Sepsis Current Awareness Bulletin June 2021

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Title: A simple measure to improve sepsis documentation and coding. Citation: Clinical Medicine; May 2021; vol. 21 (no. 3); p. 222-225 Author(s): Arberry ; Henry, Zanya; Corrah, Tumena Introduction: Sepsis incidence and mortality are increasing, yet sepsis appears to be under-recognised and under-reported. Accurate recognition and coding of sepsis allows for appropriate funding and accurate epidemiological representation. Methods: We implemented a discharge summary template for all patients discharged from our infectious diseases service and analysed sepsis documentation and coding before and after its introduction. Results: Beforehand, we found that 59% of 29 patients had sepsis, yet only 10% had it documented on their discharge summary, and 17% had it coded. Following implementation of the template, 38% of 52 patients had sepsis documented, yet only 20% of these had it coded. After delivery of a training session to the coders regarding the importance of sepsis, 38% of patients with a diagnosis of sepsis had it coded. Discussion: Despite requiring ongoing education and encouragement of clinicians and coders, implementation of the template was quick, cheap and easy and improved sepsis coding.

Title: Acupuncture modulates immunity in sepsis: Toward a science-based protocol Citation: Autonomic Neuroscience: Basic and Clinical; May 2021; vol. 232 Author(s): Pan W.-X.; Fan A.Y.; Alemi S.F.; Chen S. Abstract: Sepsis is a serious medical condition in which immune dysfunction plays a key role. Previous treatments focused on chemotherapy to control immune function; however, a recognized effective compound or treatment has yet to be developed. Recent advances indicate that a neuromodulation approach with nerve stimulation allows developing a therapeutic strategy to control inflammation and improve organ functions in sepsis. As a quick, non-invasive technique of peripheral nerve stimulation, acupuncture has emerged as a promising therapy to provide significant advantages for immunomodulation in acute inflammation. Acupuncture obtains its regulatory effect by activating the somatic-autonomic-immune reflexes, including the somatic-sympathetic-splenic reflex, the somatic-sympathetic-adrenal reflex, the somatic-vagal-splenic reflex and the somatic-vagal-adrenal reflex, which produces a systemic effect. The peripheral nerve stimulation also induces local reflexes such as the somatic-sympathetic-lung-reflex, which then produces local effects. These mechanisms offer scientific guidance to design acupuncture protocols for immunomodulation and inflammation control, leading to an evidence-based comprehensive therapy recommendation. Copyright © 2021 The Authors

Title: Antibiotic regimens for late-onset neonatal sepsis. Citation: The Cochrane database of systematic reviews; May 2021; vol. 5 ; p. CD013836 Author(s): Korang, Steven Kwasi; Safi, Sanam; Nava, Chiara; Greisen, Gorm; Gupta, Munish; Lausten-Thomsen, Ulrik; Jakobsen, Janus C

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Background: Neonatal sepsis is a major cause of morbidity and mortality. It is the third leading cause of neonatal mortality globally constituting 13% of overall neonatal mortality. Despite the high burden of neonatal sepsis, high-quality evidence in diagnosis and treatment is scarce. Due to the diagnostic challenges of sepsis and the relative immunosuppression of the newborn, many neonates receive antibiotics for suspected sepsis. Antibiotics have become the most used therapeutics in neonatal intensive care units, and observational studies in high-income countries suggest that 83% to 94% of newborns treated with antibiotics for suspected sepsis have negative blood cultures. The last Cochrane Review was updated in 2005. There is a need for an updated systematic review assessing the effects of different antibiotic regimens for late-onset neonatal sepsis. Objectives: To assess the beneficial and harmful effects of different antibiotic regimens for late-onset neonatal sepsis. Search Methods: We searched the following electronic databases: CENTRAL (2021, Issue 3); Ovid MEDLINE; Embase Ovid; CINAHL; LILACS; Science Citation Index EXPANDED and Conference Proceedings Citation Index - Science on 12 March 2021. We also searched clinical trials databases and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-RCTs. Selection Criteria: We included RCTs comparing different antibiotic regimens for late-onset neonatal sepsis. We included participants older than 72 hours of life at randomisation, suspected or diagnosed with neonatal sepsis, meningitis, osteomyelitis, endocarditis, or necrotising enterocolitis. We excluded trials that assessed treatment of fungal infections. Data Collection and Analysis: Three review authors independently assessed studies for inclusion, extracted data, and assessed risk of bias. We used the GRADE approach to assess the certainty of evidence. Our primary outcome was all-cause mortality, and our secondary outcomes were: serious adverse events, respiratory support, circulatory support, nephrotoxicity, neurological developmental impairment, necrotising enterocolitis, and ototoxicity. Our primary time point of interest was at maximum follow-up. Main Results: We included five RCTs (580 participants). All trials were at high risk of bias, and had very low-certainty evidence. The five included trials assessed five different comparisons of antibiotics. We did not conduct a meta-analysis due to lack of relevant data. Of the five included trials one trial compared cefazolin plus amikacin with vancomycin plus amikacin; one trial compared ticarcillin plus clavulanic acid with flucloxacillin plus gentamicin; one trial compared cloxacillin plus amikacin with cefotaxime plus gentamicin; one trial compared meropenem with standard care (ampicillin plus gentamicin or cefotaxime plus gentamicin); and one trial compared vancomycin plus gentamicin with vancomycin plus aztreonam. None of the five comparisons found any evidence of a difference when assessing all-cause mortality, serious adverse events, circulatory support, nephrotoxicity, neurological developmental impairment, or necrotising enterocolitis; however, none of the trials were near an information size that could contribute significantly to the evidence of the comparative benefits and risks of any particular antibiotic regimen. None of the trials assessed respiratory support or ototoxicity. The benefits and harms of different antibiotic regimens remain unclear due to the lack of well-powered trials and the high risk of systematic errors. Authors' Conclusions: Current evidence is insufficient to support any antibiotic regimen being superior to another. RCTs assessing different antibiotic regimens in late-onset neonatal sepsis with low risks of bias are warranted.

Title: Artificial Intelligence for Clinical Decision Support in Sepsis Citation: Frontiers in Medicine; May 2021; vol. 8 Author(s): Wu M.; Wei J.; Du X.; Gu R.

