Purpose

We recently identified interleukin-27 (IL-27) as a sepsis diagnostic biomarker in children. Here we assess IL-27 as a sepsis diagnostic biomarker in critically ill adults with systemic inflammatory response syndrome and sepsis.

Methods

IL-27 and procalcitonin (PCT) were measured from plasma samples in three groups: no sepsis (n = 78), pulmonary source of sepsis (n = 66), and non-pulmonary source of sepsis (n = 43). Receiver operating characteristic curves and classification and regression tree methodology were used to evaluate biomarker performance.

Results

IL-27 did not discriminate effectively between sepsis and sterile systemic inflammatory response syndrome in unselected patients. The highest area under the curve (AUC) was 0.70 (95% C.I. 0.60 - 0.80) for IL-27 in subjects with a non-pulmonary source of sepsis. A decision tree incorporating IL-27, PCT, and age had an AUC of 0.79 (0.71-0.87) in subjects with a non-pulmonary source of sepsis. Compared to children with sepsis, adults with sepsis express less IL-27.

Conclusions

IL-27 performed overall poorly in this cohort as a sepsis diagnostic biomarker. Combining IL-27, PCT, and age reasonably estimated the risk of sepsis in subjects with a non-pulmonary source of sepsis. IL-27 may be a more reliable sepsis diagnostic biomarker in children than in adults.

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.

Background

Sepsis progresses rapidly and is associated with considerable morbidity and mortality. Bedside risk stratification scores can quickly identify patients at greatest risk of poor outcomes; however, there is lack of consensus on the best scale to use.

Objective

To compare the ability of quick Sequential Organ Failure Assessment (qSOFA), the National Early Warning System (NEWS2), and the Shock Index-which does not require mental status assessment-to predict poor outcomes among patients with suspected sepsis during triage.

Design, setting, and participants

Retrospective cohort study of adults presenting to an academic emergency department (ED) from June 2012 to December 2018 who had blood cultures and intravenous antibiotics within 24 hours.

Main outcomes and measures

Clinical data were collected from the electronic health record. Patients were considered positive at qSOFA ≥2, Shock Index >0.7, or NEWS2 ≥5 scores. We calculated test characteristics and area under the receiver operating characteristics curves (AUROCs) to predict in-hospital mortality and ED-to-intensive care unit (ICU) admission.

Results

We included 23,837 ED patients; 1,921(8.1%) were qSOFA-positive, 4,273 (17.9%) Shock Index-positive, and 11,832 (49.6%) NEWS2-positive. There were 1,427 (6.0%) deaths and 3,149 (13.2%) ED-to-ICU admissions in the sample. NEWS2 had the highest sensitivity for in-hospital mortality (76.0%) and ED-to-ICU admission (78.9%). qSOFA had the highest specificity for in-hospital mortality (93.4%) and ED-to-ICU admission (95.2%). Shock Index exhibited the highest AUROC for in-hospital mortality (0.648; 95 CI, 0.635-0.662) and ED-to-ICU admission (0.680; 95% CI, 0.617-0.689). Test characteristics were similar among those with sepsis.

Conclusions

Institution priorities should drive score selection, balancing sensitivity and specificity. In our study, qSOFA was highly specific and NEWS2 was the most sensitive for ruling out patients at high risk. Performance of the Shock Index fell between qSOFA and NEWS2 and could be considered because it is easy to implement.

Background

Limited English proficiency (LEP) has been implicated in poor health outcomes. Sepsis is a frequently fatal syndrome that is commonly encountered in hospital medicine. The impact of LEP on sepsis mortality is not currently known.

Objective

To determine the association between LEP and sepsis mortality.

Design

Retrospective cohort study.

Setting

800-bed, tertiary care, academic medical center.

Patients

Electronic health record data were obtained for adults admitted to the hospital with sepsis between June 1, 2012 and December 31, 2016.

Measurements

The primary predictor was LEP. Patients were defined as having LEP if their self-reported primary language was anything other than English and interpreter services were required during hospitalization. The primary outcome was inpatient mortality. Mortality was compared across races stratified by LEP using chi-squared tests of significance. Bivariable and multivariable logistic regressions were performed to investigate the association between mortality, race, and LEP, adjusting for baseline characteristics, comorbidities, and illness severity.

