Sarah A. Sterling

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. Study Selection: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.

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.

Characteristics and Outcomes of Patients with Vasoplegic Versus Tissue Dysoxic Septic Shock

Background The current consensus definition of septic shock requires hypotension after adequate fluid challenge or vasopressor requirement. Some patients with septic shock present with hypotension and hyperlactatemia greater than 2 mmol/L (tissue dysoxic shock), whereas others have hypotension alone with normal lactate (vasoplegic shock). Objective The objective of this study was to determine differences in outcomes of patients with tissue dysoxic versus vasoplegic septic shock. Methods This was a secondary analysis of a large, multicenter randomized controlled trial. Inclusion criteria were suspected infection, two or more systemic inflammatory response criteria, and systolic blood pressure less than 90 mmHg after a fluid bolus. Patients were categorized by presence of vasoplegic or tissue dysoxic shock. Demographics and Sequential Organ Failure Assessment scores were evaluated between the groups. The primary outcome was in-hospital mortality. Results A total of 247 patients were included, 90 patients with vasoplegic shock and 157 with tissue dysoxic shock. There were no significant differences in age, race, or sex between the vasoplegic and tissue dysoxic shock groups. The group with vasoplegic shock had a lower initial Sequential Organ Failure Assessment score than did the group with tissue dysoxic shock (5.5 vs. 7.0 points; P = 0.0002). The primary outcome of in-hospital mortality occurred in 8 (9%) of 90 patients with vasoplegic shock compared with 41 (26%) of 157 in the group with tissue dysoxic shock (proportion difference, 17%; 95% confidence interval, 7%–26%; P < 0.0001; log-rank test P = 0.02). After adjusting for confounders, tissue dysoxic shock remained an independent predictor of in-hospital mortality. Conclusions In this analysis of patients with septic shock, we found a significant difference in in-hospital mortality between patients with vasoplegic versus tissue dysoxic septic shock. These findings suggest a need to consider these differences when designing future studies of septic shock therapies.

The effect of liver disease on lactate normalization in severe sepsis and septic shock: a cohort study

Objective To describe the effect of liver disease (LD) on lactate clearance during early sepsis resuscitation. Methods This is a multicenter randomized clinical trial. An initial lactate >2 mmol/L and subsequent serum lactate measurement within 6 hours were required for inclusion. LD was categorized by two methods: 1) past medical history (PMH) categorized as no LD, mild LD (no Child’s score criteria, but PMH of hepatitis B/C), cirrhosis; and 2) measurable liver dysfunction determined by the liver component of the sequential organ failure assessment (L-SOFA) score as no dysfunction (L-SOFA score 0), mild dysfunction (score 1), moderate-severe dysfunction (score 2 to 4). Primary outcome was the rate of lactate normalization. Results One hundred eighty-seven patients were included. When categorized by PMH, 169 patients had no LD, 6 mild LD, and 12 cirrhosis. 63/169 (37%) of patients with no LD achieved lactate normalization, compared to 4/6 (67%) with mild LD, and 1/12 (8%) with cirrhosis (P<0.03). Categorized by L-SOFA score, 59/124 (47%) patients with L-SOFA 0 achieved lactate normalization, compared to 6/31 (19%) with L-SOFA 1, and 3/32 (9%) with L-SOFA 2–4 (P<0.01). Relative lactate clearance [(initial lactate–subsequent lactate)/initial lactate] was lower in patients with more advanced LD by PMH (37.7 vs. 40.4 vs. 21.8, P=0.07), and lower with increasing L-SOFA score (42.0 vs. 30.1 vs. 23.4, P=0.01). Conclusion Liver dysfunction was significantly associated with impaired lactate clearance and normalization during the early resuscitation of sepsis.

Diagnostic performance of matrix-assisted laser desorption ionisation time-of-flight mass spectrometry in blood bacterial infections: a systematic review and meta-analysis.

