FcγR-mediated SARS-CoV-2 infection of monocytes activates inflammation.

SARS-CoV-2 can cause acute respiratory distress and death in some patients1. Although severe COVID-19 is linked to substantial inflammation, how SARS-CoV-2 triggers inflammation is not clear2. Monocytes and macrophages are sentinel cells that sense invasive infection to form inflammasomes that activate caspase-1 and gasdermin D, leading to inflammatory death (pyroptosis) and the release of potent inflammatory mediators3. Here we show that about 6% of blood monocytes of patients with COVID-19 are infected with SARS-CoV-2. Monocyte infection depends on the uptake of antibody-opsonized virus by Fcγ receptors. The plasma of vaccine recipients does not promote antibody-dependent monocyte infection. SARS-CoV-2 begins to replicate in monocytes, but infection is aborted, and infectious virus is not detected in the supernatants of cultures of infected monocytes. Instead, infected cells undergo pyroptosis mediated by activation of NLRP3 and AIM2 inflammasomes, caspase-1 and gasdermin D. Moreover, tissue-resident macrophages, but not infected epithelial and endothelial cells, from lung autopsies from patients with COVID-19 have activated inflammasomes. Taken together, these findings suggest that antibody-mediated SARS-CoV-2 uptake by monocytes and macrophages triggers inflammatory cell death that aborts the production of infectious virus but causes systemic inflammation that contributes to COVID-19 pathogenesis.

ACE inhibitors and angiotensin receptor blockers differentially alter the response to angiotensin II treatment in vasodilatory shock.

BACKGROUND: Angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blockers (ARB) medications are widely prescribed. We sought to assess how pre-admission use of these medications might impact the response to angiotensin-II treatment during vasodilatory shock. METHODS: In a post-hoc subgroup analysis of the randomized, placebo-controlled, Angiotensin Therapy for High Output Shock (ATHOS-3) trial, we compared patients with chronic angiotensin-converting enzyme inhibitor (ACEi) use, and patients with angiotensin receptor blocker (ARB) use, to patients without exposure to either ACEi or ARB. The primary outcome was mean arterial pressure after 1-h of treatment. Additional clinical outcomes included mean arterial pressure and norepinephrine equivalent dose requirements over time, and study-drug dose over time. Biological outcomes included baseline RAS biomarkers (renin, angiotensin-I, angiotensin-II, and angiotensin-I/angiotensin-II ratio), and the change in renin from 0 to 3 h. RESULTS: We included n = 321 patients, of whom, 270 were ACEi and ARB-unexposed, 29 were ACEi-exposed and 22 ARB-exposed. In ACEi/ARB-unexposed patients, angiotensin-treated patients, compared to placebo, had higher hour-1 mean arterial pressure (9.1 mmHg [95% CI 7.6-10.1], p < 0.0001), lower norepinephrine equivalent dose over 48-h (p = 0.0037), and lower study-drug dose over 48-h (p < 0.0001). ACEi-exposed patients treated with angiotensin-II showed similarly higher hour-1 mean arterial pressure compared to ACEi/ARB-unexposed (difference in treatment-effect: - 2.2 mmHg [95% CI - 7.0-2.6], pinteraction = 0.38), but a greater reduction in norepinephrine equivalent dose (pinteraction = 0.0031) and study-drug dose (pinteraction < 0.0001) over 48-h. In contrast, ARB-exposed patients showed an attenuated effect of angiotensin-II on hour-1 mean arterial pressure versus ACEi/ARB-unexposed (difference in treatment-effect: - 6.0 mmHg [95% CI - 11.5 to - 0.6], pinteraction = 0.0299), norepinephrine equivalent dose (pinteraction < 0.0001), and study-drug dose (pinteraction = 0.0008). Baseline renin levels and angiotensin-I/angiotensin-II ratios were highest in ACEi-exposed patients. Finally, angiotensin-II treatment reduced hour-3 renin in ACEi/ARB-unexposed and ACEi-exposed patients but not in ARB-exposed patients. CONCLUSIONS: In vasodilatory shock patients, the cardiovascular and biological RAS response to angiotensin-II differed based upon prior exposure to ACEi and ARB medications. ACEi-exposure was associated with increased angiotensin II responsiveness, whereas ARB-exposure was associated with decreased responsiveness. These findings have clinical implications for patient selection and dosage of angiotensin II in vasodilatory shock. Trial Registration ClinicalTrials.Gov Identifier: NCT02338843 (Registered January 14th 2015).

