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Abstract: Study hypothesis : Implementation of a new pathway dedicated to septic patients within the emergency department (ED) would improve early management, organ dysfunction, and outcome. Methods: During phase 1, all consecutive adult patients with infection and qualifying quick Sequential Organ Failure Assessment (qSOFA) score upon ED admission were managed according to standards of care. A multifaceted intervention was then performed (implementation phase): educational program, creation of a sepsis alert upon ED admission incorporated in the professional software, together with severity scores and Surviving Sepsis Campaign (SSC) bundle reminders, and dedication of two rooms to the management of septic patients (sepsis unit). During phase 2, patients were managed according to this new organization. Results: Of the 89,040 patients admitted to the ED over the two phases, 2,643 patients (3.2%) had sepsis including 277 with a qualifying qSOFA score on admission (phase 1, 141 patients; phase 2, 136 patients). Recommendations of SSC 3-h bundle significantly improved between the two periods regarding lactate measurement (87% vs. 96%, P = 0.006), initiation of fluid resuscitation (36% vs. 65%, P < 0.001), blood cultures sampling (83% vs. 93%, P = 0.014), and administration of antibiotics (18% vs. 46%, P < 0.001). The Sequential Organ Failure Assessment score between H0 and H12 varied significantly more during phase 2 (1.9 ± 1.9 vs. 0.8 ± 2.6, P < 0.001). Mortality significantly decreased during the second phase, on day 3 (28% vs. 15%, P = 0.008) and on day 28 (40% vs. 28%, P = 0.013). Conclusion: Systematic detection, education, and per protocol organization with a sepsis unit dedicated to the early management of septic patients appear to improve compliance with SSC bundles, organ dysfunction, and short-term mortality. These results warrant to be confirmed by prospective studies., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by the Shock Society.)

Sepsis is a syndrome which is defined as a dysregulated host response to infection leading to organ failure. Since it remains one of the leading causes of mortality worldwide, numerous drug candidates have already been tested, and continue to be developed, as potential adjunct therapies. Despite convincing mechanisms of action and robust pre-clinical data, almost all drug candidates in the field of sepsis have failed to demonstrate clinical efficacy in the past two decades. Accordingly, the development of new sepsis drugs has markedly decreased in the past few years. Nevertheless, thanks to a better understanding of sepsis pathophysiology and pathways, new promising drug candidates are currently being developed. Instead of a unique sepsis profile as initially suspected, various phenotypes have been characterised. This has  resulted in the identification of multiple targets for new drugs together with relevant biomarkers, and a better understanding of the most appropriate time to intervention. Within the entire sepsis drugs portfolio, those targeting the immune response are probably the most promising. Monoclonal antibodies targeting either cytokines or infectious agents are undoubtedly part of the potential successful therapeutic classes to come.

In sepsis, early and appropriate antibiotic therapy is key but is frequently challenging due to the increasing incidence of multidrug-resistant bacteria. The feasibility of shotgun metagenomics (SM) has been scarcely assessed in urinary tract infections (UTIs). In this study, the feasibility of SM to detect both the microbiome and the resistome in patients with confirmed UTI-related sepsis was evaluated. Urine samples were obtained from 40 adult patients with UTI-related sepsis. Conventional culture was used as a reference. Following total DNA extraction and depletion of human DNA, SM was performed using Ion Proton TM technology. Bioinformatics analysis was conducted using Geneious Ⓡ software as well as online tools from the Center for Genomic Epidemiology. For the microbiome, SM was consistently concordant when urine culture was positive with only one bacterium (mainly Escherichia coli). For the resistome, results were in agreement with antimicrobial susceptibility testing with no major discrepancies. SM consistently identified bla CTX-M genes responsible for resistance to third-generation cephalosporins. Resistance to aminoglycosides and fluoroquinolones was identified in all patients. This pilot study confirms that SM can provide clinically relevant information both on the microbiome and the resistome from urine samples of patients with UTI-related sepsis., (Copyright © 2019 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)