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Abstract: Sepsis is one of the main causes of death in critically ill patients. Despite the continuous development of medical technology in recent years, its morbidity and mortality are still high. This is mainly related to the delay in starting treatment and non-adherence of clinical guidelines. Artificial intelligence (AI) is an evolving field in medicine, which has been used to develop a variety of innovative Clinical Decision Support Systems. It has shown great potential in predicting the clinical condition of patients and assisting in clinical decision-making. AI-derived algorithms can be applied to multiple stages of sepsis, such as early prediction, prognosis assessment, mortality prediction, and optimal management. This review describes the latest literature on AI for clinical decision support in sepsis, and outlines the application of AI in the prediction, diagnosis, subphenotyping, prognosis assessment, and clinical management of sepsis. In addition, we discussed the challenges of implementing and accepting this non-traditional methodology for clinical purposes.© Copyright © 2021 Wu, Du, Gu and Wei.

Title: Challenges to Reporting the Global Trends in the Epidemiology of ICU-Treated Sepsis and Septic Shock Citation: Current Infectious Disease Reports; May 2021; vol. 23 (no. 5) Author(s): Raman V.; Laupland K.B. Purpose of Review: It is widely believed that the epidemiology of sepsis and septic shock treated in the intensive care unit (ICU) is changing. However, quantifying changes in occurrence and outcomes of ICU-treated sepsis and septic shock are challenged by a number of factors related to study designs as well as varied local resource availability and practices. The authors conducted a structured literature review to examine contemporary studies reporting trends in the prevalence, incidence and case-fatality rates of ICU-treated sepsis and septic shock around the world and further attempted to extrapolate the recent epidemiological trends. Recent Findings: During 2015-2020, 13 observational studies with heterogenous methodologies were published from predominantly high-income countries that examined selected cohorts with ICU-treated sepsis, sepsis with end-organ failure (previously known as severe sepsis) and septic shock. The prevalence of sepsis and sepsis-related diagnoses ranged widely from 4.7-42.2% of ICU admissions. The population incidence varied widely between 88 and 370 cases per 100,000 for sepsis and 19 and 79 cases per 100,000 for septic shock. Mean case-fatality rates (deaths per number of cases, %) reported primarily as in-hospital deaths reduced from approximately 40-50% reported in previous years, to 30-40% in the past 5 years. There was a lack of recent studies specifically examining mortality at the population level. Summary: Contemporary studies have observed wide variation in prevalence and incidence of sepsis and septic shock along with reports of static or decreasing case-fatality rates, but we are not able to make generalised commentary on global trends from the results of existing studies. Further data from ICUs in low-income and middle-income countries is needed, and well-designed, consistent population-based studies are required in order to establish whether the burden of sepsis and septic shock is changing. Copyright © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

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Title: Effectiveness of sepsis bundle application and outcomes predictors to cirrhotic patients with septic shock. Citation: BMC Infectious Diseases; May 2021; vol. 21 (no. 1); p. 1-8 Author(s): Yang ; Hsu, Yin-Chou Introduction: Cirrhotic patients with septic shock have a poorer prognosis compared with the general population. Our study aimed to investigate the survival benefit of the implementation of hour-1 bundle proposed by Surviving Sepsis Campaign, and to analyze the predictors associated with short-term mortality of these patients. Methods: A single-center, retrospective case-control study was conducted among adult patients who visited the emergency department between January 1, 2018 and December 31, 2019. All patients with a diagnosis of liver cirrhosis and septic shock were enrolled. Their baseline characteristics, laboratory results, source of sepsis, and sepsis bundle management were recorded. We further divided the patients into survivor and non-survivor groups to identify independent prognostic factors. Results: A total of 88 patients were eligible for this study. The overall 30-day mortality rate was 53.4% (47/88). The proportion of hour-1 bundle achievement was 30.7% (27/88). There were no significant mortality differences between the hour-1 bundle achievement and non-achievement groups (44.4% vs. 57.4%, p = 0.35). Compared with the patients in the survivor group, patients in the non-survivor group had significantly more advanced stage of cirrhosis and a lower proportion of receiving source control (4.3% vs. 22.0%, p = 0.02). The chronic liver failure-sequential organ failure assessment (CLIF-SOFA) score (adjusted hazard ratio [AHR] =1.52, p < 0.01), serum lactate (AHR =1.03, p < 0.01), and source control (AHR =0.54, p = 0.02) were identified as independent prognostic factors in the multivariate regression model. Furthermore, the CLIF-SOFA score (area under curve [AUC]: 0.81) and lactate levels (AUC: 0.77) revealed good mortality discrimination ability in cirrhotic patients with septic shock. Conclusions: The application of the hour-1 bundle did not reveal a significant survival benefit to cirrhotic patients with septic shock. Clinicians could utilize CLIF-SOFA scores and lactate levels for mortality risk stratification and put more emphasis on the feasibility of source control to improve their prognosis. Title: Future directions and priorities in sepsis epidemiology research: a call for action. Citation: Bulletin of the World Health Organization; May 2021; vol. 99 (no. 5); p. 398-401 Author(s): Cassini ; Fleischmann-Struzek, Carolin; Naghavi, Mohsen; Reinhart, Konrad; Allegranzi, Benedetta Abstract: The article examines the limitations and key priorities in research on sepsis epidemiology. Topics discussed include the challenges in the use of prospective studies based on clinical data from patient records in sepsis research, emergence of low- and middle-income countries as the nations with the biggest gap of evidence on the burden of sepsis, and the necessity for advocacy and funding of high-quality research in sepsis epidemiology.

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Title: Immune Modulation in Critically Ill Septic Patients. Citation: Medicina (Kaunas, Lithuania); May 2021; vol. 57 (no. 6) Author(s): Cutuli, Salvatore Lucio; Carelli, Simone; Grieco, Domenico Luca; De Pascale, Gennaro Abstract: Sepsis is triggered by infection-induced immune alteration and may be theoretically improved by pharmacological and extracorporeal immune modulating therapies. Pharmacological immune modulation may have long lasting clinical effects, that may even worsen patient-related outcomes. On the other hand, extracorporeal immune modulation allows short-term removal of inflammatory mediators from the bloodstream. Although such therapies have been widely used in clinical practice, the role of immune modulation in critically ill septic patients remains unclear and little evidence supports the role of immune modulation in this clinical context. Accordingly, further research should be carried out by an evidence-based and personalized approach in order to improve the management of critically ill septic patients.