Risk of Misleading Conclusions in Observational Studies of Time-to-Antibiotics and Mortality in Suspected Sepsis.

BACKGROUND: Influential studies conclude that each hour until antibiotics increases mortality in sepsis. However, these analyses often (1) adjusted for limited covariates, (2) included patients with long delays until antibiotics, (3) combined sepsis and septic shock, and (4) used linear models presuming each hour delay has equal impact. We evaluated the effect of these analytic choices on associations between time-to-antibiotics and mortality. METHODS: We retrospectively identified 104 248 adults admitted to 5 hospitals from 2015-2022 with suspected infection (blood culture collection and intravenous antibiotics ≤24 h of arrival), including 25 990 with suspected septic shock and 23 619 with sepsis without shock. We used multivariable regression to calculate associations between time-to-antibiotics and in-hospital mortality under successively broader confounding-adjustment, shorter maximum time-to-antibiotic intervals, stratification by illness severity, and removing assumptions of linear hourly associations. RESULTS: Changing covariates, maximum time-to-antibiotics, and severity stratification altered the magnitude, direction, and significance of observed associations between time-to-antibiotics and mortality. In a fully adjusted model of patients treated ≤6 hours, each hour was associated with higher mortality for septic shock (adjusted odds ratio [aOR]: 1.07; 95% CI: 1.04-1.11) but not sepsis without shock (aOR: 1.03; .98-1.09) or suspected infection alone (aOR: .99; .94-1.05). Modeling each hour separately confirmed that every hour of delay was associated with increased mortality for septic shock, but only delays >6 hours were associated with higher mortality for sepsis without shock. CONCLUSIONS: Associations between time-to-antibiotics and mortality in sepsis are highly sensitive to analytic choices. Failure to adequately address these issues can generate misleading conclusions.

Implementation of an Electronic Alert to Improve Timeliness of Second Dose Antibiotics for Patients With Suspected Serious Infections in the Emergency Department: A Quasi-Randomized Controlled Trial.

STUDY OBJECTIVE: Delays in the second dose of antibiotics in the emergency department (ED) are associated with increased morbidity and mortality in patients with serious infections. We analyzed the influence of clinical decision support to prevent delays in second doses of broad-spectrum antibiotics in the ED. METHODS: We allocated adult patients who received cefepime or piperacillin/tazobactam in 9 EDs within an integrated health care system to an electronic alert that reminded ED clinicians to reorder antibiotics at the appropriate interval vs usual care. The primary outcome was a median delay in antibiotic administration. Secondary outcomes were rates of intensive care unit (ICU) admission, hospital mortality, and hospital length of stay. We included a post hoc secondary outcome of frequency of major delay (>25% of expected interval for second antibiotic dose). RESULTS: A total of 1,113 ED patients treated with cefepime or piperacillin/tazobactam were enrolled in the study, of whom 420 remained under ED care when their second dose was due and were included in the final analysis. The clinical decision support tool was associated with reduced antibiotic delays (median difference 35 minutes, 95% confidence interval [CI], 5 to 65). There were no differences in ICU transfers, inpatient mortality, or hospital length of stay. The clinical decision support tool was associated with decreased probability of major delay (absolute risk reduction 13%, 95% CI, 6 to 20). CONCLUSIONS: The implementation of a clinical decision support alert reminding clinicians to reorder second doses of antibiotics was associated with a reduction in the length and frequency of antibiotic delays in the ED. There was no effect on the rates of ICU transfers, inpatient mortality, or hospital length of stay.

Alveolar, Endothelial, and Organ Injury Marker Dynamics in Severe COVID-19.

