Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension.

BACKGROUND: Intravenous fluids and vasopressor agents are commonly used in early resuscitation of patients with sepsis, but comparative data for prioritizing their delivery are limited. METHODS: In an unblinded superiority trial conducted at 60 U.S. centers, we randomly assigned patients to either a restrictive fluid strategy (prioritizing vasopressors and lower intravenous fluid volumes) or a liberal fluid strategy (prioritizing higher volumes of intravenous fluids before vasopressor use) for a 24-hour period. Randomization occurred within 4 hours after a patient met the criteria for sepsis-induced hypotension refractory to initial treatment with 1 to 3 liters of intravenous fluid. We hypothesized that all-cause mortality before discharge home by day 90 (primary outcome) would be lower with a restrictive fluid strategy than with a liberal fluid strategy. Safety was also assessed. RESULTS: A total of 1563 patients were enrolled, with 782 assigned to the restrictive fluid group and 781 to the liberal fluid group. Resuscitation therapies that were administered during the 24-hour protocol period differed between the two groups; less intravenous fluid was administered in the restrictive fluid group than in the liberal fluid group (difference of medians, -2134 ml; 95% confidence interval [CI], -2318 to -1949), whereas the restrictive fluid group had earlier, more prevalent, and longer duration of vasopressor use. Death from any cause before discharge home by day 90 occurred in 109 patients (14.0%) in the restrictive fluid group and in 116 patients (14.9%) in the liberal fluid group (estimated difference, -0.9 percentage points; 95% CI, -4.4 to 2.6; P = 0.61); 5 patients in the restrictive fluid group and 4 patients in the liberal fluid group had their data censored (lost to follow-up). The number of reported serious adverse events was similar in the two groups. CONCLUSIONS: Among patients with sepsis-induced hypotension, the restrictive fluid strategy that was used in this trial did not result in significantly lower (or higher) mortality before discharge home by day 90 than the liberal fluid strategy. (Funded by the National Heart, Lung, and Blood Institute; CLOVERS ClinicalTrials.gov number, NCT03434028.).

Serum citrullinated histone H3 concentrations differentiate patients with septic verses non-septic shock and correlate with disease severity.

PURPOSE: Microbial infection stimulates neutrophil/macrophage/monocyte extracellular trap formation, which leads to the release of citrullinated histone H3 (CitH3) catalyzed by peptidylarginine deiminase (PAD) 2 and 4. Understanding these molecular mechanisms in the pathogenesis of septic shock will be an important next step for developing novel diagnostic and treatment modalities. We sought to determine the expression of CitH3 in patients with septic shock, and to correlate CitH3 levels with PAD2/PAD4 and clinically relevant outcomes. METHODS: Levels of CitH3 were measured in serum samples of 160 critically ill patients with septic and non-septic shock, and healthy volunteers. Analyses of clinical and laboratory characteristics of patients were conducted. RESULTS: Levels of circulating CitH3 at enrollment were significantly increased in septic shock patients (n = 102) compared to patients hospitalized with non-infectious shock (NIC) (n = 32, p < 0.0001). The area under the curve (95% CI) for distinguishing septic shock from NIC using CitH3 was 0.76 (0.65-0.86). CitH3 was positively correlated with PAD2 and PAD4 concentrations and Sequential Organ Failure Assessment Scores [total score (r = 0.36, p < 0.0001)]. The serum levels of CitH3 at 24 h (p < 0.01) and 48 h (p < 0.05) were significantly higher in the septic patients that did not survive. CONCLUSION: CitH3 is increased in patients with septic shock. Its serum concentrations correlate with disease severity and prognosis, which may yield vital insights into the pathophysiology of sepsis.

Emergence of Extended-Spectrum ß-Lactamase Urinary Tract Infections Among Hospitalized Emergency Department Patients in the United States.

