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.

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.

Joseph A. Hippensteel

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

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.

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.

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.

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.

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.

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……