Rationale: Alveolar and endothelial injury may be differentially associated with coronavirus disease (COVID-19) severity over time. Objectives: To describe alveolar and endothelial injury dynamics and associations with COVID-19 severity, cardiorenovascular injury, and outcomes. Methods: This single-center observational study enrolled patients with COVID-19 requiring respiratory support at emergency department presentation. More than 40 markers of alveolar (including receptor for advanced glycation endproducts [RAGE]), endothelial (including angiopoietin-2), and cardiorenovascular injury (including renin, kidney injury molecule-1, and troponin-I) were serially compared between invasively and spontaneously ventilated patients using mixed-effects repeated-measures models. Ventilatory ratios were calculated for intubated patients. Associations of biomarkers with modified World Health Organization scale at Day 28 were determined with multivariable proportional-odds regression. Measurements and Main Results: Of 225 patients, 74 (33%) received invasive ventilation at Day 0. RAGE was 1.80-fold higher in invasive ventilation patients at Day 0 (95% confidence interval [CI], 1.50-2.17) versus spontaneous ventilation, but decreased over time in all patients. Changes in alveolar markers did not correlate with changes in endothelial, cardiac, or renal injury markers. In contrast, endothelial markers were similar to lower at Day 0 for invasive ventilation versus spontaneous ventilation, but then increased over time only among intubated patients. In intubated patients, angiopoietin-2 was similar (fold difference, 1.02; 95% CI, 0.89-1.17) to nonintubated patients at Day 0 but 1.80-fold higher (95% CI, 1.56-2.06) at Day 3; cardiorenovascular injury markers showed similar patterns. Endothelial markers were not consistently associated with ventilatory ratios. Endothelial markers were more often significantly associated with 28-day outcomes than alveolar markers. Conclusions: Alveolar injury markers increase early. Endothelial injury markers increase later and are associated with cardiorenovascular injury and 28-day outcome. Alveolar and endothelial injury likely contribute at different times to disease progression in severe COVID-19.

COVID-19 Seroprevalence in ED Health Care Professionals Study: A Cross-Sectional Study.

INTRODUCTION: ED health care professionals are at the frontline of evaluation and management of patients with acute, and often undifferentiated, illness. During the initial phase of the SARS-CoV-2 outbreak, there were concerns that ED health care professionals may have been at increased risk of exposure to SARS-CoV-2 due to difficulty in early identification of patients. This study assessed the seroprevalence of SARS-CoV-2 antibodies among ED health care professionals without confirmed history of COVID-19 infection at a quaternary academic medical center. METHODS: This study used a cross-sectional design. An ED health care professional was deemed eligible if they had worked at least 4 shifts in the adult emergency department from April 1, 2020, through May 31, 2020, were asymptomatic on the day of blood draw, and were not known to have had prior documented COVID-19 infection. The study period was December 17, 2020, to January 27, 2021. Eligible participants completed a questionnaire and had a blood sample drawn. Samples were run on the Roche Cobas Elecsys Anti-SARS-CoV-2 antibody assay. RESULTS: Of 103 health care professionals (16 attending physicians, 4 emergency residents, 16 advanced practice professionals, and 67 full-time emergency nurses), only 3 (2.9%; exact 95% CI, 0.6%-8.3%) were seropositive for SARS-CoV-2 antibodies. DISCUSSION: At this quaternary academic medical center, among those who volunteered to take an antibody test, there was a low seroprevalence of SARS-CoV-2 antibodies among ED clinicians who were asymptomatic at the time of blood draw and not known to have had prior COVID-19 infection.

Surveillance for Healthcare-Associated Infections: Hospital-Onset Adult Sepsis Events Versus Current Reportable Conditions.

