Robinder G Khemani, Lincoln Smith, Yolanda M Lopez-Fernandez, Jeni Kwok, Rica Morzov, Margaret J Klein, Nadir Yehya, Douglas Willson, Martin C J Kneyber, Jon Lillie, Analia Fernandez, Christopher J L Newth, Philippe Jouvet, Neal J Thomas, Pediatric Acute Respiratory Distress syndrome Incidence and Epidemiology (PARDIE) Investigators, Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network

The PALICC definition identified more children as having PARDS than the Berlin definition, and PALICC PARDS severity groupings improved the stratification of mortality risk, particularly when applied 6 h after PARDS diagnosis. The PALICC PARDS framework should be considered for use in future epidemiological and therapeutic research among children with PARDS.

Seilesh Kadambari, Heli Harvala, Peter Simmonds, Andrew J Pollard, Manish Sadarangani

Human parechovirus infections are the second most common cause of viral meningitis in children. These infections are most frequently seen in infants younger than 90 days. Clinical manifestations include encephalitis, meningitis, myocarditis, and sepsis, which can lead to serious neurodevelopmental sequelae in young infants. Molecular techniques, including PCR assays, are the preferred diagnostic methods and have contributed to an increase in reported cases, along with an increasing awareness of the causal role of human parechovirus in infant diseases.

Judith A Gilbert

Sepsis affects 27–30 million people worldwide every year, resulting in 6–9 million deaths annually. The condition occurs when the body has an extreme immune response to an infection, causing widespread inflammation. Without early diagnosis and treatment, sepsis can lead to tissue damage, organ failure, and death. The Surviving Sepsis Campaign (SSC) was formed in collaboration between the Society of Critical Care Medicine and the European Society of Intensive Care Medicine in 2002. The aim of SSC is to reduce mortality from sepsis globally, and their first evidence-based clinical practice guidelines were published in 2004, with updates every four years thereafter.

Talha Khan Burki

A new analysis of data from 133 hospital trusts in England has revealed sharp increases in the number of admissions for sepsis and recorded deaths. Brian Jarman, former president of the British Medical Association and head of the Dr Foster Unit at Imperial College London, UK, examined National Health Service (NHS) mortality data from the past few years. In the year to April, 2015, there were 55 171 hospital admissions for sepsis and 11 527 deaths. Records for 2016–17 showed 77 996 admissions and 15 851 deaths, an increase of 41% and 38%, respectively.

Abstract Background Iliopsoas abscess is a collection of pus in the iliopsoas muscle compartment. It can be primary or secondary in origin. Primary iliopsoas abscess occurs as a result of hematogenous or lymphatic seeding from a distant site. This is commonly associated with a chronic immunocompromised state and tends to occur in children and young adults. Secondary iliopsoas abscess occurs as a result of the direct spread of infection to the psoas muscle from an adjacent structure, and this may be associated with trauma and instrumentation in the inguinal region, lumbar spine, or hip region. The incidence of iliopsoas abscess is rare and often the diagnosis is delayed because of non-specific presenting symptoms. Case presentation We describe a patient with iliopsoas abscess who presented to the Emergency Department at X Hospital on three separate occasions with non-specific symptoms of thigh pain and fever before finally being admitted for treatment. This case illustrates how the diagnosis can be delayed due to its atypical presentation. Hence, highlighting the need for clinicians to have a high index of clinical suspicion for iliopsoas abscess in patients presenting with thigh pain and fever. Conclusion The classic triad of fever, flank pain, and hip movement limitation is presented in only 30% of patients with iliopsoas abscess. Clinicians should consider iliopsoas abscess as a differential diagnosis in patients presenting with fever and thigh pain. The rare condition with the varied clinical presentation means that cross-sectional imaging should be considered early to reduce the risk of fulminant sepsis.…

Chan, W.-Y., Entwisle, C., Ercoli, G., Ramos-Sevillano, E., McIlgorm, A., Cecchini, P., Bailey, C., Lam, O., Whiting, G., Green, N., Goldblatt, D., Wheeler, J. X., Brown, J. S.

Current vaccination against Streptococcus pneumoniae uses vaccines based on capsular polysaccharides from selected serotypes, and has led to non-vaccine serotype replacement disease. We have investigated an alternative serotype-independent approach, using multiple-antigen vaccines (MAV) prepared from S. pneumoniae TIGR4 lysates enriched for surface proteins by a chromatography step after culture under conditions that induce expression of heat shock proteins (Hsp, thought to be immune adjuvants). Proteomics and immunoblots demonstrated that compared to standard bacterial lysates, MAV was enriched with Hsps and contained several recognised protective protein antigens, including pneumococcal surface protein A (PspA) and pneumolysin (Ply). Vaccination of rodents with MAV induced robust antibody responses to multiple serotypes, including non-pneumococcal conjugate vaccine serotypes. Homologous and heterologous strains of S. pneumoniae were opsonised after incubation in sera from vaccinated rodents. In mouse models, active vaccination with MAV significantly protected against pneumonia, whilst passive transfer of rabbit serum from MAV vaccinated rabbits significantly protected against sepsis caused by both homologous and heterologous S. pneumoniae strains. Direct comparison of MAV preparations made with or without the heat-shock step showed no clear differences in protein antigen content and antigenicity, suggesting that the chromatography step rather than Hsp induction improved MAV antigenicity. Overall, these data suggest that the MAV approach may provide serotype-independent protection against S. pneumoniae.…

Sims, Charles R.; Warner, Matthew A.; Stelfox, Henry Thomas; Hyder, Joseph A.

Objectives: We examined recommendations within critical care guidelines to describe the pairing patterns for strength of recommendation and quality of evidence. We further identified recommendations where the reported strength of recommendation was strong while the reported quality of evidence was not high/moderate and then assessed whether such pairings were within five paradigmatic situations offered by Grading of Recommendations Assessment, Development and Evaluation methodology to justify such pairings. Data Sources and Extraction: We identified all clinical critical care guidelines published online from 2011 to 2017 by the Society of Critical Care Medicine along with individual guidelines published by Surviving Sepsis Campaign, Kidney Disease Improving Global Outcomes, American Society for Parenteral and Enteral Nutrition, and the Infectious Disease Society of America/American Thoracic Society. Data Synthesis: In all, 15 documents specifying 681 eligible recommendations demonstrated variation in strength of recommendation (strong n = 215 [31.6%], weak n = 345 [50.7%], none n = 121 [17.8%]) and in quality of evidence (high n = 41 [6.0%], moderate n = 151 [22.2%], low/very low n = 298 [43.8%], and Expert Consensus/none n = 191 [28.1%]). Strength of recommendation and quality of evidence were positively correlated (ρ = 0.66; p < 0.0001). Of 215 strong recommendations, 69 (32.1%) were discordantly paired with evidence other than high/moderate. Twenty-two of 69 (31.9%) involved Strong/Expert Consensus recommendations, a category discouraged by Grading of Recommendations Assessment, Development and Evaluation methodology. Forty-seven of 69 recommendations (68.1%) were comprised of Strong/Low or Strong/Very Low variation requiring justification within five paradigmatic scenarios. Among distribution in the five paradigmatic scenarios of Strong/Low and Strong/Very Low recommendations, the most common paradigmatic scenario was life threatening situation (n = 20/47; 42.6%). Four Strong/Low or Strong/Very Low recommendations (4/47; 8.5%) were outside Grading of Recommendations Assessment, Development and Evaluation methodology. Conclusions: Among a large, diverse assembly of critical care guideline recommendations using Grading of Recommendations Assessment, Development and Evaluation methodology, the strength of evidence of a recommendation was generally associated with the quality of evidence. However, strong recommendations were not infrequently made in the absence of high/moderate quality of evidence. To improve clarity and uptake, future guideline statements may specify why such pairings were made, avoid such pairings when outside of Grading of Recommendations Assessment, Development and Evaluation criteria, and consider separate language for Expert Consensus recommendations (good practice statements). Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (httpm://journals.lww.com/ccmjournal). This work was performed without extramural funding. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: sims.charles@mayo.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Sims, Charles R.; Warner, Matthew A.; Stelfox, Henry Thomas; Hyder, Joseph A.

Objectives: We examined recommendations within critical care guidelines to describe the pairing patterns for strength of recommendation and quality of evidence. We further identified recommendations where the reported strength of recommendation was strong while the reported quality of evidence was not high/moderate and then assessed whether such pairings were within five paradigmatic situations offered by Grading of Recommendations Assessment, Development and Evaluation methodology to justify such pairings. Data Sources and Extraction: We identified all clinical critical care guidelines published online from 2011 to 2017 by the Society of Critical Care Medicine along with individual guidelines published by Surviving Sepsis Campaign, Kidney Disease Improving Global Outcomes, American Society for Parenteral and Enteral Nutrition, and the Infectious Disease Society of America/American Thoracic Society. Data Synthesis: In all, 15 documents specifying 681 eligible recommendations demonstrated variation in strength of recommendation (strong n = 215 [31.6%], weak n = 345 [50.7%], none n = 121 [17.8%]) and in quality of evidence (high n = 41 [6.0%], moderate n = 151 [22.2%], low/very low n = 298 [43.8%], and Expert Consensus/none n = 191 [28.1%]). Strength of recommendation and quality of evidence were positively correlated (ρ = 0.66; p < 0.0001). Of 215 strong recommendations, 69 (32.1%) were discordantly paired with evidence other than high/moderate. Twenty-two of 69 (31.9%) involved Strong/Expert Consensus recommendations, a category discouraged by Grading of Recommendations Assessment, Development and Evaluation methodology. Forty-seven of 69 recommendations (68.1%) were comprised of Strong/Low or Strong/Very Low variation requiring justification within five paradigmatic scenarios. Among distribution in the five paradigmatic scenarios of Strong/Low and Strong/Very Low recommendations, the most common paradigmatic scenario was life threatening situation (n = 20/47; 42.6%). Four Strong/Low or Strong/Very Low recommendations (4/47; 8.5%) were outside Grading of Recommendations Assessment, Development and Evaluation methodology. Conclusions: Among a large, diverse assembly of critical care guideline recommendations using Grading of Recommendations Assessment, Development and Evaluation methodology, the strength of evidence of a recommendation was generally associated with the quality of evidence. However, strong recommendations were not infrequently made in the absence of high/moderate quality of evidence. To improve clarity and uptake, future guideline statements may specify why such pairings were made, avoid such pairings when outside of Grading of Recommendations Assessment, Development and Evaluation criteria, and consider separate language for Expert Consensus recommendations (good practice statements). Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (httpm://journals.lww.com/ccmjournal). This work was performed without extramural funding. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: sims.charles@mayo.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Kollef M, Burnham J.

