Sepsis Current Awareness Bulletin June 2020

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Title: Early evaluation of the 'STOP SEPSIS!' WHO Global Maternal Sepsis Awareness Campaign implemented for healthcare providers in 46 low, middle and high-income countries. Citation: BMJ open; May 2020; vol. 10 (no. 5); p. e036338 Author(s): Brizuela, Vanessa; Bonet, Mercedes; Trigo Romero, Carla Lionela; Abalos, Edgardo; Baguiya, Adama; Fawole, Bukola; Knight, Marian; Lumbiganon, Pisake; Minkauskienė, Meilė; Nabhan, Ashraf; Bique Osman, Nafissa; Qureshi, Zahida P; Souza, João Paulo; World Health Organization Global Maternal Sepsis Study Research Group Objective: To evaluate changes in awareness of maternal sepsis among healthcare providers resulting from the WHO Global Maternal Sepsis Study (GLOSS) awareness campaign.DESIGN Independent sample precampaign/postcampaign through online and paper-based surveys available for over 30 days before campaign roll-out (pre) and after study data collection (post). Descriptive statistics were used for campaign recognition and exposure, and odds ratio (OR) and perce ntage change were calculated for differences in awareness, adjusting for confounders using multivariate logistic regression. Setting and Participants: Healthcare providers from 398 participating facilities in 46 low, middle and high-income countries. Intervention: An awareness campaign to accompany GLOSS launched 3 weeks prior to data collection and lasting the entire study period (28 November 2017 to 15 January 2018) and beyond. Main Outcome Measures: Campaign recognition and exposure, and changes in awareness. Results: A total of 2188 surveys were analysed: 1155 at baseline and 1033 at postcampaign. Most survey respondents found the campaign materials helpful (94%), that they helped increase awareness (90%) and that they helped motivate to act differently (88%). There were significant changes with regard to: not having heard of maternal sepsis (-63.4% change, pre-OR/post-OR 0.35, 95% CI 0.18 to 0.68) and perception of confidence in making the right decisions with regard to maternal sepsis identification and management (7.3% change, pre-OR/post-OR 1.44, 95% CI 1.01 to 2.06). Conclusions: Awareness raising campaigns can contribute to an increase in having heard of maternal sepsis and an increase in provider perception of confidence in making correct decisions. Offering the information to make accurate and timely decisions while promoting environments that enable self-confidence and support could improve maternal sepsis identification and management.

Title: Early sepsis markers in patients admitted to intensive care unit with moderate-to-severe diabetic ketoacidosis. Citation: Annals of intensive care; May 2020; vol. 10 (no. 1); p. 58 Author(s): Blanchard, Florian; Charbit, Judith; Van der Meersch, Guillaume; Popoff, Benjamin; Picod, Adrien; Cohen, Regis; Chemouni, Frank; Gaudry, Stephane; Bihan, Helene; Cohen, Yves Background: Bacterial infections are frequent triggers for diabetic ketoacidosis. In this context, delayed antibiotic treatment is associated with increased morbidity and mortality. Unnecessary administration of antimicrobial therapy might however, also negatively impact the prognosis. The usefulness of sepsis markers in diabetic ketoacidosis has not been assessed. Thus, we sought to investigate diagnostic performances of clinical and biological sepsis markers during diabetic ketoacidosis. Methods: In this monocentric retrospective cohort study, all consecutive episodes of diabetic ketoacidosis (defined as pH ≤ 7.25, glycaemia > 300 mg/dL and presence of ketones) admitted in intensive care unit were included. A proven bacterial infection was defined as bacteriological documentation on any bacterial sample. Clinical (presence of fever: temperature > 38 °C and presence of hypothermia: temperature < 36 °C) and biological markers (whole blood count, neutrophils count, neutrophils-to-lymphocytes count ratio and procalcitonin), recorded at admission, were compared according to the presence or absence of a proven bacterial infection.

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Results: Between 2011 and 2018, among 134 episodes of diabetic ketoacidosis, 102 were included (91 patients). Twenty out of 102 were infected. At admission, procalcitonin (median: 3.58 ng/mL vs 0.52 ng/mL, p < 0.001) and presence of fever (25% vs 44%, p = 0.007) were different between episodes with and without proven bacterial infection in both univariate and multivariate analysis. Whole blood count, neutrophils count, neutrophils-to-lymphocytes count ratio and presence of hypothermia were not different between both groups. The diagnostic performance analysis for procalcitonin revealed an area under the curve of 0.87 with an optimal cutoff of 1.44 ng/mL leading to a sensitivity of 0.90 and a specificity of 0.76. Combining procalcitonin and presence of fever allowed to distinguish proven bacterial infection episodes from those without proven bacterial infection. Indeed, all patients with procalcitonin level of more than 1.44 ng/mL and fever had proven bacterial infection episodes. The presence of one of these 2 markers was associated with 46% of proven bacterial infection episodes. No afebrile patient with procalcitonin level less than 1.44 ng/mL had a proven bacterial infection. Conclusion: At admission, combining procalcitonin and presence of fever may be of value to distinguish ketoacidosis patients with and without proven bacterial infection, admitted in intensive care unit.

