Impact of Electronic Medical Record Alerts on Emergency Physician Workflow and Medical Management.

BACKGROUND: Electronic medical record (EMR) alerts are automated messages that notify the physician of important information. However, little is known about how EMR alerts affect the workflow and decision-making of emergency physicians (EPs). STUDY OBJECTIVES: This study aimed to quantify the number of EMR alerts EPs receive, the time required to resolve alerts, the types of alerts EPs receive, and the impact of alerts on patient management. METHODS: We performed a prospective observational study at a tertiary care ED with 130,000 visits annually. Research assistants observed EPs on shift from May to December 2018. They recorded the number of EMR alerts received, time spent addressing the alerts, the types of alerts received, and queried the EP to determine if the alert impacted patient management. RESULTS: Seven residents and six attending physicians were observed on a total of 17 shifts and 153 patient encounters; 78% (119) of patient encounters involved alerts. These 119 patients triggered 530 EMR alerts. EPs spent a mean of 7.06 s addressing each alert and addressed 3.46 alerts per total patient seen. In total, EPs spent approximately 24 s per patient resolving alerts. Only 12 alerts (2.26%) changed clinical management. CONCLUSION: EPs frequently receive EMR alerts, however, most alerts were not perceived to impact patient care. These alerts contribute to the high volume of interruptions EPs must contend with in the clinical environment of the ED.

Effect of Ascorbic Acid, Corticosteroids, and Thiamine on Organ Injury in Septic Shock: The ACTS Randomized Clinical Trial.

IMPORTANCE: The combination of ascorbic acid, corticosteroids, and thiamine has been identified as a potential therapy for septic shock. OBJECTIVE: To determine whether the combination of ascorbic acid, corticosteroids, and thiamine attenuates organ injury in patients with septic shock. DESIGN, SETTING, AND PARTICIPANTS: Randomized, blinded, multicenter clinical trial of ascorbic acid, corticosteroids, and thiamine vs placebo for adult patients with septic shock. Two hundred five patients were enrolled between February 9, 2018, and October 27, 2019, at 14 centers in the United States. Follow-up continued until November 26, 2019. INTERVENTIONS: Patients were randomly assigned to receive parenteral ascorbic acid (1500 mg), hydrocortisone (50 mg), and thiamine (100 mg) every 6 hours for 4 days (n = 103) or placebo in matching volumes at the same time points (n = 102). MAIN OUTCOMES AND MEASURES: The primary outcome was change in the Sequential Organ Failure Assessment (SOFA) score (range, 0-24; 0 = best) between enrollment and 72 hours. Key secondary outcomes included kidney failure and 30-day mortality. Patients who received at least 1 dose of study drug were included in analyses. RESULTS: Among 205 randomized patients (mean age, 68 [SD, 15] years; 90 [44%] women), 200 (98%) received at least 1 dose of study drug, completed the trial, and were included in the analyses (101 with intervention and 99 with placebo group). Overall, there was no statistically significant interaction between time and treatment group with regard to SOFA score over the 72 hours after enrollment (mean SOFA score change from 9.1 to 4.4 [-4.7] points with intervention vs 9.2 to 5.1 [-4.1] points with placebo; adjusted mean difference, -0.8; 95% CI, -1.7 to 0.2; P = .12 for interaction). There was no statistically significant difference in the incidence of kidney failure (31.7% with intervention vs 27.3% with placebo; adjusted risk difference, 0.03; 95% CI, -0.1 to 0.2; P = .58) or in 30-day mortality (34.7% vs 29.3%, respectively; hazard ratio, 1.3; 95% CI, 0.8-2.2; P = .26). The most common serious adverse events were hyperglycemia (12 patients with intervention and 7 patients with placebo), hypernatremia (11 and 7 patients, respectively), and new hospital-acquired infection (13 and 12 patients, respectively). CONCLUSIONS AND RELEVANCE: In patients with septic shock, the combination of ascorbic acid, corticosteroids, and thiamine, compared with placebo, did not result in a statistically significant reduction in SOFA score during the first 72 hours after enrollment. These data do not support routine use of this combination therapy for patients with septic shock. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03389555.

Renal systems biology of patients with systemic inflammatory response syndrome.