Pablo Castaño, Maribel Plaza, Fernando Molina, Carolina Hincapié, Wilmar Maya, Juan Cataño, Javier González, Alba León, Fabián Jaimes

Abstract Objective To assess the true association between appropriate prescription of antibiotics and prognosis in patients with sepsis, a key issue in health care and quality improvement strategies. Methods Prospective cohort study in three university hospitals to determine whether the empirical prescription of antibiotics was adequate or inadequate, and to compare hospital death rates and length of stay according to different classifications of antibiotics prescription. Logistic regression models for risk estimation were fitted. Results 705 patients with severe sepsis were included. No differences were found in positive culture patients (n = 545) regarding the risk of death with insufficient spectrum antibiotics, compared to patients who received adequate spectrum antibiotics (OR = 0.90; 95% CI = 0.55‐1.48). Delay in initiating antibiotics was not associated with the risk of death in patients with adequate spectrum of antibiotics, either with positive (OR = 1.04; 95% CI = 0.99‐1.08) or negative cultures (OR = 0.98; 95% CI = 0.92‐1.04). There were no differences in the length of hospital stay, according to antibiotic prescription (median 11 days, IQR = 7‐18 days for the whole cohort). Conclusions No associations were found between inadequate antibiotic prescription or delay to initiate therapy and mortality or length of stay. This article is protected by copyright. All rights reserved.

Abbasi J.

Researchers at Imperial College London are developing an artificial intelligence (AI) agent to help physicians select optimal fluid and vasopressor doses for adult patients with sepsis in intensive care units (ICUs).

Abstract Background There is a lack of data regarding the prevalence of invasive group B streptococcus (GBS) infection among neonates in China. This study aimed to investigate the incidence and mortality of invasive GBS infection and to identify the risk factors in our hospital. Methods Seventy-four cases admitted between January 2011 and December 2016 was included in this study. A retrospective matched case-control study was conducted in a tertiary maternity and paediatric hospital. Risk factors for the acquisition of invasive GBS infection and mortality were analysed by univariable and multivariable analysis. Results We collected and analysed data from 74 infants aged

Asner S, Agyeman P, Gradoux E, et al.

AbstractBackgroundPopulation-based studies assessing the impact of pneumococcal conjugate vaccines (PCV) on burden of pneumococcal sepsis in children are lacking. We aimed to assess this burden following introduction of PCV-13 in a nationwide cohort study.MethodsThe Swiss Pediatric Sepsis Study (09/2011–12/2015) prospectively recruited children

Ba, B., Gaudin, K., Desire, A., Phoeung, T., Langlois, M.-H., Behl, C. R., Unowsky, J., Patel, I. H., Malick, A. W., Gomes, M., White, N., Kauss, T.

Neonatal sepsis is a major cause of infant mortality in developing countries because of delayed injectable treatment, making it urgent to develop non-injectable formulations that can reduce treatment delays in resource limited settings. Ceftriaxone, available only for injection, needs absorption enhancers to achieve adequate bioavailability via non-parenteral administration. This article presents all available ceftriaxone human and animal non-parenteral absorption data, including unpublished work carried out by F. Hoffmann-La Roche (Roche) in the 1980s and new rabbit pre-clinical data and discusses the importance of these data for the development of non-injectable formulations for non-invasive treatment. The combined results indicate that rectal absorption of ceftriaxone is feasible and likely to lead to a bioavailable formulation that can reduce treatment delays in neonatal sepsis. A bile salt, Chenodeoxycholate sodium salt (Na-CDC) used as an absorption enhancer at a 125 mg dose together with a 500 mg dose of ceftriaxone, provided 24% rectal absorption of ceftriaxone and Cmax of 21 µg/ml with good tolerance in human subjects. The rabbit model developed can also be used to screen for bioavailability of other formulations before human assessment.…

Ilko, Steven A.; Vakkalanka, J. Priyanka; Ahmed, Azeemuddin; Harland, Karisa K.; Mohr, Nicholas M.

Objectives: Severe sepsis is a complex, resource intensive, and potentially lethal condition and rural patients have worse outcomes than urban patients. Early identification and treatment are important to improving outcomes. The objective of this study was to identify hospital-specific factors associated with inter-hospital transfer. Design: Mixed method study integrating data from a telephone survey and retrospective cohort study of state administrative claims. Setting and Subjects: Survey of Iowa emergency department administrators between May 2017 and June 2017 and cohort of adults seen in Iowa emergency departments for severe sepsis and septic shock between January 2005 and December 2013. Interventions: None. Measurements and Main Results: Multivariable logistic regression was used to identify independent predictors of inter-hospital transfer. We included 114 institutions that provided data (response rate = 99%), and responses were linked to a total of 150,845 visits for severe sepsis/septic shock. In our adjusted model, having the capability to place central venous catheters or having a subscription to a tele-ICU service was independently associated with lower odds of inter-hospital transfer (adjusted odds ratio, 0.69; 95% CI, 0.54–0.86 and adjusted odds ratio, 0.69; 95% CI, 0.54–0.88, respectively). A facility’s participation in a sepsis-specific quality improvement initiative was associated with 62% higher odds of transfer (adjusted odds ratio, 1.62; 95% CI, 1.10–2.39). Conclusions: The insertion of central venous catheters and access to a critical care physician during sepsis treatment are important capabilities in hospitals that transfer fewer sepsis patients. In the future, hospital-specific capabilities may be used to identify institutions as regional sepsis centers. This work was performed at the University of Iowa Carver College of Medicine, Iowa City, IA. Mr. Ilko and Drs. Ahmed and Mohr conceived the study, designed the data collection tool, and obtained research funding. Mr. Ilko undertook participant recruitment and data collection with data collection oversight and quality control from Dr. Ahmed. Ms. Vakkalanka and Dr. Harland were responsible for management of the datasets. Ms. Vakkalanka and Drs. Harland and Mohr provided statistical advice on study design and analyzed the data. Mr. Ilko, Ms. Vakkalanka, and Dr. Mohr drafted the article. Dr. Mohr takes responsibility for the article as a whole. All authors contributed substantially to its revision. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). This was delivered as an oral presentation, in part, at the Medical Student Research Conference at the University of Iowa, Carver College of Medicine, Iowa City, IA, on September 14, 2017. It was delivered as a poster presentation at Society for Academic Emergency Medicine Great Plains Regional Meeting in Columbia, MO, on October 7, 2017. Dr. Mohr disclosed that this research was funded by the HL007485 from the National Heart, Lung, and Blood Institute (Short Term Training for Students in the Health Professions) and support from the Department of Emergency Medicine, University of Iowa Carver College of Medicine. Mr. Ilko, Ms. Vakkalanka, and Dr. Mohr received support for article research from the NIH. Dr. Ahmed received funding from UptoDate. Dr. Harland disclosed that she does not have any potential conflicts of interest. For information regarding this article, E-mail: nicholas-mohr@uiowa.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Joseph A. Hippensteel

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 8, Page 981-983, October 15, 2018. …

Hassan Zafar, Milton H. Saier Jr.

by Hassan Zafar, Milton H. Saier Jr. The communities of beneficial bacteria that live in our intestines, the gut microbiome, are important for the development and function of the immune system. Bacteroides species make up a significant fraction of the human gut microbiome, and can be probiotic and pathogenic, depending upon various genetic and environmental factors. These can cause disease conditions such as intra-abdominal sepsis, appendicitis, bacteremia, endocarditis, pericarditis, skin infections, brain abscesses and meningitis. In this study, we identify the transport systems and predict their substrates within seven Bacteroides species, all shown to be probiotic; however, four of them (B. thetaiotaomicron, B. vulgatus, B. ovatus, B. fragilis) can be pathogenic (probiotic and pathogenic; PAP), while B. cellulosilyticus, B. salanitronis and B. dorei are believed to play only probiotic roles (only probiotic; OP). The transport system characteristics of the four PAP and three OP strains were identified and tabulated, and results were compared among the seven strains, and with E. coli and Salmonella strains. The Bacteroides strains studied contain similarities and differences in the numbers and types of transport proteins tabulated, but both OP and PAP strains contain similar outer membrane carbohydrate receptors, pore-forming toxins and protein secretion systems, the similarities were noteworthy, but these Bacteroides strains showed striking differences with probiotic and pathogenic enteric bacteria, particularly with respect to their high affinity outer membrane receptors and auxiliary proteins involved in complex carbohydrate utilization. The results reveal striking similarities between the PAP and OP species of Bacteroides, and suggest that OP species may possess currently unrecognized pathogenic potential.