Background: Similarly, to sepsis, cardiac surgery with cardiopulmonary bypass (CPB) induces major changes in leukocyte subsets. Immature granulocytes (IGs) increase both in sepsis and after open-heart surgery. Secondary infections are a major complication of cardiac surgery with CPB. We hypothesized that the assessment of leukocyte subsets with multicolor flow cytometry (FCM) could help the front-line clinician to better identify patients at high risk of infectious complications in this clinical setting., Methods: In this single-center observational pilot study, we identified 26 leukocyte subsets using three combinations of antibodies (from 5 to 10 colors per combinations): one devoted to granulocytes, one to lymphocyte subpopulations and one for rare cells (plasma cells and dendritic cells). Blood samples were obtained preoperatively and immediately after open-heart surgery under CPB in 59 patients without immuno-depression, chronic or neoplastic inflammatory disease, and immunosuppressive treatment. Secondary infections during hospital stay were recorded., Results: Patients exhibited postoperative NK and T-cell lymphopenia, increased levels of IGs and monocytes with low levels of surface HLA DR. Twelve patients developed secondary infectious complications. Only immediate postoperative IG levels were significantly higher in these patient (6.6 [6; 7.39] G/L vs. 3.8 [2.67; 5.72] G/L, P = 0.01). Patients with immediate postoperative increase of IGs developed more frequently infectious complication (10/22 [46%] vs. 2/37 [5%]: P < 0.001)., Conclusions: This study suggests that postoperative increase of IGs is related to postoperative organ failure and promises to help in early identification of patients at risk of infectious complications after open-heart surgery under CPB. © 2018 International Clinical Cytometry Society., (© 2018 International Clinical Cytometry Society.)

Background: In this study, we primarily sought to assess the ability of flow cytometry to predict early clinical deterioration and overall survival in patients with sepsis admitted in the ED and ICU., Methods: Patients admitted for community-acquired acute sepsis from 11 hospital centers were eligible. Early (day 7) and late (day 28) deaths were notified. Levels of CD64 pos granulocytes, CD16 pos monocytes, CD16 dim immature granulocytes (IGs), and T and B lymphocytes were assessed by flow cytometry using an identical, cross-validated, robust, and simple consensus standardized protocol in each center., Results: Among 1,062 patients screened, 781 patients with confirmed sepsis were studied (age, 67 ± 48 years; Simplified Acute Physiology Score II, 36 ± 17; Sequential Organ Failure Assessment, 5 ± 4). Patients were divided into three groups (sepsis, severe sepsis, and septic shock) on day 0 and on day 2. On day 0, patients with sepsis exhibited increased levels of CD64 pos granulocytes, CD16 pos monocytes, and IGs with T-cell lymphopenia. Clinical severity was associated with higher percentages of IGs and deeper T-cell lymphopenia. IG percentages tended to be higher in patients whose clinical status worsened on day 2 (35.1 ± 35.6 vs 43.5 ± 35.2, P = .07). Increased IG percentages were also related to occurrence of new organ failures on day 2. Increased IG percentages, especially when associated with T-cell lymphopenia, were independently associated with early (P < .01) and late (P < .01) death., Conclusions: Increased circulating IGs at the acute phase of sepsis are linked to clinical worsening, especially when associated with T-cell lymphopenia. Early flow cytometry could help clinicians to target patients at high risk of clinical deterioration., Trial Registry: ClinicalTrials.gov; No.: NCT01995448; URL: www.clinicaltrials.gov., (Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Objectives: Primary objective was to identify leukocyte subsets that could predict the early evolution of sepsis at 48 hours (i.e., deterioration or stability/improvement). Secondary objectives were to evaluate the prognostic value of leukocyte subsets on mortality and immunosuppressive properties of immature granulocytes., Design: Twenty-three peripheral blood leukocyte subsets were analyzed using a new-generation 10-color flow cytometry. T-cell killing activity of immature granulocytes was explored using a sorting method specifically developed., Setting: ICUs and emergency departments., Patients: All patients admitted to emergency department and ICU for sepsis ongoing for less than 24 hours were eligible. Exclusion criteria were pregnancy, age less than 18 years, solid tumors, HIV infection, hematological or inflammatory conditions, and immunosuppressive drugs. Finally, 177 patients were included., Interventions: None., Measurements and Main Results: The two most salient features of sepsis were decreased CD10 (CD10) and CD16 (CD16) expressions on granulocytes. With a threshold of 90% of CD10 and 15% of CD16 granulocytes, these immunophenotypic features, which are those of immature granulocytes, predicted sepsis deterioration at 48 hours with a sensitivity of 57% and 70% and a specificity of 78% and 82%, respectively. Survival rate at day 30 was 99% for patients without CD10 and CD16, 85% for patients with increased CD16 only, and 63% for patients with increased CD16 and CD10 granulocytes (p < 0.001). Among CD16 immature granulocytes, we identified a CD14/CD24 myeloid-derived suppressor cell subset with the capability of killing activated T cells. Consistently, an excess of CD16 immature granulocytes was associated with both CD3 and CD4 T-cell lymphopenia in deteriorating patients., Conclusions: Circulating immature granulocytes predicted early sepsis deterioration and were enriched in myeloid-derived suppressor cells which could be responsible for immunosuppression through the induction of T-cell lymphopenia.