Title: Among sepsis survivors, readmissions due to infections occur sooner and are associated with increased mortality. Citation: Anaesthesiology intensive therapy; May 2020 Author(s): Franco Palacios, Carlos; Solenkova, Natalia; Gorostiaga, Federico Purpose: Readmissions after sepsis hospitalisations are more likely to result in death compared to readmissions after non-sepsis hospitalisations. Methods: Retrospective study of one hundred and forty-seven intensive care unit survivors of severe sepsis. Results: Over a median follow-up of 565 (200-953) days, 88 patients (59.8%) were readmitted, 40 with an infectious process (45.4%) and 48 with a non-infectious condition (54.5%). Median time to first rehospitalisation for the entire cohort was 89 (19-337) days; patients admitted with an infectious cause were readmitted sooner; 65.7 (11-201) days vs. 144 (52.3-383) days, P = 0.02. Most cases of infectious readmissions were due to pneumonia (17 patients, 42.5%), and urinary tract infections (UTI) (7 patients, 17.5%). Survival rate was 45% (18/40) in those readmitted with an infectious process vs. 70.8% (34/48) in those readmitted due to a non-infectious cause, P = 0.01. In multivariate analyses, age (HR 1.04 [95% CI: 1.01-1.08]; P = 0.002) and infectious cause of readmission (HR 2.0 [95% CI: 1.005-4]; P = 0.04) remained associated with increased mortality. Conclusions: Among sepsis survivors, infections are associated with shorter time to hospital readmission and higher mortality vs non-infectious causes. Most of the infectious readmissions were due to pneumonia or UTI, which mirrored the index hospitalisations.

Title: Predictors and outcomes of sepsis-induced cardiomyopathy in critically ill patients. Citation: Acute and critical care; May 2020 Author(s): Song, Myung Jin; Lee, Sang Hoon; Leem, Ah Young; Kim, Song Yee; Chung, Kyung Soo; Kim, Eun Young; Jung, Ji Ye; Kang, Young Ae; Kim, Young Sam; Chang, Joon; Park, Moo Suk Background: Sepsis-induced cardiomyopathy (SIC) occurs frequently in critically ill patients, but the clinical features and prognostic impact of SIC on sepsis outcome remain controversial. Here, we investigated the predictors and outcomes of SIC. Methods: Patients admitted to a single medical intensive care unit from June 2016 to September 2017 were retrospectively reviewed. SIC was diagnosed by ejection fraction (EF) <50% and ≥10% decrease in baseline EF that recovered within 2 weeks.

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Results: In total, 342 patients with sepsis met the inclusion criteria, and 49 patients (14.3%) were diagnosed with SIC; the latter were compared with 259 patients whose EF was not deteriorated by sepsis (non-SIC). Low systolic blood pressure and increased left ventricular end-diastolic diameter (LVEDD) were identified as predictors of SIC. SIC and non-SIC patients did not differ significantly in terms of 28-day all-cause mortality (24.5% vs. 26.3%, P=0.936). Acute Physiology and Chronic Health Evaluation II (APACHE II; hazard ratio [HR], 1.10; 95% confidential interval [CI], 1.02-1.18; P=0.009) and delta neutrophil index (DNI; HR, 1.02; 95% CI, 1.00-1.08; P=0.026) were independent risk factors for 28-day mortality with SIC. DNI, APACHE II, and lactate were identified as risk factors for 28-day mortality in sepsis patients as a whole. Conclusion: SIC was not associated with increased mortality compared to non-SIC. Low systolic blood pressure and increased LVEDD were predictors of SIC. High APACHE II score and elevated DNI, which reflect sepsis severity, predict 28-day all-cause mortality.

Title: Treating sepsis with vitamin C, thiamine, and hydrocortisone: Exploring the quest for the magic elixir. Citation: Journal of critical care; Jun 2020; vol. 57 ; p. 231-239 Author(s): Obi, J; Pastores, S M; Ramanathan, L V; Yang, J; Halpern, N A Abstract: The administration of ascorbic acid (vitamin C) alone or in combination with thiamine (vitamin B1) and corticosteroids (VCTS) has recently been hypothesized to improve hemodynamics, end-organ function, and may even increase survival in critically ill patients. There are several clinical studies that have investigated the use of vitamin C alone or VCTS in patients with sepsis and septic shock or are ongoing. Some of these studies have demonstrated its safety and potential benefit in septic patients. However, many questions remain regarding the optimal dosing regimens and plasma concentrations, timing of administration, and adverse effects of vitamin C and thiamine. These questions exist because the bulk of research regarding the efficacy of vitamin C alone or in combination with thiamine and corticosteroids in sepsis is limited to a few randomized controlled trials, retrospective before-and-after studies, and case reports. Thus, although the underlying rationale and mechanistic pathways of vitamin C and thiamine in sepsis have been well described, the clinical impact of the VCTS regimen is complex and remains to be determined. This review aims to explore the current evidence and potential benefits and adverse effects of the VCTS regimen for the treatment of sepsis.

Title: The initial resuscitation of septic shock. Citation: Journal of critical care; Jun 2020; vol. 57 ; p. 108-117 Author(s): Cinel, Ismail; Kasapoglu, Umut S; Gul, Fethi; Dellinger, R Phillip Abstract: Septic shock is the most severe form of sepsis, characterized by (a) persistent hypotension despite fluid resuscitation and (b) the presence of tissue hypoperfusion. Delays in the diagnosis and initiation of treatment of septic shock is associated with increasing risk for mortality. Early and effective fluid resuscitation and vasopressor administration play a crucial role in maintaining tissue perfusion in septic shock patients. A low diastolic arterial pressure (DAP) correlates with severity of arteriolar vasodilation, compromises left ventricle oxygen supply and can be used for identifying septic shock patients that would potentially benefit from earlier vasopressor therapy. Controversy currently exists as to the balance of fluids and vasopressors to maintain target mean arterial pressure. The aim of this article is to review the rationale for fluid resuscitation and vasopressor therapy and the importance of both mean and diastolic blood pressure during the initial resuscitation of the septic shock. We relate our personal prescription of balancing fluids and vasopressors in the resuscitation of septic shock.