Bailly, Arthur; Ricard, Jean-Damien; Le Thuaut, Aurelie; Helms, Julie; Kamel, Toufik; Mercier, Emmanuelle; Lemiale, Virginie; Colin, Gwenhael; Mira, Jean-Paul; Clere-Jehl, Raphaël; Messika, Jonathan; Dequin, Pierre-Francois; Boulain, Thierry; Azoulay, Elie; Champigneulle, Benoit; Reignier, Jean; Lascarrou, Jean-Baptiste; for the Clinical Research in Intensive Care and Sepsis Group (CRICS-TRIGGERSEP)

Objectives: Severe hypoxemia is the most common serious adverse event during endotracheal intubation. Preoxygenation is performed routinely as a preventive measure. The relative efficacy of the various available preoxygenation devices is unclear. Here, our objective was to assess associations between preoxygenation devices and pulse oximetry values during endotracheal intubation. Design: Post hoc analysis of data from a multicenter randomized controlled superiority trial (McGrath Mac Videolaryngoscope Versus Macintosh Laryngoscope [MACMAN]) comparing videolaryngoscopy to Macintosh laryngoscopy for endotracheal intubation in critical care. Setting: Seven French ICUs. Patients: Three-hundred nineteen of the 371 critically ill adults requiring endotracheal intubation who were included in the MACMAN trial. Interventions: None. Measurements and Main Results: Minimal pulse oximetry value during endotracheal intubation was the primary endpoint. We also sought risk factors for pulse oximetry below 90%. Of 319 patients, 157 (49%) had bag-valve-mask, 71 (22%) noninvasive ventilation, 71 (22%) non-rebreathing mask, and 20 (7%) high-flow nasal oxygen for preoxygenation. Factors independently associated with minimal pulse oximetry value were the Simplified Acute Physiology Score II severity score (p = 0.03), baseline pulse oximetry (p < 0.001), baseline PaO2/FIO2 ratio (p = 0.02), and number of laryngoscopies (p = 0.001). The only independent predictors of pulse oximetry less than 90% were baseline pulse oximetry (odds ratio, 0.71; 95% CI, 0.64–0.79; p < 0.001) and preoxygenation device: with bag-valve-mask as the reference, odds ratios were 1.10 (95% CI, 0.25–4.92) with non-rebreathing mask, 0.10 (95% CI, 0.01–0.80) with noninvasive ventilation, and 5.75 (95% CI, 1.15–28.75) with high-flow nasal oxygen. Conclusions: Our data suggest that the main determinants of hypoxemia during endotracheal intubation may be related to critical illness severity and to preexisting hypoxemia. The differences across preoxygenation methods suggest that noninvasive ventilation may deserve preference in patients with marked hypoxemia before endotracheal intubation. Ongoing studies will provide further clarification about the optimal preoxygenation method for endotracheal intubation in critically ill patients. All members of the Clinical Research in Intensive Care and Sepsis Group (CRICS-TRIGGERSEP) can be found at http://www.crics.fr/. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). The nonprofit healthcare institution “Centre Hospitalier Departement de la Vendee” was the study funder and sponsor. Dr. Ricard received funding from Fisher & Paykel (travel expenses to attend scientific meetings). Dr. Le Thuaut disclosed work for hire. Dr. Messika received funding from Fisher & Paykel. Dr. Azoulay’s institution received funding from Alexion, Astellas, Baxter, Merck Sharp and Dohme, Ablynx, and Fisher & Paykel, and he received funding from lectures from Alexion, Astellas, Baxter, MSD, and Ablynx. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: jeanbaptiste.lascarrou@chunantes.fr Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

En-Shao Liu, Cheng-Hung Chiang, Wang-Ting Hung, Pei-Ling Tang, Cheng Chung Hung, Shu-Hung Kuo, Chun-Peng Liu, Yao-Shen Chen, Guang-Yuan Mar, Wei-Chun Huang

Although the association between systemic infection and cardiovascular events has been identified, an uncertainty still exists in the incidence and prognosis of sepsis in acute myocardial infarction (AMI). The purpose of our research was to assess the impact of sepsis on survival after first AMI.

Lindell, Robert B.; Nishisaki, Akira; Weiss, Scott L.; Balamuth, Fran; Traynor, Danielle M.; Chilutti, Marianne R.; Grundmeier, Robert W.; Fitzgerald, Julie C.

Objectives: To compare the performance of three methods of identifying children with severe sepsis and septic shock from the Virtual Pediatric Systems database to prospective screening using consensus criteria. Design: Observational cohort study. Setting: Single-center PICU. Patients: Children admitted to the PICU in the period between March 1, 2012, and March 31, 2014. Interventions: None. Measurements and Main Results: During the study period, all PICU patients were prospectively screened daily for sepsis, and those meeting consensus criteria for severe sepsis or septic shock on manual chart review were entered into the sepsis registry. Of 7,459 patients admitted to the PICU during the study period, 401 met consensus criteria for severe sepsis or septic shock (reference standard cohort). Within Virtual Pediatric Systems, patients identified using “Martin” (n = 970; κ = 0.43; positive predictive value = 34%; F1 = 0.48) and “Angus” International Classification of Diseases, 9th Edition, Clinical Modification codes (n = 1387; κ = 0.28; positive predictive value = 22%; F1 = 0.34) showed limited agreement with the reference standard cohort. By comparison, explicit International Classification of Diseases, 9th Edition, Clinical Modification codes for severe sepsis (995.92) and septic shock (785.52) identified a smaller, more accurate cohort of children (n = 515; κ = 0.61; positive predictive value = 57%; F1 = 0.64). PICU mortality was 8% in the reference standard cohort and the cohort identified by explicit codes; age, illness severity scores, and resource utilization did not differ between groups. Analysis of discrepancies between the reference standard and Virtual Pediatric Systems explicit codes revealed that prospective screening missed 66 patients with severe sepsis or septic shock. After including these patients in the reference standard cohort as an exploratory analysis, agreement between the cohort of patients identified by Virtual Pediatric Systems explicit codes and the reference standard cohort improved (κ = 0.73; positive predictive value = 70%; F1 = 0.75). Conclusions: Children with severe sepsis and septic shock are best identified in the Virtual Pediatric Systems database using explicit diagnosis codes for severe sepsis and septic shock. The accuracy of these codes and level of clinical detail available in the Virtual Pediatric Systems database allow for sophisticated epidemiologic studies of pediatric severe sepsis and septic shock in this large, multicenter database. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by the Endowed Chair, Department of Anesthesia and Critical Care, and Division of Emergency Medicine, The Children’s Hospital of Philadelphia, and the University of Pennsylvania Perelman School of Medicine. Dr. Nishisaki’s institution received funding from Agency for Healthcare Research and Quality R18 HS022464-01 and R18 HS024511-01 and the National Institute of Child Health and Human Development (NICHD) 1R21HD089151-01A, and he received support for article research from the National Institutes of Health. Dr. Weiss’ institution received funding from National Institute of General Medical Sciences K23GM110496, and he received funding from Bristol-Myers Squibb Company (consultant) and Medscape (honorarium for lecture). Dr. Balamuth is also supported by NICHD K23-HD082368. The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Robert B. Lindell, MD, Department of Anesthesiology and Critical Care Medicine, University of Pennsylvania Perelman School of Medicine, Children’s Hospital of Philadelphia, 34th St. & Civic Center Blvd., Philadelphia, PA 19104. E-mail: LindellR@email.chop.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Vincent, Jean-Louis; Mongkolpun, Wasineenart

Purpose of review Sepsis is a common condition in critically ill patients and associated with high morbidity and mortality. Sepsis is the result of infection by many potential pathogens, including Gram-negative bacteria. There are no specific antisepsis therapies and management relies largely on infection control and organ support, including hemodynamic stabilization. We discuss these key aspects and briefly mention potential immunomodulatory strategies. Recent findings New aspects of sepsis management include the realization that early treatment is important and that fluids and vasopressor agents should be administered simultaneously to insure rapid restoration of an adequate perfusion pressure to limit development and worsening of organ dysfunction. New immunomodulatory therapies, both suppressive and stimulatory, are being tested. Summary Early diagnosis enabling rapid treatment can optimize outcomes. The multiple components of adequate sepsis management necessitate a team approach. Correspondence to Jean-Louis Vincent, Department of Intensive Care, Erasme University Hospital, Route De Lennik 808, 1070 Brussels, Belgium. Tel: +32 2 555 3380; fax: +32 2 555 4555; e-mail: jlvincent@intensive.org Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Klompas, Michael; Rhee, Chanu

No abstract available…

Abstract Purpose This retrospective cohort study derived a “quick” version of the Pitt bacteremia score (qPitt) using binary variables in patients with Gram-negative bloodstream infections (BSI). The qPitt discrimination was then compared to quick sepsis-related organ failure assessment (qSOFA) and systemic inflammatory response syndrome (SIRS). Methods Hospitalized adults with Gram-negative BSI at Palmetto Health hospitals in Columbia, SC, USA from 2010 to 2013 were identified. Multivariate Cox proportional hazards regression was used to determine variables associated with 14-day mortality. Results Among 832 patients with Gram-negative BSI, median age was 65 years and 449 (54%) were women. After adjustments for age and Charleston comorbidity score, all five components of qPitt were independently associated with mortality: temperature 

