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.

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).

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.…

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.

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 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.…

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.

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.

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.…

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.

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.

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.…

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.

Mitchell M. Levy

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

Oscar Rojo del Moral

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 11, Page 1444-1446, December 1, 2018. …

Tang, B.-H., Wu, Y.-E., Kou, C., Qi, Y.-J., Qi, H., Xu, H.-Y., Leroux, S., Huang, X., Zhou, Y., Zheng, Y., Jacqz-Aigrain, E., Shen, A.-D., Zhao, W.

Backgrounds: Amoxicillin is widely used to treat bacterial infections in neonates. However, considerable inter-center variability in dosage regimens of antibiotic exist in clinical practice. Pharmacokinetics of amoxicillin has been described in only a few preterm neonates. Thus, we aimed to evaluate population pharmacokinetics of amoxicillin through a large samples covered entire age range of neonates and young infants, and establish evidence-based dosage regimens based on developmental pharmacokinetics–pharmacodynamics.Methods: This is a prospective, multi-center, pharmacokinetic study using an opportunistic sampling design. Amoxicillin plasma concentrations were determined using high performance liquid chromatography. Population pharmacokinetic analysis was performed using NONMEM.Results: A total of 224 pharmacokinetic samples from 187 newborns (postmenstrual age range: 28.4 – 46.3 weeks) were available for analysis. A 2-compartment model with first-order elimination was used to describe population pharmacokinetics. Covariate analysis showed that current weight, postnatal age and gestational age were significant covariates. The final model was further validated for predictive performance in an independent cohort of patients. Monte Carlo simulation demonstrated that for early-onset sepsis, the currently used dosage regimen (25mg/kg BID) resulted in 99.0% of premature neonates and 87.3% of term neonates achieving the pharmacodynamic target (% time above MIC), using MIC breakpoint of 1 mg/L. For late-onset sepsis, 86.1% of premature neonates treated with 25mg/kg TID and 79.0% of term neonates receiving 25mg/kg QID reached the pharmacodynamic target, using MIC breakpoint of 2 mg/L.Conclusion: The population pharmacokinetics of amoxicillin was assessed in neonates and young infants. A dosage regimen was established based on developmental pharmacokinetics-pharmacodynamics.…

Fernandez-Cruz, A., Alba, N., Semiglia-Chong, M. A., Padilla, B., Rodriguez-Macias, G., Kwon, M., Cercenado, E., Chamorro-de-Vega, E., Machado, M., Perez-Lago, L., de Viedma, D. G., Diez Martin, J. L., Munoz, P.

Background:We present our experience in patients with hematologic malignancy and Pseudomonas aeruginosa infection treated with ceftolozane-tazobactam.Materials/methods:We performed a single-center case-control study including all patients with hematologic malignancy and P. aeruginosa infection treated with ceftolozane-tazobactam (study group) and compared them with similar patients not treated with ceftolozane-tazobactam (control group) to assess safety and efficacy.Results:Nineteen cases and 38 controls were analyzed. Cases were younger (45.6 y vs 57.6 y, p=0.012) and less frequently had bacteremia (52.6% vs 86.8%, p=0.008). They also had a worse MASCC score (10.2 vs 16.1, p=0.0001), more hospital-acquired infections (78.9% vs 47.4%, p=0.013), and more XDR P. aeruginosa (47.4% vs 21.1%, p=0.015).Cases received a median of 14 days (7-18) of ceftolozane-tazobactam (monotherapy in 11 cases [57.9.6%]). Ceftolozane-tazobactam was mostly used as targeted therapy (16; 84.2%) because of resistance (9; 47.4%), failure (4; 21.1%), and toxicity (3; 15.8%). Ten cases had bacteremia (52.6%). The sources were pneumonia (26.3%), catheter-related bacteremia (21.1%), primary bacteremia (21.1%), perianal/genital (15.7%), urinary (10.5%), and skin/soft tissue infection (5.3%). No toxicity was attributed to ceftolozane/tazobactam. More than 60% had neutropenia, and 15.8% fulfilled the criteria for sepsis.There were no significant differences in clinical cure at day 14 (89.5% vs 71.1%, p=0.183) or recurrence (15.8% vs 10.5%, p=0.675). Thirty-day mortality was lower among cases (5.3% vs 28.9%, p=0.045).Conclusions:Ceftolozane-tazobactam was well tolerated and at least as effective as other alternatives for P. aeruginosa infection in patients with hematologic malignancy, including neutropenic patients with sepsis caused by XDR strains.…

Szakmany, Tamas; Walters, Angharad M.; Pugh, Richard; Battle, Ceri; Berridge, Damon M.; Lyons, Ronan A.