Title: Impact of the timeliness of antibiotic therapy on the outcome of patients with sepsis and septic shock Citation: Journal of Infection; May 2021; vol. 82 (no. 5); p. 125-134 Author(s): Asner S.A.; Desgranges F.; Schrijver I.T.; Calandra T. Objectives: To review the impact of the timeliness of antibiotic therapy on the outcome of patients with sepsis or septic shock. Method(s): We searched MEDLINE, EMBASE, the Cochrane Library, Web of Science, Open-SIGLE databases, ClinicalTrials.gov and the metaRegister of Controlled Trials on July 27, 2020 for relevant studies on the timing of antibiotic therapy in adult patients with sepsis or septic shock. The primary outcome measure was all-cause crude or adjusted mortality at reported time points. Result(s): We included 35 sepsis studies involving 154,330 patients. Nineteen studies (54%) provided information on the appropriateness of antibiotic therapy in 20,062 patients of whom 16,652 patients (83%) received appropriate antibiotics. Twenty-four studies (68.6%) reported an association between time-to-antibiotics and mortality. Time thresholds associated with patient's outcome varied considerably between studies consisting of a wide range of time cutoffs (1 h, 125 min, 3 h or 6 h) in 14 studies, hourly delays (derived from the analyses of time intervals ranging from to 1 to 24 h) in 8 studies or time-to-antibiotic in 2 studies. Analyses of subsets of studies that focused on patients with septic shock (11 studies, 12,756 patients) or with sepsis (6 studies, 24,281 patients) yielded similar results. Conclusion(s): While two-thirds of sepsis studies reported an association between early administration of antibiotic therapy and patient outcome, the time-to-antibitiocs metrics varied significantly across studies and no robust time thresholds emerged. Copyright © 2021 Title: Long-Term Outcomes after Sepsis Citation: Biochemistry. Biokhimiia; May 2021; vol. 86 (no. 5); p. 563-567 Author(s): Grebenchikov O.A.; Kuzovlev A.N.

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Abstract: Sepsis is one of the most serious problems in modern medicine. Long-term outcomes in septic shock patients are very discouraging: 75% individuals who survived sepsis and septic shock demonstrate signs of organ failure and experience persistent functional deficit. Acute sepsis and its management in an intensive care unit (ICU) to a great extent determine the pathogenesis of further complications. We believe that the concept of phenoptosis proposed by Prof. Skulachev deserves a special attention from anesthesiologists and ICU doctors. According to this concept, septic shock is a suicidal mechanism of programmed organism death, which protects human population from dangerously infected individuals. The article suggests a potential approach to the sepsis treatment based on the notion that septic shock can be prevented by identification and blockade of receptors involved in the processing of phenoptotic signal induced by lipopolysaccharide and other substances that initiate septic shock. In view of this, the search for agents that can block molecular mechanisms of the phenoptotic signal transmission seems very promising. Title: Maternal Sepsis: Presentation, Course, Treatment, And Outcomes. Citation: MCN: The American Journal of Maternal Child Nursing; May 2021; vol. 46 (no. 3); p. 155-160 Author(s): Stanley Sundin ; Rigg, Kendall; Kistner Ellis, Kathleen Abstract: The current adult definition of sepsis and septic shock, as developed in 1992, does not adequately define sepsis in the pregnant and peripartum women due to the alteration of sepsis presentation in the maternal population. The purpose of this study was to determine potential causative factors for sepsis with the aim of prevention and reducing morbidity and mortality. Study Design and Methods: A descriptive observational design via a retrospective medical record review was used with a convenience sample of 22 women who were identified after admission as having sepsis. The setting was the labor and delivery unit of a large urban hospital in Fort Worth, Texas, with over 5,000 births per year. Results: The most common diagnoses related to maternal sepsis included urinary tract infections, endometritis, chorioamnionitis, and wound infections. Main causative agents identified were predominantly Escherichia coli(E. coll), followed by group B streptococcus (GBS), and group A streptococcus (group A strep). The most prevalent presenting symptom was hypothermia or hyperthermia, followed by tachycardia. Primary laboratory results included above and below normal white blood cell count and elevated lactate levels. Sixty-four percent of patients diagnosed with sepsis were readmitted postpar-tum and 41% gave birth via cesarean. Clinical Implications: Findings are applicable for nursing care and maternal sepsis protocol development. Early identification of mothers at risk for maternal sepsis and tool development for early diagnosis would be beneficial to support the ongoing work on decreasing maternal morbidity and mortality that have a devastating effect on women, their families, and their health care team. Early warning signs of sepsis can be shared by nurses with new mothers and their families as part of routine postpartum discharge teaching so they know when to call their primary health care provider and when to seek care in person. Title: Metabolic Alterations in Sepsis. Citation: Journal of clinical medicine; May 2021; vol. 10 (no. 11) Author(s): Wasyluk, Weronika; Zwolak, Agnieszka

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Abstract: Sepsis is defined as "life-threatening organ dysfunction caused by a dysregulated host response to infection". Contrary to the older definitions, the current one not only focuses on inflammation, but points to systemic disturbances in homeostasis, including metabolism. Sepsis leads to sepsis-induced dysfunction and mitochondrial damage, which is suggested as a major cause of cell metabolism disorders in these patients. The changes affect the metabolism of all macronutrients. The metabolism of all macronutrients is altered. A characteristic change in carbohydrate metabolism is the intensification of glycolysis, which in combination with the failure of entering pyruvate to the tricarboxylic acid cycle increases the formation of lactate. Sepsis also affects lipid metabolism-lipolysis in adipose tissue is upregulated, which leads to an increase in the level of fatty acids and triglycerides in the blood. At the same time, their use is disturbed, which may result in the accumulation of lipids and their toxic metabolites. Changes in the metabolism of ketone bodies and amino acids have also been described. Metabolic disorders in sepsis are an important area of research, both for their potential role as a target for future therapies (metabolic resuscitation) and for optimizing the current treatment, such as clinical nutrition.

