The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) present clinical criteria for the classification of patients with sepsis. We investigated incidence and long-term outcomes of patients diagnosed with these classifications, which are currently unknown.

The Sepsis-3 Criteria emphasized the value of a change of 2 or more points in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score, introduced quick SOFA (qSOFA), and removed the systemic inflammatory response syndrome (SIRS) criteria from the sepsis definition.

Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination.

Septic shock currently refers to a state of acute circulatory failure associated with infection. Emerging biological insights and reported variation in epidemiology challenge the validity of this definition.

The Third International Consensus Definitions Task Force defined sepsis as "life-threatening organ dysfunction due to a dysregulated host response to infection." The performance of clinical criteria for this sepsis definition is unknown.

Early, goal-directed therapy (EGDT) is recommended in international guidelines for the resuscitation of patients presenting with early septic shock. However, adoption has been limited, and uncertainty about its effectiveness remains.

Early goal-directed therapy (EGDT) has been endorsed in the guidelines of the Surviving Sepsis Campaign as a key strategy to decrease mortality among patients presenting to the emergency department with septic shock. However, its effectiveness is uncertain.

In a single-center study published more than a decade ago involving patients presenting to the emergency department with severe sepsis and septic shock, mortality was markedly lower among those who were treated according to a 6-hour protocol of early goal-directed therapy (EGDT), in which intravenous fluids, vasopressors, inotropes, and blood transfusions were adjusted to reach central hemodynamic targets, than among those receiving usual care. We conducted a trial to determine whether these findings were generalizable and whether all aspects of the protocol were necessary.

Although previous studies have suggested the potential advantages of albumin administration in patients with severe sepsis, its efficacy has not been fully established.

The Surviving Sepsis Campaign recommends targeting a mean arterial pressure of at least 65 mm Hg during initial resuscitation of patients with septic shock. However, whether this blood-pressure target is more or less effective than a higher target is unknown.

Hydroxyethyl starch (HES) [corrected] is widely used for fluid resuscitation in intensive care units (ICUs), but its safety and efficacy have not been established in patients with severe sepsis.

In 1991, the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) convened a "Consensus Conference," the goals of which were "to provide a conceptual and a practical framework to define the systemic inflammatory response to infection, which is a progressive injurious process that falls under the generalized term 'sepsis' and includes sepsis-associated organ dysfunction as well." The general definitions introduced as a result of that conference have been widely used in practice and have served as the foundation for inclusion criteria for numerous clinical trials of therapeutic interventions. Nevertheless, there has been an impetus from experts in the field to modify these definitions to reflect our current understanding of the pathophysiology of these syndromes.

To define the terms "sepsis" and "organ failure" in a precise manner.

Abstract Background Clostridium perfringens can cause various infections, including food poisoning, gas gangrene, cellulitis and fasciitis. C. perfringens septicemia is rare, but is a known cause of hemolysis by damaging red blood cell, and often proves rapidly fatal in emergency department (ED) situations. Case presentation A previously healthy 76-year-old man presented to the ED 8 h after onset of acute abdominal pain and diarrhea. Laboratory examination revealed a large discrepancy between the red blood cell count of 1.91 × 106/mm3 and the hemoglobin level of 10.3 g/dL, suggesting massive intravascular hemolysis. Computed tomography revealed liver abscesses with gas. During ED treatment, the state of the patient rapidly deteriorated and he entered cardiopulmonary arrest. Blood cultures finally identified C. perfringens. Conclusion Intravascular hemolysis and red blood cell (RBC) / hemoglobin (Hb) discrepancy in the presence of infection should prompt ED physicians to consider C. perfringens septicemia and to act quickly to provide appropriate treatment.…

Kuttab, Hani I.; Lykins, Joseph D.; Hughes, Michelle D.; Wroblewski, Kristen; Keast, Eric P.; Kukoyi, Omobolawa; Kopec, Jason A.; Hall, Stephen; Ward, Michael A.

