and a clinical source of infection., Measurements and Main Results: Of the 212 patients enrolled, 14 developed shock (i.e., a decrease in systolic arterial blood pressure of >40 mm Hg) during a maximum follow-up period of 7 days after inclusion. In univariate analyses, advanced age, prior urogenital disease, an abdominal source, nosocomial infections, and bacteremia predisposed patients to shock (p < .05). For clinical variables, obtained daily for 2 days after inclusion, a low performance (p < .001), the peak respiratory rate (p < .05), the peak heart rate (p < .05), the nadir score on the Glasgow Coma Scale (p < .005), the peak and nadir white blood cell counts (p < .005), and the nadir albumin (p < .01) and peak creatinine concentrations in blood (p < .001) predicted shock development. In multivariate analysis, the presence of bacteremia, the peak respiratory rate, the nadir Glasgow Coma Scale score, and the peak white blood cell count positively and the peak erythrocyte sedimentation rate negatively contributed to prediction of shock development. In contrast, SIRS had less predictive value, mainly because of lack of predictive value of peak heart rate and temperature in multivariate models., Conclusion: In febrile medical patients with a clinical infection, the development of shock involves an interaction between circulating microbial products and the host response, which can be recognized clinically by variables easily obtained at the bedside and partly different from the set used to define SIRS.

Objective: To evaluate the capacity of cysteinyl-leukotriene generation in the progression of critical illness compared with that in healthy volunteers and to clarify interrelationships between the rate of leukotriene generation, severity of the disease, and clinical outcome., Design: Prospective, observational study., Setting: Surgical intensive care unit (ICU) in a German university hospital., Patients: We studied 14 ICU patients (nine men, five women; aged 42-82 yrs) suffering from systemic inflammatory response syndrome, sepsis, or sepsis syndrome, with a calculated sepsis severity score of 17.7+/-4.2 and a Simplified Acute Physiology score of 17.6+/-3.0. In addition, five healthy volunteers (three men, two women; aged 34-38 yrs) were included in the study., Interventions: None., Measurements and Main Results: Blood samples were obtained every second day from septic patients until discharge from the ICU or death. Leukotriene C4 (LTC4) synthesizing capacity was assessed in isolated and stimulated leukocytes (Ca-ionophore) by using combined reversed-phase, high-pressure liquid chromatography and radioimmunoassay methods. Initially, all patients synthesized less LTC4 than the healthy subjects. In patients who did not survive, the low LTC4 generation persisted throughout the observation period, whereas in surviving patients, its formation was normalized during convalescence. In surviving patients, LTC4 concentrations correlated with sepsis severity score., Conclusions: LTC4 generation is impaired in sepsis and may serve as a biomarker for survival in the critical ill.

Objectives: Procalcitonin (PCT) has been described as an early, discriminating marker of bacteria-associated sepsis in patients. However, little is known of its source and actions, in part because no appropriate animal models have been available. We tested the hypothesis that plasma PCT increases during various pathophysiological conditions, such as hemorrhagic shock and sepsis, which differ with regard to the degree of associated endotoxemia. We further hypothesized that in sepsis, PCT would be significantly different in survivors vs. nonsurvivors., Design: Prospective, blinded analysis of previously collected plasma of experimental animals., Setting: Independent nonprofit research laboratory in a trauma hospital and a contract research institute., Subjects: A total of 22 male baboons (17.5-31 kg)., Interventions: Hemorrhagic-traumatic shock was induced by hemorrhage for up to 3 hrs, reperfusion with shed blood and infusion of cobra venom factor (n = 7). By using a similar experimental setup, severe hyperdynamic sepsis was induced (n = 15) by intravenous infusion of live Escherichia coli (2 x 10(9) colony-forming units/kg) over 2 hrs, followed by antibiotic therapy (gentamicin 4 mg/kg twice a day)., Measurements and Main Results: Plasma PCT at baseline was barely detectable, but levels increased significantly (p < .05) to 2+/-1.8 pg/mL 2 hrs after the start of reperfusion in the shock group, and to 987+/-230 pg/mL at 4 hrs after E. coli in the sepsis group. Levels were maximal between 6 and 32 hrs and had returned nearly to baseline levels at 72 hrs. Interleukin-6 levels paralleled the course of PCT measurements, whereas a significant increase in neopterin was seen at 24 hrs. PCT levels were approximately three times higher in the sepsis group than in the shock group, corresponding to endotoxin levels (at the end of hemorrhage, 286+/-144 pg/mL vs. 3576+/-979 pg/mL at the end of E. coli infusion; p = .003). PCT levels were significantly different at 24 hrs between survivors (2360+/-620 pg/mL) and nonsurvivors (4776+/-563 pg/mL) in the sepsis group (p = .032), as were interleukin-6 (1562+/-267 vs. 4903+/-608 pg/mL; p = .01) and neopterin/creatinine ratio (0.400+/-0.038 vs. 0.508+/-0.037; p = .032)., Conclusions: PCT is detectable in the baboon as in humans, both in hemorrhagic shock and sepsis. PCT levels are significantly higher in sepsis than in hemorrhage, a finding that is probably related to the differences in endotoxin. The baboon can be used for the study of PCT kinetics in both models; PCT kinetics are clearly different from other markers of sepsis, either IL-6 or neopterin, in both models. There are significant differences between survivors and nonsurvivors in the sepsis model.