A systems biology approach was used to comprehensively examine the impact of renal disease and hemodialysis (HD) on patient response during critical illness. To achieve this, we examined the metabolome, proteome, and transcriptome of 150 patients with critical illness, stratified by renal function. Quantification of plasma metabolites indicated greater change as renal function declined, with the greatest derangements in patients receiving chronic HD. Specifically, 6 uremic retention molecules, 17 other protein catabolites, 7 modified nucleosides, and 7 pentose phosphate sugars increased as renal function declined, consistent with decreased excretion or increased catabolism of amino acids and ribonucleotides. Similarly, the proteome showed increased levels of low-molecular-weight proteins and acute-phase reactants. The transcriptome revealed a broad-based decrease in mRNA levels among patients on HD. Systems integration revealed an unrecognized association between plasma RNASE1 and several RNA catabolites and modified nucleosides. Further, allantoin, N1-methyl-4-pyridone-3-carboxamide, and N-acetylaspartate were inversely correlated with the majority of significantly downregulated genes. Thus, renal function broadly affected the plasma metabolome, proteome, and peripheral blood transcriptome during critical illness; changes were not effectively mitigated by hemodialysis. These studies allude to several novel mechanisms whereby renal dysfunction contributes to critical illness.

Integrative "omic" analysis of experimental bacteremia identifies a metabolic signature that distinguishes human sepsis from systemic inflammatory response syndromes.

RATIONALE: Sepsis is a leading cause of morbidity and mortality. Currently, early diagnosis and the progression of the disease are difficult to make. The integration of metabolomic and transcriptomic data in a primate model of sepsis may provide a novel molecular signature of clinical sepsis. OBJECTIVES: To develop a biomarker panel to characterize sepsis in primates and ascertain its relevance to early diagnosis and progression of human sepsis. METHODS: Intravenous inoculation of Macaca fascicularis with Escherichia coli produced mild to severe sepsis, lung injury, and death. Plasma samples were obtained before and after 1, 3, and 5 days of E. coli challenge and at the time of killing. At necropsy, blood, lung, kidney, and spleen samples were collected. An integrative analysis of the metabolomic and transcriptomic datasets was performed to identify a panel of sepsis biomarkers. MEASUREMENTS AND MAIN RESULTS: The extent of E. coli invasion, respiratory distress, lethargy, and mortality was dependent on the bacterial dose. Metabolomic and transcriptomic changes characterized severe infections and death, and indicated impaired mitochondrial, peroxisomal, and liver functions. Analysis of the pulmonary transcriptome and plasma metabolome suggested impaired fatty acid catabolism regulated by peroxisome-proliferator activated receptor signaling. A representative four-metabolite model effectively diagnosed sepsis in primates (area under the curve, 0.966) and in two human sepsis cohorts (area under the curve, 0.78 and 0.82). CONCLUSIONS: A model of sepsis based on reciprocal metabolomic and transcriptomic data was developed in primates and validated in two human patient cohorts. It is anticipated that the identified parameters will facilitate early diagnosis and management of sepsis.

Feasibility of Light and Music Therapy in the Elderly for the Prevention of Hospital-Associated Delirium.

Hospital-associated delirium is common in older adults, especially those with dementia, and is associated with high morbidity and mortality. We performed a feasibility study in the emergency department (ED) to examine the effect of light and/or music on the incidence of hospital- associated delirium. Patients aged ≥ 65 who presented to the ED and tested positive for cognitive impairment were enrolled in the study (n = 133). Patients were randomized to one of four treatment arms: music, light, music and light, and usual care. They received the intervention during their ED stay. In the control group, 7/32 patients developed delirium, while in the music-only group, 2/33 patients developed delirium (RR 0.27, 95% CI 0.06-1.23), and in the light-only group (RR 0.41, 95% CI 0.12-1.46), 3/33 patients developed delirium. In the music + light group, 8/35 patients developed delirium (RR 1.04, 95% CI 0.42--2.55). Providing music therapy and bright light therapy to ED patients was shown to be feasible. Although this small pilot study did not reach statistical significance, there was a trend towards less delirium in the music-only and light-only groups. This study lays the groundwork for future investigation into the efficacy of these interventions.

Mortality in the Emergency Department and the Effectiveness of Conventional Safety Event Reporting.

