Sepsis

American Journal of Respiratory and Critical Care Medicine, Volume 201, Issue 7, Page 755-756, April 1, 2020. …

American Journal of Respiratory and Critical Care Medicine, Volume 201, Issue 7, Page 861-863, April 1, 2020. …

American Journal of Respiratory and Critical Care Medicine, Volume 201, Issue 7, Page 789-798, April 1, 2020. …

American Journal of Respiratory and Critical Care Medicine, Volume 201, Issue 7, Page 764-766, April 1, 2020. …

Background: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, Coronavirus Disease 2019 (COVID-19), affecting thousands of people around the world. Urgent guidance for clinicians caring for the sickest of these patients is needed. Methods: We formed a panel of 36 experts from 12 countries. All panel members completed the World Health Organization conflict of interest disclosure form. The panel proposed 53 questions that are relevant to the management of COVID-19 in the ICU. We searched the literature for direct and indirect evidence on the management of COVID-19 in critically ill patients in the ICU. We identified relevant and recent systematic reviews on most questions relating to supportive care. We assessed the certainty in the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, then generated recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. Recommendations were either strong or weak, or in the form of best practice recommendations. Results: The Surviving Sepsis Campaign COVID-19 panel issued 54 statements, of which four are best practice statements, nine are strong recommendations, and 35 are weak recommendations. No recommendation was provided for six questions. The topics were: 1) infection control, 2) laboratory diagnosis and specimens, 3) hemodynamic support, 4) ventilatory support, and 5) COVID-19 therapy. Conclusion: The Surviving Sepsis Campaign COVID-19 panel issued several recommendations to help support healthcare workers caring for critically ill ICU patients with COVID-19. When available, we will provide new evidence in further releases of these guidelines. 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). All supplemental figures and tables can be viewed in the supplemental document (Supplemental Digital Content 1, http://links.lww.com/CCM/F457). Funding: There was no dedicated funding for this guideline. Conflicts of Interest: Dr. Yaseen Arabi is the principal investigator on a clinical trial for lopinavir/ritonavir and interferon in Middle East respiratory syndrome (MERS) and he was a nonpaid consultant on antiviral active for MERS-coronavirus (CoV) for Gilead Sciences and SAB Biotherapeutics. He is an investigator on REMAP-CAP trial and is a Board Members of the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC). Dr. Eddy Fan declared receiving consultancy fees from ALung Technologies and MC3 Cardiopulmonary. Dr. Maurizio Cecconi declared consultancy work with Edwards Lifesciences, Directed Systems, and Cheetah Medical. Dr. Lennie Derde is the NVIC (Dutch National ICU society) chair of Taskforce Infectious Diseases (standing committee), member of ESICM Coronavirus Taskforce (started with this outbreak), chair ESICM Clinical Training Committee, all are unpaid positions. Dr. Frederick Hyden is non-compensated consultant to Gilead Sciences (antivirals for RVIS including remdesivir), Regeneraon (monoclonals for RVIs including MERS), and SAB Biotherapeutics (polyclonal antibodies for RVIs including MERS). The remaining authors have disclosed that they have no potential conflicts of interest. This article is being co-published in Critical Care Medicine (DOI: 10.1097/CCM.0000000000004363) and Intensive Care Medicine (DOI: 10.1007/s00134-020-06022-5). For information regarding this article, Email: andrewrhodes@nhs.net Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Sepsis remains to be medically challenging with high morbidities and mortalities. A novel intervention is urgently needed in the absence of specific, targeted therapy. Neutrophils act as double-edged swords in sepsis; they can help to eradicate microbes, while contributing to tissue injury. β2 integrins are critical adhesion molecules regulating a number of neutrophil functions. β2 integrins consist of four members αLβ2, αMβ2, αXβ2 and αDβ2. Here we review the role of each β2 integrin in neutrophils and sepsis and consider future direction for therapeutic intervention.…

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.MethodsMulticenter population-based prospective study including previously healthy children ≥28 days and