STUDY OBJECTIVE: Enterobacteriaceae resistant to ceftriaxone, mediated through extended-spectrum ß-lactamases (ESBLs), commonly cause urinary tract infections worldwide, but have been less prevalent in North America. Current US rates are unknown. We determine Enterobacteriaceae antimicrobial resistance rates among US emergency department (ED) patients hospitalized for urinary tract infection. METHODS: We prospectively enrolled adults hospitalized for urinary tract infection from 11 geographically diverse university-affiliated hospital EDs during 2018 to 2019. Among participants with culture-confirmed infection, we evaluated prevalence of antimicrobial resistance, including that caused by ESBL-producing Enterobacteriaceae, resistance risk factors, and time to in vitro-active antibiotics. RESULTS: Of 527 total participants, 444 (84%) had cultures that grew Enterobacteriaceae; 89 of 435 participants (20.5%; 95% confidence interval 16.9% to 24.5%; 4.6% to 45.4% by site) whose isolates had confirmatory testing had bacteria that were ESBL producing. The overall prevalence of ESBL-producing Enterobacteriaceae infection among all participants with urinary tract infection was 17.2% (95% confidence interval 14.0% to 20.7%). ESBL-producing Enterobacteriaceae infection risk factors were hospital, long-term care, antibiotic exposure within 90 days, and a fluoroquinolone- or ceftriaxone-resistant isolate within 1 year. Enterobacteriaceae resistance rates for other antimicrobials were fluoroquinolone 32.3%, gentamicin 13.7%, amikacin 1.3%, and meropenem 0.3%. Ceftriaxone was the most common empirical antibiotic. In vitro-active antibiotics were not administered within 12 hours of presentation to 48 participants (53.9%) with ESBL-producing Enterobacteriaceae infection, including 17 (58.6%) with sepsis. Compared with other Enterobacteriaceae infections, ESBL infections were associated with longer time to in vitro-active treatment (17.3 versus 3.5 hours). CONCLUSION: Among adults hospitalized for urinary tract infection in many US locations, ESBL-producing Enterobacteriaceae have emerged as a common cause of infection that is often not initially treated with an in vitro-active antibiotic.

Development of a Simple Sequential Organ Failure Assessment Score for Risk Assessment of Emergency Department Patients With Sepsis.

OBJECTIVES: Sepsis-3 recommends using the quick Sequential Organ Failure Assessment (qSOFA) score followed by SOFA score for sepsis evaluation. The SOFA is complex and unfamiliar to most emergency physicians, while qSOFA is insensitive for sepsis screening and may result in missed cases of sepsis. The objective of this study was to devise an easy-to-use simple SOFA score for use in the emergency department (ED). METHODS: Retrospective study of ED patients with sepsis with in-hospital mortality as the primary outcome. A simple SOFA score was derived and validated and compared with SOFA and qSOFA. RESULTS: A total of 3297 patients with sepsis were included, and in-hospital mortality was 10.1%. Simple SOFA had a sensitivity and specificity of 88% and 44% in the derivation set and 93% and 44% in the validation set for in-hospital mortality, respectively. The sensitivity and specificity of qSOFA was 38% and 86% and for SOFA was 90% and 50%, respectively. There were 2760 (84%) of 3297 qSOFA-negative (<2) patients. In this group, simple SOFA had a sensitivity and specificity of 86% and 48% in the derivation set and 91% and 48% in the validation set, respectively. Sequential Organ Failure Assessment was 86% sensitive and 57% specific in qSOFA-negative patients. For all encounters, the areas under the receiver-operator characteristic curves (AUROC) were 0.82 for SOFA, 0.78 (derivation) and 0.82 (validation) for simple SOFA, and 0.68 for qSOFA. In qSOFA-negative patients, the AUROCs were 0.80 for SOFA and 0.76 (derivation) and 0.82 (validation) for simple SOFA. CONCLUSIONS: Simple SOFA demonstrates similar predictive ability for in-hospital mortality from sepsis compared to SOFA. External validation of these findings is indicated.

Sequential Organ Failure Assessment Component Score Prediction of In-hospital Mortality From Sepsis.