Background Patient mortality reviews identify care, system, and process deficiencies. Patient deaths undergo quarterly review in our academic emergency department (ED), whereas in other departments, mortality reviews are requested by the pronouncing physician within 24 hours. In the ED, individual physicians encounter barriers to 24-hour reviews, including feasibility, the perception of futility, re-exposure to traumatic events, and a high frequency of pre-hospital and non-preventable deaths. This quality review aimed to determine the preventable death rate, contributing factors to ED patient mortality, cases requiring further review, and the capture rate of individual case submissions into the patient safety reporting system. Methods A retrospective chart review was performed on all patient deaths occurring in our ED from July 2019 to February 2020. All patients 18 years or older who were pronounced dead in the ED during our data collection period were included. Patients declared deceased pre-hospital, on an inpatient floor, or in the operating room were excluded. Deaths were assessed for characteristics such as sex, presence of a pulse upon arrival, diagnostics and interventions performed, and whether the cause of death was traumatic or medical. Deaths were categorized on a 5-point Likert scale ranging from "not preventable" to "likely preventable." The presence or absence of contributing factors and the need for further review were recorded. Results Of the 166 reviewed cases, 87% (n=144) were non-preventable due to a terminal condition upon arrival, 12% (n=20) were non-preventable despite maximal efforts, 0.6% (n=1) were non-preventable despite a medical or systems error, and 0.6% (n=1) were possibly preventable due to a medical or systems error. No cases were definitively preventable. Only 1.2% (n=2) of cases required further safety review. In 55% (n=91) of cases, the patient arrived without a pulse. Medical deaths (60%, n=100) outnumbered traumatic deaths (39%, n=64). The most utilized diagnostic test was ultrasound (67%, n=111), and the most utilized intervention was advanced cardiac life support (59%, n=98). Conclusion There is a high prevalence of unpreventable deaths in the ED (99%, n=164). Only two cases (1.2%) were identified for further patient safety review. Standard safety event reporting practices correctly identified all possibly preventable ED deaths.

Multiplex PCR to diagnose bloodstream infections in patients admitted from the emergency department with sepsis.

Sepsis is caused by a heterogeneous group of infectious etiologies. Early diagnosis and the provision of appropriate antimicrobial therapy correlate with positive clinical outcomes. Current microbiological techniques are limited in their diagnostic capacities and timeliness. Multiplex PCR has the potential to rapidly identify bloodstream infections and fill this diagnostic gap. We identified patients from two large academic hospital emergency departments with suspected sepsis. The results of a multiplex PCR that could detect 25 bacterial and fungal pathogens were compared to those of blood culture. The results were analyzed with respect to the likelihood of infection, sepsis severity, the site of infection, and the effect of prior antibiotic therapy. We enrolled 306 subjects with suspected sepsis. Of these, 43 were later determined not to have infectious etiologies. Of the remaining 263 subjects, 70% had sepsis, 16% had severe sepsis, and 14% had septic shock. The majority had a definite infection (41.5%) or a probable infection (30.7%). Blood culture and PCR performed similarly with samples from patients with clinically defined infections (areas under the receiver operating characteristic curves, 0.64 and 0.60, respectively). However, blood culture identified more cases of septicemia than PCR among patients with an identified infectious etiology (66 and 46, respectively; P = 0.0004). The two tests performed similarly when the results were stratified by sepsis severity or infection site. Blood culture tended to detect infections more frequently among patients who had previously received antibiotics (P = 0.06). Conversely, PCR identified an additional 24 organisms that blood culture failed to detect. Real-time multiplex PCR has the potential to serve as an adjunct to conventional blood culture, adding diagnostic yield and shortening the time to pathogen identification.

The diagnostic accuracy of plasma neutrophil gelatinase-associated lipocalin in the prediction of acute kidney injury in emergency department patients with suspected sepsis.