Objectives: Clear understanding of the long-term consequences of critical care survivorship is essential. We investigated the care process and individual factors associated with long-term mortality among ICU survivors and explored hospital use in this group. Design: Population-based data linkage study using the Secure Anonymised Information Linkage databank. Setting: All ICUs between 2006 and 2013 in Wales, United Kingdom. Patients: We identified 40,631 patients discharged alive from Welsh adult ICUs. Interventions: None. Measurements and Main results: Primary outcome was 365-day survival. The secondary outcomes were 30- and 90-day survival and hospital utilization in the 365 days following ICU discharge. Kaplan-Meier curves were plotted to compare survival rates. Cox proportional hazards regression models were used to determine risk factors of mortality. Seven-thousand eight-hundred eighty-three patients (19.4%) died during the 1-year follow-up period. In the multivariable Cox regression analysis, advanced age and comorbidities were significant determinants of long-term mortality. Expedited discharge due to ICU bed shortage was associated with higher risk. The rate of hospitalization in the year prior to the critical care admission was 28 hospitalized days/1,000 d; post critical care was 88 hospitalized days/1,000 d for those who were still alive; and 57 hospitalized days/1,000 d and 412 hospitalized days/1,000 d for those who died by the end of the study, respectively. Conclusions: One in five ICU survivors die within 1 year, with advanced age and comorbidity being significant predictors of outcome, leading to high resource use. Care process factors indicating high system stress were associated with increased risk. More detailed understanding is needed on the effects of the potentially modifiable factors to optimize service delivery and improve long-term outcomes of the critically ill. Drs. Szakmany and Walters contributed equally to the article. Dr. Szakmany conceived and supervised the study, performed data interpretation, and developed the article. Dr. Walters extracted data, performed data analysis, and developed the article. Dr. Pugh conceived the study, performed data interpretation, and provided input on article development. Dr. Battle provided input on data interpretation, helped write the article, and provided critical input on its revisions. Dr. Berridge performed data analysis and provided critical input on article revisions. Dr. Lyons supervised the study, provided input on data interpretation, helped write the article, and provided critical input on its revisions. 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 Critical Illness Implementation Group, Welsh Assembly Government. Presented, in part, at the 46th Critical Care Congress, Honolulu, HI, January 21–25, 2017. Drs. Szakmany’s and Pugh’s institution received funding from the Critical Illness Implementation Group, Welsh Assembly Government. Dr. Szakmany’s institution also received funding from a Medical research Council Developmental Pathway Funding Scheme Grant, a patent pending on biomarker panels for sepsis, Fiona Elizabeth Agnew Trust (Fiona Elizabeth Agnew Trust – Understanding, Research and Education about Sepsis Awards Award), Welsh Intensive Care Society Research Grant, and the Society of Critical Care Medicine (travel). He received funding from Couton Mutton Diagnostics Ltd, and disclosed that he is one of the Clinical Leads of the All Wales Critical Care and Trauma Network, which oversees the strategic development of critical care services in Wales. Dr. Walters’ institution received funding from the Farr Institute Centre for Improvement of Population Health through E-records Research, which is supported by a 10- funder consortium: Arthritis Research UK, the British Heart Foundation, Cancer Research UK, the Economic and Social Research Council, the Engineering and Physical Sciences Research Council, the Medical Research Council, the National Institute of Health Research, the National Institute for Social Care and Health Research (Welsh Assembly Government), the Chief Scientist Office (Scottish Government Health Directorates), and the Wellcome Trust (MRC Grant No: MR/K006525/1). Dr. Pugh’s institution also received funding from Clinical Research Time Award, Health and Social Services Group, Welsh Government. Dr. Lyons’ institution received funding from National Health Service Wales, Medical Research Council, Economic and Social Research Council, Engineering and Physical Sciences Research Council, British Heart Foundation, Wellcome Trust, National Institute of Health Research, Welsh Government, and he received support for article research from Wellcome Trust/Charity Open Access Fund and Research Councils UK. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: szakmanyt1@cardiff.ac.uk Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Bosch, Nicholas A.; Cohen, David M.; Walkey, Allan J.