Objectives: Rapid fluid resuscitation has become standard in sepsis care, despite “low-quality” evidence and absence of guidelines for populations “at risk” for volume overload. Our objectives include as follows: 1) identify predictors of reaching a 30 mL/kg crystalloid bolus within 3 hours of sepsis onset (30by3); 2) assess the impact of 30by3 and fluid dosing on clinical outcomes; 3) examine differences in perceived “at-risk” volume-sensitive populations, including end-stage renal disease, heart failure, obesity, advanced age, or with documentation of volume “overload” by bedside examination. Design: Retrospective cohort study. All outcome analyses controlled for sex, end-stage renal disease, heart failure, sepsis severity (severe sepsis vs septic shock), obesity, Mortality in Emergency Department Sepsis score, and time to antibiotics. Setting: Urban, tertiary care center between January 1, 2014, and May 31, 2017. Patients: Emergency Department treated adults (age ≥18 yr; n = 1,032) with severe sepsis or septic shock. Interventions: Administration of IV fluids by bolus. Measurements and Main Results: In total, 509 patients received 30by3 (49.3%). Overall mortality was 17.1% (n = 176), with 20.4% mortality in the shock group. Patients who were elderly (odds ratio, 0.62; 95% CI, 0.46–0.83), male (odds ratio, 0.66; CI, 0.49–0.87), obese (odds ratio, 0.18; CI, 0.13–0.25), or with end-stage renal disease (odds ratio, 0.23; CI, 0.13–0.40), heart failure (odds ratio, 0.42; CI, 0.29–0.60), or documented volume “overload” (odds ratio, 0.30; CI, 0.20–0.45) were less likely to achieve 30by3. Failure to meet 30by3 had increased odds of mortality (odds ratio, 1.52; CI, 1.03–2.24), delayed hypotension (odds ratio, 1.42; CI, 1.02–1.99), and increased ICU stay (~2 d) (β = 2.0; CI, 0.5–3.6), without differential effects for “at-risk” groups. Higher fluid volumes administered by 3 hours correlated with decreased mortality, with a plateau effect between 35 and 45 mL/kg (p < 0.05). Conclusions: Failure to reach 30by3 was associated with increased odds of in-hospital mortality, irrespective of comorbidities. Predictors of inadequate resuscitation can be identified, potentially leading to interventions to improve survival. These findings are retrospective and require future validation. 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 grant from the National Center for Advancing Translational Sciences of the National Institutes of Health through Grant Number 5UL1TR002389-02 that funds the Institute for Translational Medicine. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: maward@medicine.wisc.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Abstract Background Diagnosis is the most strenuous step in the evaluation of neonatal sepsis. No gold standard diagnostic method is available except for blood culture. We aimed to investigate the role of positive and negative acute phase reactants, namely presepsin and fetuin-A, in the diagnosis of culture-proven late-onset sepsis. Methods A prospective, case-control study with the infants ≤32 weeks of age with a diagnosis of culture-proven late-onset sepsis was designed. Twenty-nine preterm infants with similar gestational and postnatal ages without sepsis constituted the control group. Serum values of presepsin, fetuin-A, C-reactive protein and interleukin-6 were evaluated at the enrollment, third and seventh days of the diagnosis in the infants with positive blood culture results. Results First-day presepsin values were significantly higher in the culture-positive infants than the control group [1583 ng/L (1023–1731) vs. 426 ng/L (287–589), p =  0.05). Conclusion Presepsin may be an accurate marker for both diagnosis and monitoring of treatment response for culture-proven late-onset sepsis in preterm infants. However, fetuin-A does not seem to be a useful tool for the diagnosis of sepsis.…

Ehlenbach, William J.; Sonnen, Joshua A.; Montine, Thomas J.; Larson, Eric B.

Objectives: Many survivors of sepsis suffer long-term cognitive impairment, but the mechanisms of this association remain unknown. The objective of this study was to determine whether sepsis is associated with cerebral microinfarcts on brain autopsy. Design: Retrospective cohort study. Setting and Subjects: Five-hundred twenty-nine participants of the Adult Changes in Thought, a population-based prospective cohort study of older adults carried out in Kaiser Permanente Washington greater than or equal to 65 years old without dementia at study entry and who underwent brain autopsy. Measurements and Main Results: Late-life sepsis hospitalization was identified using administrative data. We identified 89 individuals with greater than or equal to 1 sepsis hospitalization during study participation, 80 of whom survived hospitalization and died a median of 169 days after discharge. Thirty percent of participants with one or more sepsis hospitalization had greater than two microinfarcts, compared with 19% participants without (χ2p = 0.02); 20% of those with sepsis hospitalization had greater than two microinfarcts in the cerebral cortex, compared with 10% of those without (χ2p = 0.01). The adjusted relative risk of greater than two microinfarcts was 1.61 (95% CI, 1.01–2.57; p = 0.04); the relative risk for having greater than two microinfarcts in the cerebral cortex was 2.12 (95% CI, 1.12–4.02; p = 0.02). There was no difference in Braak stage for neurofibrillary tangles or consortium to establish a registry for Alzheimer’s disease score for neuritic plaques between, but Lewy bodies were less significantly common in those with sepsis. Conclusions: Sepsis was specifically associated with moderate to severe vascular brain injury as assessed by microvascular infarcts. This association was stronger for microinfarcts within the cerebral cortex, with those who experienced severe sepsis hospitalization being more than twice as likely to have evidence of moderate to severe cerebral cortical injury in adjusted analyses. Further study to identify mechanisms for the association of sepsis and microinfarcts is needed. Dr. Ehlenbach had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr. Ehlenbach helped in study concept and design, statistical analysis, and drafting of the article. Drs. Ehlenbach and Larson helped in administrative, technical, or material support and study supervision of the article. Drs. Ehlenbach, Montine, and Larson helped in obtained funding. All authors helped in acquisition, analysis, or interpretation of data and critical revision of the article for important intellectual content. Supported, in part, by the National Institutes of Health (NIH), National Institute of Aging, The Atlantic Philanthropies, The John A. Hartford Foundation, and the Starr Foundation (K23AG038352, principal investigator [PI] Dr. Ehlenbach). Additional support provided by P50AG005136 (PI Dr. Grabowski) and NIH U01AG006781 (PI Dr. Larson). Dr. Ehlenbach’s institution received funding from the National Institutes of Health (NIH). Dr. Larson’s institution received funding from the National Institute on Aging, and he received funding from UptoDate (royalties). Drs. Ehlenbach, Sonnen, Montine, and Larson report grants from the NIH paid to their institutions. For information regarding this article, E-mail: wjehlenb@wisc.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Giannini, Heather M.; Ginestra, Jennifer C.; Chivers, Corey; Draugelis, Michael; Hanish, Asaf; Schweickert, William D.; Fuchs, Barry D.; Meadows, Laurie; Lynch, Michael; Donnelly, Patrick J.; Pavan, Kimberly; Fishman, Neil O.; Hanson, C. William II; Umscheid, Craig A.