STUDY OBJECTIVE: We assess the diagnostic accuracy of plasma neutrophil gelatinase-associated lipocalin (NGAL) to predict acute kidney injury in emergency department (ED) patients with suspected sepsis. METHODS: We conducted a secondary analysis of a prospective observational study of a convenience sample of patients from 10 academic medical center EDs. Inclusion criteria were adult patients aged 18 years or older, with suspected infection or a serum lactate level greater than 2.5 mmol/L; 2 or more systemic inflammatory response syndrome criteria; and a subsequent serum creatinine level obtained within 12 to 72 hours of enrollment. Exclusion criteria were pregnancy, do-not-resuscitate status, cardiac arrest, or dialysis dependency. NGAL was measured in plasma collected at ED presentation. Acute kidney injury was defined as an increase in serum creatinine measurement of greater than 0.5 mg/dL during 72 hours. RESULTS: There were 661 patient enrolled, with 24 cases (3.6%) of acute kidney injury that developed within 72 hours after ED presentation. Median plasma NGAL levels were 134 ng/mL (interquartile range 57 to 277 ng/mL) in patients without acute kidney injury and 456 ng/mL (interquartile range 296 to 727 ng/mL) in patients with acute kidney injury. Plasma NGAL concentrations of greater than 150 ng/mL were 96% sensitive (95% confidence interval [CI] 79% to 100%) and 51% (95% CI 47% to 55%) specific for acute kidney injury. In comparison, to achieve equivalent sensitivity with initial serum creatinine level at ED presentation required a cutoff of 0.7 mg/dL and resulted in specificity of 17% (95% CI 14% to 20%). CONCLUSION: In this preliminary investigation, increased plasma NGAL concentrations measured on presentation to the ED in patients with suspected sepsis were associated with the development of acute kidney injury. Our findings support NGAL as a promising new biomarker for acute kidney injury; however, further research is warranted.

Standardization of severe sepsis management: a survey of methodologies in academic and community settings.

BACKGROUND: Evidence-based therapies for severe sepsis include early antibiotics, early goal-directed therapy, corticosteroids, recombinant human activated protein C, glucose control, and lung protective strategies. OBJECTIVE: The objective of this study was to analyze methods, challenges, and outcomes observed by hospitals that implemented a hospital-wide sepsis management protocol incorporating evidence-based therapies. METHODS: In a cross-sectional multi-center telephone survey over a 4-month period, clinicians (participants) responsible for developing a hospital sepsis protocol were questioned regarding its development and outcomes. RESULTS: Participants completing surveys represented 40 hospitals (20 academic and 20 community). Twenty-seven percent of protocol champions were Emergency physicians or nurses. Sixty-three percent reported protocol development time of 6-12 months. Eighty-eight percent of participants reported protocol initiation in the Emergency Department. Three participants reported hiring a nurse educator to implement the protocol. Ninety-five percent of participants measure lactate as part of patient screening. Protocol therapies reported included early antibiotics (98%), early goal directed-therapy (EGDT) (98%), corticosteroids (80%), and activated protein C (73%). Contributions to success included having a protocol champion (85%) and sepsis education program (65%). Twenty-one participants had recorded patient-level data, totaling 2319 protocol patients, compared to 1719 non-protocol patients, with in-hospital mortality of 23% and 44%, respectively. CONCLUSIONS: Implementation of a sepsis management protocol incorporating evidence-based therapies can be accomplished in both academic and community hospitals, with minimal additional staffing. The presence of a protocol champion and education program is crucial to success, and may result in improved patient outcome.

A prospective, multicenter derivation of a biomarker panel to assess risk of organ dysfunction, shock, and death in emergency department patients with suspected sepsis.

OBJECTIVE: To define a biomarker panel to predict organ dysfunction, shock, and in-hospital mortality in emergency department (ED) patients with suspected sepsis. DESIGN: Prospective observational study. SETTING: EDs of ten academic medical centers. PATIENTS: There were 971 patients enrolled. INCLUSION CRITERIA: 1) ED patients age > 18; 2) suspected infection or a serum lactate level > 2.5 mmol/L; and 3) two or more systemic inflammatory response syndrome criteria. EXCLUSION CRITERIA: pregnancy, do-not-resuscitate status, or cardiac arrest. MEASUREMENTS AND MAIN RESULTS: Nine biomarkers were assayed from blood draws obtained on ED presentation. Multivariable logistic regression was used to identify an optimal combination of biomarkers to create a panel. The derived formula for weighting biomarker values was used to calculate a "sepsis score," which was the predicted probability of the primary outcome of severe sepsis (sepsis plus organ dysfunction) within 72 hrs. We also assessed the ability of the sepsis score to predict secondary outcome measures of septic shock within 72 hrs and in-hospital mortality. The overall rates of each outcome were severe sepsis, 52%; septic shock, 39%; and in-hospital mortality 7%. Among the nine biomarkers tested, the optimal 3-marker panel was neutrophil gelatinase-associated lipocalin, protein C, and interleukin-1 receptor antagonist. The area under the curve for the accuracy of the sepsis score derived from these three biomarkers was 0.80 for severe sepsis, 0.77 for septic shock, and 0.79 for death. When included in multivariate models with clinical variables, the sepsis score remained highly significant (p < 0.001) for all the three outcomes. CONCLUSIONS: A biomarker panel of neutrophil gelatinase-associated lipocalin, interleukin-1ra, and Protein C was predictive of severe sepsis, septic shock, and death in ED patients with suspected sepsis. Further study is warranted to prospectively validate the clinical utility of these biomarkers and the sepsis score in risk-stratifying patients with suspected sepsis.