Title: Metric Development for the Multicenter Improving Pediatric Sepsis Outcomes (IPSO) Collaborative. Citation: Pediatrics; May 2021; vol. 147 (no. 5); p. 1-13 Author(s): Paul ; Niedner, Matthew; Brilli, Richard; Macias, Charles; Riggs, Ruth; Balamuth, Frances; Depinet, Holly; Larsen, Gitte; Huskins, Charlie; Scott, Halden; Lucasiewicz, Gloria Background: A 56 US hospital collaborative, Improving Pediatric Sepsis Outcomes, has developed variables, metrics and a data analysis plan to track quality improvement (QI)--based patient outcomes over time. Improving Pediatric Sepsis Outcomes expands on previous pediatric sepsis QI efforts by improving electronic data capture and uniformity across sites. Methods: An expert panel developed metrics and corresponding variables to assess improvements across the care delivery spectrum, including the emergency department, acute care units, hematology and oncology, and the ICU. Outcome, process, and balancing measures were represented. Variables and statistical process control charts were mapped to each metric, elucidating progress over time and informing plan-do-study-act cycles. Electronic health record (EHR) abstraction feasibility was prioritized. Time 0 was defined as time of earliest sepsis recognition (determined electronically), or as a clinically derived time 0 (manually abstracted), identifying earliest physiologic onset of sepsis. Results: Twenty-four evidence-based metrics reflected timely and appropriate interventions for a uniformly defined sepsis cohort. Metrics mapped to statistical process control charts with 44 final variables; 40 could be abstracted automatically from multiple EHRs. Variables, including high-risk conditions and bedside huddle time, were challenging to abstract (reported in <80% of encounters). Size or type of hospital, method of data abstraction, and previous QI collaboration participation did not influence hospitals' abilities to contribute data. To date, 90% of data have been submitted, representing 200 007 sepsis episodes. Conclusions: A comprehensive data dictionary was developed for the largest pediatric sepsis QI collaborative, optimizing automation and ensuring sustainable reporting. These approaches can be used in other large-scale sepsis QI projects in which researchers seek to leverage EHR data abstraction.

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Title: Neuroinflammation in sepsis: Molecular pathways of microglia activation Citation: Pharmaceuticals; May 2021; vol. 14 (no. 5) Author(s): Moraes C.A.; D'avila J.; Zaverucha-Do-valle C.; Bozza F.A.; Fleurance R.; Sharshar T. Abstract: Frequently underestimated, encephalopathy or delirium are common neurological manifestations associated with sepsis. Brain dysfunction occurs in up to 80% of cases and is directly associated with increased mortality and long-term neurocognitive consequences. Although the central nervous system (CNS) has been classically viewed as an immune-privileged system, neuroinflammation is emerging as a central mechanism of brain dysfunction in sepsis. Microglial cells are major players in this setting. Here, we aimed to discuss the current knowledge on how the brain is affected by peripheral immune activation in sepsis and the role of microglia in these processes. This review focused on the molecular pathways of microglial activity in sepsis, its regulatory mechanisms, and their interaction with other CNS cells, especially with neuronal cells and circuits.Copyright © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Title: Pathophysiology and treatment strategies of acute myopathy and muscle wasting after sepsis Citation: Journal of Clinical Medicine; May 2021; vol. 10 (no. 9) Author(s): Mankowski R.T.; Laitano O.; Clanton T.L.; Brakenridge S.C. Abstract: Sepsis survivors experience a persistent myopathy characterized by skeletal muscle weak-ness, atrophy, and an inability to repair/regenerate damaged or dysfunctional myofibers. The origins and mechanisms of this persistent sepsis-induced myopathy are likely complex and multifactorial. Nevertheless, the pathobiology is thought to be triggered by the interaction between circulating pathogens and impaired muscle metabolic status. In addition, while in the hospital, septic patients often experience prolonged periods of physical inactivity due to bed rest, which may exacerbate the myopathy. Physical rehabilitation emerges as a potential tool to prevent the decline in physical function in septic patients. Currently, there is no consensus regarding effective rehabilitation strategies for sepsis-induced myopathy. The optimal timing to initiate the rehabilitation intervention currently lacks consensus as well. In this review, we summarize the evidence on the fundamental pathobi-ological mechanisms of sepsis-induced myopathy and discuss the recent evidence on in-hospital and post-discharge rehabilitation as well as other potential interventions that may prevent physical disability and death of sepsis survivors. Copyright © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Title: Patient, provider, and system factors that contribute to health care-associated infection and sepsis development in patients after a traumatic injury: An integrative review Citation: Australian critical care : official journal of the Confederation of Australian Critical Care Nurses; May 2021; vol. 34 (no. 3); p. 269-277 Author(s): Tan D.; Wiseman T.; Betihavas V.; Rolls K.

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Objectives: Patients after traumatic injury continue to develop health care-associated infections. The aim of this review was to identify risk factors for developing hospital-acquired infection and sepsis in patients experiencing a traumatic injury. Design: This is an integrative review following the framework of Whittemore and Knafl. Data Sources: An electronic database search was undertaken using Scopus and Medline databases in early October 2019. Hand searching of key references was also conducted. The existing literature published between January 2007 and September 2019 was searched to identify clinically relevant studies that reflected current healthcare practices and systems. Review Methods: Four reviewers independently assessed articles for inclusion eligibility. Full-text versions of the articles were systematically appraised using the Critical Appraisal Skills Programme. The Preferred Reporting Items for Systematic reviews and Meta-Analyses format was used. Result(S): A total of 15 studies from the United Kingdom, the United States of America, China, and South Korea were included. Twelve of the 15 studies were focused exclusively on patient-based risk factors including gender and comorbidities. Provider-based factors were identified as nurse staffing levels between different categories of nurses with various levels of proficiency. System-level risk factors included interhospital admissions, surgical interventions, and length of stay. Conclusion(S): Hospital-acquired infections are preventable, and it is imperative that provider and system risk factors that contribute to patients with traumatic injuries from developing a hospital-acquired infection be identified. Patients with traumatic injuries are unable to amend any patient-related risk factors such as comorbidities or gender. However, the identification of provider and system risk factors that contribute to patients with traumatic injuries from developing a hospital-acquired infection would provide clinically relevant and applicable strategies at the macro and meso level being implemented. Copyright © 2020 Australian College of Critical Care Nurses Ltd. Published by Elsevier Ltd. All rights reserved.