Objectives: Develop and implement a machine learning algorithm to predict severe sepsis and septic shock and evaluate the impact on clinical practice and patient outcomes. Design: Retrospective cohort for algorithm derivation and validation, pre-post impact evaluation. Setting: Tertiary teaching hospital system in Philadelphia, PA. Patients: All non-ICU admissions; algorithm derivation July 2011 to June 2014 (n = 162,212); algorithm validation October to December 2015 (n = 10,448); silent versus alert comparison January 2016 to February 2017 (silent n = 22,280; alert n = 32,184). Interventions: A random-forest classifier, derived and validated using electronic health record data, was deployed both silently and later with an alert to notify clinical teams of sepsis prediction. Measurement and Main Result: Patients identified for training the algorithm were required to have International Classification of Diseases, 9th Edition codes for severe sepsis or septic shock and a positive blood culture during their hospital encounter with either a lactate greater than 2.2 mmol/L or a systolic blood pressure less than 90 mm Hg. The algorithm demonstrated a sensitivity of 26% and specificity of 98%, with a positive predictive value of 29% and positive likelihood ratio of 13. The alert resulted in a small statistically significant increase in lactate testing and IV fluid administration. There was no significant difference in mortality, discharge disposition, or transfer to ICU, although there was a reduction in time-to-ICU transfer. Conclusions: Our machine learning algorithm can predict, with low sensitivity but high specificity, the impending occurrence of severe sepsis and septic shock. Algorithm-generated predictive alerts modestly impacted clinical measures. Next steps include describing clinical perception of this tool and optimizing algorithm design and delivery. Drs. Giannini, Ginestra, Chivers, Draugelis, Schweickert, Fuchs, Meadows, Lynch, Donnelly, Pavan, Fishman, Hanson, and Umscheid contributed to conception and design. Drs. Giannini, Ginestra, Chivers, Draugelis, Hanish, Meadows, Lynch and Donnelly contributed to data collection. Drs. Giannini, Ginestra, Chivers, Draugelis, and Umscheid contributed to analysis and interpretation of data. Drs. Giannini, Ginestra, Chivers, and Umscheid contributed to drafting of article. Drs. Giannini, Ginestra, and Umscheid contributed to critical revision of article for important intellectual content. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by the National Center for Research Resources (grant no. UL1RR024134), which is now at the National Center for Advancing Translational Sciences (grant no. UL1TR000003). Dr. Umscheid received support for article research from the National Institutes of Health. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Dr. Schweickert received funding from Arjo, Hill Rom, the Society of Critical Care Medicine (consulting), and American College of Physicians. Dr. Umscheid’s institution received funding from National Center for Research Resources (grant no. UL1RR024134), which is now at the National Center for Advancing Translational Sciences (grant no. UL1TR000003); Agency for Healthcare Research and Quality Contracts Evidence-based Practice Center; and the U.S. Food and Drug Administration. He received funding from PCORI Advisory Panel and Northwell Health (honoraria for grand rounds). The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Craig A. Umscheid, MD, MS, Office of Clinical Excellence, University of Chicago Medicine, American School Building, 850 E. 58th Street, Suite 123, Office 128, MC 1135, Chicago, IL 60637. E-mail: craigumscheid@medicine.bsd.uchicago.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Stortz, Julie A.; Hollen, McKenzie K.; Nacionales, Dina C.; Horiguchi, Hiroyuki; Ungaro, Ricardo; Dirain, Marvin L.; Wang, Zhongkai; Wu, Quran; Wu, Kevin K.; Kumar, Ashok; Foster, Thomas C.; Stewart, Brian D.; Ross, Julia A.; Segal, Marc; Bihorac, Azra; Brakenridge, Scott; Moore, Frederick A.; Wohlgemuth, Stephanie E.; Leeuwenburgh, Christiaan; Mohr, Alicia M.; Moldawer, Lyle L.; Efron, Philip A.