Under-recognized Etiology of Altered Mental Status in a Patient with Alcoholism.

Wernicke's encephalopathy is an important condition for the emergency physician (EP) to consider in patients at risk for malnutrition. A 60-year-old man with history of alcoholism presented with word-finding difficulties, dysmetria, ataxia, and personality changes. After treatment with high-dose thiamine, his neurological status returned to his baseline. Although EPs routinely prescribe thiamine for patients with alcoholism, the common initial dose of 100 mg per day is likely subtherapeutic, and the population of patients at risk for malnutrition is much broader than only those with alcoholism, and includes those with cancer, anorexia nervosa, hyperemesis gravidarum, and others. EPs must be aware of this low-cost, readily available prophylaxis to prevent long-term neurological morbidity.

Inadequate blood volume collected for culture: a survey of health care professionals.

Adequate blood culture volume is the single most important determinant for yield of organisms. We sought to determine whether health care professionals are aware of the current evidence-based recommendations for blood culture collection. An anonymous survey of employees qualified to collect blood cultures was conducted (July-October 2004) in an urban tertiary care facility. The survey asked,"What volume of blood should be collected in one bottle for a blood culture?" Of the 360 employees of the hospital surveyed, 355 returned evaluable answers for blood culture volume collected. Overall, 79% (95% confidence interval [CI], 74%-83%) answered less than 10 mL, and 44% (95% CI, 39%-49%) answered less than 5 mL of blood. When examined by occupation, 90% (95% CI, 86%-94%) of nurses, 97% (95% CI, 91%-100%) of technicians, and 55% (95% CI, 46%-64%) of physicians answered less than 10 mL; 52% (95% CI, 45%-59%) of nurses, 63% (95% CI, 46%-79%) of technicians, and 26% (95% CI, 18%-35%) of physicians answered less than 5 mL. Of all respondents, 21% (95% CI, 17%-25%) answered 1 mL or less. Our findings reveal that a high percentage of health care personnel do not know the optimal volume of blood recommended for collection. Because volume remains the most important determinant for the optimal yield of organisms, these findings raise an important quality assurance issue.

Effective lactate clearance is associated with improved outcome in post-cardiac arrest patients.

INTRODUCTION: Early, effective lactate clearance has been shown to be associated with improved mortality in patients with trauma, burns, and sepsis. We investigated whether early, high lactate clearance was associated with reduced mortality in post-cardiac arrest patients. METHODS: We performed a retrospective analysis of post-cardiac arrest patients in an urban emergency department. Inclusion criteria included pre-hospital cardiac arrest patients over the age of 18. Exclusion criteria were traumatic arrest, successful resuscitation prior to the arrival of emergency medical services, and cardiac arrest in the presence of pre-hospital providers. Primary endpoints consisted of survival to 24h and survival to hospital discharge. RESULTS: A total of 79 patients were analyzed with a mean age of 64+/-17 and mean APACHE II score of 37.7+/-5. Of the 79 patients, 27 (34%) died within 24h and 66 (84%) died during the hospital course. The mean initial lactate level for the overall group was 15+/-5.2mmol/dl with a mean lactate of 14.4+/-5.1mmol/dl in the survivors and 16+/-5.3mmol/dl in the non-survivors (p>0.05). Lactate clearance at both 6 and 12h was significantly higher for both 24-h and overall in-hospital survival (p<0.05). A multivariable analysis showed that high lactate clearance at 12h was predictive of 24-h survival (p<0.05). CONCLUSIONS: Early, effective lactate clearance is associated with decreased early and overall in-hospital mortality in post-cardiac arrest patients. These findings suggest that post-arrest tissue hypo-perfusion plays in an important role in early as well as overall mortality.