Title: Predicting In-Hospital Cardiac Arrest In Patients With Sepsis Using A Machine Learning Algorithm: A National Cohort Study. Citation: Journal of the American College of Cardiology (JACC); May 2021; vol. 77 (no. 18); p. 1500-1500 Author(s): Qian ; Sherrod IV, Charles Fox; Hsiung, Jo-Ching; Ling, Dean-An; Wu, I-Ju; Liu, Ye; Hsu, Wan-Ting; Duazo, Catherine; Hsu, Tzu-Chun; Lee, Chien-Chang Background: Little is known about the risk of in-hospital cardiac arrest (IHCA) among patients with sepsis. We aimed to characterize the incidence and outcome of IHCA among patients with sepsis in a national database. We then determined the major risk factors associated with IHCA among sepsis patients. Methods: We used data from a population-based cohort study based on the National Health Insurance Research Database of Taiwan (NHRID) between 2000 and 2013. We used Martin’s implementation that combined the explicit ICD-9 CM codes for sepsis and six major organ dysfunction categories. IHCA among sepsis patients was identified by the presence of cardiopulmonary resuscitation procedures. Survival post-IHCA was analyzed with Cox models using inverse probability of treatment weighting (IPTW). Associated risk factors were identified with a machine learning algorithm LASSO regression, adjusting for competing risks. Results: We identified a total of 20,022 patients with sepsis, among whom 2,168 developed IHCA. Sepsis patients with higher burden of comorbidities and organ dysfunction were more likely to develop IHCA. Acute respiratory failure, hematological dysfunction, renal dysfunction and hepatic dysfunction were associated with increased risk of IHCA. Regarding

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the source of infection, patients with respiratory tract infection were at the highest risk, whereas patients with urinary tract infections and primary bacteremia were less likely to develop IHCA. The risk of IHCA correlated well with age and revised cardiac risk index. The final competing risk model concluded that acute respiratory failure, male gender, and diabetes are the three strongest predictors for IHCA. IHCA was associated with an increased 30-day mortality rate, IPTW-weighted hazard ratio (HR): 4.77 (95% CI: 4.60, 4.95) and this association persisted up to 1 year after hospital discharge, 5.19 (95% CI: 5.06, 5.35). Conclusion: IHCA in sepsis patients was associated with worse short- and long-term survival. Risk of IHCA among hospitalized sepsis patients was strongly correlated with age and cardiac risk index. The three identified risk factors can help clinicians to recognize patients at higher risk for IHCA Title: Rapid versus standard antimicrobial susceptibility testing to guide treatment of bloodstream infection. Citation: The Cochrane database of systematic reviews; May 2021; vol. 5 ; p. CD013235 Author(s): Anton-Vazquez, Vanesa; Hine, Paul; Krishna, Sanjeev; Chaplin, Marty; Planche, Timothy Background: Rapid antimicrobial susceptibility tests are expected to reduce the time to clinically important results of a blood culture. This might enable clinicians to better target therapy to a person's needs, and thereby, improve health outcomes (mortality, length of hospital stay), and reduce unnecessary prescribing of broad-spectrum antibiotics; thereby reducing antimicrobial resistance rates. Objectives: To assess the effects of rapid susceptibility testing versus standard susceptibility testing for bloodstream infections (BSIs). Search Methods: To identify studies with selected outcomes, we searched the Cochrane Infectious Diseases Group Specialised Register, CENTRAL, MEDLINE, LILACS, and two trials registries, between 1987 and October 2020. We used 'bloodstream infection' and 'antimicrobial susceptibility tests' as search terms. We had no language or publication status limitations. Selection Criteria: Randomized controlled trials (RCTs) comparing rapid antimicrobial susceptibility testing (with a time-to-result of ≤ 8 hours) versus conventional antimicrobial susceptibility testing in people with a BSI caused by any bacteria, as identified by a positive blood culture. Data Collection and Analysis: Two review authors independently screened references, full-text reports of potentially relevant studies, extracted data from the studies, and assessed risk of bias. Any disagreement was discussed and resolved with a third review author. For mortality, a dichotomous outcome, we extracted the number of events in each arm, and presented a risk ratio (RR) with 95% confidence interval (CI) to compare rapid susceptibility testing to conventional methods. We used Review Manager 5.4 to meta-analyse the data. For other outcomes, which are time-to-event outcomes (time-to-discharge from hospital, time-to-first appropriate antibiotic change), we conducted qualitative narrative synthesis, due to heterogeneity of outcome measures. Main Results: We included six trials, with 1638 participants. For rapid antimicrobial susceptibility testing compared to conventional methods, there was little or no difference in mortality between groups (RR 1.10, 95% CI 0.82 to 1.46; 6 RCTs, 1638 participants; low-certainty evidence). In subgroup analysis, for rapid genotypic or molecular antimicrobial susceptibility testing compared to conventional methods, there was little or no difference in mortality between groups (RR 1.02, 95% CI 0.69 to 1.49; 4 RCTs, 1074 participants; low-

