Sepsis

American Journal of Respiratory and Critical Care Medicine, Volume 203, Issue 2, Page 202-210, January 15, 2021. …

American Journal of Respiratory and Critical Care Medicine, Volume 203, Issue 2, Page 157-158, January 15, 2021. …

by Alexandre Gaudet, Matthieu Devos, Sylvain Keignart, Olivier Pouly, Sylvain Lecailtel, Frédéric Wallet, Saad Nseir Background Early distinguishing ventilator-associated tracheobronchitis (VAT) and ventilator-associated pneumonia (VAP) remains difficult in the daily practice. However, this question appears clinically relevant, as treatments of VAT and VAP currently differ. In this study, we assessed the accuracy of sepsis criteria according to the Sepsis-3 definition in the early distinction between VAT and VAP. Methods Retrospective single-center cohort, including all consecutive patients with a diagnosis of VAT (n = 70) or VAP (n = 136), during a 2-year period. Accuracy of sepsis criteria according to Sepsis-3, total SOFA and respiratory SOFA, calculated at time of microbiological sampling were assessed in differentiating VAT from VAP, and in predicting mortality on ICU discharge. Results Sensitivity and specificity of sepsis criteria were found respectively at 0.4 and 0.91 to distinguish VAT from VAP, and at 0.38 and 0.75 for the prediction of mortality in VA-LRTI. A total SOFA ≥ 6 and a respiratory SOFA ≥ 3 were identified as the best cut-offs for these criteria in differentiating VAT from VAP, with sensitivity and specificity respectively found at 0.63 and 0.69 for total SOFA, and at 0.49 and 0.7 for respiratory SOFA. Additionally, for prediction of mortality, a total SOFA ≥ 7 and a respiratory SOFA = 4 were identified as the best-cut-offs, respectively yielding sensitivity and specificity at 0.56 and 0.61 for total SOFA, and at 0.22 and 0.95 for respiratory SOFA. Conclusions Sepsis criteria according to the Sepsis-3 definition show a high specificity but a low sensitivity for the diagnosis of VAP. Our results do not support the use of these criteria for the early diagnosis of VAP in patients with VA-LRTI.…

Sepsis is a life-threatening condition that arises from a poorly regulated inflammatory response to pathogenic organisms. Current treatments are limited to antibiotics, fluid resuscitation, and other supportive therapies. New targets for monitoring disease progression and therapeutic interventions are therefore critically needed. We previously reported that lipocalin-2 (Lcn2), a bacteriostatic mediator with potent pro-apoptotic activities, was robustly induced in sepsis. Other studies showed that Lcn2 was a predictor of mortality in septic patients. However, how Lcn2 is regulated during sepsis is poorly understood. We evaluated how IkB, an inducer of Lcn2, was regulated in sepsis using both the cecal ligation and puncture (CLP) and endotoxemia (LPS) animal models. We show that Nfkbiz, the gene encoding for IkB, was rapidly stimulated but, unlike Lcn2, whose expression persists during sepsis, mRNA levels of Nfkbiz decline to near basal levels several hours after its induction. In contrast, we observed that IkB expression remained highly elevated in septic animals following CLP but not LPS, indicating the occurrence of a CLP-specific mechanism that extends IkB half-life. By using aninhibitor of IkB, we determined that the expression of Lcn2 was largely controlled by IkB. Altogether, these data indicate that the high IkB expression in tissues likely contributes to the elevated expression of Lcn2 in sepsis. Since IkB is also capable of promoting or repressing other inflammatory genes, it might exert a central role in sepsis.…

Sepsis remains a major cause of death. Every year more than one in four people die of sepsis in the world (Rhodes et al., 2017). Some people with a weakened immune system are more likely to acquire an infection that could lead to sepsis and have higher mortality (Gotts and Matthay, 2016). The spleen plays important roles in immune response and antigen processing (Lewis et al., 2019). Its first role is to serve as a reservoir of lymphocytes and erythrocytes, the second is as a place where opsonization occurs, and the third role is as a filter for removing encapsulated bacteria (Mebius and Kraal, 2005; Sadarangani, 2018).

Sepsis was redefined in 2016 (Sepsis-3) as a dysregulated host response to infection that leads to life-threatening organ dysfunction. This definition places the pathophysiological emphasis on the host rather than the triggering pathogen, and facilitates differentiation of uncomplicated from “bad” infection. It is therefore an all-encompassing umbrella syndrome covering a wide range of pathogens (bacterial, viral, fungal, and parasitic), numerous anatomical sites of infection, and a multitude of clinical manifestations of organ dysfunction that frequently overlap with non-infectious inflammatory conditions.