BACKGROUND: US hospitals are required by the Centers for Medicare and Medicaid Services to publicly report central line-associated bloodstream infections (CLABSIs), catheter-associated urinary tract infections (CAUTIs), Clostridioidesdiffficile, methicillin-resistant Staphylococcus aureus bacteremia, and selected surgical site infections for benchmarking and pay-for-performance programs. It is unclear, however, to what extent these conditions capture the full breadth of serious healthcare-associated infections (HAIs). The Centers for Disease Control and Prevention's (CDC's) hospital-onset Adult Sepsis Event (HO-ASE) definition could facilitate more comprehensive and efficient surveillance for serious HAIs, but the overlap between HO-ASE and currently reportable HAIs is unknown. METHODS: We retrospectively assessed the overlap between HO-ASEs and reportable HAIs among adults hospitalized between June 2015-June 2018 in 3 hospitals. Medical record reviews were conducted for 110 randomly selected HO-ASE cases to determine clinical correlates. RESULTS: Among 282 441 hospitalized patients, 2301 (0.8%) met HO-ASE criteria and 1260 (0.4%) had reportable HAIs. In-hospital mortality rates were higher with HO-ASEs than reportable HAIs (28.6% vs 12.9%). Mortality rates for HO-ASE missed by reportable HAIs were substantially higher than mortality rates for reportable HAIs missed by HO-ASE (28.1% vs 6.3%). Reportable HAIs were only present in 334/2301 (14.5%) HO-ASEs, most commonly CLABSIs (6.0% of HO-ASEs), C. difficile (5.0%), and CAUTIs (3.0%). On medical record review, most HO-ASEs were caused by pneumonia (39.1%, of which only 34.9% were ventilator-associated), bloodstream infections (17.4%, of which only 10.5% were central line-associated), non-C. difficile intra-abdominal infections (14.5%), urinary infections (7.3%, of which 87.5% were catheter-associated), and skin/soft tissue infections (6.4%). CONCLUSIONS: CDC's HO-ASE definition detects many serious nosocomial infections missed by currently reportable HAIs. HO-ASE surveillance could increase the efficiency and clinical significance of surveillance while identifying new targets for prevention.

Procalcitonin-Guided Use of Antibiotics for Lower Respiratory Tract Infection.

BACKGROUND: The effect of procalcitonin-guided use of antibiotics on treatment for suspected lower respiratory tract infection is unclear. METHODS: In 14 U.S. hospitals with high adherence to quality measures for the treatment of pneumonia, we provided guidance for clinicians about national clinical practice recommendations for the treatment of lower respiratory tract infections and the interpretation of procalcitonin assays. We then randomly assigned patients who presented to the emergency department with a suspected lower respiratory tract infection and for whom the treating physician was uncertain whether antibiotic therapy was indicated to one of two groups: the procalcitonin group, in which the treating clinicians were provided with real-time initial (and serial, if the patient was hospitalized) procalcitonin assay results and an antibiotic use guideline with graded recommendations based on four tiers of procalcitonin levels, or the usual-care group. We hypothesized that within 30 days after enrollment the total antibiotic-days would be lower - and the percentage of patients with adverse outcomes would not be more than 4.5 percentage points higher - in the procalcitonin group than in the usual-care group. RESULTS: A total of 1656 patients were included in the final analysis cohort (826 randomly assigned to the procalcitonin group and 830 to the usual-care group), of whom 782 (47.2%) were hospitalized and 984 (59.4%) received antibiotics within 30 days. The treating clinician received procalcitonin assay results for 792 of 826 patients (95.9%) in the procalcitonin group (median time from sample collection to assay result, 77 minutes) and for 18 of 830 patients (2.2%) in the usual-care group. In both groups, the procalcitonin-level tier was associated with the decision to prescribe antibiotics in the emergency department. There was no significant difference between the procalcitonin group and the usual-care group in antibiotic-days (mean, 4.2 and 4.3 days, respectively; difference, -0.05 day; 95% confidence interval [CI], -0.6 to 0.5; P=0.87) or the proportion of patients with adverse outcomes (11.7% [96 patients] and 13.1% [109 patients]; difference, -1.5 percentage points; 95% CI, -4.6 to 1.7; P<0.001 for noninferiority) within 30 days. CONCLUSIONS: The provision of procalcitonin assay results, along with instructions on their interpretation, to emergency department and hospital-based clinicians did not result in less use of antibiotics than did usual care among patients with suspected lower respiratory tract infection. (Funded by the National Institute of General Medical Sciences; ProACT ClinicalTrials.gov number, NCT02130986 .).

Sedation - Effects of disorders of abuse on therapeutic efficacy (SEDATE): A retrospective cohort study.