Objective: Atrial fibrillation frequently develops in patients with sepsis and is associated with increased morbidity and mortality. Unfortunately, risk factors for new-onset atrial fibrillation in sepsis have not been clearly elucidated. Clarification of the risk factors for atrial fibrillation during sepsis may improve our understanding of the mechanisms of arrhythmia development and help guide clinical practice. Data Sources: Medline, Embase, Web of Science, and Cochrane CENTRAL. Study Selection: We conducted a systematic review and meta-analysis to identify risk factors for new-onset atrial fibrillation during sepsis. Data Extraction: We extracted the adjusted odds ratio for each risk factor associated with new-onset atrial fibrillation during sepsis. For risk factors present in more than one study, we calculated pooled odds ratios (meta-analysis). We classified risk factors according to type and quantified the factor effect sizes. We then compared sepsis-associated atrial fibrillation risk factors with risk factors for community-associated atrial fibrillation. Data Synthesis: Forty-four factors were examined as possible risk factors for new-onset atrial fibrillation in sepsis, 18 of which were included in meta-analyses. Risk factors for new-onset atrial fibrillation included demographic factors, comorbid conditions, and most strongly, sepsis-related factors. Sepsis-related factors with a greater than 50% change in odds of new-onset atrial fibrillation included corticosteroid use, right heart catheterization, fungal infection, vasopressor use, and a mean arterial pressure target of 80–85 mm Hg. Several cardiovascular conditions that are known risk factors for community-associated atrial fibrillation were not identified as risk factors for new-onset atrial fibrillation in sepsis. Conclusions: Our study shows that risk factors for new-onset atrial fibrillation during sepsis are mainly factors that are associated with the acute sepsis event and are not synonymous with risk factors for community-associated atrial fibrillation. Our results provide targets for future studies focused on atrial fibrillation prevention and have implications for several key areas in the management of patients with sepsis such as glucocorticoid administration, vasopressor selection, and blood pressure targets. Dr. Bosch takes responsibility for the integrity of the work as a whole, from inception to published article, and he drafted the article. Drs. Bosch and Walkey substantially contributed to the conception and design of this study. Drs. Bosch and Cohen acquired the data. Drs. Bosch, Cohen, and Walkey were involved in the interpretation of data and revised it critically 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). Supported, in part, by National Heart, Lung, and Blood Institute grants 5K01HL116768-03 and 1R01HL136660-01 (to Dr. Walkey). Dr. Walkey’s institution received funding from the National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute; he received royalties from UptoDate; and he received support for article research from the NIH. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: nicholas.bosch@bmc.org Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Lai, Chih-Cheng; Wang, Ya-Hui; Wang, Cheng-Yi; Wang, Hao-Chien; Yu, Chong-Jen; Chen, Likwang; on the behalf of Taiwan Clinical Trial Consortium for Respiratory Diseases (TCORE)