Over the past months, the pandemic spread of SARS-CoV-2 (severe acute respiratory syndrome virus 2) has claimed more than 1.5 million lives (WHO, 2020). Current mortality rates with severe COVID-19 (coronavirus disease 2019) are approximately 5%, which is relatively high as compared to death from influenza (Faust and del Rio, 2020, Iuliano et al., 2018, WHO, 2020). Although pulmonary factors such as diffuse alveolar damage and pneumonia are major immediate causes of death in patients with COVID-19, recent studies have proposed that endotheliitis and thromboses contribute to the severity of pulmonary damage (Ackermann et al., 2020, Bryce et al., 2020, Lax et al., 2020, Levi et al., 2020, Varga et al., 2020).

American Journal of Respiratory and Critical Care Medicine, Volume 203, Issue 1, Page 125-127, January 1, 2021. …

Objectives: To examine long-term mortality, resource utilization, and healthcare costs in sepsis patients compared to hospitalized nonsepsis controls. Design: Propensity-matched population-based cohort study using administrative data. Setting: Ontario, Canada. PATIENTS: We identified a cohort of adults (≥ 18) admitted to hospitals in Ontario between April 1, 2012, and March 31, 2016, with follow-up to March 31, 2017. Sepsis patients were flagged using a validated International Classification of Diseases, 10th Revision-coded algorithm (Sepsis-2 definition), including cases with organ dysfunction (severe sepsis) and without (nonsevere). Remaining hospitalized patients were potential controls. Cases and controls were matched 1:1 on propensity score, age, sex, admission type, and admission date. INTERVENTIONS: None. Measurements and Main Results: Differences in mortality, rehospitalization, hospital length of stay, and healthcare costs were estimated, adjusting for remaining confounders using Cox regression and generalized estimating equations. Of 270,669 sepsis cases, 196,922 (73%) were successfully matched: 64,204 had severe and 132,718 nonsevere sepsis (infection without organ dysfunction). Over follow-up (median 2.0 yr), severe sepsis patients had higher mortality rates than controls (hazard ratio, 1.66; 95% CI, 1.63–1.68). Both severe and nonsevere sepsis patients had higher rehospitalization rates than controls (hazard ratio, 1.53; 95% CI, 1.50–1.55 and hazard ratio, 1.41; 95% CI, 1.40–1.43, respectively). Incremental costs (Canadian dollar 2018) in sepsis cases versus controls at 1-year were: $29,238 (95% CI, $28,568–$29,913) for severe and $9,475 (95% CI, $9,150–$9,727) for nonsevere sepsis. Conclusions: Severe sepsis was associated with substantially higher long-term risk of death, rehospitalization, and healthcare costs, highlighting the need for effective postdischarge care for sepsis survivors. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http:/journals.lww.com/ccmjournal). Drs. McIntyre, Doig, Taljaard, Krahn, Fergusson, Forster, and Thavorn developed the initial concept, wrote the original grant application, and acquired funding for the project. Ms. Farrah, Mr. Talarico, and Dr. Thavorn contributed to the acquisition of data. Ms. Farrah carried out analysis of the data and drafted initial versions of the article. All authors collaborated to develop the final design of the study; contributed to interpretation of the data and reviewed the article for important intellectual content and made suggestions for improvement as appropriate, providing expertise in their respective fields; and approved the final version. This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC). This study also received funding from the Innovation Fund of the Alternative Funding Plan for the Academic Health Sciences Centres of Ontario through The Ottawa Hospital Academic Medical Organization Innovation Fund (grant number 2017-24). Parts of this material are based on data and information compiled and provided by: MOHLTC, Cancer Care Ontario, and The Canadian Institute for Health Information. Ms. Farrah and Dr. Thavorn’s institution received funding from The Ottawa Hospital Academic Medical Organization. The remaining authors have disclosed that they do not have any potential conflicts of interest. The analyses, conclusions, opinions, and statements expressed herein are solely those of the authors and do not reflect those of the funding or data sources; no endorsement is intended or should be inferred. For information regarding this article, E-mail: kthavorn@ohri.ca Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