BACKGROUND: The impact of alcohol or opioid use disorders on medication dosing for procedural sedation in the emergency department (ED) is unclear, as most of the literature is from gastrointestinal endoscopy. Exploring how these patient factors affect sedative and analgesic medications may inform more nuanced sedation strategies in the emergency department. METHODS: This was a retrospective chart-review cohort study across five EDs from 2015 to 2020. Included were adult patients who underwent procedural sedation in the ED, categorized into three a priori groups: alcohol use disorder (AUD), opioid use disorder (OUD), and individuals with neither (non-SUD). Wilcoxon test was used to compare the time-averaged dose of agents between groups. Logistic regression was used to model multi-agent sedations. The propofol time-averaged dose was the primary outcome. Secondary outcomes included other agents, sedation duration, and switching to other agents. RESULTS: 2725 sedations were included in the analysis. 59 patients had a history of AUD, and 40 had a history of OUD. Time-averaged doses of medications did not differ significantly between AUD and non-SUD patients. Likewise, patients with OUD did not receive different doses of medications compared to non-SUD. The propofol doses for non-SUD, AUD, and OUD were 0.033 IQR 0.04; 0.042 IQR 0.05; and 0.058 IQR 0.04 mg/kg*min, respectively. Sedation duration was not different across groups. Having AUD or OUD is not associated with increased odds of requiring multiple sedative agents. CONCLUSION: Although sedation in patients with AUD or OUD may be associated with significant case bias, these patient factors did not significantly alter outcomes compared to the general population. This study suggests there is no evidence to proactively adjust medication strategy in ED patients with AUD or OUD.

F-Actin is associated with a worsening qSOFA score and intensive care unit admission in emergency department patients at risk for sepsis.

Objective: We previously demonstrated that plasma levels of F-actin and Thymosin Beta 4 differs among patients with septic shock, non-infectious systemic inflammatory syndrome and healthy controls and may serve as biomarkers for the diagnosis of sepsis. The current study aims to determine if these proteins are associated with or predictive of illness severity in patients at risk for sepsis in the Emergency Department (ED).Methods: Prospective, biomarker study enrolling patients (>18 years) who met the Shock Precautions on Triage Sepsis rule placing them at-risk for sepsis.Results: In this study of 203 ED patients, F-actin plasma levels had a linear trend of increase when the quick Sequential Organ Failure Assessment (qSOFA) score increased. F-actin was also increased in patients who were admitted to the Intensive Care Unit (ICU) from the ED, and in those with positive urine cultures. Thymosin Beta 4 was not associated with or predictive of any significant outcome measures.Conclusion: Increased levels of plasma F-actin measured in the ED were associated with incremental illness severity as measured by the qSOFA score and need for ICU admission. F-actin may have utility in risk stratification of undifferentiated patients in the ED presenting with signs and symptoms of sepsis.

Antibiotic Delays and Feasibility of a 1-Hour-From-Triage Antibiotic Requirement: Analysis of an Emergency Department Sepsis Quality Improvement Database.

STUDY OBJECTIVE: We identify factors associated with delayed emergency department (ED) antibiotics and determine feasibility of a 1-hour-from-triage antibiotic requirement in sepsis. METHODS: We studied all ED adult septic patients in accordance with Centers for Medicare & Medicaid Services Severe Sepsis and Septic Shock National Quality Measures in 2 consecutive 12-month intervals. During the second interval, a quality improvement intervention was conducted: a sepsis screening protocol plus case-specific feedback to clinicians. Data were abstracted retrospectively through electronic query and chart review. Primary outcomes were antibiotic delay greater than 3 hours from documented onset of hypoperfusion (per Centers for Medicare & Medicaid Services Severe Sepsis and Septic Shock National Quality Measures) and antibiotic delay greater than 1 hour from triage (per 2018 Surviving Sepsis Campaign recommendations). RESULTS: We identified 297 and 357 septic patients before and during the quality improvement intervention, respectively. Before and during quality improvement intervention, antibiotic delay in accordance with Centers for Medicare & Medicaid Services measures occurred in 30% and 21% of cases (-9% [95% confidence interval -16% to -2%]); and in accordance with 2018 Surviving Sepsis Campaign recommendations, 85% and 71% (-14% [95% confidence interval -20% to -8%]). Four factors were independently associated with both definitions of antibiotic delay: vague (ie, nonexplicitly infectious) presenting symptoms, triage location to nonacute areas, care before the quality improvement intervention, and lower Sequential [Sepsis-related] Organ Failure Assessment scores. Most patients did not receive antibiotics within 1 hour of triage, with the exception of a small subset post-quality improvement intervention who presented with explicit infectious symptoms and triage hypotension. CONCLUSION: The quality improvement intervention significantly reduced antibiotic delays, yet most septic patients did not receive antibiotics within 1 hour of triage. Compliance with the 2018 Surviving Sepsis Campaign would require a wholesale alteration in the management of ED patients with either vague symptoms or absence of triage hypotension.