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Title: Enhancing sepsis management through machine learning techniques: A review. Citation: Medicina intensiva; May 2020 Author(s): Ocampo-Quintero, N; Vidal-Cortés, P; Del Río Carbajo, L; Fdez-Riverola, F; Reboiro-Jato, M; Glez-Peña, D Abstract: Sepsis is a major public health problem and a leading cause of death in the world, where delay in the beginning of treatment, along with clinical guidelines non-adherence have been proved to be associated with higher mortality. Machine Learning is increasingly being adopted in developing innovative Clinical Decision Support Systems in many areas of medicine, showing a great potential for automatic prediction of diverse patient conditions, as well as assistance in clinical decision making. In this context, this work conducts a narrative review to provide an overview of how specific Machine Learning techniques can be used to improve sepsis management, discussing the main tasks addressed, the most popular methods and techniques, as well as the obtained results, in terms of both intelligent system accuracy and clinical outcomes improvement.

Title: Association between vitamin D status and sepsis in children: A meta-analysis of observational studies. Citation: Clinical Nutrition; Jun 2020; vol. 39 (no. 6); p. 1735-1741 Author(s): Xiao ; Zhang, Xiaoyan; Ying, Junjie; Zhou, Yan; Li, Xihong; Mu, Dezhi; Qu, Yi Abstract: The consequences of vitamin D deficiency regarding sepsis in children remain controversial. We conducted a meta-analysis of studies evaluating the association between vitamin D status and sepsis in children. We used EMBASE, Ovid Medline and Cochrane Library to conduct a meta-analysis of studies published in English before November 21, 2017. Among 1146 initially identified studies, we included 13 studies according to predefined inclusion criteria comprising 975 patients and 770 control participants. According to a random effects model, the mean difference in 25(OH)D levels (nmol/L) between participants with sepsis (444) and controls (528) was (mean difference, −18.55; 95% confidence interval (CI), −19.45 to −17.66, p < 0.05). The association between vitamin D deficiency and sepsis was significant, with an odds ratio (OR) = 1.13 (95% CI, 1.18 to 1.50, p < 0.05). Factors that could explain differences in the results include the study location/medical conditions, study design, 25(OH)D assay methods, diagnostic sepsis at different ages, diagnostic criteria for sepsis, and sepsis with comorbidities. The association between vitamin D deficiency/lower 25(OH)D levels and sepsis was significant in children and neonates. Further studies are required to confirm the results by considering more confounders.

Title: Mortality in sepsis and septic shock in Europe, North America and Australia between 2009 and 2019- results from a systematic review and meta-analysis. Citation: Critical Care; May 2020; vol. 24 (no. 1); p. 1-9 Author(s): Bauer ; Gerlach, Herwig; Vogelmann, Tobias; Preissing, Franziska; Stiefel, Julia; Adam, Daniel Background: Sepsis and septic shock remain drivers for mortality in critically ill patients. The heterogeneity of the syndrome hinders the generation of reproducible numbers on mortality risks. Consequently, mortality rates range from 15 to 56%. We aimed to update and extend the existing knowledge from meta-analyses and estimate 30- and 90-day mortality rates for sepsis and septic shock separately, stratify rates by region and study type and assess mortality rates across different sequential organ failure assessment (SOFA) scores. Methods: We performed a systematic review of articles published in PubMed or in the Cochrane Database, between 2009 and 2019 in English language including interventional and observational studies. A meta-analysis of pooled 28/30- and 90-day mortality rated separately for sepsis and septic

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shock was done using a random-effects model. Time trends were assessed via Joinpoint methodology and for the assessment of mortality rate over different SOFA scores, and linear regression was applied. Results: Four thousand five hundred records were identified. After title/abstract screening, 783 articles were assessed in full text for eligibility. Of those, 170 studies were included. Average 30-day septic shock mortality was 34.7% (95% CI 32.6-36.9%), and 90-day septic shock mortality was 38.5% (95% CI 35.4-41.5%). Average 30-day sepsis mortality was 24.4% (95% CI 21.5-27.2%), and 90-day sepsis mortality was 32.2% (95% CI 27.0-37.5%). Estimated mortality rates from RCTs were below prospective and retrospective cohort studies. Rates varied between regions, with 30-day septic shock mortality being 33.7% (95% CI 31.5-35.9) in North America, 32.5% (95% CI 31.7-33.3) in Europe and 26.4% (95% CI 18.1-34.6) in Australia. A statistically significant decrease of 30-day septic shock mortality rate was found between 2009 and 2011, but not after 2011. Per 1-point increase of the average SOFA score, average mortality increased by 1.8-3.3%. Conclusion: Trends of lower sepsis and continuous septic shock mortality rates over time and regional disparities indicate a remaining unmet need for improving sepsis management. Further research is needed to investigate how trends in the burden of disease influence mortality rates in sepsis and septic shock at 30- and 90-day mortality over time.