Abstract Background Urinary tract infections (UTIs) are one of the most frequent diseases encountered by humans worldwide. The presence of multidrug-resistant (MDR) uropathogenic Escherichia coli (UPEC) harboring several virulence factors, is a major risk factor for inpatients. We sought to investigate the rate of antibiotic resistance and virulence-associated genes among the UPECs isolated from an Iranian symptomatic population. Methods A total of 126 isolates from inpatients with UTI from different wards were identified as UPEC using the conventional microbiological tests. After identification of UPECs, all the isolates were subjected to antimicrobial susceptibility test and polymerase chain reaction (PCR) to identify the presence of 9 putative virulence genes and their association with the clinical outcomes or antimicrobial resistance. Results The data showed that the highest and the lowest resistance rates were observed against ampicillin (88.9%), and imipenem (0.8%), respectively. However, the frequency of resistance to ciprofloxacin was found to be 55.6%. High prevalence of MDR (77.8%) and extended-spectrum β-lactamase (ESBL) (54.8%) were substantial. PCR results revealed the frequency of virulence genes ranged from 0 to 99.2%. Among 9 evaluated genes, the frequency of 4 genes (fimH, sfa, iutA, and PAI marker) was > 50% among all the screened isolates. The iutA, pap GII, and hlyA genes were more detected in the urosepsis isolates with significantly different frequencies. The different combinations of virulence genes were characterized as urovirulence patterns. The isolates recovered from pyelonephritis, cystitis, and urosepsis cases revealed 27, 22, and 6 virulence patterns, respectively. A significant difference was determined between ESBL production with pap GII, iutA, and PAI marker genes. Conclusions Our study highlighted the MDR UPEC with high heterogeneity of urovirulence genes. Considering the high rate of ciprofloxacin resistance, alternative drugs and monitoring of the susceptibility profile for UPECs are recommended.…

Pepper, Dominique J.; Demirkale, Cumhur Y.; Sun, Junfeng; Rhee, Chanu; Fram, David; Eichacker, Peter; Klompas, Michael; Suffredini, Anthony F.; Kadri, Sameer S.

Objectives: Observational studies suggest obesity is associated with sepsis survival, but these studies are small, fail to adjust for key confounders, measure body mass index at inconsistent time points, and/or use administrative data to define sepsis. To estimate the relationship between body mass index and sepsis mortality using detailed clinical data for case detection and risk adjustment. Design: Retrospective cohort analysis of a large clinical data repository. Setting: One-hundred thirty-nine hospitals in the United States. Patients: Adult inpatients with sepsis meeting Sepsis-3 criteria. Exposure: Body mass index in six categories: underweight (body mass index < 18.5 kg/m2), normal weight (body mass index = 18.5–24.9 kg/m2), overweight (body mass index = 25.0–29.9 kg/m2), obese class I (body mass index = 30.0–34.9 kg/m2), obese class II (body mass index = 35.0–39.9 kg/m2), and obese class III (body mass index ≥ 40 kg/m2). Measurements: Multivariate logistic regression with generalized estimating equations to estimate the effect of body mass index category on short-term mortality (in-hospital death or discharge to hospice) adjusting for patient, infection, and hospital-level factors. Sensitivity analyses were conducted in subgroups of age, gender, Elixhauser comorbidity index, Sequential Organ Failure Assessment quartiles, bacteremic sepsis, and ICU admission. Main Results: From 2009 to 2015, we identified 55,038 adults with sepsis and assessable body mass index measurements: 6% underweight, 33% normal weight, 28% overweight, and 33% obese. Crude mortality was inversely proportional to body mass index category: underweight (31%), normal weight (24%), overweight (19%), obese class I (16%), obese class II (16%), and obese class III (14%). Compared with normal weight, the adjusted odds ratio (95% CI) of mortality was 1.62 (1.50–1.74) for underweight, 0.73 (0.70–0.77) for overweight, 0.61 (0.57–0.66) for obese class I, 0.61 (0.55–0.67) for obese class II, and 0.65 (0.59–0.71) for obese class III. Results were consistent in sensitivity analyses. Conclusions: In adults with clinically defined sepsis, we demonstrate lower short-term mortality in patients with higher body mass indices compared with those with normal body mass indices (both unadjusted and adjusted analyses) and higher short-term mortality in those with low body mass indices. Understanding how obesity improves survival in sepsis would inform prognostic and therapeutic strategies. The findings and conclusions in this study are those of the authors and do not necessarily represent the official position of the National Institutes of Health. Drs. Pepper, Demirkale, Sun, and Kadri had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis, including and especially any adverse effects. Drs. Pepper, Demirkale, Sun, Rhee, Fram, Eichacker, Klompas, Suffredini, and Kadri contributed substantially to the study design, data analysis, and interpretation. Drs. Pepper and Kadri drafted the article. Drs. Demirkale, Sun, Rhee, Fram, Eichacker, Klompas, and Suffredini revised it critically for important intellectual content. Drs. Pepper, Demirkale, Sun, Rhee, Fram, Eichacker, Klompas, Suffredini, and Kadri approve the final version to be published. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by the National Institutes of Health Intramural Research Program, Clinical Center. Dr. Pepper received other support from intramural funding from the National Institutes of Health (NIH). Drs. Pepper, Demirkale, Sun, Fram, Eichacker, Suffredini, and Kadri received support for article research from the NIH. Drs. Pepper, Demirkale, Sun, Suffredini, and Kadri disclosed government support. Dr. Rhee’s institution received support for article research from Agency for Healthcare Research and Quality (AHRQ) (grant number K08HS025008), and he received support for article research from AHRQ. Dr. Fram’s institution received funding from the NIH; he received funding from Commonwealth Informatics (stockholder); and he disclosed work for hire. Dr. Klompas’ institution received funding from the Centers for Disease Control and Prevention. Address requests for reprints to: Dominique J. Pepper, MD, MBChB, Critical Care Medicine Department, National Institutes of Health, Building 10, Room 2C145 Bethesda, MD 20892. E-mail: dominiquepepper@gmail.com Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

These two cases encapsulate a common dilemma for clinicians who are trying to implement the recommendation of the Surviving Sepsis Campaign to administer broad-spectrum antibiotics within 1 hour after a patient’s presentation with possible sepsis. Both patients meet Surviving Sepsis Campaign……

Kim, Joohae; Kim, Young Ae; Hwangbo, Bin; Kim, Min Jeong; Cho, Hyunsoon; Hwangbo, Yul; Lee, Eun Sook

Objectives: Although the effect of antihypertensive agents on sepsis has been studied, evidence for survival benefit was limited in the literature. We investigated differences in sepsis-related outcomes depending on the antihypertensive drugs given prior to sepsis in patients with hypertension. Design: Population-based cohort study. Setting: Sample cohort Database of the National Health Insurance Service from 2003 to 2013 in South Korea. Patients: Patients over 30 years old who were diagnosed with sepsis after receiving hypertension treatment. Interventions: None. Measurements and Main Results: Primary outcomes, 30-day and 90-day mortality rates, were analyzed for differences among three representative antihypertensive medications: angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, calcium channel blockers, and thiazides. In total, 4,549 patients diagnosed with hypertension prior to hospitalization for sepsis were identified. The 30-day mortality was significantly higher among patients who did not receive any medications within 1 month before sepsis (36.8%) than among patients who did (32.0%; p < 0.001). The risk for 90-days mortality was significantly lower in prior angiotensin-converting enzyme inhibitors or angiotensin II receptor blocker users (reference) than in other drug users (odds ratio, 1.27; 95% CI, 1.07–1.52). There was no difference in the risk for 30-day and 90-day mortality depending on whether calcium channel blockers or thiazides were used. Use of calcium channel blockers was associated with a decreased risk for inotropic agent administration, compared with those of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (odds ratio, 1.23; 95% CI, 1.05–1.44) and thiazides (odds ratio, 1.33; 95% CI, 1.12–1.58). Conclusions: In patients with sepsis, lower mortality rate was associated with prior use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers not with use of calcium channel blockers or thiazides. The requirement of inotropic agents was significantly lower in prior use of calcium channel blockers, although the survival benefits were not prominent. Drs. J. Kim and Y. A. Kim equally contributed to this work. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by a grant from the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1520240). Dr. Lee disclosed work for hire. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: hbb@ncc.re.kr Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Pickkers P, Mehta RL, Murray PT, et al.

This randomized clinical trial determines the optimal therapeutic dose, effect on kidney function, and adverse effects of human recombinant alkaline phosphatase in patients who are critically ill with sepsis-associated acute kidney injury.

Lankadeva, Yugeesh R.; Kosaka, Junko; Iguchi, Naoya; Evans, Roger G.; Booth, Lindsea C.; Bellomo, Rinaldo; May, Clive N

Objectives: To examine the effects of fluid bolus therapy on systemic hemodynamics, renal blood flow, intrarenal perfusion and oxygenation, PO2, renal function, and fluid balance in experimental early septic acute kidney injury. Design: Interventional study. Setting: Research institute. Subjects: Adult Merino ewes. Interventions: Implantation of flow probes on the pulmonary and renal arteries and laser Doppler oxygen-sensing probes in the renal cortex, medulla, and within a bladder catheter in sheep. Infusion of Escherichia coli to induce septic acute kidney injury (n = 8). After 24, 25, and 26 hours of sepsis, fluid bolus therapy (500 mL of Hartmann’s solution over 15 min) was administered. Measurements and Main Results: In conscious sheep, infusion of Escherichia coli decreased creatinine clearance and increased plasma creatinine, renal blood flow (+46% ± 6%) and cortical perfusion (+25% ± 4%), but medullary perfusion (–48% ± 5%), medullary PO2 (–56% ± 4%), and urinary PO2 (–54% ± 3%) decreased (p < 0.01). The first fluid bolus therapy increased blood pressure (+6% ± 1%), central venous pressure (+245% ± 65%), cardiac output (+11% ± 2%), medullary PO2 (+280% ± 90%), urinary PO2 (+164% ± 80%), and creatinine clearance (+120% ± 65%) at 30 minutes. The following two boluses had no beneficial effects on creatinine clearance. The improvement in medullary oxygenation dissipated following the third fluid bolus therapy. Study animals retained 69% of the total volume and 80% of sodium infused. Throughout the study, urinary PO2 correlated significantly with medullary PO2. Conclusions: In early experimental septic acute kidney injury, fluid bolus therapy transiently improved renal function and medullary PO2, as also reflected by increased urinary PO2. These initial effects of fluid bolus therapy dissipated within 4 hours, despite two additional fluid boluses, and resulted in significant volume retention. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by a grant from the National Health and Medical Research Council of Australia (APP1050672), and by funding from the Victorian Government Operational Infrastructure Support Grant. Dr. Lankadeva was supported by Postdoctoral Fellowships by the National Heart Foundation of Australia (100869; 101853). Dr. Booth received other support from the National Health and Medical Research Council of Australia early career fellowship and the Australian Academy of Technology and Engineering travel fellowship. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: clive.may@florey.edu.au Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Schlosser, Kenny; Wang, Jia-Pey; dos Santos, Claudia; Walley, Keith R.; Marshall, John; Fergusson, Dean A.; Winston, Brent W.; Granton, John; Watpool, Irene; Stewart, Duncan J.; McIntyre, Lauralyn A.; Mei, Shirley H. J.; on behalf of the Canadian Critical Care Trials Group and the Canadian Critical Care Translational Biology Group