OBJECTIVES: Early organ dysfunction in sepsis confers a high risk of in-hospital mortality, but the relative contribution of specific types of organ failure to overall mortality is unclear. The objective of this study was to assess the predictive ability of individual types of organ failure to in-hospital mortality or prolonged intensive care. METHODS: Retrospective cohort study of adult emergency department patients with sepsis from October 1, 2013, to November 10, 2015. Multivariable regression was used to assess the odds ratios of individual organ failure types for the outcomes of in-hospital death (primary) and in-hospital death or ICU stay ≥ 3 days (secondary). RESULTS: Of 2796 patients, 283 (10%) experienced in-hospital mortality, and 748 (27%) experienced in-hospital mortality or an ICU stay ≥ 3 days. The following components of Sequential Organ Failure Assessment (SOFA) score were most predictive of in-hospital mortality (descending order): coagulation (odds ratio [OR]: 1.60, 95% confidence interval [CI]: 1.32-1.93), hepatic (1.58, 95% CI: 1.32-1.90), respiratory (OR: 1.33, 95% CI: 1.21-1.47), neurologic (OR: 1.20, 95% CI: 1.07-1.35), renal (OR: 1.14, 95% CI: 1.02-1.27), and cardiovascular (OR: 1.13, 95% CI: 1.01-1.25). For mortality or ICU stay ≥3 days, the most predictive SOFA components were respiratory (OR: 1.97, 95% CI: 1.79-2.16), neurologic (OR: 1.72, 95% CI: 1.54-1.92), cardiovascular (OR: 1.38, 95% CI: 1.23-1.54), coagulation (OR: 1.31, 95% CI: 1.10-1.55), and renal (OR: 1.19, 95% CI: 1.08-1.30) while hepatic SOFA (OR: 1.16, 95% CI: 0.98-1.37) did not reach statistical significance (P = .092). CONCLUSION: In this retrospective study, SOFA score components demonstrated varying predictive abilities for mortality in sepsis. Elevated coagulation or hepatic SOFA scores were most predictive of in-hospital death, while an elevated respiratory SOFA was most predictive of death or ICU stay >3 days.

Untargeted Metabolomics Differentiates l-Carnitine Treated Septic Shock 1-Year Survivors and Nonsurvivors.

l-Carnitine is a candidate therapeutic for the treatment of septic shock, a condition that carries a ≥40% mortality. Responsiveness to l-carnitine may hinge on unique metabolic profiles that are not evident from the clinical phenotype. To define these profiles, we performed an untargeted metabolomic analysis of serum from 21 male sepsis patients enrolled in a placebo-controlled l-carnitine clinical trial. Although treatment with l-carnitine is known to induce changes in the sepsis metabolome, we found a distinct set of metabolites that differentiated 1-year survivors from nonsurvivors. Following feature alignment, we employed a new and innovative data reduction strategy followed by false discovery correction, and identified 63 metabolites that differentiated carnitine-treated 1-year survivors versus nonsurvivors. Following identification by MS/MS and database search, several metabolite markers of vascular inflammation were determined to be prominently elevated in the carnitine-treated nonsurvivor cohort, including fibrinopeptide A, allysine, and histamine. While preliminary, these results corroborate that metabolic profiles may be useful to differentiate l-carnitine treatment responsiveness. Furthermore, these data show that the metabolic signature of l-carnitine-treated nonsurvivors is associated with a severity of illness (e.g., vascular inflammation) that is not routinely clinically detected.

Association Between Early Hyperoxia Exposure After Resuscitation From Cardiac Arrest and Neurological Disability: Prospective Multicenter Protocol-Directed Cohort Study.