Objective: We examined the pattern of organ system dysfunction, the evolution of this pattern over time, and the relationship of these features to mortality in patients who had sepsis syndrome., Design: Prospective, multicenter, observational study., Setting: Intensive care units in tertiary referral teaching hospitals., Patients: A total of 287 patients who had sepsis syndrome were prospectively identified in intensive care units. MATERIALS AND MEASUREMENTS: Cardiovascular, pulmonary, neurologic, coagulation, renal, and hepatic dysfunction were assessed at onset and on day 3 of sepsis syndrome. Organ dysfunction was classified as normal, mild, moderate, severe, and extreme dysfunction. We calculated the occurrence rate and associated 30-day mortality rate of organ dysfunction at the onset of sepsis syndrome. We then measured the change in organ dysfunction from onset to day 3 of sepsis syndrome and determined, for individual organ systems, the associated 30-day mortality rate., Results: At the onset of sepsis syndrome, clinically significant pulmonary dysfunction was the most common organ failure, but was not related to 30-day mortality. Clinically significant cardiovascular, neurologic, coagulation, renal, and hepatic dysfunction were less common at the onset of sepsis syndrome but were significantly associated with the 30-day mortality rate. Worsening neurologic, coagulation, and renal dysfunction from onset to day 3 of sepsis syndrome were associated with significantly higher 30-day mortality than with improvement or no change in organ dysfunction., Conclusions: Increased mortality rate in sepsis syndrome is associated with a pattern characterized by failure of nonpulmonary organ systems and, in particular, worsening neurologic, coagulation, and renal dysfunction over the first 3 days. Although initial pulmonary dysfunction is common in patients with sepsis syndrome, it is not associated with an increased mortality rate.

Objectives: Plasma proinflammatory, anti-inflammatory cytokine, and soluble tumor necrosis factor (TNF) receptor concentrations were examined in hospitalized patients after abdominal and thoracoabdominal aortic aneurysm (TAAA) repair, with and without left atrial femoral bypass. Changes in plasma cytokine concentrations were related to the duration of visceral ischemia and the frequency rate of postoperative, single, or multiple system organ dysfunction (MSOD)., Design: Prospective, observational study., Setting: Two academic referral centers in the United States and The Netherlands., Patients: We included 16 patients undergoing TAAA repair without left atrial femoral bypass, 12 patients undergoing TAAA repair with left atrial femoral bypass, and nine patients undergoing infrarenal aortic aneurysm repair., Measurements and Main Results: Timed, arterial blood sampling for proinflammatory and anti-inflammatory cytokine and soluble TNF receptor concentrations (p55 and p75), and prospective assessment of postoperative single and MSOD. Plasma appearance of TNF-alpha, interleukin (IL)-6, IL-8, and IL-10 peaked 1 to 4 hrs after TAAA repair, and concentrations were significantly elevated compared with infrarenal abdominal aortic aneurysm repair (p < .05). Left atrial femoral bypass significantly reduced the duration of visceral ischemia (p < .05) and the systemic TNF-alpha, p75, and IL-10 responses (p < .05). Plasma TNF-alpha concentrations >150 pg/mL were more common in patients with extended visceral ischemia times (>40 mins). Additionally, patients with early peak TNF-alpha concentrations >150 pg/mL and IL-6 levels >1,000 pg/mL developed MSOD more frequently than patients without these elevated plasma cytokine levels (both p < .05)., Conclusions: Thoracoabdominal aortic aneurysm repair results in the increased plasma appearance of TNF-alpha, IL-6, IL-8, IL-10, and shed TNF receptors. The frequency and magnitude of postoperative organ dysfunction after TAAA repair is associated with an increased concentration of the cytokines, TNF-alpha, and IL-6 and the increased plasma levels of these cytokines appear to require extended visceral ischemia times.