Title: SARS-CoV-2 and viral sepsis: observations and hypotheses. Citation: Lancet; May 2020; vol. 395 (no. 10235); p. 1517-1520 Author(s): Li ; Liu, Liang; Zhang, Dingyu; Xu, Jiuyang; Dai, Huaping; Tang, Nan; Su, Xiao; Cao, Bin Abstract: Since the outbreak of coronavirus disease 2019 (COVID-19), clinicians have tried every effort to understand the disease, and a brief portrait of its clinical features have been identified. In clinical practice, we noticed that many severe or critically ill COVID-19 patients developed typical clinical manifestations of shock, including cold extremities and weak peripheral pulses, even in the absence of overt hypotension. Understanding the mechanism of viral sepsis in COVID-19 is warranted for exploring better clinical care for these patients. With evidence collected from autopsy studies on COVID-19 and basic science research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV, we have put forward several hypotheses about SARS-CoV-2 pathogenesis after multiple rounds of discussion among basic science researchers, pathologists, and clinicians working on COVID-19. We hypothesise that a process called viral sepsis is crucial to the disease mechanism of COVID-19. Although these ideas might be proven imperfect or even wrong later, we believe they can provide inputs and guide directions for basic research at this moment.

Title: Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19). Citation: Intensive Care Medicine; May 2020; vol. 46 (no. 5); p. 854-887 Author(s): Alhazzani ; Møller, Morten Hylander; Arabi, Yaseen M.; Loeb, Mark; Gong, Michelle Ng; Fan, Eddy; Oczkowski, Simon; Levy, Mitchell M.; Derde, Lennie; Dzierba, Amy; Du, Bin; Aboodi, Michael; Wunsch, Hannah; Cecconi, Maurizio; Koh, Younsuck; Chertow, Daniel S.; Maitland, Kathryn; Alshamsi, Fayez; Belley-Cote, Emilie; Greco, Massimiliano 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

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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 4 are best practice statements, 9 are strong recommendations, and 35 are weak recommendations. No recommendation was provided for 6 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 recommendations in further releases of these guidelines.

Title: Accelerated Biologic Aging, Chronic Stress, and Risk for Sepsis and Organ Failure Following Trauma. Citation: Journal of Trauma Nursing; May 2020; vol. 27 (no. 3); p. 131-140 Author(s): NeSmith ; Medeiros, Regina S.; Holsten Jr, Steven B.; Zhu, Haidong; Looney, Stephen W.; Dong, Yanbin Abstract: The article discusses a 2020 study on the potential pretrauma stress-posttrauma outcomes relationship. Results showed support for the hypothesis that pretrauma chronic stress accelerates biologic aging in trauma patients aged 18-44 years, with links to sepsis and organ failure susceptibility, and non-links to mean cytokine levels and chronic stress. Also noted are the results' possible identification of individuals at risk for such outcomes and of the appropriate interventions.

Title: Active antibiotic discontinuation in suspected but not confirmed early-onset neonatal sepsis-A quality improvement initiative Citation: Acta Paediatrica, International Journal of Paediatrics; Jun 2020; vol. 109 (no. 6); p. 1125-1130 Author(s): Dretvik T.; Solevag A.L.; Finvag A.; Klingenberg C.; Stordal E.H.; Stordal K. Aim: To study whether a simple targeted intervention could reduce unwarranted antibiotic treatment in near-term and term neonates with suspected, but not confirmed early-onset sepsis. Method(s): A quality improvement initiative in three Norwegian neonatal intensive care units. The intervention included an inter-hospital clinical practice guideline for discontinuing antibiotics after 36-48 hours if sepsis was no longer suspected and blood cultures were negative in neonates >= 34+0 weeks of gestation. Two units used procalcitonin in decision-making. We compared data 12-14 months before and after guideline implementation. The results are presented as median with interquartile ranges. Result(s): A total of 284 infants (2.5% of all births >= 34+0 weeks of gestation) received antibiotics before and 195 (1.8%) after guideline implementation (P =.0018). The two units that used procalcitonin discontinued antibiotics earlier after guideline implementation than the unit without procalcitonin. Neonates not diagnosed with sepsis were treated 49 (31-84) hours before and 48 (36-72) hours after guideline implementation (P =.68). In all infants, including those diagnosed with sepsis, antibiotic treatment duration was reduced from 108 (60-144) to 96 (48-120) hours (P =.013). Conclusion(s): Antibiotic treatment duration for suspected, but not confirmed early-onset sepsis did not change. However, treatment duration for all infants and the proportion of infants commenced on antibiotics were reduced. Copyright © 2020 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd

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Title: Lower vs Higher Fluid Volumes During Initial Management of Sepsis: A Systematic Review With Meta-Analysis and Trial Sequential Analysis Citation: Chest; Jun 2020; vol. 157 (no. 6); p. 1478-1496 Author(s): Meyhoff T.S.; Moller M.H.; Hjortrup P.B.; Perner A.; Wetterslev J.; Cronhjort M. Objective: IV fluids are recommended during the initial management of sepsis, but the quality of evidence is low, and clinical equipoise exists. We aimed to assess patient-important benefits and harms of lower vs higher fluid volumes in adult patients with sepsis. Method(s): We conducted a systematic review with meta-analysis and trial sequential analysis (TSA) of randomized clinical trials of IV fluid volume separation in adult patients with sepsis. We adhered to our published protocol; the Cochrane handbook; the Preferred Reporting Items for Systematic Reviews and Meta-Analyses; and the Grading of Recommendations Assessment, Development and Evaluation statements. The primary outcomes were all-cause mortality, serious adverse events (SAEs), and quality of life. Result(s): We included nine trials (n = 637); all were published after 2015 and had an overall high risk of bias. We found no statistically significant difference between lower vs higher fluid volumes in all-cause mortality (relative risk [RR], 0.87; 95% CI, 0.69-1.10; I2 = 0%; TSA-adjusted CI, 0.34-2.22) or SAEs (RR, 0.91; 95% CI, 0.78-1.05; I2 = 0%; TSA-adjusted CI, 0.68-1.21). No trials reported on quality of life. We did not find differences in the secondary or exploratory outcomes. The quality of evidence was very low across all outcomes. Conclusion(s): In this systematic review, we found very low quantity and quality of evidence supporting the decision on the volumes of IV fluid therapy in adults with sepsis. Trial Registry: ClinicalTrials.gov; No.: NCT03668236; URL: www.clinicaltrials.gov;Copyright © 2020 American College of Chest Physicians