Objectives: This study aimed to compare the effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on the risk and outcomes of sepsis in patients with chronic obstructive pulmonary disease. Design: A retrospective study. Setting: Taiwan’s National Health Insurance Research Database. Patients: All patients with chronic obstructive pulmonary disease who received angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for more than 90 days between 2000 and 2005 were recruited for this study. Pairwise matching (1:1) of the angiotensin-converting enzyme inhibitor and angiotensin receptor blocker groups resulted in two similar subgroups with 5,959 patients in each. Interventions: None. Measurements and Main Results: The primary outcome was sepsis, and the secondary outcome was death. The occurrence rate of sepsis was 3.67 per 100 person-years for the patients receiving angiotensin-converting enzyme inhibitors and 2.87 per 100 person-years for those receiving angiotensin receptor blockers. In addition, the patients receiving angiotensin-converting enzyme inhibitors had a higher risk of septic shock (adjusted hazard ratio, 1.45; 95% CI, 1.26–1.67) and mortality (adjusted hazard ratio, 1.31; 95% CI, 1.22–1.40) than those receiving angiotensin receptor blockers. No matter whether the patients had prior severe exacerbation before the index date, those receiving angiotensin-converting enzyme inhibitors had a higher risk of sepsis, septic shock, and mortality than those receiving angiotensin receptor blockers (all p < 0.001). Conclusions: Angiotensin receptor blockers were associated with lower rates of sepsis and mortality than angiotensin-converting enzyme inhibitors in the patients with chronic obstructive pulmonary disease. The similar findings were also noted in subgroup analysis. Members of Taiwan Clinical Trial Consortium for Respiratory Diseases (TCORE) are listed in the acknowledgments. 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 grants from National Science Council (104-2314-B-002-185-MY2, 101-2325-B-002-064, 102-2325-B-002-087, 103-2325-B-002-027, 104-2325-B-002-035, 105-2325-B-002-030, 104-2314-B-567-002, 105-2314-B-567-001), and from National Health Research Institutes (intramural funding). Dr. Cheng-Yi Wang 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: cywang@mospital.com Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Scott HF, Balamuth F, Paul RM.

To the Editor Dr Evans and colleagues demonstrated that delivery of bundled care within 1 hour was associated with a significant reduction in pediatric sepsis mortality in 59 hospitals in New York State, although individual bundle elements were not. Prior pediatric studies have similarly shown that timely bundled sepsis care was associated with improved outcomes, despite differences in bundle components and population. These studies together suggest that delivery of locally defined best care, including timely fluid and antibiotics, improves outcomes, even when bundle details differ.

Evans IR, Angus DC, Seymour CW.

In Reply Dr Scott and colleagues discuss the contribution of the New York pediatric sepsis mandate analysis to prior literature and highlight challenges to the study of time-sensitive sepsis bundles in children. We agree that there is heterogeneity of sepsis cases and criteria for treatment across New York hospitals. We were encouraged that our findings were consistent after extensive adjustment for measured confounders in multiple sensitivity analyses. We also agree that consensus definitions for pediatric sepsis and time to treatment will allow for more efficient study of existing and new quality improvement and policy initiatives in sepsis.

Emanuele Rezoagli

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 12, Page 1570-1572, December 15, 2018. …

Legrand M, Kellum JA.

Following esophageal resection for cancer, a 73-year-old man was admitted to the ICU with pneumonia and progressive acute respiratory failure, and he was placed on mechanical ventilation. At day 5, his creatinine level continued to increase. How would you proceed?…

Meihong Deng, Yiting Tang, Wenbo Li, Xiangyu Wang, Rui Zhang, Xianying Zhang, Xin Zhao, Jian Liu, Cheng Tang, Zhonghua Liu, Yongzhuo Huang, Huige Peng, Lehui Xiao, Daolin Tang, Melanie J. Scott, Qingde Wang, Jing Liu, Xianzhong Xiao, Simon Watkins, Jianhua Li, Huan Yang, Haichao Wang, Fangping Chen, Kevin J. Tracey, Timothy R. Billiar, Ben Lu

Caspase-11, a cytosolic LPS receptor, mediates endotoxic shock. Deng and colleagues demonstrate that hepatocyte-released HMGB1 mediates caspase-11-dependent pyroptosis and lethality in sepsis by delivering extracellular LPS into the cytosol of macrophages and endothelial cells, where LPS activates caspase-11.