Objectives: Our goal was to “reverse translate” the human response to surgical sepsis into the mouse by modifying a widely adopted murine intra-abdominal sepsis model to engender a phenotype that conforms to current sepsis definitions and follows the most recent expert recommendations for animal preclinical sepsis research. Furthermore, we aimed to create a model that allows the study of aging on the long-term host response to sepsis. Design: Experimental study. Setting: Research laboratory. Subjects: Young (3–5 mo) and old (18–22 mo) C57BL/6j mice. Interventions: Mice received no intervention or were subjected to polymicrobial sepsis with cecal ligation and puncture followed by fluid resuscitation, analgesia, and antibiotics. Subsets of mice received daily chronic stress after cecal ligation and puncture for 14 days. Additionally, modifications were made to ensure that “Minimum Quality Threshold in Pre-Clinical Sepsis Studies” recommendations were followed. Measurements and Main Results: Old mice exhibited increased mortality following both cecal ligation and puncture and cecal ligation and puncture + daily chronic stress when compared with young mice. Old mice developed marked hepatic and/or renal dysfunction, supported by elevations in plasma aspartate aminotransferase, blood urea nitrogen, and creatinine, 8 and 24 hours following cecal ligation and puncture. Similar to human sepsis, old mice demonstrated low-grade systemic inflammation 14 days after cecal ligation and puncture + daily chronic stress and evidence of immunosuppression, as determined by increased serum concentrations of multiple pro- and anti-inflammatory cytokines and chemokines when compared with young septic mice. In addition, old mice demonstrated expansion of myeloid-derived suppressor cell populations and sustained weight loss following cecal ligation and puncture + daily chronic stress, again similar to the human condition. Conclusions: The results indicate that this murine cecal ligation and puncture + daily chronic stress model of surgical sepsis in old mice adhered to current Minimum Quality Threshold in Pre-Clinical Sepsis Studies guidelines and met Sepsis-3 criteria. In addition, it effectively created a state of persistent inflammation, immunosuppression, and weight loss, thought to be a key aspect of chronic sepsis pathobiology and increasingly more prevalent after human sepsis. Dr. Stortz, Mr. Hollen, Dr. Nacionales, Dr. Horiguchi, and Dr. Kumar contributed extensively to data collection as well as drafting of the article, revision of its content, and approval of the article in its final form. Mr. Ungaro, Mr. Dirain, Mr. Wang, Mr. Q. Wu, Dr. K. Wu, and Dr. Ross contributed to data analysis and interpretation. Drs. Stortz, Foster, Stewart, Segal, Bihorac, Brakenridge, Moore, Wohlgemuth, Leeuwenburgh, Mohr, Moldawer, and Efron contributed to the conception and design of the project as well as data analysis, interpretation, drafting of the article, revision of its content, and approval of the article in its final form. 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 following National Institutes of Health grants: R01 GM-040586 and R01 GM-104481 (to Dr. Moldawer), R01 GM-113945 (to Dr. Efron), P50 GM-111152 (to Drs. Bihorac, Brakenridge, Moore, Mohr, Moldawer, and Efron) awarded by the National Institute of General Medical Sciences (NIGMS), and the National Institutes of Aging grants R01AG049711, R01AG052258, and the Evelyn F. McKnight Brain Research Foundation (to Dr. Foster). In addition, this work was supported, in part, by a postgraduate training grant T32 GM-008721 (to Dr. Stortz) in burns, trauma, and perioperative injury by NIGMS. Dr. Stortz, Ms. Hollen, Drs. Nacionales and Horiguchi, Mr. Ungaro, Mr. Dirain, Mr. Wang, Mr. Q. Wu, and Drs. K. Wu, Kumar, Foster, Stewart, Ross, Segal, Bihorac, Brakenridge, Moore, Leeuwenburgh, Mohr, Moldawer, and Efron received support for article research from the National Institutes of Health (NIH). Dr. Stortz, Ms. Hollen, Drs. Nacionales and Horiguchi, Mr. Ungaro, Mr. Dirain, Mr. Wang, Mr. Q. Wu, and Drs. Stewart’s, Ross’, and Brakenridge’s institutions received funding from the National Institute of General Medical Sciences. Dr. Foster’s institution received funding from the National Institute on Aging. Dr. Bihorac’s institution received funding from R01 GM-110240 and P50 GM- 111152. Dr. Moore’s institution received funding from the NIH. Dr. Wohlgemuth disclosed that she does not have any potential conflicts of interest. For information regarding this article, E-mail: philip.efron@surgery.ufl.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Abstract Background In most developing countries, puerperal sepsis is treated empirically with broad spectrum antibiotics due to lack of resources for culture and antibiotics susceptibility testing. However, empirical treatment does not guarantee treatment success and may promote antimicrobial resistance. We set to determine etiological agents and susceptibility pattern to commonly prescribed antimicrobial agents, among women suspected of puerperal sepsis, and admitted at Muhimbili National Hospital. Methods Hospital based cross-sectional study conducted at tertiary hospital from December 2017 to April 2018. The study recruited post-delivery women suspected with puerperal sepsis. Socio- demographic, clinical and obstetric information were collected using structured questionnaire. Blood and endocervical swab samples were collected for aerobic culture. Blood culture bottles were incubated in BACTEC FX40 (Becton–Dickinson, Sparks, MD, USA). Positive blood cultures and cervical swabs were inoculated onto sheep blood agar, MacConkey agar, chocolate agar and Sabouraud’s dextrose agar, incubated aerobically at 37 °C for 18–24 h. Antimicrobial susceptibility was determined by Kirby-Bauer disc diffusion method. Results A total of 197women were recruited, of whom 50.3% had spontaneous vaginal delivery, while 49.2% had caesarean section. Bacteraemia was detected in 22 (11.2%) women, along with 86 (43.6%) isolated from endocervical swabs. Gram-negative bacilli were the predominant isolates detected in 92(46.7%) cases. Majority of the isolates were E. coli 68(61.8%) followed by Klebsiella spp. 22(20.0%). E. coli were highly susceptible to meropenem (97.0%), while resistance to ceftriaxone, ampicillin and ceftazidime was 64.7, 67.6 and 63.2%, respectively. Klebsiella spp. were susceptible to meropenem (86.4%) and resistant to ceftriaxone (77.3%), gentamicin (86.4%), ampicillin (81.8%) and ceftazidime (86.4%). Staphylococcus aureus isolates were 100% susceptible to clindamycin. The proportion of extended spectrum beta lactamase producers among gram-negative bacilli was 64(69.6%) and 53.8% of S. aureus isolates were resistant to methicillin. Conclusion In this study puerperal sepsis was mostly caused by E. coli and Klebsiella spp. Causative agents exhibited very high levels of resistance to most antibiotics used in empiric treatment calling for review of treatment guidelines and strict infection control procedures.…

Weiss, Scott L.; Zhang, Donglan; Bush, Jenny; Graham, Kathryn; Starr, Jonathan; Tuluc, Florin; Henrickson, Sarah; Kilbaugh, Todd; Deutschman, Clifford S.; Murdock, Deborah; McGowan, Francis X. Jr; Becker, Lance; Wallace, Douglas C.