Abstract Background The goal of the study was to evaluate a potential role for tumor necrosis factor alpha (TNF-α) genetic variability as biomarker in sepsis. In particular, we aimed to determine if single nucleotide polymorphisms (SNPs) of TNF-α gene are associated with sepsis in terms of risk, severity and outcome. Methods We performed a prospective study on 163 adult critically ill septic patients (septic shock 65, sepsis 98, further divided in 40 survivors and 123 deceased) and 232 healthy controls. Genotyping of TNF-α SNPs (-308G/A, -238G/A, -376G/A and +489G/A) was performed for all patients and controls and plasma cytokine levels were measured during the first 24 h after sepsis onset. Results TNF-α +489G/A A-allele carriage was associated with significantly lower risk of developing sepsis and sepsis shock (AA+AG vs GG: OR = 0.53; p = 0.004; 95% CI = 0.34–0.82 and OR = 0.39; p = 0.003; 95% CI = 0.21–0.74, respectively) but not with sepsis-related outcomes. There was no significant association between any of the other TNF-α promoter SNPs, or their haplotype frequencies and sepsis or septic shock risk. Circulating TNF-α levels were higher in septic shock; they were not correlated with SNP genotype distribution; GG homozygosity for each polymorphism was correlated with higher TNF-α levels in septic shock. Conclusions TNF-α +489G/A SNP A-allele carriage may confer protection against sepsis and septic shock development but apparently does not influence sepsis-related mortality. Promoter TNF-α SNPs did not affect transcription and were not associated with distinct sepsis, septic shock risk or outcomes.…