Greg S. Martin

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 11, Page 1360-1361, December 1, 2018. …

Iram Yunus, Anum Fasih, Yanzhi Wang

by Iram Yunus, Anum Fasih, Yanzhi Wang Objective The primary objective of this study was to determine the correlation between procalcitonin values and illness severity by evaluating the degree of end organ dysfunction using the Sequential Organ Failure Assessment score, length of stay and the severity of sepsis (sepsis alone vs. septic shock), The hypothesis that procalcitonin values would be higher in sicker patients was formulated before data collection began. Secondary outcomes studied in relation to procalcitonin levels included infection characteristics such as the site of infection, microbial agent and dialysis dependent CKD. Design Unblinded retrospective cohort study. September 2014-December 2016. Setting 364 patients with a diagnosis of sepsis or severe sepsis who were admitted to the general medical ward and ICU at Methodist Medical Center and Proctor Hospital in Peoria, Illinois, USA. Results This study demonstrates the following: Weak positive correlation between procalcitonin and SOFA score. Negligible correlation with length of stay. Higher values in patients who died than in patients who survived to discharge (p = 0.058). Sensitivity and specificity of procalcitonin for septic shock was 63 and 65% respectively. Sites typically infected by gram negative bacteria have higher procalcitonin values than sites infected by gram positive bacteria (p = 0.03). Higher procalcitonin in bacteremia than non-bacteremic infections (p = 0.004). Higher procalcitonin in dialysis-dependent CKD patients (p = 0.020). Conclusions Procalcitonin has a higher specificity for bacterial infections than other acute phase reactants. Although initial procalcitonin value may be helpful in the determination of illness severity, it is not always a reliable prognostic indicator and carries little significance as a standalone value. Procalcitonin values may be influenced by preexisting comorbid conditions such as chronic kidney disease, which are associated with higher procalcitonin values at baseline. Procalcitonin can provide invaluable information when viewed as one piece of a clinical puzzle, and is most powerful when the interpreting physician is aware of how values are influenced by the different clinical scenarios presented in this article.…

Fortenberry, James D.; Nguyen, Trung; Grunwell, Jocelyn R.; Aneja, Rajesh K.; Wheeler, Derek; Hall, Mark; Fleming, Geoffrey; Tarrago, Rod; Buttram, Sandra; Dalton, Heidi; Han, Yong; Easley, Kirk A.; Knezevic, Andrea; Dai, Tian; Paden, Matthew; Carcillo, Joseph A.; for the Thrombocytopenia-Associated Multiple Organ Failure (TAMOF) Network Study Group