Objectives: Limited data exist about the timing and significance of mitochondrial alterations in children with sepsis. We therefore sought to determine if alterations in mitochondrial respiration and content within circulating peripheral blood mononuclear cells were associated with organ dysfunction in pediatric sepsis. Design: Prospective observational study Setting: Single academic PICU. Patients: One-hundred sixty-seven children with sepsis/septic shock and 19 PICU controls without sepsis, infection, or organ dysfunction. Interventions: None. Measurements and Main Results: Mitochondrial respiration and content were measured in peripheral blood mononuclear cells on days 1–2, 3–5, and 8–14 after sepsis recognition or once for controls. Severity and duration of organ dysfunction were determined using the Pediatric Logistic Organ Dysfunction score and organ failure-free days through day 28. Day 1–2 maximal uncoupled respiration (9.7 ± 7.7 vs 13.7 ± 4.1 pmol O2/s/106 cells; p = 0.02) and spare respiratory capacity (an index of bioenergetic reserve: 6.2 ± 4.3 vs 9.6 ± 3.1; p = 0.005) were lower in sepsis than controls. Mitochondrial content, measured by mitochondrial DNA/nuclear DNA, was higher in sepsis on day 1–2 than controls (p = 0.04) and increased in sepsis patients who had improving spare respiratory capacity over time (p = 0.005). Mitochondrial respiration and content were not associated with day 1–2 Pediatric Logistic Organ Dysfunction score, but low spare respiratory capacity was associated with higher Pediatric Logistic Organ Dysfunction score on day 3–5. Persistently low spare respiratory capacity was predictive of residual organ dysfunction on day 14 (area under the receiver operating characteristic, 0.72; 95% CI, 0.61–0.84) and trended toward fewer organ failure-free days although day 28 (β coefficient, –0.64; 95% CI, –1.35 to 0.06; p = 0.08). Conclusions: Mitochondrial respiration was acutely decreased in peripheral blood mononuclear cells in pediatric sepsis despite an increase in mitochondrial content. Over time, a rise in mitochondrial DNA tracked with improved respiration. Although initial mitochondrial alterations in peripheral blood mononuclear cells were unrelated to organ dysfunction, persistently low respiration was associated with slower recovery from organ dysfunction. 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). Dr. Weiss’ institution received funding from Eunice Kennedy Shriver National Institute of Child Health and Human Development K12HD047349, National Institute of General Medical Sciences K23GM110496, Society of Critical Care Medicine (SCCM) Weil Research Grant; he disclosed that the study was also supported by the Center for Mitochondrial and Epigenomic Medicine (although grants awarded to Dr. Wallace including National Institutes of Health (NIH) NS021328, MH108592, OD010944 and U.S. Department of Defense grant W81XWH-16-1-0401) and Department of Anesthesiology and Critical Care at the Children’s Hospital of Philadelphia; and he received funding from Bristol-Myers Squibb (Advisory Panel Member). Drs. Weiss, Zhang, Starr, Henrickson, and Kilbaugh received support for article research from the NIH. Dr. Deutschman received funding from SCCM (Scientific Editor for Critical Care Medicine); Department of Anesthesiology, NYU; St. Johns University; Western Ireland Critical Care Society; and International Society of Thrombosis and Hemostasis. Dr. McGowan’s institution received funding from Merck and the NIH. Dr. Becker’s institution received funding from Nihon Kohden, the NIH, and United Therapeutics, and he received other funding from Northwell Health, Philips, and Zoll. The remaining authors have disclosed that they do not have any potential conflicts of interest. This study was performed at the Children’s Hospital of Philadelphia. For information regarding this article, E-mail: WeissS@email.chop.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Pepper, Dominique J.; Sun, Junfeng; Cui, Xizhong; Welsh, Judith; Natanson, Charles; Eichacker, Peter Q.