BACKGROUND: Studies examining the association between hyperoxia exposure after resuscitation from cardiac arrest and clinical outcomes have reported conflicting results. Our objective was to test the hypothesis that early postresuscitation hyperoxia is associated with poor neurological outcome. METHODS: This was a multicenter prospective cohort study. We included adult patients with cardiac arrest who were mechanically ventilated and received targeted temperature management after return of spontaneous circulation. We excluded patients with cardiac arrest caused by trauma or sepsis. Per protocol, partial pressure of arterial oxygen (Pao2) was measured at 1 and 6 hours after return of spontaneous circulation. Hyperoxia was defined as a Pao2 >300 mm Hg during the initial 6 hours after return of spontaneous circulation. The primary outcome was poor neurological function at hospital discharge, defined as a modified Rankin Scale score >3. Multivariable generalized linear regression with a log link was used to test the association between Pao2 and poor neurological outcome. To assess whether there was an association between other supranormal Pao2 levels and poor neurological outcome, we used other Pao2 cut points to define hyperoxia (ie, 100, 150, 200, 250, 350, 400 mm Hg). RESULTS: Of the 280 patients included, 105 (38%) had exposure to hyperoxia. Poor neurological function at hospital discharge occurred in 70% of patients in the entire cohort and in 77% versus 65% among patients with versus without exposure to hyperoxia respectively (absolute risk difference, 12%; 95% confidence interval, 1-23). Hyperoxia was independently associated with poor neurological function (relative risk, 1.23; 95% confidence interval, 1.11-1.35). On multivariable analysis, a 1-hour-longer duration of hyperoxia exposure was associated with a 3% increase in risk of poor neurological outcome (relative risk, 1.03; 95% confidence interval, 1.02-1.05). We found that the association with poor neurological outcome began at ≥300 mm Hg. CONCLUSIONS: Early hyperoxia exposure after resuscitation from cardiac arrest was independently associated with poor neurological function at hospital discharge.

Association Between Elevated Mean Arterial Blood Pressure and Neurologic Outcome After Resuscitation From Cardiac Arrest: Results From a Multicenter Prospective Cohort Study.

OBJECTIVES: Laboratory studies suggest elevated blood pressure after resuscitation from cardiac arrest may be protective; however, clinical data are limited. We sought to test the hypothesis that elevated postresuscitation mean arterial blood pressure is associated with neurologic outcome. DESIGN: Preplanned analysis of a prospective cohort study. SETTING: Six academic hospitals in the United States. PATIENTS: Adult, nontraumatic cardiac arrest patients treated with targeted temperature management after return of spontaneous circulation. INTERVENTIONS: Mean arterial blood pressure was measured noninvasively after return of spontaneous circulation and every hour during the initial 6 hours after return of spontaneous circulation. MEASURES AND MAIN RESULTS: We calculated the mean arterial blood pressure and a priori dichotomized subjects into two groups: mean arterial blood pressure 70-90 and greater than 90 mm Hg. The primary outcome was good neurologic function, defined as a modified Rankin Scale less than or equal to 3. The modified Rankin Scale was prospectively determined at hospital discharge. Of the 269 patients included, 159 (59%) had a mean arterial blood pressure greater than 90 mm Hg. Good neurologic function at hospital discharge occurred in 30% of patients in the entire cohort and was significantly higher in patients with a mean arterial blood pressure greater than 90 mm Hg (42%) as compared with mean arterial blood pressure 70-90 mm Hg (15%) (absolute risk difference, 27%; 95% CI, 17-37%). In a multivariable Poisson regression model adjusting for potential confounders, mean arterial blood pressure greater than 90 mm Hg was associated with good neurologic function (adjusted relative risk, 2.46; 95% CI; 2.09-2.88). Over ascending ranges of mean arterial blood pressure, there was a dose-response increase in probability of good neurologic outcome, with mean arterial blood pressure greater than 110 mm Hg having the strongest association (adjusted relative risk, 2.97; 95% CI, 1.86-4.76). CONCLUSIONS: Elevated blood pressure during the initial 6 hours after resuscitation from cardiac arrest was independently associated with good neurologic function at hospital discharge. Further investigation is warranted to determine if targeting an elevated mean arterial blood pressure would improve neurologic outcome after cardiac arrest.

Inhaled nitric oxide to treat intermediate risk pulmonary embolism: A multicenter randomized controlled trial.