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certainty evidence). For phenotypic rapid susceptibility testing compared to conventional methods, there was little or no difference in mortality between groups (RR 1.37, 95% CI 0.80 to 2.35; 2 RCTs, 564 participants; low-certainty evidence). In qualitative analysis, rapid susceptibility testing may make little or no difference in time-to-discharge (4 RCTs, 1165 participants; low-certainty evidence). In qualitative analysis, rapid genotypic susceptibility testing compared to conventional testing may make little or no difference in time-to-appropriate antibiotic (3 RCTs, 929 participants; low-certainty evidence). In subgroup analysis, rapid phenotypic susceptibility testing compared to conventional testing may improve time-to-appropriate antibiotic (RR -17.29, CI -45.05 to 10.47; 2 RCTs, 564 participants; low-certainty evidence). Authors' Conclusions: The theoretical benefits of rapid susceptibility testing have not been demonstrated to directly improve mortality, time-to-discharge, or time-to-appropriate antibiotic in these randomized studies. Future large prospective studies should be designed to focus on the most clinically meaningful outcomes, and aim to optimize blood culture pathways. Title: Safety-driven design of machine learning for sepsis treatment. Citation: Journal of Biomedical Informatics; May 2021; vol. 117 Author(s): Jia ; Lawton, Tom; Burden, John; McDermid, John; Habli, Ibrahim Abstract: Machine learning (ML) has the potential to bring significant clinical benefits. However, there are patient safety challenges in introducing ML in complex healthcare settings and in assuring the technology to the satisfaction of the different regulators. The work presented in this paper tackles the urgent problem of proactively assuring ML in its clinical context as a step towards enabling the safe introduction of ML into clinical practice. In particular, the paper considers the use of deep Reinforcement Learning, a type of ML, for sepsis treatment. The methodology starts with the modelling of a clinical workflow that integrates the ML model for sepsis treatment recommendations. Then safety analysis is carried out based on the clinical workflow, identifying hazards and safety requirements for the ML model. In this paper the design of the ML model is enhanced to satisfy the safety requirements for mitigating a major clinical hazard: sudden change of vasopressor dose. A rigorous evaluation is conducted to show how these requirements are met. A safety case is presented, providing a basis for regulators to make a judgement on the acceptability of introducing the ML model into sepsis treatment in a healthcare setting. The overall argument is broad in considering the wider patient safety considerations, but the detailed rationale and supporting evidence presented relate to this specific hazard. Whilst there are no agreed regulatory approaches to introducing ML into healthcare, the work presented in this paper has shown a possible direction for overcoming this barrier and exploit the benefits of ML without compromising safety.

Title: Sepsis as a pan-endocrine illness-endocrine disorders in septic patients Citation: Journal of Clinical Medicine; May 2021; vol. 10 (no. 10) Author(s): Wasyluk W.; Wasyluk M.; Zwolak A. Abstract: Sepsis is defined as "life-threatening organ dysfunction caused by a dysregulated host response to infection". One of the elements of dysregulated host response is an endocrine system disorder. Changes in its functioning in the course of sepsis affect almost all hormonal axes. In sepsis, a function disturbance of the hypothalamic-pituitary-adrenal

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axis has been described, in the range of which the most important seems to be hypercortisolemia in the acute phase. Imbalance in the hypothalamic-pituitary-thyroid axis is also described. The most typical manifestation is a triiodothyronine concentration decrease and reverse triiodothyronine concentration increase. In the somatotropic axis, a change in the secretion pattern of growth hormone and peripheral resistance to this hormone has been described. In the hypothalamic-pituitary-gonadal axis, the reduction in testosterone concentration in men and the stress-induced "hypothalamic amenorrhea" in women have been described. Catecholamine and beta-adrenergic stimulation disorders have also been reported. Disorders in the endocrine system are part of the "dysregulated host response to infection". They may also affect other components of this dysregulated response, such as metabolism. Hormonal changes occurring in the course of sepsis require further research, not only in order to explore their potential significance in therapy, but also due to their promising prognostic value. Copyright © 2021, MDPI AG. All rights reserved. Title: Sepsis Subclasses: A Framework for Development and Interpretation*. Citation: Critical Care Medicine; May 2021; vol. 49 (no. 5); p. 748-759 Author(s): DeMerle ; Angus, Derek C.; Baillie, J. Kenneth; Brant, Emily; Calfee, Carolyn S.; Carcillo, Joseph; Chang, Chung-Chou H.; Dickson, Robert; Evans, Idris; Gordon, Anthony C.; Kennedy, Jason; Knight, Julian C.; Lindsell, Christopher J.; Liu, Vincent; Marshall, John C.; Randolph, Adrienne G.; Scicluna, Brendon P.; Shankar-Hari, Manu; Shapiro, Nathan I.; Sweeney, Timothy E. Abstract: Sepsis is defined as a dysregulated host response to infection that leads to life-threatening acute organ dysfunction. It afflicts approximately 50 million people worldwide annually and is often deadly, even when evidence-based guidelines are applied promptly. Many randomized trials tested therapies for sepsis over the past 2 decades, but most have not proven beneficial. This may be because sepsis is a heterogeneous syndrome, characterized by a vast set of clinical and biologic features. Combinations of these features, however, may identify previously unrecognized groups, or "subclasses" with different risks of outcome and response to a given treatment. As efforts to identify sepsis subclasses become more common, many unanswered questions and challenges arise. These include: 1) the semantic underpinning of sepsis subclasses, 2) the conceptual goal of subclasses, 3) considerations about study design, data sources, and statistical methods, 4) the role of emerging data types, and 5) how to determine whether subclasses represent "truth." We discuss these challenges and present a framework for the broader study of sepsis subclasses. This framework is intended to aid in the understanding and interpretation of sepsis subclasses, provide a mechanism for explaining subclasses generated by different methodologic approaches, and guide clinicians in how to consider subclasses in bedside care. Title: Sepsis-Pathophysiology and Therapeutic Concepts Citation: Frontiers in Medicine; May 2021; vol. 8 Author(s): Jarczak D.; Kluge S.; Nierhaus A. Abstract: Sepsis is a life-threatening condition and a global disease burden. Today, the heterogeneous syndrome is defined as severe organ dysfunction caused by a dysregulated host response to infection, with renewed emphasis on immune pathophysiology. Despite all efforts of experimental and clinical research during the last three decades, the ability to positively influence course and outcome of the syndrome remains limited. Evidence-based