Objectives: Severe sepsis is a significant cause of healthcare utilization and morbidity among pediatric patients. However, little is known about how commonly survivors acquire new medical devices during pediatric severe sepsis hospitalization. We sought to determine the rate of new device acquisition (specifically, tracheostomy placement, gastrostomy tube placement, vascular access devices, ostomy procedures, and amputation) among children surviving hospitalizations with severe sepsis. For contextualization, we compare this to rates of new device acquisition among three comparison cohorts: 1) survivors of all-cause pediatric hospitalizations; 2) matched survivors of nonsepsis infection hospitalizations; and 3) matched survivors of all-cause nonsepsis hospitalization with similar organ dysfunction. Design: Observational cohort study. Setting: Nationwide Readmission Database (2016), including all-payer hospitalizations from 27 states. Patients: Eighteen-thousand two-hundred ten pediatric severe sepsis hospitalizations; 532,738 all-cause pediatric hospitalizations; 16,173 age- and sex-matched nonsepsis infection hospitalizations; 15,025 organ dysfunction matched all-cause nonsepsis hospitalizations; and all with live discharge. Measurements and Main Results: Among 18,210 pediatric severe sepsis hospitalizations, 1,024 (5.6%) underwent device placement. Specifically, 3.5% had new gastrostomy, 3.1% new tracheostomy, 0.6% new vascular access devices, 0.4% new ostomy procedures, and 0.1% amputations. One-hundred forty hospitalizations (0.8%) included two or more new devices. After applying the Nationwide Readmissions Database sampling weights, there were 55,624 pediatric severe sepsis hospitalizations and 1,585,194 all-cause nonsepsis hospitalizations with live discharge in 2016. Compared to all-cause pediatric hospitalizations, severe sepsis hospitalizations were eight-fold more likely to involve new device acquisition (6.4% vs 0.8%; p < 0.001). New device acquisition was also higher in severe sepsis hospitalizations compared with matched nonsepsis infection hospitalizations (5.1% vs 1.2%; p < 0.01) and matched all-cause hospitalizations with similar organ dysfunction (4.7% vs 2.8%; p < 0.001). Conclusions: In this nationwide, all-payer cohort of U.S. pediatric severe sepsis hospitalizations, one in 20 children surviving severe sepsis experienced new device acquisition. The procedure rate was nearly eight-fold higher than all-cause, nonsepsis pediatric hospitalizations, and four-fold higher than matched nonsepsis infection hospitalizations. 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). This material is the result of work supported with resources and use of facilities at the Ann Arbor VA Medical Center. This work was supported by grants K08 GM115859 (to Dr. Prescott) and K12 HL138039 (to Drs. Donnelly) from the National Institutes of Health. Drs. Donnelly and Prescott received support for article research from the National Institutes of Health (NIH). Dr. Donnelly’s institution received funding from the NIH/National Heart, Lung, and Blood Institute. Dr. Cornell received funding from PreDxion Bio (board member). Dr. Prescott’s institution received funding from the NIH/National Institute of General Medical Sciences, and she disclosed government work. Dr. Hensley disclosed that he does not have any potential conflicts of interest. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the U.S. government. For information regarding this article, E-mail: ecarlton@med.umich.edu Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: Sepsis results in organ dysfunction caused by a dysregulated host response, in part related to the immune response of a severe infection. Mesenchymal stromal cells are known to modulate the immune response, and expression of stromal cell–derived factor-1 regulates mobilization of neutrophils from the bone marrow. We are investigating the importance of stromal cell-derived factor-1 in mesenchymal stromal cells and its role in promoting neutrophil function after the onset of cecal ligation and puncture–induced sepsis. Stromal cell–derived factor-1 expression was silenced in mesenchymal stromal cells, compared with the control scrambled construct mesenchymal stromal cells. Design: Animal study and cell culture. Setting: Laboratory investigation. Subjects: BALB/c mice. Interventions: Polymicrobial sepsis was induced by cecal ligation and puncture. shSCR mesenchymal stromal cells and shSDF-1 mesenchymal stromal cells were delivered by tail vein injections to septic mice. The mice were assessed for survival, bacterial clearance, and the inflammatory response during sepsis in each of the groups. Mesenchymal stromal cells were also assessed for their ability to promote bacterial phagocytosis by neutrophils. Measurements and Main Results: Injection of shSCR mesenchymal stromal cells after the onset of sepsis led to an increase in mouse survival (70%) at 7 days, whereas survival of mice receiving shSDF-1 mesenchymal stromal cells was significantly diminished (33%). The loss of survival benefit in mice receiving shSDF-1 mesenchymal stromal cells was associated with less efficient bacterial clearance compared with shSCR mesenchymal stromal cells. Although shSCR mesenchymal stromal cells, or their conditioned medium, were able to increase neutrophil phagocytosis of bacteria, this effect was significantly blunted with shSDF-1 mesenchymal stromal cells. Assessment of peritoneal inflammation revealed that neutrophils were significantly increased and more immature in septic mice receiving shSDF-1 mesenchymal stromal cells. This response was associated with hypocellularity and increased neutrophil death in the bone marrow of mice receiving shSDF-1 mesenchymal stromal cells. Conclusions: Expression of stromal cell-derived factor-1 in mesenchymal stromal cells enhances neutrophil function with increased phagocytosis, more efficient clearance of bacteria, and bone marrow protection from depletion of cellular reserves during sepsis. 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 National Institutes of Health grants R01GM118456 and P01HL108801 (to Dr. Perrella), U01AI38318 (to Drs. Perrella and Lederer), K08GM126313 (to Dr. Ghanta), and T32HL007633 (to Drs. Ghanta and Ng). Drs. Kwon, Ng, Liu, and Perrella’s institutions received funding from the National Institutes of Health (NIH). Drs. Kwon, Ghanta, Ng, Tsoyi, Lederer, Chung, Liu, and Perrella received support for article research from the NIH. Dr. Chung disclosed government work. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: mperrella@rics.bwh.harvard.edu Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: Recent evidence from the fields of microbiology and immunology, as well as a small number of human sepsis studies, suggest that epigenetic regulation may play a central role in the pathogenesis of sepsis. The term “epigenetics” refers to regulatory mechanisms that control gene expression but are not related to changes in DNA sequence. These include DNA methylation, histone modifications, and regulation of transcription via non-coding RNAs. Epigenetic modifications, occurring in response to external stressors, lead to changes in gene expression, and thus lie at the intersection between genetics and the environment. In this review, we examine data from in vitro studies, animal studies, and the existing human sepsis studies in epigenetics to demonstrate that epigenetic mechanisms are likely central to the pathogenesis of sepsis and that epigenetic therapies may have potential in the treatment of sepsis and its associated organ failures. Data Sources: Online search of published scientific literature via Pubmed using the term “epigenetics” in combination with the terms “sepsis”, “infection”, “bacterial infection”, “viral infection”, “critical illness”, “acute respiratory distress syndrome”, and “acute lung injury”. Study Selection: Articles were chosen for inclusion based on their relevance to sepsis, acute inflammation, sepsis-related immune suppression, and sepsis-related organ failure. Reference lists were reviewed to identify additional relevant articles. Data Extraction: Relevant data was extracted and synthesized for narrative review. Data Synthesis: Epigenetic regulation is a key determinant of gene expression in sepsis. At the onset of infection, host-pathogen interactions often result in epigenetic alterations to host cells that favor pathogen survival. In parallel, the host inflammatory response is characterized by epigenetic modifications in key regulatory genes, including tumor necrosis factor and interleukin-1β. In human sepsis patients, multiple epigenetic modifying enzymes show differential expression in early sepsis, suggesting a role for epigenetics in coordinating the response to infection. In the later stages of sepsis, epigenetic modifications accompany endotoxin tolerance and the immune-suppressed state. In animal models, treatment with epigenetic modifiers can mitigate the effects of sepsis and improve survival as well as reverse sepsis-associated organ injury. Conclusions: Epigenetic modifications are associated with key phases of sepsis, from the host-pathogen interaction, to acute inflammation, to immune suppression. Epigenetic markers show promise in the diagnosis and prognosis of sepsis and epigenetic modifying agents show promise as therapeutic tools in animal models of sepsis. Human studies in the area of epigenetics are sorely lacking and should be a priority for sepsis researchers. All authors contributed to the conception, research, and writing of the article. Supported, in part, by grant from the McLaughlin Foundation Accelerator Grant in Genomic Medicine and Health Informatics (2015–2016) and Canadian Institutes of Health Research (Grant Number MOP-130331 to Dr. dos Santos). The authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Claudia C. dos Santos, MD, MSc, FRCPC, Interdepartmental Division of Critical Care, Keenan Center for Biomedical Research, Saint Michael’s Hospital, University of Toronto, 30 Bond Street, Room 4-008, Toronto, ON, M5B 1WB, Canada. E-mail: DosSantosC@smh.ca Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: To assess whether the triage model Sepsis Alert for Emergency Departments results in improved initial care of patients with severe infections. Design: Interventional study comparing patient care before and after the start of a new triage model, including 90-day follow-up. Setting: Eight emergency departments in Skåne County, Sweden. Subjects: Patients with suspected severe infection. Interventions: Patients with severely deviating vital signs and suspected infection were triaged into a designated sepsis line called Sepsis Alert, for rapid evaluation supported by an infectious disease specialist. Also, all emergency department staff participated in a designated sepsis education before the model was introduced. Measurements and Main Results: Medical records were evaluated for a 3-month period 1 year before the triage system was started in 2016 and for a 3-month period 1 year after. Of 195,607 patients admitted to these emergency departments during two 3-month periods, a total of 5,321 patients presented severely abnormal vital signs. Of these, 1,066 patients who presented with fever greater thanor equal to 38°C or history of fever/chills were considered to be patients at risk of having severe sepsis. Among patients triaged according to Sepsis Alert, 89.3% received antibiotic treatment within 1 hour after arrival to the emergency department (median time to antibiotics, 26 min), which was significantly better than before the start of the new triage: 67.9% (median time to antibiotics, 37 min) (p < 0.001). Additionally, sepsis treatment quality markers were significantly improved after the introduction of Sepsis Alert, including number of blood cultures and lactate measurements taken, percentage of patients receiving IV fluids, and appropriate initial antibiotic treatment. There were no differences in 28- or 90-day mortality rates. Conclusions: The implementation of the new triage model Sepsis Alert with special attention to severe sepsis patients led to faster and more accurate antibiotic treatment and improved diagnostic procedures and supportive care. 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). Dr. Lanbeck received funding from Chalmers Technical University, Gothenburg. Dr. Åkesson received funding from Hansa Biopharma. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: mari.rosenqvist@med.lu.se Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