Objectives: Cellular Immunotherapy for Septic Shock is the first-in-human clinical trial evaluating allogeneic mesenchymal stem/stromal cells in septic shock patients. Here, we sought to determine whether plasma cytokine profiles may provide further information into the safety and biological effects of mesenchymal stem/stromal cell treatment, as no previous study has conducted a comprehensive analysis of circulating cytokine levels in critically ill patients treated with mesenchymal stem/stromal cells. Design: Phase 1 dose-escalation trial. Patients: The interventional cohort (n = 9) of septic shock patients received a single dose of 0.3, 1.0, or 3.0 million mesenchymal stem/stromal cells/kg body weight (n = 3 per dose). The observational cohort received no mesenchymal stem/stromal cells (n = 21). Interventions: Allogeneic bone marrow-derived mesenchymal stem/stromal cells. Measurements and Main Results: Serial plasma samples were collected at study baseline prior to mesenchymal stem/stromal cell infusion (0 hr), 1 hour, 4 hours, 12 hours, 24 hours, and 72 hours after mesenchymal stem/stromal cell infusion/trial enrollment. Forty-nine analytes comprised mostly of cytokines along with several biomarkers were measured. We detected no significant elevations in a broad range of pro-inflammatory cytokines and biomarkers between the interventional and observational cohorts. Stratification of the interventional cohort by mesenchymal stem/stromal cell dose further revealed patient-specific and dose-dependent perturbations in cytokines, including an early but transient dampening of pro-inflammatory cytokines (e.g., interleukin-1β, interleukin-2, interleukin-6, interleukin-8, and monocyte chemoattractant protein 1), suggesting that mesenchymal stem/stromal cell treatment may alter innate immune responses and underlying sepsis biology. Conclusions: A single infusion of up to 3 million cells/kg of allogeneic mesenchymal stem/stromal cells did not exacerbate elevated cytokine levels in plasma of septic shock patients, consistent with a safe response. These data also offer insight into potential biological mechanisms of mesenchymal stem/stromal cell treatment and support further investigation in larger randomized controlled trials. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Drs. Stewart, McIntyre, and Mei are co-senior authors. Drs. Schlosser, Stewart, McIntyre, and Mei, and Ms. Wang designed and did the study concept. Ms. Wang performed measurements for data acquisition. Drs. Schlosser, Stewart, McIntyre, and Mei, and Ms. Wang analyzed and interpreted the data. Dr. Schlosser drafted the initial article. All authors were involved in critical revisions of the article for important intellectual content. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Drs. McIntyre’s and Mei’s institutions received funding from Ontario Institute of Regenerative Medicine (OIRM) Disease Team Grant (to Dr. Mei) and from the Canadian Institutes of Health Research (CIHR) Operating Grant (to Dr. McIntyre). Dr. Walley disclosed he was a founder and shareholder of Cyon Therapeutics. Dr. Fergusson’s institution received funding from CIHR. Dr. Granton received other funding from Actelion, Bayer, and Bellepheron as a member of steering or adjudication committees for clinical trials in pulmonary hypertension and from Actelion and Bayer for support of pulmonary hypertension research. Dr. Granton disclosed off-label product use of stem cells. Dr. Stewart holds a patent for mesenchymal stem/stromal cell (MSC) therapy for the treatment of acute lung injury. Dr. Mei has received personal fees from Northern Therapeutics that are outside of this submitted work. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: smei@ohri.ca Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Cressman A, MacFadden D, Verma A, et al.

AbstractBackgroundPhysicians face competing demands of maximizing pathogen coverage, while minimizing unnecessary use of broad-spectrum antibiotics when managing sepsis. We sought to identify physicians’ perceived likelihood of coverage achieved by their usual empiric antibiotic regimen, along with minimum thresholds of coverage they would be willing to accept when managing these patients.MethodsWe conducted a scenario-based survey of internal medicine physicians from across Canada using a 2 x 2 factorial design, varied by infection source (undifferentiated vs. genitourinary) and severity (mild vs. severe) denoted by the Quick Sepsis Related Organ Failure Assessment (qSOFA) score. For each scenario, participants selected their preferred empiric antibiotic regimen, estimated the likelihood of coverage achieved by that regimen and considered their minimum threshold of coverage.ResultsWe had 238 respondents including 87 (36.6%) residents and 151 attending physicians (63.4%). The perceived likelihood of antibiotic coverage and minimum thresholds of coverage for each scenario were: 1) severe undifferentiated 90% [interquartile range (IQR) 89.5–95.0] and 90% [IQR 80–95], 2) mild undifferentiated 89% [IQR 80–95] and 80% [IQR 70–89.5], 3) severe GU 91% [IQR 87.3–95.0] and 90% [IQR 80.0–90.0], and 4) mild GU 90% [IQR 81.8–91.3%] and 80% [IQR 71.8–90]. Illness severity and infectious diseases specialty predicted higher thresholds of coverage whereas less clinical experience and lower self-reported prescribing intensity predicted lower thresholds of coverage.ConclusionPathogen coverage of 80% and 90% are physician-acceptable thresholds for managing patients with mild and severe sepsis from bacterial infections. These data may inform clinical guidelines and decision-support tools to improve empiric antibiotic prescribing.

Grumaz, Silke; Grumaz, Christian; Vainshtein, Yevhen; Stevens, Philip; Glanz, Karolina; Decker, Sebastian O.; Hofer, Stefan; Weigand, Markus A.; Brenner, Thorsten; Sohn, Kai

Objectives: Culture-based diagnostics represent the standard of care in septic patients, but are highly insensitive and in many cases unspecific. We recently demonstrated the general feasibility of next-generation sequencing-based diagnostics using free circulating nucleic acids (cell-free DNA) in plasma samples of septic patients. Within the presented investigation, higher performance of next-generation sequencing-based diagnostics was validated by comparison to matched blood cultures. Design: A secondary analysis of a prospective, observational, single-center study. Setting: Surgical ICU of a university hospital and research laboratory. Patients: Fifty patients with septic shock, 20 uninfected patients with elective surgery as control cohort. Interventions: None. Measurements and Main Results: From 256 plasma samples of 48 septic patients at up to seven consecutive time points within the 28-day observation period, cell-free DNA was isolated and analyzed by next-generation sequencing and relevance scoring. In parallel, results from culture-based diagnostics (e.g., blood culture) were obtained. Plausibility of blood culture and next-generation sequencing results as well as adequacy of antibiotic therapy was evaluated by an independent expert panel. In contrast to blood culture with a positivity rate of 33% at sepsis onset, the positivity rate for next-generation sequencing-based pathogen identification was 72%. Over the whole study period, blood culture positivity was 11%, and next-generation sequencing positivity was 71%. Ninety-six percent of positive next-generation sequencing results for acute sepsis time points were plausible and would have led to a change to a more adequate therapy in 53% of cases as assessed by the expert evaluation. Conclusions: Our results show that next-generation sequencing-based analyses of bloodstream infections provide a valuable diagnostic platform for the identification of clinically relevant pathogens with higher sensitivity and specificity than blood culture, indicating that patients might benefit from a more appropriate therapy based on next-generation sequencing-based diagnosis. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Drs. Brenner and Sohn share senior authorship. Drs. S. Grumaz, Decker, Hofer, Brenner, and Sohn conceived of, designed, and supervised the study. Drs. Decker, Hofer, and Brenner collected clinical samples and clinical data. Drs. S. Grumaz, C. Grumaz, and Glanz performed all sample processing and next-generation sequencing experiments. Drs. Vainshtein and Stevens performed bioinformatic data processing and statistical analyses. Drs. S. Grumaz, C. Grumaz, Stevens, and Sohn analyzed the data. Drs. Hofer, Weigand, Brenner, and Sohn provided materials. Drs. S. Grumaz and C. Grumaz prepared the tables and figures. Drs. S. Grumaz and Sohn wrote the article with contributions from all other authors. All authors read, critically revised, and approved the final article. A data visualization tool associated with this article can be viewed here: https://lippincott.shinyapps.io/Sohn/. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by the Fraunhofer IGB (Stuttgart, Germany), Fraunhofer Future Foundation, Department of Anesthesiology (University of Heidelberg, Germany), Heidelberg Foundation of Surgery (University of Heidelberg, Germany). Our study sponsors were not involved in study design, collection, analysis, or interpretation of data. Drs. Decker and Brenner received project funding from Heidelberg Foundation of Surgery. Drs. S. Grumaz, Stevens, and Sohn disclosed that they are co-founders of the company Noscendo active in molecular diagnostics for infectious diseases. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: kai.sohn@igb.fraunhofer.de Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Bartoletti M, Giannella M, Lewis R, et al.