Objective: The objective was to compare the resolution of organ dysfunction, 28-day mortality, and biochemical markers in children with thrombocytopenia-associated multiple organ failure who received therapeutic plasma exchange versus no therapeutic plasma exchange. Design: Observational longitudinal cohort study. Setting: Nine U.S. PICUs. Patients: Eighty-one children with sepsis-induced thrombocytopenia-associated multiple organ failure. Interventions: Therapeutic plasma exchange. Measurements and Main Results: Adjusted relative risk for 28-day mortality was modeled using standard multivariate regression with propensity score weighting to reduce covariate confounding. Change from baseline Pediatric Logistic Organ Dysfunction scores between therapeutic plasma exchange and no therapeutic plasma exchange differed in temporal pattern during the first week (p = 0.009). By day 4, mean Pediatric Logistic Organ Dysfunction score declined by 7.9 points (95% CI, –10.8 to –5.1) in the therapeutic plasma exchange–treated group compared with no change with no therapeutic plasma exchange. Use of therapeutic plasma exchange was associated with reduced 28-day mortality by multivariate analysis (adjusted relative risk, 0.45; 95% CI, 0.23–0.90; p = 0.02) and by propensity score weighting (adjusted relative risk, 0.46; 95% CI, 0.22–0.97; p = 0.04). Conclusions: Therapeutic plasma exchange use in thrombocytopenia-associated multiple organ failure was associated with a decrease in organ dysfunction. After accounting for several risk factors, 28-day all-cause mortality was lower in children treated with therapeutic plasma exchange compared with those receiving no therapeutic plasma exchange. A multicenter randomized clinical trial is necessary to determine a causal relationship. Drs. Fortenberry, Nguyen, and Carcillo conceived and designed the study. Drs. Fortenberry and Nguyen drafted the initial article. Mr. Easley, Ms. Knezevic, and Dr. Dai conducted statistical analyses, aided with data interpretation, and edited the article. Dr. Grunwell interpreted the data, and drafted and provided critical revision of the article. Drs. Aneja, Wheeler, Hall¸ Fleming, Tarrago, Buttram, Dalton, Han, and Paden recruited patients, and acquired data. All authors read and provided final approval of the version submitted for publication. 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 Children’s Miracle Network. Dr. Grunwell is supported by the Atlanta Pediatric Scholars Program grant K12HD072245. Dr. Carcillo received funding through the National Institutes of Health GM108618. Dr. Nguyen’s institution received funding from the National Institutes of Health (NIH). Drs. Nguyen, Grunwell, and Carcillo received support for article research from the NIH. Dr. Grunwell’s institution received funding from the Children’s Miracle Network, and she is supported by the Atlanta Pediatric Scholars Program grant K12HD072245. Dr. Aneja received funding from UptoDate. Drs. Grunwell, Wheeler, and Dalton disclosed off-label product use of therapeutic plasma exchange for sepsis-induced thrombocytopenia–associated multiple organ failure in children. Dr. Hall received funding from Bristol Myers-Squibb (advisory board) and La Jolla Pharmaceuticals (consultant). Dr. Fleming disclosed that he is a member of the American Board of Medical Specialties Vision Commission. Dr. Dalton received funding fromInnovative ECMO Concepts (consultant). Dr. Dai was paid as a graduate research assistant to work on clinical research studies, but was not paid for her analysis work for the Thrombocytopenia-Associated Multiple Organ Failure study. Dr. Paden received funding from expert witness work, and he disclosed off-label product use of apheresis for sepsis. Dr. Carcillo received funding through the NIH GM108618 and the National Institute of General Medical Sciences. The remaining authors have disclosed that they do not have any potential conflicts of interest. Current address for Dr. Tarrago: Seattle Children’s Hospital, Seattle, WA; Dr. Han: Children’s Mercy, Kansas City, MO; Dr. Knezevic: Memorial Sloan Kettering Cancer Center, New York City, NY; Dr. Dai: Amgen, Thousand Oaks, CA. For information regarding this article, E-mail: james.fortenberry@choa.org Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Birnie E, Claushuis T, Koh G, et al.

AbstractBackgroundInfection with the gram-negative bacillus Burkholderia pseudomallei (melioidosis) is an important cause of pneumosepsis in Southeast Asia and has a mortality of up to 40%. We aimed to assess the role of platelets in the host response against B. pseudomallei infection.MethodsAssociation between platelet counts and mortality was determined in 1160 patients with culture-proven melioidosis. Mice treated with (low- or high-dose) platelet-depleting antibody were inoculated intranasally with B. pseudomallei and killed. Additional studies using functional glycoprotein Ibα–deficient mice were conducted.ResultsThrombocytopenia was present in 31% of patients at admission and predicted mortality in melioidosis patients even after adjustment for confounders. In our murine-melioidosis model, platelet counts decreased, and mice treated with a platelet-depleting antibody showed enhanced mortality and higher bacterial loads compared to mice with normal platelet counts. Low platelet counts had a modest impact on early-pulmonary neutrophil influx. Reminiscent of their role in hemostasis, platelet depletion impaired vascular integrity, resulting in early lung bleeding. Glycoprotein Ibα–deficient mice had reduced platelet counts during B. pseudomallei infection together with an impaired local host defense in the lung.ConclusionsThrombocytopenia predicts mortality in melioidosis patients and, during experimental melioidosis, platelets play a protective role in both innate immunity and vascular integrity.

Acute kidney injury is a frequent complication in patients hospitalized in the intensive care unit (ICU) for septic shock and is associated with high mortality. Acute kidney injury associated with sepsis is characterized by a distinct pathophysiology, and patients with acute kidney injury and……

Abstract Background Listeria monocytogenes is a food-borne, facultative intracellular bacterium that causes severe diseases such as sepsis and meningoencephalitis in immunocompromised hosts. Because it stimulates robust T-lymphocyte-mediated responses, attenuated L. monocytogenes are candidate vaccine vectors for tumor immunotherapy. Case We report a case of bacteremia caused by vaccine strain L. monocytogenes (Axalimogene filolisbac) occurring 31 months after immunization against human papilloma virus (HPV) associated cervical cancer. Conclusion Receipt of a L. monocytogenes-based vaccine is a novel risk factor for delayed L. monocytogenes bacteremia.…

Lewis JM, Henrion M, Rylance J.