Objective: To compare therapeutic interventions during initial resuscitation derived from echocardiographic assessment of hemodynamics and from the Surviving Sepsis Campaign guidelines in intensive care unit septic patients., Design and Setting: Prospective, descriptive study in two intensive care units of teaching hospitals., Methods: The number of ventilated patients with septic shock who were studied was 46. Transesophageal echocardiography was first performed (T1<3 hrs after intensive care unit admission) to adapt therapy according to the following predefined hemodynamic profiles: fluid loading (index of collapsibility of the superior vena cava≥36%), inotropic support (left ventricular fractional area change<45% without relevant index of collapsibility of the superior vena cava), or increased vasopressor support (right ventricular systolic dysfunction, unremarkable transesophageal echocardiography study consistent with sustained vasoplegia). Agreement for treatment decision between transesophageal echocardiography and Surviving Sepsis Campaign guidelines was evaluated. A second transesophageal echocardiography assessment (T2) was performed to validate therapeutic interventions., Results: Although transesophageal echocardiography and Surviving Sepsis Campaign approaches were concordant to manage fluid loading in 32 of 46 patients (70%), echocardiography led to the absence of blood volume expansion in the remaining 14 patients who all had a central venous pressure<12 mm Hg. Accordingly, the agreement was weak between transesophageal echocardiography and Surviving Sepsis Campaign for the decision of fluid loading (κ: 0.37 [0.16;0.59]). With a cut-off value<8 mm Hg for central venous pressure, κ was 0.33 [-0.03;0.69]. Inotropes were prescribed based on transesophageal echocardiography assessment in 14 patients but would have been decided in only four patients according to Surviving Sepsis Campaign guidelines. As a result, the agreement between the two approaches for the decision of inotropic support was weak (κ: 0.23 [-0.04;0.50]). No right ventricular dysfunction was observed. No patient had anemia and only three patients with transesophageal echocardiography documented left ventricular systolic dysfunction had a central venous oxygen saturation<70%., Conclusions: A weak agreement was found in the prescription of fluid loading and inotropic support derived from early transesophageal echocardiography assessment of hemodynamics and Surviving Sepsis Campaign guidelines in patients presenting with septic shock.

Purpose: The purpose of this study is to evaluate the feasibility and interest of real-time polymerase chain reaction (RT-PCR) testing for bacterial genomes in body fluids other than blood in patients with acute severe sepsis., Methods: Twenty-six consecutive patients admitted for severe sepsis or septic shock were prospectively studied. Body fluids were sampled as clinically indicated and tested using standard microbiological methods and modified RT-PCR methods (universal PCR and specific PCRs). Results of standard microbiological tests were compared with those of PCR tests., Results: Direct RT-PCR testing was successfully performed on all nonblood body fluids. Of 29 body fluids collected, 23 were positive for at least 1 microorganism with conventional tests. Of 18 microbiological tests positive for a single microorganism, 15 fully agreed with RT-PCR assays, and the remaining 3 samples were infected with bacteria not screened by PCR testing. Among the 5 polymicrobial results obtained with conventional tests, RT-PCR agreed in 4 patients. The RT-PCR tests allowed additional clinically relevant bacterial identification in 3 of 6 samples with negative microbiological culture., Conclusions: Our results indicate that direct PCR testing may improve the detection of bacteria in body fluids other than blood in patients with acute severe sepsis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Thrombocytopenia is frequently encountered in critically ill patients with the sepsis syndrome, but its mechanisms frequently remain undetermined. Hemophagocytosis has been reported as a cause of thrombocytopenia in various diseases. This prospective study was designed to assess: (1) the incidence of hemophagocytosis in patients suffering from both the sepsis syndrome and unexplained thrombocytopenia, and (2) the circulating level of the macrophage-colony-stimulating factor (M-CSF) according to the presence or absence of hemophagocytosis., Methods: Fifty consecutive patients diagnosed with both the sepsis syndrome and thrombocytopenia of undetermined origin were studied. Hemophagocytosis was diagnosed based on microscopical examination of sternal bone marrow aspiration by two independent observers. Serum M-CSF concentrations were measured in each patient and compared with levels of a normal population (n = 59). Causes and severity of sepsis syndromes as well as serum M-CSF levels were compared between patients with and without hemophagocytosis., Results: Hemophagocytosis was diagnosed in 32 patients (64%). Mean serum M-CSF levels were increased in patients when compared with normal subjects (539 +/- 141 versus 208 +/- 82 IU/mL: P < 0.001), and higher in patients with than without hemophagocytosis (580 +/- 145 versus 457 +/- 89 IU/mL: P = 0.01). Multiorgan dysfunction and infection were independent risk factors of hemophagocytosis (odds ratio = 31.3 and 6.8, 95% confidence interval (CI) = 5.4 to 177.6 and 1.0 to 47.4, P <0.0001 and P = 0.03, respectively)., Conclusions: Hemophagocytosis is a frequent cause of unexplained thrombocytopenia in patients with severe sepsis syndrome. Our results suggest that M-CSF is overproduced in the sepsis syndrome, particularly when hemophagocytosis is present. The role of M-CSF in the initiation and development of hemophagocytosis remains to be determined.