AbstractWe analyzed the impact of continuous/ extended infusion (C/EI) versus intermittent infusion of piperacillin-tazobactam (TZP) and carbapenems on 30-day mortality of patients with liver cirrhosis and bloodstream infection (BSI).METHODSThe BICRHOME study was a prospective, multicenter study enrolling 312 cirrhotic patients with BSI. In this secondary analysis we selected patients receiving TZP or carbapenems as adequate empiric treatment. The 30-day mortality of patients receiving C/EI or intermittent infusion of TZP or carbapenems was assessed with Kaplan-Meier curves, Cox-regression model and estimation of the average treatment effect (ATE) using propensity score matching.RESULTSOverall, 119 patients received TZP or carbapenems as empiric treatment. Patients who received C/EI had a significantly lower mortality rate (16% vs 36%, P=0.047). In a Cox-regression model, the administration of C/EI was associated with a significantly lower mortality [HR 0.41(95% CI 0.11–0.936), P=0.04] when adjusted for severity of illness, and an ATE of 25.6% reduction in 30-day mortality risk (95% CI 18.9–32.3, P

Abstract Background The aim of the present study was to gain national data on the clinical and microbiological characteristics of community-acquired infections in the Faroe Islands and to compare these data with data from other geographical areas. Methods A prospective, observational study involving all patients > = 16 years admitted at the Department of Medicine at the National Hospital, Torshavn, Faroe Islands from October 2013 until April 2015. Results Of 5279 admissions, 1054 cases were with community-acquired infection and were included in the study. Out of these 1054 cases, 471 did not meet the criteria for SIRS (Systemic Inflammatory Response Syndrome), while the remaining 583 cases had sepsis. Mean age was 68 years. At least one comorbidity was found in 80% of all cases. Documented infections were present in 75%, and a plausible pathogen was identified in 29% of all cases. The most common gram-positive pathogen was Staphylococcus aureus, and the most frequent gram-negative pathogen was Escherichia coli. The most common focus of infection was lower respiratory tract, followed by urinary tract, and skin-soft tissue/bone-joint. Bacteremia was found in 10% of the cases. Conclusion In community-acquired infections in hospitalized patients in the Faroe Islands the lower respiratory tract and the urinary tract were the most frequent foci of infection. Gram-negative pathogens and Escherichia coli were the most frequent pathogens in infection without Systemic Inflammatory Response Syndrome, in sepsis and in bacteremia. Our data on clinical characteristics and microbiological etiology provide new information which may be used to develop local guidelines for the managing of patients admitted with community-acquired infections.…

Toliver-Kinsky, T., Cui, W., Törö, G., Lee, S.-J., Shatalin, K., Nudler, E., Szabo, C.

The biological mediator hydrogen sulfide (H2S) is produced by bacteria and has been shown to be cytoprotective against oxidative stress and to increase the sensitivity of various bacteria to a range of antibiotic drugs. Here we evaluated whether bacterial H2S provides resistance against the immune response, using two bacterial species that are common sources of nosocomial infections, Escherichia coli and Staphylococcus aureus. Elevations in H2S increased the resistance of both species to immune-mediated killing. Clearance of infections with wild type and genetically H2S-deficient E. coli and S. aureus was compared in vitro and in mouse models of abdominal sepsis and burn wound infection. Also, inhibitors of H2S-producing enzymes were used to assess bacterial killing by leukocytes. We found that inhibition of bacterial H2S production can increase susceptibility of both bacterial species to rapid killing by immune cells and can improve bacterial clearance after severe burn, an injury that increases susceptibility to opportunistic infections. These findings support the role of H2S as a bacterial defense mechanism against the host response and implicate bacterial H2S inhibition as a potential therapeutic intervention in the prevention or treatment of infections.…

Johnson J, Milstone A.

infection prevention and controlneonatal sepsislow resource settings…

Barak Pertzov, Noa Eliakim-Raz, Heyam Atamna, Anca Zalmanovici Trestioreanu, Dafna Yahav, Leonard Leibovici

The pleiotropic effect of Hydroxymethylglutaryl-CoA reductase inhibitors (statins) might have a beneficial effect in sepsis through several mechanisms.

Hotchkiss, Richard S.; Colston, Elizabeth; Yende, Sachin; Angus, Derek C.; Moldawer, Lyle L.; Crouser, Elliott D.; Martin, Greg S.; Coopersmith, Craig M.; Brakenridge, Scott; Mayr, Florian B.; Park, Pauline K.; Ye, June; Catlett, Ian M.; Girgis, Ihab G.; Grasela, Dennis M.

Objectives: To assess for the first time the safety and pharmacokinetics of an antiprogrammed cell death-ligand 1 immune checkpoint inhibitor (BMS-936559, Bristol-Myers Squibb, Princeton, NJ) and its effect on immune biomarkers in participants with sepsis-associated immunosuppression. Design: Randomized, placebo-controlled, dose-escalation. Setting: Seven U.S. hospital ICUs. Study Population: Twenty-four participants with sepsis, organ dysfunction (hypotension, acute respiratory failure, and/or acute renal injury), and absolute lymphocyte count less than or equal to 1,100 cells/μL. Interventions: Participants received single-dose BMS-936559 (10–900 mg; n = 20) or placebo (n = 4) infusions. Primary endpoints were death and adverse events; key secondary endpoints included receptor occupancy and monocyte human leukocyte antigen-DR levels. Measurements and Main Results: The treated group was older (median 62 yr treated pooled vs 46 yr placebo), and a greater percentage had more than 2 organ dysfunctions (55% treated pooled vs 25% placebo); other baseline characteristics were comparable. Overall mortality was 25% (10 mg dose: 2/4; 30 mg: 2/4; 100 mg: 1/4; 300 mg: 1/4; 900 mg: 0/4; placebo: 0/4). All participants had adverse events (75% grade 1–2). Seventeen percent had a serious adverse event (3/20 treated pooled, 1/4 placebo), with none deemed drug-related. Adverse events that were potentially immune-related occurred in 54% of participants; most were grade 1–2, none required corticosteroids, and none were deemed drug-related. No significant changes in cytokine levels were observed. Full receptor occupancy was achieved for 28 days after BMS-936559 (900 mg). At the two highest doses, an apparent increase in monocyte human leukocyte antigen-DR expression (> 5,000 monoclonal antibodies/cell) was observed and persisted beyond 28 days. Conclusions: In this first clinical evaluation of programmed cell death protein-1/programmed cell death-ligand 1 pathway inhibition in sepsis, BMS-936559 was well tolerated, with no evidence of drug-induced hypercytokinemia or cytokine storm, and at higher doses, some indication of restored immune status over 28 days. Further randomized trials on programmed cell death protein-1/programmed cell death-ligand 1 pathway inhibition are needed to evaluate its clinical safety and efficacy in patients with sepsis. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported by Bristol-Myers Squibb. Drs. Hotchkiss’s, Yende’s, Angus’s, Moldawer’s, Crouser’s, Martin’s, Coopersmith’s, Brakenridge’s, Mayr’s, and Park’s institution received funding from Bristol-Myers Squibb. Drs. Hotchkiss, Colston, Yende, Angus, and Moldawer received support for article research from Bristol-Myers Squibb. Drs. Hotchkiss, Colston, Moldawer, Crouser, Martin, Coopersmith, Brakenridge, Mayr, Park, Catlett, and Grasela disclosed off-label product use of antiprogrammed cell death-ligand 1 inhibitor (BMS-936559) for the treatment of immune suppression in the context of severe sepsis. Drs. Colston and Grasela disclosed they are shareholders of Bristol-Myers Squibb. Dr. Hotchkiss receives research grant support and serves on advisory boards to Bristol-Myers Squibb. Dr. Yende received grant support from Bristol-Myers Squibb for the design of this study. Dr. Angus received consulting fees from Bristol-Myers Squibb for advice on study design. Dr. Martin’s institution received funding from the National Institutes of Health. Dr. Coopersmith’s institution received funding from the Society of Critical Care Medicine (president in 2015). Dr. Park’s institution received funding from the National Institutes of Health, and she received other support from the U.S. Food and Drug Administration/Biomedical Advanced Research and Development Authority and Atox Bio. Drs. Colston, Ye, Catlett, Girgis, and Grasela disclosed that they are employees of Bristol-Myers Squibb. Study registration number (ClinicalTrials.gov): NCT02576457. Data sharing: BMS policy on data sharing may be found at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html. For information regarding this article, E-mail: richardshotchkiss@wustl.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Kushimoto, Shigeki; Abe, Toshikazu; Ogura, Hiroshi; Shiraishi, Atsushi; Saitoh, Daizoh; Fujishima, Seitaro; Mayumi, Toshihiko; Hifumi, Toru; Shiino, Yasukazu; Nakada, Taka-aki; Tarui, Takehiko; Otomo, Yasuhiro; Okamoto, Kohji; Umemura, Yutaka; Kotani, Joji; Sakamoto, Yuichiro; Sasaki, Junichi; Shiraishi, Shin-ichiro; Takuma, Kiyotsugu; Tsuruta, Ryosuke; Hagiwara, Akiyoshi; Yamakawa, Kazuma; Masuno, Tomohiko; Takeyama, Naoshi; Yamashita, Norio; Ikeda, Hiroto; Ueyama, Masashi; Fujimi, Satoshi; Gando, Satoshi;