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therapy still consists of basic causal and supportive measures, while adjuvant interventions such as blood purification or targeted immunotherapy largely remain without proof of effectiveness so far. With this review, we aim to provide an overview of sepsis immune pathophysiology, to update the choice of therapeutic approaches targeting different immunological mechanisms in the course of sepsis and septic shock, and to call for a paradigm shift from the pathogen to the host response as a potentially more promising angle.© Copyright © 2021 Jarczak, Kluge and Nierhaus. Title: Skin and sepsis: contribution of dermatology to a rapid diagnosis Citation: Infection; 2021 Author(s): Pulido-Perez A.; Bergon-Sendin M.; Suarez-Fernandez R.; Munoz-Martin P.; Bouza E. Abstract: In patients who develop sepsis, whether due to primary, secondary or metastatic lesions, the skin is frequently affected. However, there are unresolved aspects regarding the general clinical manifestations in the skin or the prognosis and/or therapeutic implications. The main challenge in the approach to sepsis is its early diagnosis and management. In this review, we address the sepsis-skin relationship and the potential impact of early dermatological intervention on the septic patient through ten basic questions. We found little evidence of the participation of the dermatologist in sepsis alert programs. There are early skin changes that may alert clinicians on a possible sepsis, such as skin mottling or variations in acral skin temperature. In addition, the skin is an accessible and highly cost-effective tissue for etiological studies of some forms of sepsis (e.g., meningococcal purpura) and its involvement defines the prognosis of certain patients (e.g., infective endocarditis). Copyright © 2021, Springer-Verlag GmbH Germany, part of Springer Nature. Title: Stress and the Gut-Brain Axis: Implications for Cancer, Inflammation and Sepsis. Citation: The Journal of surgical research; May 2021; vol. 266 ; p. 336-344 Author(s): Moughnyeh, Mohamad M; Brawner, Kyle M; Kennedy, Bethany A; Yeramilli, Venkata A; Udayakumar, Neha; Graham, Jessica A; Martin, Colin A Background: The gut-brain axis has been discussed, directly or indirectly, for centuries, with the ideas of the gut affecting anything from moods to overall physiology being discussed across the centuries. With a recent explosion in research that looks to the microbiota as a mechanistic link between the gut and the brain, one sees that the gut-brain axis has various means of communication, such as through the vagus nerve and the enteric nervous system and can use the metabolites in the gut to communicate to the brain. Methods: The purpose of this review is to view the gut-brain axis through the lens of stress and how stress, from the prenatal period all the way through adulthood can impact the physiology of a human being. Studies have shown multiple mechanisms of measurable change with disruption in the microbiota that lead to behavioral changes. There are also effects of gut inflammation on the brain and the corresponding systemic response observed. Conclusion: The overall literature is encouraging that the more understanding of the gut-brain axis, the greater ability to wield that understanding for therapeutic benefits.

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Title: Taking aim at sepsis: Targeted solutions tool. Citation: Patient Safety Monitor Journal; May 2021; vol. 22 (no. 5); p. 4-5 Author(s): Ward, Brian Title: Teaching Evidence-Based Sepsis Care: A Sepsis Escape Room Citation: The Journal of Continuing Education in Nursing; May 2021; vol. 52 (no. 5); p. 217 Author(s): Paula M Gabriel, Casey L Lieb, Sara Holland, James Ballinghoff, Pamela Z Cacchione, Lauren McPeake Background: Using evidence-based sepsis guidelines, nurse educators identified the nursing skills required to recognize and treat sepsis. Method: Nurse educators created an innovative, interactive sepsis escape room to provide sepsis education. The escape room included a manikin, puzzles, distractors, riddles, and props. Participants were given 20 minutes to solve four puzzles/riddles to treat the sepsis patient and escape the room. Results: All but two (N = 16) groups solved the clues and riddles to prioritize treatment in the allotted time. Evaluations were excellent. Mean score (1 = poor to 5 = outstanding) for overall escape room experience was 4.92. Adherence data improved on the Surviving Sepsis Campaign sepsis performance measure intervention bundles (SEP 1-3 care bundles) 2 months following the escape room. Bundles are a group of interventions that improve care. Conclusion: The escape room engaged nurses in educational gaming, stimulating critical thinking and problem solving contributing to improved clinical outcomes.

Title: Technical assessment of the neonatal early-onset sepsis risk calculator. Citation: The Lancet. Infectious diseases; May 2021; vol. 21 (no. 5); p. e134 Author(s): Benitz, William E; Achten, Niek B Abstract: The use of the neonatal early-onset sepsis risk calculator, developed by Kaiser Permanente Northern California (CA, USA), is increasing for the management of late preterm and full term newborn babies at risk for early-onset sepsis. The calculator is based on a robust logistic regression model that provides quantitative individualised estimates of early-onset sepsis risk. Low sensitivity for prediction of sepsis at birth shows that standard perinatal risk factors alone are insufficient for ascertainment of neonatal early-onset sepsis. Performance is improved by the addition of physical examination findings at birth, but the sensitivity of combined findings remains limited. The present implementation of the calculator integrates risk factors and examination findings. A methodological error in adapting the regression for application in the population (rather than the development sample) and several subsequent modifications compromise the accuracy of quantitative predictions of the absolute risk of sepsis, but these factors are not expected to seriously undermine the use of the calculator for risk stratification. The calculator has served as an instrument of change away from previously recommended categorical risk ascertainment strategies, and its implementation reduces the need for diagnostic testing and empirical antibiotic treatment without apparent ill effects. However, the calculator should not be relied on to provide accurate estimates for individuals with regard to absolute risk of early-onset sepsis in newborn babies.

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Title: The Association Between Antibiotic Delay Intervals and Hospital Mortality Among Patients Treated in the Emergency Department for Suspected Sepsis*. Citation: Critical Care Medicine; May 2021; vol. 49 (no. 5); p. 741-747 Author(s): Taylor ; Anderson, William E.; Beam, Kent; Taylor, Brice; Ellerman, Justin; Kowalkowski, Marc A.

Objectives: Rapid delivery of antibiotics is a cornerstone of sepsis therapy, although time targets for specific components of antibiotic delivery are unknown. We quantified time intervals comprising the task of antibiotic delivery and evaluated the association between interval delays and hospital mortality among patients treated in the emergency department for suspected sepsis. Design: Retrospective cohort. Setting: Twelve hospitals in Southeastern United States from 2014 to 2017. Patients: Twenty-four thousand ninety-three encounters among 20,026 adults with suspected sepsis in 12 emergency departments. Measurements and main results: We divided antibiotic administration into two intervals: time from emergency department triage to antibiotic order (recognition delay) and time from antibiotic order to infusion (administration delay). We used generalized linear mixed models to evaluate associations between these intervals and hospital mortality. Median time from emergency department triage to antibiotic administration was 3.4 hours (interquartile range, 2.0-6.0 hr), separated into a median recognition delay (time from emergency department triage to antibiotic order) of 2.7 hours(interquartile range, 1.5-4.7 hr) and median administration delay (time from antibiotic order to infusion) of 0.6 hours (0.3-1.2 hr). Adjusting for other risk factors, both recognition delay and administration delay were associated with mortality, but pairwise comparison with a no-delay reference group was not significant for up to 6 hours of recognition delay or up to 1.5 hours of administration delay. Conclusions: Both recognition delays and administration delays were associated with increased hospital mortality, but only for longer delays. These results suggest that both metrics may be important to measure and improve for patients with suspected sepsis but do not support targets less than 1 hour.