Early goal-directed therapy in severe sepsis and septic shock revisited: concepts, controversies, and contemporary findings.

Studies of acute myocardial infarction, trauma, and stroke have been translated into improved outcomes by earlier diagnosis and application of therapy at the most proximal stage of hospital presentation. Most therapies for these diseases are instituted prior to admission to an ICU; this approach to the sepsis patient has been lacking. In response, a trial comparing early goal-directed therapy (EGDT) vs standard care was performed using specific criteria for the early identification of high-risk sepsis patients, verified definitions, and a consensus-derived protocol to reverse the hemodynamic perturbations of hypovolemia, vasoregulation, myocardial suppression, and increased metabolic demands. Five years after the EGDT publication, there has been much discussion generated with regard to the concepts of EGDT, as well as debate fueled regarding diagnostic and therapeutic interventions. However, during this time period further investigations by the primary investigators and others have brought additional contemporary findings. EGDT modulates some of the components of inflammation, as reflected by improved organ function. The end points used in the EGDT protocol, the outcome results, and the cost-effectiveness have subsequently been externally validated, revealing similar or even better findings than those from the original trial. Although EGDT is faced with challenges, a coordinated approach to sepsis management is necessary to duplicate the progress in outcomes seen in patients with conditions such as acute myocardial infarction, stroke, and trauma.

Host gene expression classifiers diagnose acute respiratory illness etiology.

Acute respiratory infections caused by bacterial or viral pathogens are among the most common reasons for seeking medical care. Despite improvements in pathogen-based diagnostics, most patients receive inappropriate antibiotics. Host response biomarkers offer an alternative diagnostic approach to direct antimicrobial use. This observational cohort study determined whether host gene expression patterns discriminate noninfectious from infectious illness and bacterial from viral causes of acute respiratory infection in the acute care setting. Peripheral whole blood gene expression from 273 subjects with community-onset acute respiratory infection (ARI) or noninfectious illness, as well as 44 healthy controls, was measured using microarrays. Sparse logistic regression was used to develop classifiers for bacterial ARI (71 probes), viral ARI (33 probes), or a noninfectious cause of illness (26 probes). Overall accuracy was 87% (238 of 273 concordant with clinical adjudication), which was more accurate than procalcitonin (78%, P < 0.03) and three published classifiers of bacterial versus viral infection (78 to 83%). The classifiers developed here externally validated in five publicly available data sets (AUC, 0.90 to 0.99). A sixth publicly available data set included 25 patients with co-identification of bacterial and viral pathogens. Applying the ARI classifiers defined four distinct groups: a host response to bacterial ARI, viral ARI, coinfection, and neither a bacterial nor a viral response. These findings create an opportunity to develop and use host gene expression classifiers as diagnostic platforms to combat inappropriate antibiotic use and emerging antibiotic resistance.

Clinical review: New technologies -- venturing out of the intensive care unit.

The delivery of critical care is no longer limited to the intensive care unit. The information gained by utilization of new technologies has proven beneficial in some populations. Research into earlier and more widespread use of these modalities may prove to be of even greater benefit to critically ill patients.

Age-related differences in biomarkers of acute inflammation during hospitalization for sepsis.

The authors aimed to evaluate age-related differences in inflammation biomarkers during the first 72 h of hospitalization for sepsis. This was a secondary analysis of a prospective observational cohort of adult patients (n = 855) from 10 urban academic emergency departments with confirmed infection and two or more systemic inflammatory response syndrome criteria. Six inflammation-related biomarkers were analyzed-chemokine (CC-motif) ligand-23, C-reactive protein, interleukin-1 receptor antagonist, neutrophil gelatinase-associated lipocalin (NGAL), peptidoglycan recognition protein, and tumor necrosis factor receptor-1a (TNFR-1a)-measured at presentation and 3, 6, 12, 24, 48, or 72 h later. The median age was 56 (interquartile range, 43 - 72) years, and sepsis severity was 38% sepsis, 16% severe sepsis without shock, and 46% septic shock; the overall 30-day mortality was 12%. Older age was associated with higher sepsis severity: 41% of subjects aged 18 to 34 years had severe sepsis or septic shock compared with 71% for those aged 65 years or older (P < 0.001). In longitudinal models adjusting for demographics, comorbidities, and infection source, older age was associated with higher baseline values for chemokine (CC-motif) ligand-23, interleukin-1 receptor antagonist, NGAL, and TNFR-1a (all P < 0.05). However, older adults had higher mean values during the entire 72-h period only for NGAL and TNFR-1a and higher final 72-h values only for TNFR-1a. Adjustment or stratification by sepsis severity did not change the age-inflammation associations. Although older adults had higher levels of inflammation at presentation and an increased incidence of severe sepsis and septic shock, these age-related differences in inflammation largely resolved during the first 72 h of hospitalization.