Abstract Background: Matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF MS) has shown promise in decreasing time to identification of causative organisms compared to traditional methods; however, the utility of MALDI-TOF MS in a heterogeneous clinical setting is uncertain. Objectives: To perform a systematic review on the operational performance of the Bruker MALDI-TOF MS system and evaluate published cut-off values compared to traditional blood cultures. Methods: A comprehensive literature search was performed. Studies were included if they performed direct MALDI-TOF MS analysis of blood culture specimens in human patients with suspected bacterial infections using the Bruker Biotyper software. Sensitivities and specificities of the combined studies were estimated using a hierarchical random effects linear model (REML) incorporating cut-off scores of ≥1.7 and ≥2.0. Results: Fifty publications were identified, with 11 studies included after final review. The estimated sensitivity utilising a cut-off of ≥2.0 from the combined studies was 74.6% (95% CI = 67.9–89.3%), with an estimated specificity of 88.0% (95% CI = 74.8–94.7%). When assessing a cut-off of ≥1.7, the combined sensitivity increases to 92.8% (95% CI = 87.4–96.0%), but the estimated specificity decreased to 81.2% (95% CI = 61.9–96.6%). Conclusions: In this analysis, MALDI-TOF MS showed acceptable sensitivity and specificity in bacterial speciation with the current recommended cut-off point compared to blood cultures; however, lowering the cut-off point from ≥2.0 to ≥1.7 would increase the sensitivity of the test without significant detrimental effect on the specificity, which could improve clinician confidence in their results.

A Systematic Review of the Impact of Physician Implicit Racial Bias on Clinical Decision Making

OBJECTIVES Disparities in diagnosis and treatment of racial minorities exist in the emergency department (ED). A better understanding of how physician implicit (unconscious) bias contributes to these disparities may help identify ways to eliminate such racial disparities. The objective of this systematic review was to examine and summarize the evidence on the association between physician implicit racial bias and clinical decision making. METHODS Based on PRISMA guidelines, a structured electronic literature search of PubMed, CINAHL, Scopus, and PsycINFO databases was conducted. Eligible studies were those that: 1) included physicians, 2) included the Implicit Association Test as a measure of implicit bias, 3) included an assessment of physician clinical decision making, and 4) were published in peer-reviewed journals between 1998 and 2016. Articles were reviewed for inclusion by two independent investigators. Data extraction was performed by one investigator and checked for accuracy by a second investigator. Two investigators independently scored the quality of articles using a modified version of the Downs and Black checklist. RESULTS Of the 1,154 unique articles identified in the initial search, nine studies (n = 1,910) met inclusion criteria. Three of the nine studies involved emergency providers including residents, attending physicians, and advanced practice providers. The majority of studies used clinical vignettes to examine clinical decision making. Studies that included emergency medicine (EM) providers had vignettes relating to treatment of acute myocardial infarction, pain, and pediatric asthma. An implicit preference favoring white people was common across providers, regardless of specialty. Two of the nine studies found evidence of a relationship between implicit bias and clinical decision making; one of these studies included EM providers. This one study found that EM and internal medicine residents who demonstrated an implicit preference for white individuals were more likely to treat white patients and not black patients with thrombolysis for myocardial infarction. Evidence from the two studies reporting a relationship between physician implicit racial bias and decision making was low in quality. CONCLUSIONS The current literature indicates that although many physicians, regardless of specialty, demonstrate an implicit preference for white people, this bias does not appear to impact their clinical decision making. Further studies on the impact of implicit racial bias on racial disparities in ED treatment are needed.

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.

Design and Rationale of a Randomized Trial of a Care Transition Strategy in Patients with Acute Heart Failure Discharged from the Emergency Department: GUIDED-HF (Get with the Guidelines in Emergency Department Patients with Heart Failure)

GUIDED-HF (Get With the Guidelines in Emergency Department Patients With Heart Failure) is a multicenter randomized trial of a patient-centered transitional care intervention in patients with acute heart failure (AHF) who are discharged either directly from the emergency department (ED) or after a brief period of ED-based observation. To optimize care and reduce ED and hospital revisits, there has been significant emphasis on improving transitions at the time of hospital discharge for patients with HF. Such efforts have been almost exclusively directed at hospitalized patients; individuals with AHF who are discharged from the ED or ED-based observation are not included in these transitional care initiatives. Patients with AHF discharged directly from the ED or after a brief period of ED-based observation are randomly assigned to our transition GUIDED-HF strategy or standard ED discharge. Patients in the GUIDED arm receive a tailored discharge plan via the study team, based on their identified barriers to outpatient management and associated guideline-based interventions. This plan includes conducting a home visit soon after ED discharge combined with close outpatient follow-up and subsequent coaching calls to improve postdischarge care and avoid subsequent ED revisits and inpatient admissions. Up to 700 patients at 11 sites will be enrolled over 3 years of the study. GUIDED-HF will test a novel approach to AHF management strategy that includes tailored transitional care for patients discharged from the ED or ED-based observation. If successful, this program may significantly alter the current paradigm of AHF patient care. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT02519283.