No abstract available…

Objectives: Oxidative stress appears to initiate organ failure in sepsis, justifying treatment with antioxidants such as vitamin C at megadoses. We have therefore investigated the safety and efficacy of megadose sodium ascorbate in sepsis. Design: Interventional study. Setting: Research Institute. Subjects: Adult Merino ewes. Interventions: Sheep were instrumented with pulmonary and renal artery flow-probes, and laser-Doppler and oxygen-sensing probes in the kidney. Conscious sheep received an infusion of live Escherichia coli for 31 hours. At 23.5 hours of sepsis, sheep received fluid resuscitation (30 mL/kg, Hartmann solution) and were randomized to IV sodium ascorbate (0.5 g/kg over 0.5 hr + 0.5 g/kg/hr for 6.5 hr; n = 5) or vehicle (n = 5). Norepinephrine was titrated to restore mean arterial pressure to baseline values (~80 mm Hg). Measurements and Main Results: Sepsis-induced fever (41.4 ± 0.2°C; mean ± SE), tachycardia (141 ± 2 beats/min), and a marked deterioration in clinical condition in all cases. Mean arterial pressure (86 ± 1 to 67 ± 2 mm Hg), arterial PO2 (102.1 ± 3.3 to 80.5 ± 3.4 mm Hg), and renal medullary tissue PO2 (41 ± 5 to 24 ± 2 mm Hg) decreased, and plasma creatinine doubled (71 ± 2 to 144 ± 15 µmol/L) (all p < 0.01). Direct observation indicated that in all animals, sodium ascorbate dramatically improved the clinical state, from malaise and lethargy to a responsive, alert state within 3 hours. Body temperature (39.3 ± 0.3°C), heart rate (99.7 ± 3 beats/min), and plasma creatinine (32.6 ± 5.8 µmol/L) all decreased. Arterial (96.5 ± 2.5 mm Hg) and renal medullary PO2 (48 ± 5 mm Hg) increased. The norepinephrine dose was decreased, to zero in four of five sheep, whereas mean arterial pressure increased (to 83 ± 2 mm Hg). We confirmed these physiologic findings in a coronavirus disease 2019 patient with shock by compassionate use of 60 g of sodium ascorbate over 7 hours. Conclusions: IV megadose sodium ascorbate reversed the pathophysiological and behavioral responses to Gram-negative sepsis without adverse side effects. Clinical studies are required to determine if such a dose has similar benefits in septic patients. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by a grant from the National Health and Medical Research Council of Australia (GNT 1050672) and, in part, by funding from the Victorian Government Operational Infrastructure Support Grant. Supported by a Future Leader Fellowship by the National Heart Foundation of Australia (101853; to Dr. Lankadeva). For information regarding this article, E-mail: clive.may@florey.edu.au This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: Complex critical syndromes like sepsis and coronavirus disease 2019 may be composed of underling “endotypes,” which may respond differently to treatment. The aim of this study was to test whether a previously defined bacterial sepsis endotypes classifier recapitulates the same clinical and immunological endotypes in coronavirus disease 2019. Design: Prospective single-center observational cohort study. Setting: Patients were enrolled in Athens, Greece, and blood was shipped to Inflammatix (Burlingame, CA) for analysis. Patients: Adult patients within 24 hours of hospital admission with coronavirus disease 2019 confirmed by polymerase chain reaction and chest radiography. Interventions: None. Measurements and Main results: We studied 97 patients with coronavirus disease 2019, of which 50 went on to severe respiratory failure (SRF) and 16 died. We applied a previously defined 33-messenger RNA classifier to assign endotype (Inflammopathic, Adaptive, or Coagulopathic) to each patient. We tested endotype status against other clinical parameters including laboratory values, severity scores, and outcomes. Patients were assigned as Inflammopathic (29%), Adaptive (44%), or Coagulopathic (27%), similar to our prior study in bacterial sepsis. Adaptive patients had lower rates of SRF and no deaths. Coagulopathic and Inflammopathic endotypes had 42% and 18% mortality rates, respectively. The Coagulopathic group showed highest D-dimers, and the Inflammopathic group showed highest C-reactive protein and interleukin-6 levels. Conclusions: Our predefined 33-messenger RNA endotypes classifier recapitulated immune phenotypes in viral sepsis (coronavirus disease 2019) despite its prior training and validation only in bacterial sepsis. Further work should focus on continued validation of the endotypes and their interaction with immunomodulatory therapy. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Drs. Sweeney, Liesenfeld, and Giamarellos-Bourboulis designed the study. Drs. Kotsaki, Kanavou, Leventogiannis, Kontogeorgou, and Giamarellos-Bourboulis conducted the clinical study. Drs. Sweeney and Wacker performed statistical analysis. Dr. Rawling, Dr. Remmel, Ms. Coyle, and Dr. Midic performed clinical sample and data processing. Dr. Sweeney wrote the initial manuscript draft. All authors critically reviewed. Drs. Sweeney, Liesenfeld, Wacker, He, Rawling, and Midic received funding from Inflammatix. Drs. He and Kontogeorgou disclosed work for hire. Dr. Sweeney, Dr. Liesenfeld, Dr. Wacker, Dr. He, Dr. Rawling, Ms. Coyle, Dr. Midic are employees of, and stockholders in, Inflammatix, which has exclusive license to the patent covering the 33-messenger RNA set. Dr. Giamarellos-Bourboulis has received honoraria from AbbVie USA, Abbott CH, InflaRx GmbH, MSD Greece, XBiotech, and Angelini Italy; independent educational grants from AbbVie, Abbott, Astellas Pharma Europe, AxisShield, bioMérieux, InflaRx GmbH, and XBiotech; and funding from the FrameWork 7 program HemoSpec (granted to the National and Kapodistrian University of Athens), the Horizon2020 Marie-Curie Project European Sepsis Academy (granted to the National and Kapodistrian University of Athens), and the Horizon 2020 European Grant ImmunoSep (granted to the Hellenic Institute for the Study of Sepsis). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: tsweeney@inflammatix.com Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: To examine long-term mortality, resource utilization, and healthcare costs in sepsis patients compared to hospitalized nonsepsis controls. Design: Propensity-matched population-based cohort study using administrative data. Setting: Ontario, Canada. PATIENTS: We identified a cohort of adults (≥ 18) admitted to hospitals in Ontario between April 1, 2012, and March 31, 2016, with follow-up to March 31, 2017. Sepsis patients were flagged using a validated International Classification of Diseases, 10th Revision-coded algorithm (Sepsis-2 definition), including cases with organ dysfunction (severe sepsis) and without (nonsevere). Remaining hospitalized patients were potential controls. Cases and controls were matched 1:1 on propensity score, age, sex, admission type, and admission date. INTERVENTIONS: None. Measurements and Main Results: Differences in mortality, rehospitalization, hospital length of stay, and healthcare costs were estimated, adjusting for remaining confounders using Cox regression and generalized estimating equations. Of 270,669 sepsis cases, 196,922 (73%) were successfully matched: 64,204 had severe and 132,718 nonsevere sepsis (infection without organ dysfunction). Over follow-up (median 2.0 yr), severe sepsis patients had higher mortality rates than controls (hazard ratio, 1.66; 95% CI, 1.63–1.68). Both severe and nonsevere sepsis patients had higher rehospitalization rates than controls (hazard ratio, 1.53; 95% CI, 1.50–1.55 and hazard ratio, 1.41; 95% CI, 1.40–1.43, respectively). Incremental costs (Canadian dollar 2018) in sepsis cases versus controls at 1-year were: $29,238 (95% CI, $28,568–$29,913) for severe and $9,475 (95% CI, $9,150–$9,727) for nonsevere sepsis. Conclusions: Severe sepsis was associated with substantially higher long-term risk of death, rehospitalization, and healthcare costs, highlighting the need for effective postdischarge care for sepsis survivors. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http:/journals.lww.com/ccmjournal). Drs. McIntyre, Doig, Taljaard, Krahn, Fergusson, Forster, and Thavorn developed the initial concept, wrote the original grant application, and acquired funding for the project. Ms. Farrah, Mr. Talarico, and Dr. Thavorn contributed to the acquisition of data. Ms. Farrah carried out analysis of the data and drafted initial versions of the article. All authors collaborated to develop the final design of the study; contributed to interpretation of the data and reviewed the article for important intellectual content and made suggestions for improvement as appropriate, providing expertise in their respective fields; and approved the final version. This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC). This study also received funding from the Innovation Fund of the Alternative Funding Plan for the Academic Health Sciences Centres of Ontario through The Ottawa Hospital Academic Medical Organization Innovation Fund (grant number 2017-24). Parts of this material are based on data and information compiled and provided by: MOHLTC, Cancer Care Ontario, and The Canadian Institute for Health Information. Ms. Farrah and Dr. Thavorn’s institution received funding from The Ottawa Hospital Academic Medical Organization. The remaining authors have disclosed that they do not have any potential conflicts of interest. The analyses, conclusions, opinions, and statements expressed herein are solely those of the authors and do not reflect those of the funding or data sources; no endorsement is intended or should be inferred. For information regarding this article, E-mail: kthavorn@ohri.ca Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