Results

Among 8,974 patients with sepsis, we found that 1 in 5 had LEP, 62% of whom were Asian. LEP was highly associated with death across all races except those identifying as Black and Latino. LEP was associated with a 31% increased odds of mortality after adjusting for illness severity, comorbidities, and other baseline characteristics, including race (OR 1.31, 95% CI 1.06-1.63, P = .02).

Conclusions

In a single-center study of patients hospitalized with sepsis, LEP was associated with mortality across nearly all races. This is a novel finding that will require further exploration into the causal nature of this association.

Rationale

We previously identified two acute respiratory distress syndrome (ARDS) subphenotypes in two separate randomized controlled trials with differential response to positive end-expiratory pressure.

Objectives

To identify these subphenotypes in a third ARDS cohort, to test whether subphenotypes respond differently to fluid management strategy, and to develop a practical model for subphenotype identification.

Methods

We used latent class analysis of baseline clinical and plasma biomarker data to identify subphenotypes in FACTT (Fluid and Catheter Treatment Trial; n = 1,000). Logistic regression was used to test for an interaction between subphenotype and treatment for mortality. We used stepwise modeling to generate a model for subphenotype identification in FACTT and validated its accuracy in the two cohorts in which we previously identified ARDS subphenotypes.

Measurements and main results

We confirmed that a two-class (two-subphenotype) model best described the study population. Subphenotype 2 was again characterized by higher inflammatory biomarkers and hypotension. Fluid management strategy had significantly different effects on 90-day mortality in the two subphenotypes (P = 0.0039 for interaction); mortality in subphenotype 1 was 26% with fluid-liberal strategy versus 18% with fluid-conservative, whereas mortality in subphenotype 2 was 40% with fluid-liberal strategy versus 50% in fluid-conservative. A three-variable model of IL-8, bicarbonate, and tumor necrosis factor receptor-1 accurately classified the subphenotypes.

Conclusions

This analysis confirms the presence of two ARDS subphenotypes that can be accurately identified with a limited number of variables and that responded differently to randomly assigned fluid management. These findings support the presence of ARDS subtypes that may require different treatment approaches.

Background

ARDS is a heterogeneous syndrome that encompasses lung injury from both direct and indirect sources. Direct ARDS (pneumonia, aspiration) has been hypothesized to cause more severe lung epithelial injury than indirect ARDS (eg, nonpulmonary sepsis); however, this hypothesis has not been well studied in humans.

Methods

We measured plasma biomarkers of lung epithelial and endothelial injury and inflammation in a single-center study of 100 patients with ARDS and severe sepsis and in a secondary analysis of 853 patients with ARDS drawn from a multicenter randomized controlled trial. Biomarker levels in patients with direct vs indirect ARDS were compared in both cohorts.

Results

In both studies, patients with direct ARDS had significantly higher levels of a biomarker of lung epithelial injury (surfactant protein D) and significantly lower levels of a biomarker of endothelial injury (angiopoietin-2) than those with indirect ARDS. These associations were robust to adjustment for severity of illness and ARDS severity. In the multicenter study, patients with direct ARDS also had lower levels of von Willebrand factor antigen and IL-6 and IL-8, markers of endothelial injury and inflammation, respectively. The prognostic value of the biomarkers was similar in direct and indirect ARDS.

Conclusions

Direct lung injury in humans is characterized by a molecular phenotype consistent with more severe lung epithelial injury and less severe endothelial injury. The opposite pattern was identified in indirect lung injury. Clinical trials of novel therapies targeted specifically at the lung epithelium or endothelium may benefit from preferentially enrolling patients with direct and indirect ARDS, respectively.