No abstract available…

Abstract Background Cellulitis, a frequent cause of admission of adult patients to medical wards, occasionally evolves to sepsis. In this study we analyze the factors related to sepsis development. Methods Prospective and observational study of 606 adult patients with cellulitis admitted to several Spanish hospitals. Comorbidities, microbiological, clinical, lab, diagnostic, and treatment data were analyzed. Sepsis was diagnosed according to the criteria of the 2016 International Sepsis Definitions Conference. Multiple logistic regression modelling was performed to determine the variables independently associated with sepsis development. Results Mean age was 63.4 years and 51.8% were men. Overall 65 (10.7%) patients developed sepsis, 7 (10.8%) of whom died, but only 4 (6.2%) due to cellulitis. Drawing of blood (P 

Sepsishematopoietic cell transplant…

AbstractBackgroundSepsis, a life-threatening immunological response to an infection, disproportionality affects allogeneic hematopoietic cell transplant (HCT) recipients and is challenging to define. Clinical criteria that predict mortality and intensive care unit endpoints in patients with suspected infections (SI) have been adopted in sepsis definitions, but their predictive value among immunocompromised populations is largely unknown. Here, we evaluate three criteria among allogeneic HCT recipients.MethodsWe evaluated Systemic Inflammatory Response Syndrome (SIRS), quick-Sequential Organ Failure Assessment (qSOFA), and National Early Warning Score (NEWS) criteria in relation to short-term mortality among HCT recipients with SIs. Data from the first 100-days post-transplant were analyzed for patients transplanted between September 2010 - July 2017. We used the following cut-points (qSOFA/SIRS: 2+; NEWS: 7+) and restricted to first SI per hospital encounter.ResultsOf the 880 HCT recipients who experienced ≥ 1 SI, 58 (6.6%) died within 28 days and 22 (2.5%) within 10 days of a SI. In relation to 10-day mortality, SIRS was the most sensitive: 91.3% (95% CI:72.0 – 98.9%) but least specific: 35.0% (32.6 – 37.5%) whereas qSOFA was the most specific: 90.5% (88.9 – 91.9%) but least sensitive: 47.8% (26.8 – 69.4%). NEWS was moderately sensitive 78.3% (56.3 – 92.5%) and specific 70.2% (67.8 – 72.4%).ConclusionNEWS outperformed qSOFA and SIRS, but all three criteria had low to moderate predictive accuracy and the magnitude of the known predictive limitations of qSOFA and SIRS were at least as large as in general populations. Our data suggest that population-specific sepsis criteria are needed for immunocompromised patients.

Abstract Background Vitamin D deficiency has been related to the risk of sepsis. However, previous studies showed inconsistent results regarding the association between serum 25-hydroxyvitamin D (25 (OH) D) and mortality risk in septic patients. We aimed to evaluate the relationship between serum 25 (OH) D at admission and mortality risk in adult patients in a meta-analysis. Methods Follow-up studies that provided data of multivariate adjusted relative risk (RR) between serum 25 (OH) D and mortality risk in septic patients were retrieved via systematic search of PubMed and Embase databases. A random effect model was used to pool the results. Results Eight studies with 1736 patients were included. Results of overall meta-analysis showed that lower 25 (OH) D at admission was independently associated with increased risk or mortality (adjusted RR: 1.93, p 

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.