No abstract available…

AbstractBackgroundThe role of primary immunodeficiencies (PID) in susceptibility to sepsis remains unknown. It is unclear whether children with sepsis benefit from genetic investigations. We hypothesized that sepsis may represent the first manifestation of underlying PID. We applied whole-exome sequencing (WES) to a national cohort of children with sepsis to identify rare, predicted pathogenic variants in PID genes.MethodsWe conducted a multicenter, population-based, prospective study including previously healthy children aged ≥28 days and

AbstractBackgroundSepsis is an important cause of mortality globally, although population incidence estimates from low-income settings, including sub-Saharan Africa, are absent. We aimed to estimate sepsis incidence burden using routinely available data from a large urban hospital in Malawi.MethodsWe linked routine-care databases at Queen Elizabeth Central Hospital, Blantyre, Malawi, to provide admission and discharge data for 217 149 adults from 2013–2016. Using a definition of sepsis based on systemic inflammatory response syndrome criteria and Blantyre census population data, we calculated population incidence estimates of sepsis and severe sepsis and used negative binomial regression to assess for trends over time. Missing data were multiply imputed with chained equations.ResultsWe estimate that the incidence rate of emergency department–attending sepsis and severe sepsis in adults was 1772 per 100 000 person-years (95% confidence interval [CI], 1754–1789) and 303 per 100 000 person-years (95% CI, 295–310), respectively, between 2013 and 2016, with a year-on-year decrease in incidence. In-hospital mortality for patients admitted to the hospital with sepsis and severe sepsis was 23.7% (95% CI, 22.7–24.7%) and 28.1% (95% CI, 26.1 – 30.0%), respectively, with no clear change over time.ConclusionsSepsis incidence is higher in Blantyre, Malawi, than in high-income settings, from where the majority of sepsis incidence data are derived. Worldwide sepsis burden is likely to be underestimated, and data from low-income countries are needed to inform the public health response.

T. Hosoda et al.

American Journal of Respiratory and Critical Care Medicine, Volume 202, Issue 12, Page 1625-1635, December 15, 2020. …

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) present clinical criteria for the classification of patients with sepsis. We investigated incidence and long-term outcomes of patients diagnosed with these classifications, which are currently unknown.

The Sepsis-3 Criteria emphasized the value of a change of 2 or more points in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score, introduced quick SOFA (qSOFA), and removed the systemic inflammatory response syndrome (SIRS) criteria from the sepsis definition.

Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination.

Septic shock currently refers to a state of acute circulatory failure associated with infection. Emerging biological insights and reported variation in epidemiology challenge the validity of this definition.

The Third International Consensus Definitions Task Force defined sepsis as "life-threatening organ dysfunction due to a dysregulated host response to infection." The performance of clinical criteria for this sepsis definition is unknown.

Early, goal-directed therapy (EGDT) is recommended in international guidelines for the resuscitation of patients presenting with early septic shock. However, adoption has been limited, and uncertainty about its effectiveness remains.

Early goal-directed therapy (EGDT) has been endorsed in the guidelines of the Surviving Sepsis Campaign as a key strategy to decrease mortality among patients presenting to the emergency department with septic shock. However, its effectiveness is uncertain.

In a single-center study published more than a decade ago involving patients presenting to the emergency department with severe sepsis and septic shock, mortality was markedly lower among those who were treated according to a 6-hour protocol of early goal-directed therapy (EGDT), in which intravenous fluids, vasopressors, inotropes, and blood transfusions were adjusted to reach central hemodynamic targets, than among those receiving usual care. We conducted a trial to determine whether these findings were generalizable and whether all aspects of the protocol were necessary.

Although previous studies have suggested the potential advantages of albumin administration in patients with severe sepsis, its efficacy has not been fully established.

The Surviving Sepsis Campaign recommends targeting a mean arterial pressure of at least 65 mm Hg during initial resuscitation of patients with septic shock. However, whether this blood-pressure target is more or less effective than a higher target is unknown.

Hydroxyethyl starch (HES) [corrected] is widely used for fluid resuscitation in intensive care units (ICUs), but its safety and efficacy have not been established in patients with severe sepsis.

In 1991, the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) convened a "Consensus Conference," the goals of which were "to provide a conceptual and a practical framework to define the systemic inflammatory response to infection, which is a progressive injurious process that falls under the generalized term 'sepsis' and includes sepsis-associated organ dysfunction as well." The general definitions introduced as a result of that conference have been widely used in practice and have served as the foundation for inclusion criteria for numerous clinical trials of therapeutic interventions. Nevertheless, there has been an impetus from experts in the field to modify these definitions to reflect our current understanding of the pathophysiology of these syndromes.

To define the terms "sepsis" and "organ failure" in a precise manner.