Utilization of a multidisciplinary emergency department sepsis huddle to reduce time to antibiotics and improve SEP-1 compliance.

Sepsis is a significant public health crisis in the United States, contributing to 50% of inpatient hospital deaths. Given its dramatic health effects and implications in the setting of new CMS care guidelines, ED leaders have renewed focus on appropriate and timely sepsis care, including timely administration of antibiotics in patients at risk for sepsis. Modeling the success of multidisciplinary bedside huddles in improving compliance with appropriate care in other healthcare settings, a Sepsis Huddle was implemented in a large, academic ED, with the goal of driving compliance with standardized sepsis care as described in the CMS SEP-1 measure. A retrospective cohort analysis was performed, with the primary finding that utilization of the Sepsis Huddle resulted in antibiotics being administered on average 41 min sooner than when the Sepsis Huddle was not performed. Given that literature suggests that early administration of appropriate antibiotic therapy is a major driver of mortality reduction in patients with sepsis, this study represents a proof of concept that utilization of a Sepsis Huddle may serve to improve outcomes among ED patients at risk for sepsis.

Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial.

Importance: Data on the efficacy of hydroxychloroquine for the treatment of coronavirus disease 2019 (COVID-19) are needed. Objective: To determine whether hydroxychloroquine is an efficacious treatment for adults hospitalized with COVID-19. Design, Setting, and Participants: This was a multicenter, blinded, placebo-controlled randomized trial conducted at 34 hospitals in the US. Adults hospitalized with respiratory symptoms from severe acute respiratory syndrome coronavirus 2 infection were enrolled between April 2 and June 19, 2020, with the last outcome assessment on July 17, 2020. The planned sample size was 510 patients, with interim analyses planned after every 102 patients were enrolled. The trial was stopped at the fourth interim analysis for futility with a sample size of 479 patients. Interventions: Patients were randomly assigned to hydroxychloroquine (400 mg twice daily for 2 doses, then 200 mg twice daily for 8 doses) (n = 242) or placebo (n = 237). Main Outcomes and Measures: The primary outcome was clinical status 14 days after randomization as assessed with a 7-category ordinal scale ranging from 1 (death) to 7 (discharged from the hospital and able to perform normal activities). The primary outcome was analyzed with a multivariable proportional odds model, with an adjusted odds ratio (aOR) greater than 1.0 indicating more favorable outcomes with hydroxychloroquine than placebo. The trial included 12 secondary outcomes, including 28-day mortality. Results: Among 479 patients who were randomized (median age, 57 years; 44.3% female; 37.2% Hispanic/Latinx; 23.4% Black; 20.1% in the intensive care unit; 46.8% receiving supplemental oxygen without positive pressure; 11.5% receiving noninvasive ventilation or nasal high-flow oxygen; and 6.7% receiving invasive mechanical ventilation or extracorporeal membrane oxygenation), 433 (90.4%) completed the primary outcome assessment at 14 days and the remainder had clinical status imputed. The median duration of symptoms prior to randomization was 5 days (interquartile range [IQR], 3 to 7 days). Clinical status on the ordinal outcome scale at 14 days did not significantly differ between the hydroxychloroquine and placebo groups (median [IQR] score, 6 [4-7] vs 6 [4-7]; aOR, 1.02 [95% CI, 0.73 to 1.42]). None of the 12 secondary outcomes were significantly different between groups. At 28 days after randomization, 25 of 241 patients (10.4%) in the hydroxychloroquine group and 25 of 236 (10.6%) in the placebo group had died (absolute difference, -0.2% [95% CI, -5.7% to 5.3%]; aOR, 1.07 [95% CI, 0.54 to 2.09]). Conclusions and Relevance: Among adults hospitalized with respiratory illness from COVID-19, treatment with hydroxychloroquine, compared with placebo, did not significantly improve clinical status at day 14. These findings do not support the use of hydroxychloroquine for treatment of COVID-19 among hospitalized adults. Trial Registration: ClinicalTrials.gov: NCT04332991.