Abstract Background Treatment decisions on critically ill patients with circulatory shock lack consensus. In an international survey, we aimed to evaluate the indications, current practice, and therapeutic goals of inotrope therapy in the treatment of patients with circulatory shock. Methods From November 2016 to April 2017, an anonymous web-based survey on the use of cardiovascular drugs was accessible to members of the European Society of Intensive Care Medicine (ESICM). A total of 14 questions focused on the profile of respondents, the triggering factors, first-line choice, dosing, timing, targets, additional treatment strategy, and suggested effect of inotropes. In addition, a group of 42 international ESICM experts was asked to formulate recommendations for the use of inotropes based on 11 questions. Results A total of 839 physicians from 82 countries responded. Dobutamine was the first-line inotrope in critically ill patients with acute heart failure for 84% of respondents. Two-thirds of respondents (66%) stated to use inotropes when there were persistent clinical signs of hypoperfusion or persistent hyperlactatemia despite a supposed adequate use of fluids and vasopressors, with (44%) or without (22%) the context of low left ventricular ejection fraction. Nearly half (44%) of respondents stated an adequate cardiac output as target for inotropic treatment. The experts agreed on 11 strong recommendations, all of which were based on excellent (> 90%) or good (81–90%) agreement. Recommendations include the indications for inotropes (septic and cardiogenic shock), the choice of drugs (dobutamine, not dopamine), the triggers (low cardiac output and clinical signs of hypoperfusion) and targets (adequate cardiac output) and stopping criteria (adverse effects and clinical improvement). Conclusion Inotrope use in critically ill patients is quite heterogeneous as self-reported by individual caregivers. Eleven strong recommendations on the indications, choice, triggers and targets for the use of inotropes are given by international experts. Future studies should focus on consistent indications for inotrope use and implementation into a guideline for circulatory shock that encompasses individualized targets and outcomes.

Abstract Background Vasopressors are commonly applied to restore and maintain blood pressure in patients with sepsis. We aimed to evaluate the current practice and therapeutic goals regarding vasopressor use in septic shock as a basis for future studies and to provide some recommendations on their use. Methods From November 2016 to April 2017, an anonymous web-based survey on the use of vasoactive drugs was accessible to members of the European Society of Intensive Care Medicine (ESICM). A total of 17 questions focused on the profile of respondents, triggering factors, first choice agent, dosing, timing, targets, additional treatments, and effects of vasopressors. We investigated whether the answers complied with current guidelines. In addition, a group of 34 international ESICM experts was asked to formulate recommendations for the use of vasopressors based on 6 questions with sub-questions (total 14). Results A total of 839 physicians from 82 countries (65% main specialty/activity intensive care) responded. The main trigger for vasopressor use was an insufficient mean arterial pressure (MAP) response to initial fluid resuscitation (83%). The first-line vasopressor was norepinephrine (97%), targeting predominantly a MAP > 60–65 mmHg (70%), with higher targets in patients with chronic arterial hypertension (79%). The experts agreed on 10 recommendations, 9 of which were based on unanimous or strong (≥ 80%) agreement. They recommended not to delay vasopressor treatment until fluid resuscitation is completed but rather to start with norepinephrine early to achieve a target MAP of ≥ 65 mmHg. Conclusion Reported vasopressor use in septic shock is compliant with contemporary guidelines. Future studies should focus on individualized treatment targets including earlier use of vasopressors.

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Copyright of Annales Françaises de Médecine d'Urgence is the property of John Libbey Eurotext Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract Background In the Emergency Department (ED), early and accurate recognition of infection is crucial to prompt antibiotic therapy but the initial presentation of patients is variable and poorly characterized. Lymphopenia is commonly associated with bacteraemia and poor outcome in intensive care unit patients. The objective of this retrospective study was to assess the prevalence of community-acquired infection in a cohort of unselected patients admitted to the ED with undifferentiated symptoms and severe lymphopenia. Methods This is a retrospective single-center study conducted over a 1 year-period before the COVID-19 pandemic. Consecutive adult patients admitted to the ED with severe lymphopenia (lymphocyte count