OBJECTIVE: To test the hypothesis that adjunctive inhaled NO would improve RV function and viability in acute PE. METHODS: This was a randomized, placebo-controlled, double blind trial conducted at four academic hospitals. Eligible patients had acute PE without systemic arterial hypotension but had RV dysfunction and a treatment plan of standard anticoagulation. Subjects received either oxygen plus 50 parts per million nitrogen (placebo) or oxygen plus 50 ppm NO for 24 h. The primary composite endpoint required a normal RV on echocardiography and a plasma troponin T concentration <14 pg/mL. The secondary endpoint required a blood brain natriuretic peptide concentration <90 pg/mL and a Borg dyspnea score ≤ 2. The sample size of N = 76 tested if 30% more patients treated with NO would achieve the primary endpoint with 80% power and alpha = 5%. RESULTS: We randomized 78 patients and after two withdrawals, 38 were treated per protocol in each group. Patients were well matched for baseline conditions. At 24 h, 5/38 (13%) of patients treated with placebo and 9/38 (24%) of patients treated with NO reached the primary endpoint (P = 0.375). The secondary endpoint was reached in 34% with placebo and 13% of the NO (P = 0.11). In a pre-planned post-hoc analysis, we examined how many patients with RV hypokinesis or dilation at enrollment resolved these abnormalities; 29% more patients treated with NO resolved both abnormalities at 24 h (P = 0.010, Cochrane's Q test). CONCLUSIONS: In patients with severe submassive PE, inhaled nitric oxide failed to increase the proportion of patients with a normal troponin and echocardiogram but increased the probability of eliminating RV hypokinesis and dilation on echocardiography. CLINICAL TRIAL REGISTRATION: NCT01939301.

Liberal Versus Restrictive Intravenous Fluid Therapy for Early Septic Shock: Rationale for a Randomized Trial.

Prompt intravenous fluid therapy is a fundamental treatment for patients with septic shock. However, the optimal approach for administering intravenous fluid in septic shock resuscitation is unknown. Two competing strategies are emerging: a liberal fluids approach, consisting of a larger volume of initial fluid (50 to 75 mL/kg [4 to 6 L in an 80-kg adult] during the first 6 hours) and later use of vasopressors, versus a restrictive fluids approach, consisting of a smaller volume of initial fluid (≤30 mL/kg [≤2 to 3 L]), with earlier reliance on vasopressor infusions to maintain blood pressure and perfusion. Early fluid therapy may enhance or maintain tissue perfusion by increasing venous return and cardiac output. However, fluid administration may also have deleterious effects by causing edema within vital organs, leading to organ dysfunction and impairment of oxygen delivery. Conversely, a restrictive fluids approach primarily relies on vasopressors to reverse hypotension and maintain perfusion while limiting the administration of fluid. Both strategies have some evidence to support their use but lack robust data to confirm the benefit of one strategy over the other, creating clinical and scientific equipoise. As part of the National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Network, we designed a randomized clinical trial to compare the liberal and restrictive fluids strategies, the Crystalloid Liberal or Vasopressor Early Resuscitation in Sepsis trial. The purpose of this article is to review the current literature on approaches to early fluid resuscitation in adults with septic shock and outline the rationale for the upcoming trial.

Randomized trial of inhaled nitric oxide to treat acute pulmonary embolism: The iNOPE trial.

BACKGROUND: The study hypothesis is that administration of inhaled nitric oxide (NO) plus oxygen to subjects with submassive pulmonary embolism (PE) will improve right ventricular (RV) systolic function and reduce RV strain and necrosis, while improving patient dyspnea, more than treatment with oxygen alone. METHODS: This article describes the rationale and protocol for a registered (NCT01939301), nearly completed phase II, 3-center, randomized, double-blind, controlled trial. Eligible patients have pulmonary imaging-proven acute PE. Subjects must be normotensive, and have RV dysfunction on echocardiography or elevated troponin or brain natriuretic peptide and no fibrinolytics. Subjects receive NO plus oxygen or placebo for 24 hours (±3 hours) with blood sampling before and after treatment, and mandatory echocardiography and high-sensitivity troponin posttreatment to assess the composite primary end point. The sample size of N=78 was predicated on 30% more NO-treated patients having a normal high-sensitivity troponin (<14 pg/mL) and a normal RV on echocardiography at 24 hours with α=.05 and ß=.20. Safety was ensured by continuous spectrophotometric monitoring of percentage of methemoglobinemia and a predefined protocol to respond to emergent changes in condition. Blinding was ensured by identical tanks, software, and physical shielding of the device display and query of the clinical care team to assess blinding efficacy. RESULTS: We have enrolled 78 patients over a 31-month period. No patient has been withdrawn as a result of a safety concern, and no patient has had a serious adverse event related to NO. CONCLUSIONS: We present methods and a protocol for the first double-blinded, randomized trial of inhaled NO to treat PE.