The effect of etomidate on mortality in sepsis remains unclear.

Critical Care Medicine www.ccmjournal.org e95 The Effect of Etomidate on Mortality in Sepsis Remains Unclear To the Editor: We read with interest the meta-analysis by Chan et al (1) regarding the effect of single-dose etomidate on mortality and adrenal insufficiency in patients with sepsis. In this report, the authors concluded that etomidate usage for rapid sequence intubation (RSI) is associated with higher rates of mortality in sepsis. We have serious concerns with this conclusion, given the methods to determine study inclusion into this meta-analysis. First, the authors pooled results from both nonrandomized studies and randomized controlled trials (RCTs) in their final analysis (their Fig. 2A), a practice that is not recommended and analyzes data that are not comparable (2). Although the authors state that they included only RCTs in a sensitivity analysis (their Fig. 2B), a practice that is recommended, two included studies were not RCTs evaluating etomidate vs. other induction agents, but rather were secondary analyses of RCTs of other therapeutic agents (3, 4). Based on this major distinction, the inclusion of these two studies is inappropriate and violates the first inclusion criteria listed by the authors. The first study in question by Cuthbertson et al (3) was the most significantly weighted contributor (37.66%) to the pooled relative risk for all-cause mortality. This study, however, was a subanalysis of the CORTICUS study, an RCT evaluating hydrocortisone use in septic shock (5). Not only was randomization not directed based on induction agent but also the use of etomidate was actually discouraged in that study, creating a potential significant source of selection bias and unmeasured confounders. Of the 499 patients who were included in the Cuthbertson subanalysis, only 96 (19%) were given etomidate for RSI. The second, a study by Cherfan et al, was a nested cohort study of an RCT evaluating hydrocortisone use in cirrhotic patients with sepsis (5). Randomization of induction agent was not performed, again creating a potential for bias. Had Chen et al actually only included RCTs that randomized subjects to etomidate vs. other induction agents for intubation, as is recommended, their conclusions would have been significantly different. The results of such an analysis result in no significant difference in pooled mortality between etomidateand non–etomidate-treated subjects (relative risk, 1.2; 95% confidence interval, 0.84–1.72), as shown in the forest plot in Figure 1. While we appreciate effort by Chan et al to further evaluate this area, we contend that the results presented in their article are misleading. Currently, as highlighted by the results we present here, the effect of single-dose etomidate on mortality in sepsis is unclear. Furthermore, it appears that there are insufficient data to conduct a conclusive meta-analysis at this time. This highlights the need for a large, randomized clinical trial evaluating the effect of etomidate on morbidity and mortality when used for RSI in patients with sepsis. Dr. Jones has received grant support from the National Institutes of Health (NIH) and Thermoscientific. Dr. Sterling has received funding from NIH. Dr. Puskarich has received grant support from the American Heart Association and royalties from Up To Date Online.

The impact of the TelEmergency program on rural emergency care: An implementation study

Introduction Timely, appropriate intervention is key to improving outcomes in many emergent conditions. In rural areas, it is particularly challenging to assure quality, timely emergency care. The TelEmergency (TE) program, which utilizes a dual nurse practitioner and emergency medicine-trained, board-certified physician model, has the potential to improve access to quality emergency care in rural areas. The objective of this study was to examine how the implementation of the TE program impacts rural hospital Emergency Department (ED) operations. Methods Methods included a before and after study of the effect of the TE program on participating rural hospitals between January 2007 and December 2008. Data on ED and hospital operations were collected one year prior to and one year following the implementation of TE. Data from participating hospitals were combined and compared for the two time periods. Results Nine hospitals met criteria for inclusion and participated in the study. Total ED volumes did not significantly change with TE implementation, but ED admissions to the same rural hospital significantly increased following TE implementation (6.7% to 8.1%, p-value = 0.02). Likewise, discharge rates from the ED declined post-initiation (87.1% to 80.0%, p-value = 0.003). ED deaths and transfer rates showed no significant change, while the rate of patient discharge against medical advice significantly increased with TE use. Discussion In this analysis, we found a significant increase in the rate of ED admissions to rural hospitals with TE use. These findings may have important implications for the quality of emergency care in rural areas and the sustainability of rural hospitals’ EDs.