To the Editor Dr Rudd and colleagues concluded that the quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA) score was superior to the systemic inflammatory response syndrome (SIRS) score and a baseline risk model in predicting in-hospital mortality in low- and middle-income countries (LMICs), an issue that has been debated since its introduction in the Sepsis-3 definitions. We are concerned that the treatment of missing data may have introduced significant bias.

Rudd KE, Seymour CW, Angus DC.

In Reply We agree with Dr Lewis and colleagues that missing data can be an important limitation in clinical research, including our analysis of the predictive validity of the qSOFA score and SIRS criteria. There are 2 issues related to missing data: (1) why missing data are present and (2) the approach to missing data during analysis. First, missing data were present in all 9 cohorts included in the study. Many sites lacked electronic health record systems, had limited medical staff available to collect and record serial vital signs, and were unable to routinely perform laboratory testing for every patient with suspected infection because of limited laboratory and financial resources. Given this reality, the diagnosis of sepsis in LMICs will not always be informed by complete data. Therefore, it is useful for clinicians in low-resource settings to understand the performance of alternative scoring systems in situations in which some variables, though important predictors of clinical outcome, may be missing.

Rhee, Chanu; Jentzsch, Maximilian S.; Kadri, Sameer S.; Seymour, Christopher W.; Angus, Derek C.; Murphy, David J.; Martin, Greg S.; Dantes, Raymund B.; Epstein, Lauren; Fiore, Anthony E.; Jernigan, John A.; Danner, Robert L.; Warren, David K.; Septimus, Edward J.; Hickok, Jason; Poland, Russell E.; Jin, Robert; Fram, David; Schaaf, Richard; Wang, Rui; Klompas, Michael; for the Centers for Disease Control and Prevention (CDC) Prevention Epicenters Program

Objectives: Administrative claims data are commonly used for sepsis surveillance, research, and quality improvement. However, variations in diagnosis, documentation, and coding practices for sepsis and organ dysfunction may confound efforts to estimate sepsis rates, compare outcomes, and perform risk adjustment. We evaluated hospital variation in the sensitivity of claims data relative to clinical data from electronic health records and its impact on outcome comparisons. Design, Setting, and Patients: Retrospective cohort study of 4.3 million adult encounters at 193 U.S. hospitals in 2013–2014. Interventions: None. Measurements and Main Results: Sepsis was defined using electronic health record–derived clinical indicators of presumed infection (blood culture draws and antibiotic administrations) and concurrent organ dysfunction (vasopressors, mechanical ventilation, doubling in creatinine, doubling in bilirubin to ≥ 2.0 mg/dL, decrease in platelets to < 100 cells/µL, or lactate ≥ 2.0 mmol/L). We compared claims for sepsis prevalence and mortality rates between both methods. All estimates were reliability adjusted to account for random variation using hierarchical logistic regression modeling. The sensitivity of hospitals’ claims data was low and variable: median 30% (range, 5–54%) for sepsis, 66% (range, 26–84%) for acute kidney injury, 39% (range, 16–60%) for thrombocytopenia, 36% (range, 29–44%) for hepatic injury, and 66% (range, 29–84%) for shock. Correlation between claims and clinical data was moderate for sepsis prevalence (Pearson coefficient, 0.64) and mortality (0.61). Among hospitals in the lowest sepsis mortality quartile by claims, 46% shifted to higher mortality quartiles using clinical data. Using implicit sepsis criteria based on infection and organ dysfunction codes also yielded major differences versus clinical data. Conclusions: Variation in the accuracy of claims data for identifying sepsis and organ dysfunction limits their use for comparing hospitals’ sepsis rates and outcomes. Using objective clinical data may facilitate more meaningful hospital comparisons.