Objectives: To investigate the impact of body temperature on disease severity, implementation of sepsis bundles, and outcomes in severe sepsis patients. Design: Retrospective sub-analysis. Setting: Fifty-nine ICUs in Japan, from January 2016 to March 2017. Patients: Adult patients with severe sepsis based on Sepsis-2 were enrolled and divided into three categories (body temperature < 36°C, 36–38°C, > 38°C), using the core body temperature at ICU admission. Interventions: None. Measurements and Main Results: Compliance with the bundles proposed in the Surviving Sepsis Campaign Guidelines 2012, in-hospital mortality, disposition after discharge, and the number of ICU and ventilator-free days were evaluated. Of 1,143 enrolled patients, 127, 565, and 451 were categorized as having body temperature less than 36°C, 36–38°C, and greater than 38°C, respectively. Hypothermia—body temperature less than 36°C—was observed in 11.1% of patients. Patients with hypothermia were significantly older than those with a body temperature of 36–38°C or greater than 38°C and had a lower body mass index and higher prevalence of septic shock than those with body temperature greater than 38°C. Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores on the day of enrollment were also significantly higher in hypothermia patients. Implementation rates of the entire 3-hour bundle and administration of broad-spectrum antibiotics significantly differed across categories; implementation rates were significantly lower in patients with body temperature less than 36°C than in those with body temperature greater than 38°C. Implementation rate of the entire 3-hour resuscitation bundle + vasopressor use + remeasured lactate significantly differed across categories, as did the in-hospital and 28-day mortality. The odds ratio for in-hospital mortality relative to the reference range of body temperature greater than 38°C was 1.760 (95% CI, 1.134–2.732) in the group with hypothermia. The proportions of ICU-free and ventilator-free days also significantly differed between categories and were significantly smaller in patients with hypothermia. Conclusions: Hypothermia was associated with a significantly higher disease severity, mortality risk, and lower implementation of sepsis bundles. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by funds of the Japanese Association for Acute Medicine. Dr. Gando’s institution received funding from Japan Society for the Promotion of Science (Grant-in-aid for Scientific Research); he received funding from Asahi Kasei Pharma (lecture fee); and he disclosed that this article is supported by the Japanese Association for Acute Medicine. The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Shigeki Kushimoto, MD, Division of Emergency and Critical Care Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980–8574, Japan. E-mail: kussie@emergency-medicine.med.tohoku.ac.jp Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Lu, Chunmei; Liu, Qing; Yuan, Hao; Wang, Laishuan

Objectives: We aimed to implement our Smart Use of Antibiotics Program to ensure the proper use of antimicrobials, improve patient care and outcomes, and reduce the risks of adverse effects and antimicrobial resistance. Design: We compared the time periods before (baseline) and after (intervention) the implementation of an antibiotic protocol by performing surveillance and assessments of all antibiotic use during a 29-month interrupted period. Setting: Level 3–4 neonatal ICU in one referral center. Patients: All 13,540 infants who received antibiotics during their hospital stay from 2015 to 2017. Interventions: Prospective audit of targeted antibiotic stewardship program. Measurements and Main Results: The primary outcome was the change in total antibiotic days of therapy per 1,000 patient-days between the baseline and intervention periods. The secondary outcomes included readmissions for infection, late-onset sepsis (length of stay), necrotizing enterocolitis, or death in infants at 32 weeks of gestation or younger and the prevalence of multidrug-resistant organism colonization. No differences in safety outcomes were observed between the intervention and baseline periods. Following the implementation of our Smart Use of Antibiotics Program, the total quantity of antibiotics in the intervention phase was significantly decreased from 543 days of therapy per 1,000 patient-days to 380 days of therapy/1,000 patient-days compared with that of baseline (p = 0.0001), which occurred in parallel with a reduction in length of stay from 11.4% during the baseline period to 6.5% during the intervention period (p = 0.01). A reduced multidrug-resistant organism rate was also observed following Smart Use of Antibiotics Program implementation (1.4% vs 1.0%; p = 0.02). The overall readmission rate did not differ between the two periods (1.2% vs 1.1%; p = 0.16). Conclusions: Smart Use of Antibiotics Program implementation was effective in reducing antibiotic exposure without affecting quality of care. Antibiotic stewardship programs are attainable through tailoring to special stewardship targets even in a developing country. Dr. Lu disclosed work for hire. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: laishuanwang@yahoo.com Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Christopher Hansen

American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 2, Page 232-234, January 15, 2019. …

Chung, Kuei-Pin; Chen, Guan-Yuan; Chuang, Tzu-Yi; Huang, Yen-Tsung; Chang, Hou-Tai; Chen, Yen-Fu; Liu, Wei-Lun; Chen, Yi-Jung; Hsu, Chia-Lin; Huang, Miao-Tzu; Kuo, Ching-Hua; Yu, Chong-Jen

Objectives: Recent metabolomic studies of sepsis showed that increased circulatory acylcarnitines were associated with worse survival. However, it is unknown whether plasma carnitine and acylcarnitines can reflect the severity of sepsis, and the role of specific acylcarnitines in prognostic assessment need further confirmation. This study aimed to clarify these questions. Design: Prospective multicenter cohort studies with derivation and validation cohort design. Setting: ICUs at two medical centers and three regional hospitals in Taiwan. Patients: Patients with sepsis and acute organ dysfunction were enrolled. Recruitment of the derivation (n = 90) and validation cohorts (n = 120) occurred from October 2010 through March 2012 and January 2013 through November 2014, respectively. Interventions: Plasma samples were collected immediately after admission, and the levels of carnitine and acylcarnitines were measured by ultra-high performance liquid chromatography-mass spectrometry. Measurements and Main Results: In the derivation cohort, increased plasma levels of short- and medium-chain acylcarnitines were significantly associated with hepatobiliary dysfunction, renal dysfunction, thrombocytopenia, and hyperlactatemia. However, acetylcarnitine is the only acylcarnitine significantly correlating with various plasma cytokine concentrations and also associated with blood culture positivity and 28-day mortality risk. The association between plasma acetylcarnitine and multiple organ dysfunction severity, blood culture positivity, and 28-day mortality, was confirmed in the validation cohort. Patients with high plasma acetylcarnitine (≥ 6,000 ng/mL) had significantly increased 28-day mortality compared with those with plasma acetylcarnitine less than 6,000 ng/mL (52.6% vs 13.9%; hazard ratio, 5.293; 95% CI, 2.340–11.975; p < 0.001 by Cox proportional hazard model). Conclusions: We confirm that plasma acetylcarnitine can reflect the severity of organ dysfunction, inflammation, and infection in sepsis and can serve as a prognostic biomarker for mortality prediction. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by the National Science Council (No. 100-2321-B-002-019), Excellent Translational Medicine Research Projects of National Taiwan University College of Medicine and National Taiwan University Hospital (No. 102C101-42), National Taiwan University Hospital (No. 105-S-3080), and Taoyuan General Hospital, Department of Health and Welfare (PTH10326, North 101–15). Drs. G.-Y. Chen and M.-T. Huang disclosed government work. Dr. M.-T. Huang received support for article research from the National Science Council, Taiwan. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: kuoch@ntu.edu.tw; jefferycjyu@ntu.edu.tw Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Yuuki Bamba, Hiroshi Moro, Nobumasa Aoki, Takeshi Koizumi, Yasuyoshi Ohshima, Satoshi Watanabe, Takuro Sakagami, Toshiyuki Koya, Toshinori Takada, Toshiaki Kikuchi

by Yuuki Bamba, Hiroshi Moro, Nobumasa Aoki, Takeshi Koizumi, Yasuyoshi Ohshima, Satoshi Watanabe, Takuro Sakagami, Toshiyuki Koya, Toshinori Takada, Toshiaki Kikuchi Background Presepsin is a widely recognized biomarker for sepsis. However, little is known about the usefulness of presepsin in invasive fungal infection. The aim of this study was to determine the plasma levels of presepsin in fungal bloodstream infections and to investigate whether it reflects the disease severity, similar to its utility in bacterial infections. Methods We prospectively measured presepsin in plasma samples from participants with fungemia from April 2016 to December 2017. The associations of C-reactive protein, procalcitonin, and presepsin concentrations with the severity of fungemia were statistically analyzed. In vitro assay was performed by incubating Escherichia coli, Candida albicans, and lipopolysaccharide to whole blood cells collected from healthy subjects; after 3 h, the presepsin concentration was measured in the supernatant and was compared among the bacteria, fungi, and LPS groups. Results Presepsin was increased in 11 patients with fungal bloodstream infections. Serial measurement of presepsin levels demonstrated a prompt decrease in 7 patients in whom treatment was effective, but no decrease or further increase in the patients with poor improvement. Additionally, presepsin concentrations were significantly correlated with the Sequential Organ Failure Assessment score (r = 0.89, p < 0.001). In vitro assay with co-incubation of C. albicans and human whole blood cells indicated that the viable cells of C. albicans caused an increase in presepsin, as seen with E. coli. Conclusions Plasma presepsin levels increased in patients with fungal bloodstream infection, with positive association with the disease severity. Presepsin could be a useful biomarker of sepsis secondary to fungal infections.…

James, K. L., Mogen, A. B., Brandwein, J. N., Orsini, S. S., Ridder, M. J., Markiewicz, M. A., Bose, J. L., Rice, K. C.