The Impact of the Sepsis-3 Septic Shock Definition on Previously Defined Septic Shock Patients.

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.

Serial Procalcitonin Predicts Mortality in Severe Sepsis Patients: Results From the Multicenter Procalcitonin MOnitoring SEpsis (MOSES) Study.

OBJECTIVES: To prospectively validate that the inability to decrease procalcitonin levels by more than 80% between baseline and day 4 is associated with increased 28-day all-cause mortality in a large sepsis patient population recruited across the United States. DESIGN: Blinded, prospective multicenter observational clinical trial following an Food and Drug Administration-approved protocol. SETTING: Thirteen U.S.-based emergency departments and ICUs. PATIENTS: Consecutive patients meeting criteria for severe sepsis or septic shock who were admitted to the ICU from the emergency department, other wards, or directly from out of hospital were included. INTERVENTIONS: Procalcitonin was measured daily over the first 5 days. MEASUREMENTS AND MAIN RESULTS: The primary analysis of interest was the relationship between a procalcitonin decrease of more than 80% from baseline to day 4 and 28-day mortality using Cox proportional hazards regression. Among 858 enrolled patients, 646 patients were alive and in the hospital on day 4 and included in the main intention-to-diagnose analysis. The 28-day all-cause mortality was two-fold higher when procalcitonin did not show a decrease of more than 80% from baseline to day 4 (20% vs 10%; p = 0.001). This was confirmed as an independent predictor in Cox regression analysis (hazard ratio, 1.97 [95% CI, 1.18-3.30; p < 0.009]) after adjusting for demographics, Acute Physiology and Chronic Health Evaluation II, ICU residence on day 4, sepsis syndrome severity, antibiotic administration time, and other relevant confounders. CONCLUSIONS: Results of this large, prospective multicenter U.S. study indicate that inability to decrease procalcitonin by more than 80% is a significant independent predictor of mortality and may aid in sepsis care.

Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016.

OBJECTIVE: To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012." DESIGN: A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS: The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. RESULTS: The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. CONCLUSIONS: Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality.

An Emergency Department Validation of the SEP-3 Sepsis and Septic Shock Definitions and Comparison With 1992 Consensus Definitions.

STUDY OBJECTIVE: The Third International Consensus Definitions Task Force (SEP-3) proposed revised criteria defining sepsis and septic shock. We seek to evaluate the performance of the SEP-3 definitions for prediction of inhospital mortality in an emergency department (ED) population and compare the performance of the SEP-3 definitions to that of the previous definitions. METHODS: This was a secondary analysis of 3 prospectively collected, observational cohorts of infected ED subjects aged 18 years or older. The primary outcome was all-cause inhospital mortality. In accordance with the SEP-3 definitions, we calculated test characteristics of sepsis (quick Sequential Organ Failure Assessment [qSOFA] score ≥2) and septic shock (vasopressor dependence plus lactate level >2.0 mmol/L) for mortality and compared them to the original 1992 consensus definitions. RESULTS: We identified 7,754 ED patients with suspected infection overall; 117 had no documented mental status evaluation, leaving 7,637 patients included in the analysis. The mortality rate for the overall population was 4.4% (95% confidence interval [CI] 3.9% to 4.9%). The mortality rate for patients with qSOFA score greater than or equal to 2 was 14.2% (95% CI 12.2% to 16.2%), with a sensitivity of 52% (95% CI 46% to 57%) and specificity of 86% (95% CI 85% to 87%) to predict mortality. The original systemic inflammatory response syndrome-based 1992 consensus sepsis definition had a 6.8% (95% CI 6.0% to 7.7%) mortality rate, sensitivity of 83% (95% CI 79% to 87%), and specificity of 50% (95% CI 49% to 51%). The SEP-3 septic shock mortality was 23% (95% CI 16% to 30%), with a sensitivity of 12% (95% CI 11% to 13%) and specificity of 98.4% (95% CI 98.1% to 98.7%). The original 1992 septic shock definition had a 22% (95% CI 17% to 27%) mortality rate, sensitivity of 23% (95% CI 18% to 28%), and specificity of 96.6% (95% CI 96.2% to 97.0%). CONCLUSION: Both the new SEP-3 and original sepsis definitions stratify ED patients at risk for mortality, albeit with differing performances. In terms of mortality prediction, the SEP-3 definitions had improved specificity, but at the cost of sensitivity. Use of either approach requires a clearly intended target: more sensitivity versus specificity.