Background:The Acute Respiratory Distress Syndrome (ARDS) is a heterogeneous syndrome that encompasses lung injury from both direct and indirect sources. Direct ARDS (pneumonia, aspiration) has been hypothesized to cause more severe lung epithelial injury than indirect ARDS (e.g. non-pulmonary sepsis); however, this hypothesis has not been well-studied in humans. Methods:We measured plasma biomarkers of lung epithelial and endothelial injury and inflammation in a single center study of 100 patients with ARDS and severe sepsis, and in a secondary analysis of 853 ARDS patients drawn from a multicenter randomized controlled trial. Biomarker levels in patients with direct vs indirect ARDS were compared in both cohorts. Results:In both studies, direct ARDS patients had significantly higher levels of a biomarker of lung epithelial injury (surfactant protein-D) and significantly lower levels of a biomarker of endothelial injury (angiopoietin-2), compared with indirect ARDS patients. These associations were robust to adjustment for severity of illness and ARDS severity. In the multicenter study, direct ARDS patients also had lower levels of von Willebrand factor antigen and interleukins 6 and 8, markers of endothelial injury and inflammation, respectively. The prognostic value of the biomarkers was similar in direct and indirect ARDS. Conclusions:Direct lung injury in humans is characterized by a molecular phenotype consistent with more severe lung epithelial injury and less severe endothelial injury. The opposite pattern was identified in indirect lung injury. Clinical trials of novel therapies targeted specifically at the lung epithelium or endothelium may benefit from preferentially enrolling patients with direct or indirect ARDS, respectively.The Acute Respiratory Distress Syndrome (ARDS) is a heterogeneous syndrome that encompasses lung injury from both direct and indirect sources. Direct ARDS (pneumonia, aspiration) has been hypothesized to cause more severe lung epithelial injury than indirect ARDS (e.g. non-pulmonary sepsis); however, this hypothesis has not been well-studied in humans.We measured plasma biomarkers of lung epithelial and endothelial injury and inflammation in a single center study of 100 patients with ARDS and severe sepsis, and in a secondary analysis of 853 ARDS patients drawn from a multicenter randomized controlled trial. Biomarker levels in patients with direct vs indirect ARDS were compared in both cohorts.In both studies, direct ARDS patients had significantly higher levels of a biomarker of lung epithelial injury (surfactant protein-D) and significantly lower levels of a biomarker of endothelial injury (angiopoietin-2), compared with indirect ARDS patients. These associations were robust to adjustment for severity of illness and ARDS severity. In the multicenter study, direct ARDS patients also had lower levels of von Willebrand factor antigen and interleukins 6 and 8, markers of endothelial injury and inflammation, respectively. The prognostic value of the biomarkers was similar in direct and indirect ARDS.Direct lung injury in humans is characterized by a molecular phenotype consistent with more severe lung epithelial injury and less severe endothelial injury. The opposite pattern was identified in indirect lung injury. Clinical trials of novel therapies targeted specifically at the lung epithelium or endothelium may benefit from preferentially enrolling patients with direct or indirect ARDS, respectively.

Rationale

Current clinical prediction scores for acute lung injury (ALI) have limited positive predictive value. No studies have evaluated predictive plasma biomarkers in a broad population of critically ill patients or as an adjunct to clinical prediction scores.

Objectives

To determine whether plasma angiopoietin-2 (Ang-2), von Willebrand factor (vWF), interleukin-8 (IL-8), and/or receptor for advanced glycation end products (sRAGE) predict ALI in critically ill patients.

Methods

Plasma samples were drawn from critically ill patients (n = 230) identified in the emergency department. Patients who had ALI at baseline or in the subsequent 6 hours were excluded, and the remaining patients were followed for development of ALI.

Measurements and main results

Nineteen patients developed ALI at least 6 hours after the sample draw. Higher levels of Ang-2 and IL-8 were significantly associated with increased development of ALI (P = 0.0008, 0.004, respectively). The association between Ang-2 and subsequent development of ALI was robust to adjustment for sepsis and vasopressor use. Ang-2 and the Lung Injury Prediction Score each independently discriminated well between those who developed ALI and those who did not (area under the receiver operating characteristic curve, 0.74 for each), and using the two together improved the area under the curve to 0.84 (vs. 0.74, P = 0.05). In contrast, plasma levels of sRAGE and vWF were not predictive of ALI.