Staphylococcus aureus nitric oxide synthase (saNOS) is a major contributor to virulence, stress resistance, and physiology, yet the specific mechanism(s) by which saNOS intersects with other known regulatory circuits are largely unknown. The SrrAB two-component system, which modulates gene expression in response to the reduced state of respiratory menaquinones, is a positive regulator of nos expression. Several SrrAB-regulated genes were also previously-shown to be induced in an aerobically-respiring nos mutant, suggesting potential interplay between saNOS and SrrAB. Therefore, a combination of genetic, molecular and physiological approaches was employed to characterize a nos srrAB mutant, which had significant reductions in maximum specific growth rate and oxygen consumption when cultured in conditions promoting aerobic respiration. The nos srrAB mutant secreted elevated lactate levels, correlating with increased transcription of lactate dehydrogenases. Expression of nitrate and nitrite reductase genes were also significantly enhanced in the nos srrAB double mutant, and its aerobic growth defect could be partially rescued with supplementation with nitrate, nitrite, or ammonia. Furthermore, elevated ornithine and citrulline levels and highly upregulated expression of arginine deiminase genes were observed in the double mutant. These data suggest that dual deficiency in saNOS and SrrAB limits S. aureus to fermentative metabolism, with a reliance on nitrate assimilation and the urea cycle to help fuel energy production. The nos, srrAB, and nos srrAB mutants showed comparable defects in endothelial intracellular survival, whereas srrAB and nos srrAB mutants were highly attenuated during murine sepsis, suggesting that SrrAB-mediated metabolic versatility is dominant in vivo.…

Abstract Background The aim of this study was to evaluate whether Interleukin-6 (IL-6) could be a faster indicator of treatment success in adults with severe sepsis and septic shock compared to procalcitonin (PCT) and C-reactive protein (CRP). Methods Data from adult patients with severe sepsis and septic shock managed at the medical intensive care unit (ICU) of the University Hospital Leipzig between September 2009 and January 2012 were analyzed retrospectively. Values for CRP, PCT and IL-6 on admission as well as after 24 and 48–72 h were collected. Antibiotic therapy was defined as clinically successful if the patient survived ICU stay. Results A total of 328 patients with severe sepsis and septic shock with adequate data quality were included. After 48–72 h, the median IL-6 was significantly lower in survivors than in non-survivors (114.2 pg/ml vs. 746.6 pg/ml; p 

Walley, Keith R.; Boyd, John H.; Kong, HyeJin Julia; Russell, James A.

Objectives: Low low-density lipoprotein levels are associated with increased mortality in sepsis. Whether low low-density lipoprotein levels contribute causally to adverse sepsis outcome is unknown. Design: Retrospective analysis of two sepsis patient cohorts using a Mendelian Randomization strategy. Setting: Sepsis patients enrolled into clinical research cohorts at tertiary care teaching hospitals. Patients: The first cohort included 200 sepsis patients enrolled in an observational study in a hospital Emergency Department. The second cohort included genotyped patients enrolled in the Vasopressin and Septic Shock Trial. Interventions: Retrospective analysis of these patient datasets. In 632 patients enrolled in Vasopressin and Septic Shock Trial, Proprotein Convertase Subtilisin/Kexin type 9, and 3-Hydroxy-3-Methylglutaryl-CoA Reductase single nucleotide polymorphisms known to be associated with low-density lipoprotein levels were genotyped, and a genetic score related to low-density lipoprotein levels was calculated. Measurements and Main Results: In the first cohort, we replicated the finding that low low-density lipoprotein levels are associated with increased 28-day mortality. In genotyped patients in the Vasopressin and Septic Shock Trial trial, we found that the 3-Hydroxy-3-Methylglutaryl-CoA Reductase genetic score, known to be directly related to low low-density lipoprotein levels, was not associated with increased mortality. Surprisingly the Proprotein Convertase Subtilisin/Kexin type 9 genetic score, known to be directly related to low low-density lipoprotein levels, was associated with decreased (not increased) mortality. Conclusions: Both 3-Hydroxy-3-Methylglutaryl-CoA Reductase and Proprotein Convertase Subtilisin/Kexin type 9 genetic scores should have been associated with increased mortality if low low-density lipoprotein levels contributed causally to sepsis mortality. But this was not the case, and the opposite was observed for the Proprotein Convertase Subtilisin/Kexin type 9 genetic score. This suggests that low-density lipoprotein levels, per se, do not contribute causally to adverse sepsis outcomes. The Proprotein Convertase Subtilisin/Kexin type 9 genetic score finding raises the possibility that increased low-density lipoprotein clearance (the effect of these Proprotein Convertase Subtilisin/Kexin type 9 genotypes) may contribute to improved sepsis outcomes. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by the Canadian Institutes of Health Research FDN 154311. Dr. Walley is supported by the Canadian Institutes of Health Research (CIHR) FDN 154311. Dr. Boyd disclosed he is a Co-Founder of Cyon Therapeutics, a biotech company aiming to develop Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors for sepsis. Ms. Kong’s institution received funding from CIHR. Dr. Russell received funding from Asahi Kasei Pharma America (developing thrombomodulin in sepsis), consulting fees from Cubist Pharmaceuticals (now owned by Merck, formerly Trius Pharmaceuticals, developing antibiotics), Ferring Pharmaceuticals (which manufactures vasopressin and is developing selepressin), Grifols (which sells albumin), MedImmune (regarding sepsis), Leading Biosciences (developing a sepsis therapeutic), La Jolla Pharmaceuticals (developing a sepsis therapeutic), CytoVale (developing a sepsis diagnostic), Asahi Kesai (developing a sepsis therapeutic), Sirius Genomics (now closed, formerly involved in pharmacogenomics research in sepsis), and received grant support from Sirius Genomics and Ferring Pharmaceuticals that was provided to and administered by University of British Columbia (UBC). Drs. Walley, Boyd, and Russell report being inventors on patents owned by the UBC that are related to PCSK9 inhibitor(s) and sepsis and related to the use of vasopressin in septic shock. For information regarding this article, E-mail: Keith.Walley@hli.ubc.ca Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Abstract Purpose The management of early- (EOS) and late-onset sepsis (LOS) and neonatal intensive care units (NICUs) has not been extensively evaluated. Methods 231 highly specialized level 1 and level 2 NICUs in Germany were asked to participate in an internet-based survey. Results The final analysis of anonymized datasets from 80 NICUs (response rate 34.6 %) compared university hospitals and regional neonatal referral centers. The survey describes potential areas of improvement concerning empirical treatment of infants with LOS with vancomycin and 3rd generation cephalosporins, minimal volume of blood sampling for aerobic culture, consideration of lumbar tap in any child with blood culture positive LOS and drug monitoring details for gentamicin and vancomycin. Conclusion In summary, this survey reveals a significant gap between recent national German guidelines and daily practices in German NICUs.…

Mitchell M. Levy

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 11, Page 1406-1412, December 1, 2018. …

Barbash, Ian J.; Davis, Billie; Kahn, Jeremy M.

Objectives: The Centers for Medicare and Medicaid Services requires hospitals to report compliance with a sepsis treatment bundle as part of its Inpatient Quality Reporting Program. We used recently released data from this program to characterize national performance on the sepsis measure, known as SEP-1. Design: Cross-sectional study of United States hospitals participating in the Centers for Medicare and Medicaid Services Hospital Inpatient Quality Reporting Program linked to Centers for Medicare and Medicaid Services’ Healthcare Cost Reporting Information System. Setting: General, short-stay, acute-care hospitals in the United States. Measurements and Main Results: We examined the hospital factors associated with reporting SEP-1 data, the hospital factors associated with performance on the SEP-1 measure, and the relationship between SEP-1 performance and performance on other quality measures related to time-sensitive medical conditions. A total of 3,283 hospitals were eligible for the analysis, of which 2,851 (86.8%) reported SEP-1 performance data. SEP-1 reporting was more common in larger, nonprofit hospitals. The most common reason for nonreporting was an inadequate case volume. Among hospitals reporting SEP-1 performance data, overall bundle compliance was generally low, but it varied widely across hospitals (mean and SD: 48.9% ± 19.4%). Compared with hospitals with worse SEP-1 performance, hospitals with better SEP-1 performance tended to be smaller, for-profit, nonteaching, and with intermediate-sized ICUs. Better hospital performance on SEP-1 was associated with higher rates of timely head CT interpretation for stroke patients (rho = 0.16; p < 0.001), more frequent aspirin administration for patients with chest pain or heart attacks (rho = 0.24; p < 0.001) and shorter median time to electrocardiogram for patients with chest pain (rho = –0.12; p < 0.001). Conclusions: The majority of eligible hospitals reported SEP-1 data, and overall bundle compliance was highly variable. SEP-1 performance was associated with structural hospital characteristics and performance on other measures of hospital quality, providing preliminary support for SEP-1 performance as a marker of timely hospital sepsis care. Supported, in part, by Agency for Healthcare Research and Quality (to Dr. Barbash, K08HS025455), National Institutes of Health (to Dr. Kahn, K24HL133444). Dr. Barbash received support for article research from the Agency for Healthcare Research and Quality. Dr. Kahn’s institution received funding from the NIH, and he received support for article research from the NIH. Dr. Davis has disclosed that she does not have any potential conflicts of interest. For information regarding this article, E-mail: barbashij@upmc.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Adriana Cabal, Daniela Schmid, Sarah Lepuschitz, Anna Stöger, Marion Blaschitz, Franz Allerberger, Werner Ruppitsch, Markus Hell

In July 2018 four female patients hospitalized in the same maternal ward were diagnosed with puerperal sepsis caused by Steptococcus pyogenes.All were assisted by the same midwife in their deliveries. For active case finding diverse specimens were taken from the patients and the staff. By using a new core genome Multilocus Sequence Typing scheme, we confirmed here the transmission of a GAS strain by the only midwife involved in all deliveries that suffered from a panaritium. Still, proper hand hygiene before, during and after delivery assistance is of utmost importance.