Utilizing Geographic Information Systems to Identify Clusters of Severe Sepsis Patients Presenting in the Out-of-Hospital Environment.

UNLABELLED: Understanding the geographic distribution of critical illness within a community may provide public health stakeholders with information that can be used to expedite access to specialized care. We hypothesized that severe sepsis patients transported by emergency medical services (EMS) exhibit geospatial clustering and that prehospital providers would recognize sepsis more frequently in patients transported from sepsis clusters. Retrospective review of a prospective, observational study of patients with severe sepsis transported to the emergency department (ED) by EMS and treated with early goal-directed therapy (EGDT). INCLUSION CRITERIA: suspected infection, 2 or more criteria for systemic inflammation, and either systolic blood pressure <90 mmHg after a fluid bolus or lactate >4 mmol/liter. EXCLUSION CRITERIA: age <18 or need for immediate surgery. Patient location at the time of EMS activation was recorded. Analysis of the addresses identified clusters, defined as a location in which EMS transported more than one patient experiencing the above associated signs and symptoms of septic shock. Other data collected included self-reported patient location as private residence or chronic care facility. One hundred sixty severe sepsis patients transported by EMS were eligible for analysis, presenting from 125 locations. Ninety-one patients (57%) presented from a private residence and 69 (37%) from a chronic care facility. Fifty (31%) patients were transported from 15 locations, with 25 of those transported from just 4 locations. Cluster patients tended to be older, come from medical facilities, and were more likely to have sepsis recognized by prehospital providers. Results from this study demonstrate low pre-hospital recognition of sepsis, as well as geospatially clustered presentations, most notably from skilled nursing facilities. Community education, public health initiatives, and EMS interventions could be targeted in such clusters of cases in order to both improve sepsis recognition and potentially expedite time-sensitive interventions.

Longitudinal Trends in the Prevalence of Diabetes Mellitus in an Urban Emergency Department.

OBJECTIVE: The objective of this study was to examine the longitudinal trends in diabetes mellitus (DM) in emergency department (ED) patients and evaluate the factors associated with those trends. METHODS: We conducted a retrospective analysis of all patients who presented to the ED from 2006 to 2011. The presence of DM, height, and weight were recorded prospectively. The study was conducted in the ED of an urban, academic hospital with an average yearly volume of approximately 62,000 patients. Inclusion criteria were age 16 years and older; presentation to the ED for any reason; and documentation of height, weight, and history of DM. Data were analyzed in 1-year blocks, then examined for trends using linear regression analysis. Data also were examined by obesity class: normal (body mass index [BMI] 20-24.9 kg/m(2)), overweight (BMI 25-29.9 kg/m(2)), obese (BMI 30-39.9 kg/m(2)), and extreme obesity (BMI >40 kg/m(2)). RESULTS: There was a statistically significant increase in the prevalence of type 2 DM during the study period. The percentage of type 2 DM for all patient visits increased progressively from 10.7% to 16.1% (r(2) 0.97). Progressive increases in yearly type 2 DM prevalence were observed for all BMI classes. The rate of change in the increase of DM was related directly to the degree of obesity. For the normal weight category, the percentage of patients with DM increased 0.5%/year (r(2) 0.92), overweight 0.7%/year (r(2) 0.88), obesity 1.0%/year (r(2) 0.90), and extreme obesity 1.4%/year (r(2) 0.94). Patient age increased slightly for all obesity groups, accounting for a 0.2% to 0.4%/year increase in the prevalence of DM in the population. CONCLUSIONS: In this longitudinal analysis, we found an increase in the prevalence of patients with DM and an increase in ED visits by patients with DM. Our results indicate that these increases are influenced most significantly by the obesity level of the patient.