Conclusions

Plasma biomarkers such as Ang-2 can improve clinical prediction scores and identify patients at high risk for ALI. In addition, the early rise of Ang-2 emphasizes the importance of endothelial injury in the early pathogenesis of ALI.

Background

Multiple scoring systems have been developed for both the intensive care unit (ICU) and the emergency department (ED) to risk stratify patients and predict mortality. However, it remains unclear whether the additional data needed to compute ICU scores improves mortality prediction for critically ill patients compared to the simpler ED scores.

Methods

We studied a prospective observational cohort of 227 critically ill patients admitted to the ICU directly from the ED at an academic, tertiary care medical center. We compared Acute Physiology and Chronic Health Evaluation (APACHE) II, APACHE III, Simplified Acute Physiology Score (SAPS) II, Modified Early Warning Score (MEWS), Rapid Emergency Medicine Score (REMS), Prince of Wales Emergency Department Score (PEDS), and a pre-hospital critical illness prediction score developed by Seymour et al. (JAMA 2010, 304(7):747-754). The primary endpoint was 60-day mortality. We compared the receiver operating characteristic (ROC) curves of the different scores and their calibration using the Hosmer-Lemeshow goodness-of-fit test and visual assessment.

Results

The ICU scores outperformed the ED scores with higher area under the curve (AUC) values (p = 0.01). There were no differences in discrimination among the ED-based scoring systems (AUC 0.698 to 0.742; p = 0.45) or among the ICU-based scoring systems (AUC 0.779 to 0.799; p = 0.60). With the exception of the Seymour score, the ED-based scoring systems did not discriminate as well as the best-performing ICU-based scoring system, APACHE III (p = 0.005 to 0.01 for comparison of ED scores to APACHE III). The Seymour score had a superior AUC to other ED scores and, despite a lower AUC than all the ICU scores, was not significantly different than APACHE III (p = 0.09). When data from the first 24 h in the ICU was used to calculate the ED scores, the AUC for the ED scores improved numerically, but this improvement was not statistically significant. All scores had acceptable calibration.

Conclusions

In contrast to prior studies of patients based in the emergency department, ICU scores outperformed ED scores in critically ill patients admitted from the emergency department. This difference in performance seemed to be primarily due to the complexity of the scores rather than the time window from which the data was derived.

Objectives

The acute respiratory distress syndrome is common in critically ill patients. Recognition is crucial because acute respiratory distress syndrome is associated with a high mortality rate, and low tidal volume ventilation improves mortality. However, acute respiratory distress syndrome often goes unrecognized. Risk factors for under-recognition and trends over time have not been fully described.

Design

Retrospective chart review of patients with acute respiratory distress syndrome from a prospective cohort study of critically ill patients. For each patient's ICU stay, we searched the chart for terms that indicated that acute respiratory distress syndrome was diagnosed, in the differential diagnosis, or treated with low tidal volume ventilation.

Setting

ICUs at a tertiary hospital at the University of California, San Francisco between 2008 and 2016.

Patients

Critically ill patients with acute respiratory distress syndrome.

Interventions

None.

Measurements and main results

Acute respiratory distress syndrome was recognized in 70% of patients, and recognition increased from 60% in 2008-2009 to 92% in 2016 (p = 0.004). Use of tidal volumes less than 6.5 mL/kg also increased (p < 0.001) from 20% to 92%. Increased acute respiratory distress syndrome severity (p = 0.01) and vasopressor use (p = 0.04) were associated with greater recognition. Clinician diagnosis of acute respiratory distress syndrome and inclusion of acute respiratory distress syndrome in the differential diagnosis were associated with tidal volumes less than 6.5 mL/kg (51% use of tidal volume ≤ 6.5 mL/kg if acute respiratory distress syndrome recognized vs 15% if not recognized; p = 0.002). Diagnosing acute respiratory distress syndrome was associated with lower tidal volume in multivariate analysis.

Conclusions

Although acute respiratory distress syndrome recognition and low tidal volume ventilation use have increased over time, they remain less than universal. Clinician recognition of acute respiratory distress syndrome is associated with both systemic and respiratory severity of illness and is also associated with use of low tidal volume ventilation.