Objective: To address three controversial components in the Centers for Medicare and Medicaid Service’s sepsis bundle for performance measure (SEP-1): antibiotics within 3 hours, a 30 mL/kg fluid infusion for all hypotensive patients, and repeat lactate measurements within 6 hours if initially elevated. We hypothesized that antibiotic- and fluid-focused bundles like SEP-1 would probably show benefit, but evidence supporting specific antibiotic timing, fluid dosing, or serial lactate requirements would not be concordant. Therefore, we performed a meta-analysis of studies of sepsis bundles like SEP-1. Data Sources: PubMed, Embase, ClinicalTrials.gov through March 15, 2018. Study Selection: Studies comparing survival in septic adults receiving versus not receiving antibiotic- and fluid-focused bundles. Data Extraction: Two investigators (D.J.P., P.Q.E.). Data Synthesis: Seventeen observational studies (11,303 controls and 4,977 bundle subjects) met inclusion criteria. Bundles were associated with increased odds ratios of survival (odds ratio [95% CI]) in 15 studies with substantial heterogeneity (I2 = 61%; p < 0.01). Survival benefits were consistent in the five largest (1,697–12,486 patients per study) (1.20 [1.11–1.30]; I2 = 0%) and six medium-sized studies (167–1,029) (2.03 [1.52–2.71]; I2 = 8%) but not the six smallest (64–137) (1.25 [0.42–3.66]; I2 = 57%). Bundles were associated with similarly increased survival benefits whether requiring antibiotics within 1 hour (n = 7 studies) versus 3 hours (n = 8) versus no specified time (n = 2); or 30 mL/kg fluid (n = 7) versus another volume (≥ 2 L, n = 1; ≥ 20 mL/kg, n = 2; 1.5–2 L or 500 mL, n = 1 each; none specified, n = 4) (p = 0.19 for each comparison). In the only study employing serial lactate measurements, survival was not increased versus others. No study had a low risk of bias or assessed potential adverse bundle effects. Conclusions: Available studies support the notion that antibiotic- and fluid-focused sepsis bundles like SEP-1 improve survival but do not demonstrate the superiority of any specific antibiotic time or fluid volume or of serial lactate measurements. Until strong reproducible evidence demonstrates the safety and benefit of any fixed requirement for these interventions, the present findings support the revision of SEP-1 to allow flexibility in treatment according to physician judgment. The National Institutes of Health had no role in study design or data collection, analysis, or interpretation. Drs. Pepper and Eichacker had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis, including and especially any adverse effects, and drafted the article. Dr. Pepper, Dr. Sun, Ms. Welsh, and Drs. Cui, Natanson, and Eichacker contributed substantially to the study design, data analysis, and interpretation, and approve the final version to be published. Dr. Sun, Ms. Welsh, and Drs. Cui and Natanson revised the article 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 Institutes of Health intramural funding. Drs. Pepper, Sun, Cui, Natanson, and Eichacker received support for article research from the National Institutes of Health. Drs. Pepper, Sun, and Cui, Ms. Welsh, and Dr. Eichacker disclosed government work. Clinical Trial Registration numbers: International Prospective Register of Systematic Reviews (PROSPERO) 2017: CRD42017080258. For information regarding this article, E-mail: peichacker@cc.nih.gov Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Miao, Huijie; Shi, Jingyi; Wang, Chunxia; Lu, Guoping; Zhu, Xiaodong; Wang, Ying; Cui, Yun; Zhang, Yucai

Objectives: Continuous renal replacement therapy becomes available utilization for pediatric critically ill, but the impact of mortality rate in severe sepsis remains no consistent conclusion. The aim of the study is to assess the effect of continuous renal replacement therapy in pediatric patients with severe sepsis and the impact this therapy may have on their mortality. Design: Propensity score-matched cohort study analyzing data prospectively collected by the PICUs over 2 years (2016–2018). Setting: Four PICUs of tertiary university children’s hospital in China. Patients: The consecutive patients with severe sepsis admitted to study PICUs were enrolled from July 2016 to June 2018. Interventions: The patients were divided into the continuous renal replacement therapy group and the conventional (noncontinuous renal replacement therapy) group. Measurements and Main Results: A total of 324 patients with severe sepsis were enrolled. The hospital mortality rate was 35.6% (64/180) in the continuous renal replacement therapy group and 47.9% (69/144) in the noncontinuous renal replacement therapy group. After propensity score adjustment, the hospital mortality rate was 21.3% (29/136) in the continuous renal replacement therapy group and 32.4% (44/136) in the noncontinuous renal replacement therapy group. In subgroup analysis, the relative risk of dying was 0.447 (95% CI, 0.208–0.961) only in patients complicated by acute respiratory distress syndrome (p = 0.037), but not in patients with shock, acute kidney injury, acute liver dysfunction, encephalopathy, and fluid overload greater than 10%. The mean duration of continuous renal replacement therapy was 45 hours (26–83 hr) with an ultrafiltration rate of 50 mL/kg/hr. The level of interleukin-6 was decreased, and the percent of natural killer cells (%) was improved in the continuous renal replacement therapy group compared with the noncontinuous renal replacement therapy group. Furthermore, continuous renal replacement therapy was an independently significant risk factor for hospital mortality in pediatric patients with severe sepsis, and the interval between continuous renal replacement therapy initiation and PICU admission was an independent risk factor for hospital mortality in patients receiving continuous renal replacement therapy. Conclusions: Continuous renal replacement therapy with an ultrafiltration rate of 50 mL/kg/hr decreases hospital mortality rate in pediatric severe sepsis, especially in patients with acute respiratory distress syndrome. Drs. Miao and Shi contributed equally to this work. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by grants from the Science and Technology Commission of Shanghai Municipality (16411970300,18411951000), funded by Clinical Multicenter Study supported by Clinical Research Center of Shanghai Jiao Tong University School of Medicine (DLY201618, 20171928), New Advanced Technology Project at the Shanghai City Hospital Development Center (SHDC12014116). Drs. Wang and Zhang received funding from Clinical Multicenter Study supported by Clinical Research Center of Shanghai Jiao Tong University School of Medicine (DLY201618, 20171928). Dr. Zhang received funding from Science and Technology Commission of Shanghai Municipality (16411970300); Science and Technology Commission of Shanghai Municipality (18411951000). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: zyucai2018@163.com This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Hallie C. Prescott