Presenting Symptoms Independently Predict Mortality in Septic Shock: Importance of a Previously Unmeasured Confounder.

OBJECTIVES: Presenting symptoms in patients with sepsis may influence rapidity of diagnosis, time-to-antibiotics, and outcome. We tested the hypothesis that vague presenting symptoms are associated with delayed antibiotics and increased mortality. We further characterized individual presenting symptoms and their association with mortality. DESIGN: Retrospective cohort study. SETTING: Emergency department of large, urban, academic U.S. hospital. PATIENTS: All adult patients with septic shock treated in the emergency department between April 2014 and March 2016. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 654 septic shock cases, 245 (37%) presented with vague symptoms. Time-to-antibiotics from first hypotension or elevated lactate was significantly longer for those with vague symptoms versus those with explicit symptoms of infection (1.6 vs 0.8 hr; p < 0.01), and in-hospital mortality was also substantially higher (34% vs 16%; p < 0.01). Patients with vague symptoms were older and sicker as evidenced by triage hypotension, Sequential Organ Failure Assessment score, initial serum lactate, and need for intubation. In multivariate analysis, vague symptoms were independently associated with mortality (adjusted odds ratio, 2.12; 95% CI, 1.32-3.40; p < 0.01), whereas time-to-antibiotics was not associated with mortality (adjusted odds ratio, 1.01; 95% CI, 0.94-1.08; p = 0.78). Of individual symptoms, only the absence of fever, chills, or rigors (odds ratio, 2.70; 95% CI, 1.63-4.47; p < 0.01) and presence of shortness of breath (odds ratio, 1.97; 95% CI, 1.23-3.15; p < 0.01) were independently associated with mortality. CONCLUSIONS: More than one third of patients with septic shock presented to the emergency department with vague symptoms that were not specific to infection. These patients had delayed antibiotic administration and higher risk of mortality even after controlling for demographics, illness acuity, and time-to-antibiotics in multivariate analysis. These findings suggest that the nature of presenting symptoms is an important component of sepsis clinical phenotyping and may be an important confounder in sepsis epidemiologic studies.

Compliance With the National SEP-1 Quality Measure and Association With Sepsis Outcomes: A Multicenter Retrospective Cohort Study.

OBJECTIVES: Many septic patients receive care that fails the Centers for Medicare and Medicaid Services' SEP-1 measure, but it is unclear whether this reflects meaningful lapses in care, differences in clinical characteristics, or excessive rigidity of the "all-or-nothing" measure. We compared outcomes in cases that passed versus failed SEP-1 during the first 2 years after the measure was implemented. DESIGN: Retrospective cohort study. SETTING: Seven U.S. hospitals. PATIENTS: Adult patients included in SEP-1 reporting between October 2015 and September 2017. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 851 sepsis cases in the cohort, 281 (33%) passed SEP-1 and 570 (67%) failed. SEP-1 failures had higher rates of septic shock (20% vs 9%; p < 0.001), hospital-onset sepsis (11% vs 4%; p = 0.001), and vague presenting symptoms (46% vs 30%; p < 0.001). The most common reasons for failure were omission of 3- and 6-hour lactate measurements (228/570 failures, 40%). Only 86 of 570 failures (15.1%) had greater than 3-hour delays until broad-spectrum antibiotics. Cases that failed SEP-1 had higher in-hospital mortality rates (18.4% vs 11.0%; odds ratio, 1.82; 95% CI, 1.19-2.80; p = 0.006), but this association was no longer significant after adjusting for differences in clinical characteristics and severity of illness (adjusted odds ratio, 1.36; 95% CI, 0.85-2.18; p = 0.205). Delays of greater than 3 hours until antibiotics were significantly associated with death (adjusted odds ratio, 1.94; 95% CI, 1.04-3.62; p = 0.038), whereas failing SEP-1 for any other reason was not (adjusted odds ratio, 1.10; 95% CI, 0.70-1.72; p = 0.674). CONCLUSIONS: Crude mortality rates were higher in sepsis cases that failed versus passed SEP-1, but there was no difference after adjusting for clinical characteristics and severity of illness. Delays in antibiotic administration were associated with higher mortality but only accounted for a small fraction of SEP-1 failures. SEP-1 may not clearly differentiate between high- and low-quality care, and detailed risk adjustment is necessary to properly interpret associations between SEP-1 compliance and mortality.