Title: Clinical outcomes of empirical high-dose meropenem in critically ill patients with sepsis and septic shock: A randomized controlled trial Citation: Journal of Intensive Care; Apr 2020; vol. 8 (no. 1) Author(s): Lertwattanachai T.; Montakantikul P.; Dilokpattanamongkol P.; Tangsujaritvijit V.; Sanguanwit P.; Sueajai J.; Auparakkitanon S. Background: Appropriate antimicrobial dosing is challenging because of changes in pharmacokinetics (PK) parameters and an increase in multidrug-resistant (MDR) organisms in critically ill patients. This study aimed to evaluate the effects of an empirical therapy of high-dose versus standard-dose meropenem in sepsis and septic shock patients. Method(s): We performed a prospective randomized open-label study to compare the changes of modified sequential organ failure assessment (mSOFA) score and other clinical outcomes of the high-dose meropenem (2-g infusion over 3 h every 8 h) versus the standard-dose meropenem (1-g infusion over 3 h every 8 h) in sepsis and septic shock patients. Patients' characteristics, clinical and microbiological outcomes, 14 and 28-day mortality, vasopressor- and ventilator-free days, intensive care unit (ICU) and hospital-free days, percent of the time of antibiotic concentrations above the minimum inhibitory concentration (%T>MIC), and safety were assessed. Result(s): Seventy-eight patients were enrolled. Median delta mSOFA was comparable between two groups (- 1 in the high-dose group vs. - 1 in the standard-dose group; P value = 0.75). There was no difference between the two groups regarding clinical and microbiological cure, 14- and 28-day mortality, vasopressor- and ventilator-free days, and ICU- and hospital-free days. In patients admitted from the emergency department (ED) with a mSOFA score >= 7, the high-dose group demonstrated significantly better microbiological cure compared with the standard-dose group (75% (9/12 patients) vs. 20% (2/10 patients); P value = 0.03). Likewise, the high-dose group presented higher microbiological cure rate in patients admitted from ED who had either APACHE II score > 20 (83.3% (10/12) vs. 28.6% (2/7); P value = 0.045) or on mechanical ventilator (87.5% (7/8) vs. 23.1% (3/13); P

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value = 0.008) than the standard-dose group. Adverse events were comparable between the two groups. Conclusion(s): Empirical therapy with the high-dose meropenem presented comparable clinical outcomes to the standard-dose meropenem in sepsis and septic shock patients. Besides, subgroup analysis manifested superior microbiological cure rate in sepsis or septic shock patients admitted from ED. Trial registration: ClinicalTrials.gov, NCT03344627, registered on November 17, 2017Copyright © 2020 The Author(s).

Title: Clinical characteristics and outcomes of patients with septic arthritis treated without surgery Citation: European Journal of Clinical Microbiology and Infectious Diseases; May 2020; vol. 39 (no. 5); p. 897-901 Author(s): Lieber S.B.; Shmerling R.H.; Paz Z.; Alpert N.; Fowler M.L. Abstract: Septic arthritis (SA) is typically managed with antibiotic therapy with or without surgery. Little is known about how patients without surgery differ from their operatively managed counterparts. We compared SA patients who received antibiotic treatment with and without surgery. We conducted a retrospective study of patients with monoarticular septic arthritis admitted to a single tertiary care centre between 1998 and 2015. All 441 monoarticular septic arthritis patients received antibiotics; 382 were also managed operatively and 59 nonoperatively. Nonoperative patients were older (64.4 vs 58.3 years old; p = 0.02) and less likely to have prior joint pathology (44.1% vs 67.5%; p < 0.001). Nonoperative patients presented more often with sepsis (37.3% vs 31.9; p = 0.02) and were more frequently admitted to the intensive care unit (23.7% vs 16.5%; p = 0.04). Nonoperative patients were less often discharged to a rehabilitation facility (37.9% vs 55.8%; p = 0.002) and less frequently readmitted to hospital within 60 days of initial discharge (15.3% vs 18.6%; p = 0.05). However, nonoperative patients were more likely to expire within 30 days after hospital discharge (11.9% vs 3.9%; p = 0.009). Nonoperative patients were sicker at presentation; despite deferral of surgery, they had a relatively high survival rate (88%). Among survivors whose data was available, there were no significant sequelae in post-discharge imaging. These findings support the nonsurgical approach as effective for patients with septic arthritis who are not critically ill at time of presentation.Copyright © 2020, Springer-Verlag GmbH Germany, part of Springer Nature.