American Journal of Respiratory and Critical Care Medicine, Volume 200, Issue 3, Page 272-273, August 1, 2019. …

Sivasubramanium V. Bhavani, Kyle A. Carey, Emily R. Gilbert, Majid Afshar, Philip A. Verhoef, Matthew M. Churpek

American Journal of Respiratory and Critical Care Medicine, Volume 200, Issue 3, Page 327-335, August 1, 2019. …

Park, Clarice Hyesuk Lee; de Almeida, Juliano Pinheiro; de Oliveira, Gisele Queiroz; Rizk, Stéphanie Itala; Fukushima, Julia Tizue; Nakamura, Rosana Ely; Mourão, Matheus Moraes; Galas, Filomena Regina Barbosa Gomes; Abdala, Edson; Pinheiro Freire, Maristela; Kalil Filho, Roberto; Costa Auler, Jose Otavio Jr; Nardelli, Pasquale; Martin, Greg S.; Landoni, Giovanni; Hajjar, Ludhmila Abrahao

Objective: To investigate the effects of the administration of 4% albumin on lactated Ringer’s, when compared with lactated Ringer’s alone, in the early phase of sepsis in cancer patients. Design: Single-center, randomized, double-blind, controlled-parallel trial. Setting: A tertiary care university cancer hospital. Patients: Cancer patients with severe sepsis or septic shock. Interventions: Between October 2014 and December 2016, patients were randomly assigned to receive either bolus of albumin in a lactated Ringer’s solution or lactated Ringer’s solution alone during the first 6 hours of fluid resuscitation after intensive care medicine (ICU) admission. Primary outcome was defined as death from any cause at 7 days. Secondary outcomes were defined as death from any cause within 28 days, change in Sequence Organ Failure Assessment scores from baseline to day 7, days alive and free of mechanical ventilation, days alive and free of vasopressor, renal replacement therapy during ICU stay, and length of ICU and hospital stay. Measurements and Main Results: A total of 360 patients were enrolled in the trial. At 7 days, 46 of 180 patients (26%) died in the albumin group and 40 of 180 (22%) died in the lactated Ringer’s group (p = 0.5). At 28 days, 96 of 180 patients (53%) died in the albumin group and 83 of 180 (46%) died in the lactated Ringer’s group (p = 0.2). No significant differences in secondary outcomes were observed. Conclusions: Adding albumin to early standard resuscitation with lactated Ringer’s in cancer patients with sepsis did not improve 7-day survival. 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 departmental funds only. Dr. Martin received funding from Grifols. The remaining authors have disclosed that they do not have any potential conflicts of interest. This work was performed at the Cancer Institute of the University of Sao Paulo, Sao Paulo, Brazil. For information regarding this article, E-mail: landoni.giovanni@hsr.it Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Hensley, Matthew K.; Donnelly, John P.; Carlton, Erin F.; Prescott, Hallie C.

Objective: Cancer and its treatment are known to be important risk factors for sepsis, contributing to an estimated 12% of U.S. sepsis admissions in the 1990s. However, cancer treatment has evolved markedly over the past 2 decades. We sought to examine how cancer-related sepsis differs from non–cancer-related sepsis. Design: Observational cohort. Setting: National Readmissions Database (2013–2014), containing all-payer claims for 49% of U.S. population. Patients: A total of 1,104,363 sepsis hospitalizations. Interventions: We identified sepsis hospitalizations in the U.S. National Readmissions Database using explicit codes for severe sepsis, septic shock, or Dombrovskiy criteria (concomitant codes for infection and organ dysfunction). We classified hospitalizations as cancer-related versus non–cancer-related sepsis based on the presence of secondary diagnosis codes for malignancy. We compared characteristics (site of infection and organ dysfunction) and outcomes (in-hospital mortality and 30-d readmissions) of cancer-related versus non–cancer-related sepsis hospitalizations. We also completed subgroup analyses by age, cancer types, and specific cancer diagnoses. Measurements and Main Results: There were 27,481,517 hospitalizations in National Readmissions Database 2013–2014, of which 1,104,363 (4.0%) were for sepsis and 4,150,998 (15.1%) were cancer related. In-hospital mortality in cancer-related sepsis was 27.9% versus 19.5% in non–cancer-related sepsis. The median count of organ dysfunctions was indistinguishable, but the rate of specific organ dysfunctions differed by small amounts (e.g., hematologic dysfunction 20.1% in cancer-related sepsis vs 16.6% in non–cancer-related sepsis; p < 0.001). Cancer-related sepsis was associated with an adjusted absolute increase in in-hospital mortality ranging from 2.2% to 15.2% compared with non–cancer-related sepsis. The mortality difference was greatest in younger adults and waned with age. Patients (23.2%) discharged from cancer-related sepsis were rehospitalized within 30 days, compared with 20.1% in non–cancer-related sepsis (p < 0.001). Conclusions: In this cohort of over 1 million U.S. sepsis hospitalizations, more than one in five were cancer related. The difference in mortality varies substantially across age spectrum and is greatest in younger adults. Readmissions were more common after cancer-related sepsis. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the U.S. government. 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 K08 GM115859 (to Dr. Prescott) and K12 HL138039 (to Dr. Donnelly) from the National Institutes of Health. Dr. Donnelly’s institution received funding from the National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute. Drs. Donnelly and Prescott received support for article research from the NIH. Dr. Prescott’s institution received funding from the NIH, and she disclosed government work. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: hematthe@med.umich.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Shuhe Li, Xiaoguang Hu, Jinghong Xu, Fa Huang, Zilu Guo, Li Tong, Ka Yin Lui, Lu Cao, Yanping Zhu, Jiyou Yao, Xiaobin Lin, Xiangdong Guan, Changjie Cai