Microcirculatory perfusion disturbances in septic shock: results from the ProCESS trial.

BACKGROUND: We sought to determine the effects of alternative resuscitation strategies on microcirculatory perfusion and examine any association between microcirculatory perfusion and mortality in sepsis. METHODS: This was a prospective, formally designed substudy of participants in the Protocolized Care in Early Septic Shock (ProCESS) trial. We recruited from six sites with the equipment and training to perform these study procedures. All subjects were adults with septic shock, and each was assigned to alternative resuscitation strategies. The two main analyses assessed (1) the impact of resuscitation strategies on microcirculatory perfusion parameters and (2) the association of microcirculatory perfusion with 60-day in-hospital mortality. We measured sublingual microcirculatory perfusion using sidestream dark field in vivo video microscopy at the completion of the 6-h ProCESS resuscitation protocol and then again at 24 and 72 h. RESULTS: We enrolled 207 subjects (demographics were similar to the overall ProCESS cohort) and observed 40 (19.3%) deaths. There were no differences in average perfusion characteristics between treatment arms. Analyzing the relationship between microcirculatory perfusion and mortality, we found an association between vascular density parameters and mortality. Total vascular density (beta = 0.006, p < 0.003), perfused vascular density (beta = 0.005, p < 0.04), and De Backer score (beta = 0.009, p < 0.01) were higher overall in survivors in a generalized estimating equation model, and this association was significant at the 72-h time point (p < 0.05 for each parameter). CONCLUSIONS: Microcirculatory perfusion did not differ between three early septic shock treatment arms. We found an association between microcirculatory perfusion parameters of vascular density at 72 h and mortality. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00510835 . Registered on August 2, 2007.

In vivo quantification of rolling and adhered leukocytes in human sepsis.

BACKGROUND: The use of in vivo videomicroscopy at the bedside has demonstrated microcirculatory flow disturbances in sepsis. The ability of in vivo videomicroscopy to detect changes in the prevalence of rolling and adhered leukocytes that occur in sepsis is not well-described in humans. We sought to (1) develop methodology for accessing and quantifying sublingual leukocyte rolling and adherence with sidestream dark field (SDF) imaging; (2) compare the number of rolling and adhered leukocytes between patients with septic shock and non-infected controls; and (3) compare the number of rolling and adhered leukocytes between survivors and non-survivors of septic shock. METHODS: We included adult (age > 18 years) patients in the emergency department presenting with septic shock prospectively enrolled in the ProCESS trial. We recruited comparison non-infected patients as emergency department controls. Using a SDF videomicroscope, we obtained image sequences from the sublingual mucosa, quantifying rolling and adhered leukocytes per 1 mm × 1 mm visual field in a standardized 3-s clip. We report data as median and interquartile range and depicted as box plots. We compared groups using the Mann-Whitney U test, considering a p value < 0.05 significant. RESULTS: We included a total of 64 patients with septic shock and 32 non-infected controls. The median number of adhered leukocytes per field in the sepsis group was 1.0 (IQR 0-3.5) compared to 0 (0-0) in the non-infected group (p < 0.001). The median number of rolling leukocytes was 26 (10.3-42) in the sepsis group and 9.8 (4.8-17.3) in the non-infected group (p < 0.001) per field. Among the patients with sepsis (n = 64), there was an increased number of adhered leukocytes in non-survivors compared to survivors (3.0 (1-5.5) vs. 1.0 (0-3.0)) (p < 0.05); however, there was no difference in rolling leukocytes (35 (20-48) vs. 26 (10-41)) (p = 0.31). CONCLUSIONS: Our results demonstrated a higher number of rolling and adhered leukocytes in patients with septic shock when compared to non-infected controls, and an increased number of adhered leukocytes in non-survivors. TRIAL REGISTRATION: ClinicalTrials.gov , NCT00793442 ; Registered on 19 November 2008 PG0GM076659 (US NIH Grant/Contract). First submitted 18 July 2007. First posted 2 August 2007.