Title: Frequency and management of maternal infection in health facilities in 52 countries (GLOSS): a 1-week inception cohort study Citation: The Lancet Global Health; May 2020; vol. 8 (no. 5) Author(s): Bonet M.; Brizuela V.; Abalos E.; Cuesta C.; Baguiya A.; Chamillard M.; Fawole B.; Knight M.; Kouanda S.; Lumbiganon P.; Nabhan A.; Nadisauskiene R.J.; Abdulkadir A.; Adanu R.M.; et al Background: Maternal infections are an important cause of maternal mortality and severe maternal morbidity. We report the main findings of the WHO Global Maternal Sepsis Study, which aimed to assess the frequency of maternal infections in health facilities, according to maternal characteristics and outcomes, and coverage of core practices for early identification and management. Method(s): We did a facility-based, prospective, 1-week inception cohort study in 713 health facilities providing obstetric, midwifery, or abortion care, or where women could be admitted because of complications of pregnancy, childbirth, post-partum, or post-abortion, in 52 low-income and middle-income countries (LMICs) and high-income countries (HICs). We obtained data from hospital records for all pregnant or recently pregnant women hospitalised with suspected or confirmed infection. We calculated ratios of infection and infection-related severe maternal outcomes (ie, death or near-miss) per 1000 livebirths and the proportion of intrahospital fatalities across country income groups, as well as the distribution of demographic, obstetric, clinical characteristics and outcomes, and coverage of a set of core practices for identification and management across infection severity groups.

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Finding(s): Between Nov 28, 2017, and Dec 4, 2017, of 2965 women assessed for eligibility, 2850 pregnant or recently pregnant women with suspected or confirmed infection were included. 70.4 (95% CI 67.7-73.1) hospitalised women per 1000 livebirths had a maternal infection, and 10.9 (9.8-12.0) women per 1000 livebirths presented with infection-related (underlying or contributing cause) severe maternal outcomes. Highest ratios were observed in LMICs and the lowest in HICs. The proportion of intrahospital fatalities was 6.8% among women with severe maternal outcomes, with the highest proportion in low-income countries. Infection-related maternal deaths represented more than half of the intrahospital deaths. Around two-thirds (63.9%, n=1821) of the women had a complete set of vital signs recorded, or received antimicrobials the day of suspicion or diagnosis of the infection (70.2%, n=1875), without marked differences across severity groups. Interpretation(s): The frequency of maternal infections requiring management in health facilities is high. Our results suggest that contribution of direct (obstetric) and indirect (non-obstetric) infections to overall maternal deaths is greater than previously thought. Improvement of early identification is urgently needed, as well as prompt management of women with infections in health facilities by implementing effective evidence-based practices. Funding(s): UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, Development and Research Training in Human Reproduction, WHO, Merck for Mothers, and United States Agency for International Development.Copyright © 2020 This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL

Title: Mortality and host response aberrations associated with transient and persistent acute kidney injury in critically ill patients with sepsis: a prospective cohort study. Citation: Intensive care medicine; Jun 2020 Author(s): Uhel, Fabrice; Peters-Sengers, Hessel; Falahi, Fahimeh; Scicluna, Brendon P; van Vught, Lonneke A; Bonten, Marc J; Cremer, Olaf L; Schultz, Marcus J; van der Poll, Tom; MARS consortium Purpose: Sepsis is the most frequent cause of acute kidney injury (AKI). The "Acute Disease Quality Initiative Workgroup" recently proposed new definitions for AKI, classifying it as transient or persistent. We investigated the incidence, mortality, and host response aberrations associated with transient and persistent AKI in sepsis patients. Methods: A total of 1545 patients admitted with sepsis to 2 intensive care units in the Netherlands were stratified according to the presence (defined by any urine or creatinine RIFLE criterion within the first 48 h) and evolution of AKI (with persistent defined as remaining > 48 h). We determined 30-day mortality by logistic regression adjusting for confounding variables and analyzed 16 plasma biomarkers reflecting pathways involved in sepsis pathogenesis (n = 866) and blood leukocyte transcriptomes (n = 392). Results: AKI occurred in 37.7% of patients, of which 18.4% was transient and 81.6% persistent. On admission, patients with persistent AKI had higher disease severity scores and more frequently had severe (injury or failure) RIFLE AKI stages than transient AKI patients. Persistent AKI, but not transient AKI, was associated with increased mortality by day 30 and up to 1 year. Persistent AKI was associated with enhanced and sustained inflammatory and procoagulant responses during the first 4 days, and a more severe loss of vascular integrity compared with transient AKI. Baseline blood gene expression showed minimal differences with respect to the presence or evolution of AKI. Conclusion: Persistent AKI is independently associated with sepsis mortality, as well as with sustained inflammatory and procoagulant responses, and loss of vascular integrity as compared with transient AKI.

Title: Biomarkers of sepsis: time for a reappraisal. Citation: Critical care (London, England); Jun 2020; vol. 24 (no. 1); p. 287

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Author(s): Pierrakos, Charalampos; Velissaris, Dimitrios; Bisdorff, Max; Marshall, John C; Vincent, Jean-Louis Introduction: Sepsis biomarkers can have important diagnostic, therapeutic, and prognostic functions. In a previous review, we identified 3370 references reporting on 178 different biomarkers related to sepsis. In the present review, we evaluate the progress in the research of sepsis biomarkers. Methods: Using the same methodology as in our previous review, we searched the PubMed database from 2009 until September 2019 using the terms "Biomarker" AND "Sepsis." There were no restrictions by age or language, and all studies, clinical and experimental, were included. Results: We retrieved a total of 5367 new references since our previous review. We identified 258 biomarkers, 80 of which were new compared to our previous list. The majority of biomarkers have been evaluated in fewer than 5 studies, with 81 (31%) being assessed in just a single study. Apart from studies of C-reactive protein (CRP) or procalcitonin (PCT), only 26 biomarkers have been assessed in clinical studies with more than 300 participants. Forty biomarkers have been compared to PCT and/or CRP for their diagnostic value; 9 were shown to have a better diagnostic value for sepsis than either or both of these biomarkers. Forty-four biomarkers have been evaluated for a role in answering a specific clinical question rather than for their general diagnostic or prognostic properties in sepsis. Conclusions: The number of biomarkers being identified is still increasing although at a slower rate than in the past. Most of the biomarkers have not been well-studied; in particular, the clinical role of these biomarkers needs to be better evaluated.