The Impact of Timing of Antibiotics on Outcomes in Severe Sepsis and Septic Shock: A Systematic Review and Meta-Analysis.

OBJECTIVES: We sought to systematically review and meta-analyze the available data on the association between timing of antibiotic administration and mortality in severe sepsis and septic shock. DATA SOURCES: A comprehensive search criteria was performed using a predefined protocol. INCLUSION CRITERIA: adult patients with severe sepsis or septic shock, reported time to antibiotic administration in relation to emergency department triage and/or shock recognition, and mortality. EXCLUSION CRITERIA: immunosuppressed populations, review article, editorial, or nonhuman studies. DATA EXTRACTION: Two reviewers screened abstracts with a third reviewer arbitrating. The effect of time to antibiotic administration on mortality was based on current guideline recommendations: 1) administration within 3 hours of emergency department triage and 2) administration within 1 hour of severe sepsis/septic shock recognition. Odds ratios were calculated using a random effect model. The primary outcome was mortality. DATA SYNTHESIS: A total of 1,123 publications were identified and 11 were included in the analysis. Among the 11 included studies, 16,178 patients were evaluable for antibiotic administration from emergency department triage. Patients who received antibiotics more than 3 hours after emergency department triage (< 3 hr reference) had a pooled odds ratio for mortality of 1.16 (0.92-1.46; p = 0.21). A total of 11,017 patients were evaluable for antibiotic administration from severe sepsis/septic shock recognition. Patients who received antibiotics more than 1 hour after severe sepsis/shock recognition (< 1 hr reference) had a pooled odds ratio for mortality of 1.46 (0.89-2.40; p = 0.13). There was no increased mortality in the pooled odds ratios for each hourly delay from less than 1 to more than 5 hours in antibiotic administration from severe sepsis/shock recognition. CONCLUSION: Using the available pooled data, we found no significant mortality benefit of administering antibiotics within 3 hours of emergency department triage or within 1 hour of shock recognition in severe sepsis and septic shock. These results suggest that currently recommended timing metrics as measures of quality of care are not supported by the available evidence.

Plasma Glycoproteomics Reveals Sepsis Outcomes Linked to Distinct Proteins in Common Pathways.

OBJECTIVE: Sepsis remains a predominant cause of mortality in the ICU, yet strategies to increase survival have proved largely unsuccessful. This study aimed to identify proteins linked to sepsis outcomes using a glycoproteomic approach to target extracellular proteins that trigger downstream pathways and direct patient outcomes. DESIGN: Plasma was obtained from the Lactate Assessment in the Treatment of Early Sepsis cohort. N-linked plasma glycopeptides were quantified by solid-phase extraction coupled with mass spectrometry. Glycopeptides were assigned to proteins using RefSeq (National Center of Biotechnology Information, Bethesda, MD) and visualized in a heat map. Protein differences were validated by immunoblotting, and proteins were mapped for biological processes using Database for Annotation, Visualization and Integrated Discovery (National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, MD) and for functional pathways using Kyoto Encyclopedia of Genes and Genomes (Kanehisa Laboratories, Kyoto, Japan) databases. SETTING: Hospitalized care. PATIENTS: Patients admitted to the emergency department were enrolled in the study when the diagnosis of sepsis was made, within 6 hours of presentation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 501 glycopeptides corresponding to 234 proteins were identified. Of these, 66 glycopeptides were unique to the survivor group and corresponded to 54 proteins, 60 were unique to the nonsurvivor group and corresponded to 43 proteins, and 375 were common responses between groups and corresponded to 137 proteins. Immunoblotting showed that nonsurvivors had increased total kininogen; decreased total cathepsin-L1, vascular cell adhesion molecule, periostin, and neutrophil gelatinase-associated lipocalin; and a two-fold decrease in glycosylated clusterin (all p < 0.05). Kyoto Encyclopedia of Genes and Genomes analysis identified six enriched pathways. Interestingly, survivors relied on the extrinsic pathway of the complement and coagulation cascade, whereas nonsurvivors relied on the intrinsic pathway. CONCLUSION: This study identifies proteins linked to patient outcomes and provides insight into unexplored mechanisms that can be investigated for the identification of novel therapeutic targets.