Abstract Background Community-acquired sepsis is a life-threatening systemic reaction, which starts within ≤72 h of hospital admittance in an infected patient without recent exposure to healthcare risks. Our aim was to evaluate the characteristics and the outcomes concerning community-acquired sepsis among patients admitted to a Hungarian high-influx national medical center. Methods A retrospective, observational cohort study of consecutive adult patients hospitalized with community-acquired sepsis during a 1-year period was executed. Clinical and microbiological data were collected, patients with pre-defined healthcare associations were excluded. Sepsis definitions and severity were given according to ACCP/SCCM criteria. The primary outcome was in-hospital all-cause mortality. Secondary outcomes were intensive care unit (ICU) admittance, length-of-stay (LOS), source control and bacteraemia rates. Statistical differences were explored with classical comparison tests, predictors of in-hospital all-cause mortality were modelled by multivariate logistic regression. Results 214 patients (median age 60.0 ± 33.1 years, 57% female, median Charlson score 4.0 ± 5.0) were included, 32.7% of them (70/214) had severe sepsis, and 28.5% (61/214) had septic shock. Prevalent sources of infections were genitourinary (53/214, 24.8%) and abdominal (52/214, 24.3%). The causative organisms were dominantly E. coli (60/214, 28.0%), S. pneumoniae (18/214, 8.4%) and S. aureus (14/214, 6.5%), and bacteraemia was documented in 50.9% of the cases (109/214). In-hospital mortality was high (30/214, 14.0%), and independently associated with shock, absence of fever, male gender and the need for ICU admittance, but source control and de-escalation of empirical antimicrobial therapy were protective. ICU admittance was 27.1% (58/214), source control was achieved in 18.2% (39/214). Median LOS was 10.0 ± 8.0, ICU LOS was 8.0 ± 10.8 days. Conclusions Community-acquired sepsis poses a significant burden of disease with characteristic causative agents and sources. Patients at a higher risk for poor outcomes might be identified earlier by the contributing factors shown above.…

Pascal M Lavoie, Constantin R Popescu, Elizabeth M Molyneux, James L Wynn, Msandeni Chiume, Kristina Keitel, Norman Lufesi, Gillian A Levine, J Mark Ansermino, Niranjan Kissoon

Clinicians involved in the care of young infants are aware of the consequences of not administering or of delaying antibiotics in cases of bacterial sepsis. Those who have seen such cases might be quicker to prescribe antibiotics in the future, even if sepsis is a remote possibility. However, this practice is not without risks. Exposure to broad-spectrum antibiotics alters the body's microbiota, increases opportunistic infections, and promotes antimicrobial resistance (AMR), which may restrict future treatment options for the child.

Kashiouris, Markos G.; Zemore, Zachary; Kimball, Zachary; Stefanou, Christos; Fowler, Alpha A. III; Fisher, Bernard; de Wit, Marjolein; Pedram, Sammy; Sessler, Curtis N.

Objectives: There is mounting evidence that delays in appropriate antimicrobial administration are responsible for preventable deaths in patients with sepsis. Herein, we examine the association between potentially modifiable antimicrobial administration delays, measured by the time from the first order to the first administration (antimicrobial lead time), and death among people who present with new onset of sepsis. Design: Observational cohort and case-control study. Setting: The emergency department of an academic, tertiary referral center during a 3.5-year period. Patients: Adult patients with new onset of sepsis or septic shock. Interventions: None. Measurements and Main Results: We enrolled 4,429 consecutive patients who presented to the emergency department with a new diagnosis of sepsis. We defined 0–1 hour as the gold standard antimicrobial lead time for comparison. Fifty percent of patients had an antimicrobial lead time of more than 1.3 hours. For an antimicrobial lead time of 1–2 hours, the adjusted odds ratio of death at 28 days was 1.28 (95% CI, 1.07–1.54; p = 0.007); for an antimicrobial lead time of 2–3 hours was 1.07 (95% CI, 0.85–1.36; p = 0.6); for an antimicrobial lead time of 3–6 hours was 1.57 (95% CI, 1.26–1.95; p < 0.001); for an antimicrobial lead time of 6–12 hours was 1.36 (95% CI, 0.99–1.86; p = 0.06); and for an antimicrobial lead time of more than 12 hours was 1.85 (95% CI, 1.29–2.65; p = 0.001). Conclusions: Delays in the first antimicrobial execution, after the initial clinician assessment and first antimicrobial order, are frequent and detrimental. Biases inherent to the retrospective nature of the study apply. Known biologic mechanisms support these findings, which also demonstrate a dose-response effect. In contrast to the elusive nature of sepsis onset and sepsis onset recognition, antimicrobial lead time is an objective, measurable, and modifiable process. This work has been performed at the Virginia Commonwealth University Medical Center. A limited abstract of this research was presented, in part, at the CHEST International Congress, Bangkok, Thailand, April 11, 2019. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: mkashiouris@vcu.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Rubin R.

This Medical News story examines the popularity of the “Marik protocol,” a combination of high–dose vitamin C, corticosteroids, and thiamine to treat sepsis.