Title: Accelerated brain aging in sepsis survivors with cognitive long-term impairment. Citation: The European journal of neuroscience; Jun 2020 Author(s): Seidel, Gundula; Gaser, Christian; Götz, Theresa; Günther, Albrecht; Hamzei, Farsin Abstract: In the last years, cognitive impairment was emphasized to be a prominent long-term sequela of sepsis. The level of cognitive impairment is comparable with that in mild cognitive impairment (MCI) patients. Whether sepsis survivors also show a comparable brain atrophy is still unclear. For the analysis of brain atrophy, a novel method named Brain Age Gap Estimation (BrainAGE) was used. In this analysis approach, an algorithm identifies age-specific atrophy across the whole brain and calculates a BrainAGE score in years. In case of accelerated brain atrophy, the BrainAGE score is increased in comparison to the healthy age reference group, indicating a difference in estimated chronological age. 20 survivors of severe sepsis (longer than 2 years post sepsis) with persistent cognitive deficits were investigated with a battery of neuropsychological tests. Their MRI images were compared to an age- and sex-matched control group. Sepsis survivors showed a significant higher BrainAGE score of 4.5 years compared to healthy controls. We also found a close relationship between the BrainAGE score and severity of cognitive impairment (a higher BrainAGE score was associated with more severe cognitive impairment). Consequently, sepsis survivors with persistent cognitive impairment showed an accelerated brain aging, which was closely associated with the severity of cognitive impairment (similar to MCI patients).

Title: Sepsis With Preexisting Heart Failure: Management of Confounding Clinical Features. Citation: Journal of intensive care medicine; Jun 2020 ; p. 885066620928299 Author(s): Jones, Timothy W; Smith, Susan E; Van Tuyl, Joseph S; Newsome, Andrea Sikora Abstract: Preexisting heart failure (HF) in patients with sepsis is associated with worse clinical outcomes. Core sepsis management includes aggressive volume resuscitation followed by vasopressors (and potentially inotropes) if fluid is inadequate to restore perfusion; however, large fluid boluses and vasoactive agents are concerning amid the cardiac dysfunction of HF. This review

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summarizes evidence regarding the influence of HF on sepsis clinical outcomes, pathophysiologic concerns, resuscitation targets, hemodynamic interventions, and adjunct management (ie, antiarrhythmics, positive pressure ventilatory support, and renal replacement therapy) in patients with sepsis and preexisting HF. Patients with sepsis and preexisting HF receive less fluid during resuscitation; however, evidence suggests traditional fluid resuscitation targets do not increase the risk of adverse events in HF patients with sepsis and likely improve outcomes. Norepinephrine remains the most well-supported vasopressor for patients with sepsis with preexisting HF, while dopamine may induce more cardiac adverse events. Dobutamine should be used cautiously given its generally detrimental effects but may have an application when combined with norepinephrine in patients with low cardiac output. Management of chronic HF medications warrants careful consideration for continuation or discontinuation upon development of sepsis, and β-blockers may be appropriate to continue in the absence of acute hemodynamic decompensation. Optimal management of atrial fibrillation may include β-blockers after acute hemodynamic stabilization as they have also shown independent benefits in sepsis. Positive pressure ventilatory support and renal replacement must be carefully monitored for effects on cardiac function when HF is present.

Title: Implementation of the National Early Warning Score in patients with suspicion of sepsis: evaluation of a system-wide quality improvement project. Citation: The British journal of general practice : the journal of the Royal College of General Practitioners; Jun 2020; vol. 70 (no. 695); p. e381 Author(s): Pullyblank, Anne; Tavaré, Alison; Little, Hannah; Redfern, Emma; le Roux, Hein; Inada-Kim, Matthew; Cheema, Kate; Cook, Adam; West of England Patient Safety Collaborative Background: The National Early Warning Score (NEWS) was introduced to standardise early warning scores (EWS) in England. It has been recommended that NEWS should be used in pre-hospital care but there is no published evidence that this improves outcomes. In 2015, the West of England Academic Health Science Network region standardised to NEWS across all healthcare settings. Calculation of NEWS was recommended for acutely unwell patients at referral into secondary care. Aim: To evaluate whether implementation of NEWS across a healthcare system affects outcomes, specifically addressing the effect on mortality in patients with suspicion of sepsis (SOS). Design and Setting: A quality improvement project undertaken across the West of England from March 2015 to March 2019, with the aim of standardising to NEWS in secondary care and introducing NEWS into community and primary care. METHOD: Data from the national dashboard for SOS for the West of England were examined over time and compared to the rest of England. Quality improvement methodology and statistical process control charts were used to measure improvement. RESULTS There was a reduction in mortality in the SOS cohort in the West of England, which was not seen in the rest of England over the time period of the project. Admissions did not increase. By March 2019, the West of England had the lowest mortality in the SOS cohort in England. Conclusion: To the authors' knowledge, this is the first study demonstrating that use of NEWS in pre-hospital care is associated with improved outcomes in patients with SOS.