Metabolomic derangements are associated with mortality in critically ill adult patients.

OBJECTIVE: To identify metabolomic biomarkers predictive of Intensive Care Unit (ICU) mortality in adults. RATIONALE: Comprehensive metabolomic profiling of plasma at ICU admission to identify biomarkers associated with mortality has recently become feasible. METHODS: We performed metabolomic profiling of plasma from 90 ICU subjects enrolled in the BWH Registry of Critical Illness (RoCI). We tested individual metabolites and a Bayesian Network of metabolites for association with 28-day mortality, using logistic regression in R, and the CGBayesNets Package in MATLAB. Both individual metabolites and the network were tested for replication in an independent cohort of 149 adults enrolled in the Community Acquired Pneumonia and Sepsis Outcome Diagnostics (CAPSOD) study. RESULTS: We tested variable metabolites for association with 28-day mortality. In RoCI, nearly one third of metabolites differed among ICU survivors versus those who died by day 28 (N = 57 metabolites, p<.05). Associations with 28-day mortality replicated for 31 of these metabolites (with p<.05) in the CAPSOD population. Replicating metabolites included lipids (N = 14), amino acids or amino acid breakdown products (N = 12), carbohydrates (N = 1), nucleotides (N = 3), and 1 peptide. Among 31 replicated metabolites, 25 were higher in subjects who progressed to die; all 6 metabolites that are lower in those who die are lipids. We used Bayesian modeling to form a metabolomic network of 7 metabolites associated with death (gamma-glutamylphenylalanine, gamma-glutamyltyrosine, 1-arachidonoylGPC(20:4), taurochenodeoxycholate, 3-(4-hydroxyphenyl) lactate, sucrose, kynurenine). This network achieved a 91% AUC predicting 28-day mortality in RoCI, and 74% of the AUC in CAPSOD (p<.001 in both populations). CONCLUSION: Both individual metabolites and a metabolomic network were associated with 28-day mortality in two independent cohorts. Metabolomic profiling represents a valuable new approach for identifying novel biomarkers in critically ill patients.

An integrated transcriptome and expressed variant analysis of sepsis survival and death.

BACKGROUND: Sepsis, a leading cause of morbidity and mortality, is not a homogeneous disease but rather a syndrome encompassing many heterogeneous pathophysiologies. Patient factors including genetics predispose to poor outcomes, though current clinical characterizations fail to identify those at greatest risk of progression and mortality. METHODS: The Community Acquired Pneumonia and Sepsis Outcome Diagnostic study enrolled 1,152 subjects with suspected sepsis. We sequenced peripheral blood RNA of 129 representative subjects with systemic inflammatory response syndrome (SIRS) or sepsis (SIRS due to infection), including 78 sepsis survivors and 28 sepsis non-survivors who had previously undergone plasma proteomic and metabolomic profiling. Gene expression differences were identified between sepsis survivors, sepsis non-survivors, and SIRS followed by gene enrichment pathway analysis. Expressed sequence variants were identified followed by testing for association with sepsis outcomes. RESULTS: The expression of 338 genes differed between subjects with SIRS and those with sepsis, primarily reflecting immune activation in sepsis. Expression of 1,238 genes differed with sepsis outcome: non-survivors had lower expression of many immune function-related genes. Functional genetic variants associated with sepsis mortality were sought based on a common disease-rare variant hypothesis. VPS9D1, whose expression was increased in sepsis survivors, had a higher burden of missense variants in sepsis survivors. The presence of variants was associated with altered expression of 3,799 genes, primarily reflecting Golgi and endosome biology. CONCLUSIONS: The activation of immune response-related genes seen in sepsis survivors was muted in sepsis non-survivors. The association of sepsis survival with a robust immune response and the presence of missense variants in VPS9D1 warrants replication and further functional studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT00258869. Registered on 23 November 2005.