Title: The physical and mental impact of surviving sepsis – a qualitative study of experiences and perceptions among a Swedish sample. Citation: Archives of Public Health; May 2021; vol. 79 (no. 1); p. 1-9 Author(s): Apitzsch ; Larsson, Lotta; Larsson, Anna-Karin; Linder, Adam Background: Sepsis is a critical illness with high morbidity and mortality rates. Each year, sepsis affects about 48.9 million people all over the world. This study aims to illuminate how sepsis survivors experience sepsis and the impact of sepsis, as well as the health-related quality of life thereafter. Methods: An interview study with eight sepsis survivors was carried out in Sweden with an inductive qualitative method. The data were analyzed with content analysis. Results: Four themes were identified during the analysis; The experience of health care and being a sepsis patient, New circumstances´ impact on life, Family and social interactions, and The psychological impact on life. The lack of information about how sepsis can impact the survivors’ lives and what to expect can lead to prolonged agony. The long recovery time comes as an unexpected and unpleasant surprise to those affected. Initially, the sepsis survivors are almost euphoric that they have survived, which can later lead to chock and trauma when they realize that they could have died. This insight needs to be processed in order to reach reconciliation with life after sepsis.

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Conclusion: Sepsis has a huge impact on both physical and mental aspects of life. Many survivors suffer from persistent residual symptoms of varying degrees, to which they have to adapt. The sepsis survivors need individually adjusted information about the sepsis recovery trajectory, and what to expect during and after the hospital stay. Title: Therapeutic approaches targeting renin-angiotensin system in sepsis and its complications Citation: Pharmacological Research; May 2021; vol. 167 Author(s): Ning L.; Rong J.; Xu Y.; Zhang Z. Abstract: Sepsis, caused by the inappropriate host response to infection, is characterized by excessive inflammatory response and organ dysfunction, thus becomes a critical clinical problem. Commonly, sepsis may progress to septic shock and severe complications, including acute kidney injury (AKI), acute respiratory distress syndrome (ARDS), sepsis-induced myocardial dysfunction (SIMD), liver dysfunction, cerebral dysfunction, and skeletal muscle atrophy, which predominantly contribute to high mortality. Additionally, the global pandemic of coronavirus disease 2019 (COVID-19) raised the concern of development of effectve therapeutic strategies for viral sepsis. Renin-angiotensin system (RAS) may represent as a potent therapeutic target for sepsis therapy. The emerging role of RAS in the pathogenesis of sepsis has been investigated and several preclinical and clinical trials targeting RAS for sepsis treatment revealed promising outcomes. Herein, we attempt to review the effects and mechanisms of RAS manipulation on sepsis and its complications and provide new insights into optimizing RAS interventions for sepsis treatment.Copyright © 2021 Elsevier Ltd Title: Toward More Rational Time-to-Antibiotic Metrics for Suspected Sepsis*. Citation: Critical Care Medicine; May 2021; vol. 49 (no. 5); p. 858-860 Author(s): Rhee ; Heil, Emily L. Title: Trajectories of depression in sepsis survivors: an observational cohort study. Citation: Critical Care; Apr 2021; vol. 25 (no. 1); p. 1-11 Author(s): Boede ; Gensichen, Jochen S.; Jackson, James C.; Eißler, Fiene; Lehmann, Thomas; Schulz, Sven; Petersen, Juliana J.; Wolf, Florian P.; Dreischulte, Tobias; Schmidt, Konrad F. R. Background: Advances in critical care medicine have led to a growing number of critical illness survivors. A considerable part of them suffers from long-term sequelae, also known as post-intensive care syndrome. Among these, depressive symptoms are frequently observed. Depressive symptom trajectories and associated factors of critical illness survivors have rarely been investigated. Study objective was to explore and compare different trajectories of depressive symptoms in sepsis survivors over 1 year after discharge from ICU. Methods: Data of a randomized controlled trial on long-term post-sepsis care were analyzed post hoc. Depressive symptoms were collected at 1, 6 and 12 months post-ICU discharge using the Major Depression Inventory (MDI), among others. Statistical analyses comprised descriptive analysis, univariate and multivariate, linear and logistic regression models and Growth Mixture Modeling.

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Results: A total of 224 patients were included into this analysis. We identified three latent classes of depressive symptom trajectories: Over the course of 1 year, 152 patients recovered from mild symptoms, 27 patients showed severe persistent symptoms, and 45 patients recovered from severe symptoms. MDI sum scores significantly differed between the three classes of depressive symptom trajectories at 1 and 6 months after ICU discharge (p < 0.024 and p < 0.001, respectively). Compared with other classes, patients with the mild recovered trajectory showed lower levels of chronic pain (median sum score of 43.3 vs. 60.0/53.3 on the Graded Chronic Pain Scale, p < 0.010) and posttraumatic stress (4.6% with a sum score of ≥ 35 on the Posttraumatic Stress Scale 10 vs. 48.1%/33.3%, p < 0.003); and higher levels of health-related quality of life (HRQOL) using the Short Form-36 scale within 1 month after ICU discharge (p < 0.035). Conclusions: In the first year after discharge from ICU, sepsis survivors showed three different trajectories of depressive symptoms. Course and severity of depressive symptoms were associated with chronic pain, posttraumatic stress and reduced HRQOL at discharge from ICU. Regular screening of sepsis survivors on symptoms of depression, chronic pain and posttraumatic stress within 1 year after ICU may be considered. Sources Used: The following databases are used in the creation of this bulletin: CINAHL, BNI, EMBASE & Medline. Disclaimer: The results of your literature search are based on the request that you made, and consist of a list of references, some with abstracts. Royal United Hospital Bath Healthcare Library will endeavour to use the best, most appropriate and most recent sources available to it, but accepts no liability for the information retrieved, which is subject to the content and accuracy of databases, and the limitations of the search process. The library assumes no liability for the interpretation or application of these results, which are not intended to provide advice or recommendations on patient care.