Title: Association between prior metformin therapy and sepsis in diabetes patients: a nationwide sample cohort study. Citation: Journal of anesthesia; Jun 2020; vol. 34 (no. 3); p. 358-366 Author(s): Oh, Tak Kyu; Song, In-Ae Purpose: There have been no large-scale studies on whether metformin therapy might have a potential benefit for lowering mortality. Thus, this study aimed to investigate the association between prior metformin therapy and the development of sepsis as well as the association between prior metformin therapy and 30-day mortality in sepsis patients.

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Methods: We evaluated adult diabetes patients registered in the 2010 sample cohort database of the National Health Insurance Service in South Korea. Diabetes was identified according to the International Classification of Disease-10 diagnostic system (E10-E14). The cohorts were divided into the metformin user group (i.e., those who had been prescribed continuous oral metformin over a period of ≥ 90 days) and the control group (i.e., all other individuals). The primary endpoint was the development of sepsis between 2011 and 2015, and the secondary endpoint was 30-day mortality among diabetes patients diagnosed with sepsis. Results: In total, 77,337 patients (34,041 in the metformin user group and 43,296 in the control group) were included in the analysis, among whom 2512 patients (3.2%) were diagnosed with sepsis between 2011 and 2015. After propensity score adjustment, metformin use was not significantly associated with both the risk of sepsis (OR: 0.92, 95%CI 0.82-1.03; P = 0.143) and the risk of 30-day mortality after diagnosis of sepsis (OR: 0.94, 95%CI 0.75-1.17; P = 0.571). Conclusions: Prior metformin therapy was not significantly associated with the risk of sepsis and 30-day mortality after diagnosis of sepsis among diabetes patients.

Title: Discriminatory ability and prognostic evaluation of presepsin for sepsis-related acute respiratory distress syndrome. Citation: Scientific reports; Jun 2020; vol. 10 (no. 1); p. 9114 Author(s): Zhao, Jiangnan; Tan, Yan; Wang, Li; Shi, Yi Abstract: Sepsis-related acute respiratory distress syndrome (ARDS) has worse clinical outcomes than non-sepsis-related ARDS. Presepsin is known to be elevated in sepsis, but little is known about its discriminatory ability and prognostic evaluation in patients with sepsis-related ARDS. This study was a multicenter prospective cohort study of 225 consecutive ARDS patients. Patients with sepsis-related ARDS had higher presepsin levels than patients with non-sepsis-related ARDS (P < 0.001). The area under the receiver operating characteristic (ROC) curve of presepsin (0.81) was significantly greater than that of PCT (0.62) in diagnosing sepsis-related ARDS (P = 0.001). Among patients with sepsis-related ARDS, presepsin levels were significantly higher in non-survivors than in survivors (P < 0.001). Presepsin was found to be an independent predictor of in-hospital mortality in sepsis-related ARDS. Based on ROC analysis, the addition of presepsin improved discrimination based on SOFA or APACHE II scores from 0.77 to 0.87 or 0.73 to 0.85 (all P < 0.05), respectively. The levels of plasma presepsin were positively correlated with disease severity, as determined by the SOFA score in the sepsis-related ARDS group (P < 0.001). Presepsin is a valuable biomarker for early stratification of sepsis-related ARDS. Higher plasma presepsin levels are associated with increased mortality in sepsis-related ARDS.

Title: Pharmacokinetics, Pharmacodynamics, and Safety of Nivolumab in Patients With Sepsis-Induced Immunosuppression: A Multicenter, Open-Label Phase 1/2 Study. Citation: Shock (Augusta, Ga.); Jun 2020; vol. 53 (no. 6); p. 686-694 Author(s): Watanabe, Eizo; Nishida, Osamu; Kakihana, Yasuyuki; Odani, Motoi; Okamura, Tatsuaki; Harada, Tomohiro; Oda, Shigeto Background: Sepsis often induces an immunosuppressive state, which is associated with high mortality rates. Immunostimulation may be beneficial for sepsis. We investigated the pharmacokinetics, pharmacodynamics, and safety of nivolumab, a human programmed death-1 immune checkpoint inhibitor approved for the treatment of several cancers. Methods: In this multicenter, open-label phase 1/2 study, a single 480 or 960 mg nivolumab dose was intravenously infused into Japanese patients with immunosuppressive sepsis. Doses were selected to mimic the exposure achieved with the approved dosage for cancer patients (3 mg/kg every 2 weeks [Q2W]). Results: Single 480 and 960 mg nivolumab doses were intravenously infused into five and eight patients, respectively. The maximum concentration after 480 mg (132 µg/mL) was similar to the

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predicted concentration at the end of infusion with 3 mg/kg Q2W (117 µg/mL). The concentration on Day 28 after 960 mg (33.1 µg/mL) was within the predicted trough concentration range for 3 mg/kg Q2W (90% prediction interval 19.0-163 µg/mL). Absolute lymphocyte counts and monocyte human leukocyte antigen-DR subtype expression levels appeared to increase over time. The incidences of adverse events (AEs) were 80% and 50% in the 480 mg and 960 mg groups, respectively. Drug-related AEs were observed in only one patient in the 480 mg group. No deaths related to nivolumab occurred. Conclusions: A single dose of 960 mg nivolumab appeared to be well tolerated and sufficient to maintain nivolumab blood concentrations. Both 480 mg and 960 mg nivolumab seemed to improve immune system indices over time. Trial Registration: JAPIC, JapicCTI-173600.

Sources Used: The following databases are used in the creation of this bulletin: BNI, CINAHL, 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