Incidence of #Maternal #Sepsis and Sepsis-Related Maternal #Deaths in the #USA (JAMA, abstract)

[Source: JAMA, full page: (LINK). Abstract, edited.]

Research Letter / September 3, 2019

Incidence of Maternal Sepsis and Sepsis-Related Maternal Deaths in the United States

Matthew K. Hensley, MD, MPH1; Melissa E. Bauer, DO2; Lindsay K. Admon, MD, MSc3; et al Hallie C. Prescott, MD, MSc4

Author Affiliations: 1 Department of Internal Medicine, University of Michigan, Ann Arbor; 2 Department of Anesthesiology, University of Michigan, Ann Arbor; 3 Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor; 4 VA Center for Clinical Management Research, HSR&D Center of Innovation, Ann Arbor, Michigan

JAMA. 2019;322(9):890-892. doi:10.1001/jama.2019.9818



Maternal sepsis is a leading cause of maternal morbidity and mortality. However, population-based estimates of maternal sepsis occurring after delivery hospitalization have been limited because previous studies have focused on select populations or have not followed up patients longitudinally.1,2 Thus, the burden of maternal sepsis and sepsis-related deaths may be underestimated. We assessed the nationwide incidence and outcomes of maternal sepsis within 42 days of delivery hospitalization discharge using all-payer data.

Keywords: Sepsis; Pregnancy; USA.



Prospective Research of #Human #Parechovirus and #Cytokines in #CSF of Young #Children Less than One Year with #Sepsis-like Illness: Comparison with #Enterovirus (J Clin Virol., abstract)

[Source: Journal of Clinical Virology, full page: (LINK). Abstract, edited.]

Journal of Clinical Virology / Available online 15 August 2019 / In Press, Journal Pre-proof

Prospective Research of Human Parechovirus and Cytokines in Cerebrospinal Fluid of Young Children Less than One Year with Sepsis-like Illness: Comparison with Enterovirus

Su Eun Park ab1, Duyeal Song c1, Kyunghwa Shin c, Sang Ook Nam ab, Ara Ko ab, Ju Hyun Kong ab, Young Mi Kim d, Gyu Min Yeon e, Yun-Jin Lee ab

{a} Department of Pediatrics, Pusan National University Children’s Hospital, Pusan National University School of Medicine – 20 Geumoro, Mulgeumeup, 50612, Yangsan, South Korea; {b} Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital – 20 Geumoro, Mulgeumeup, 50612, Yangsan, South Korea; {c} Department of Laboratory Medicine, Pusan National University Yangsan Hospital – 20 Geumoro, Mulgeumeup, 50612, Yangsan, South Korea; {d} Department of Pediatrics, Pusan National University Hospital – 179, Gudeok-ro, 49241, Busan, South Korea; {e} Department of Pediatrics, Kosin University Gospel Hospital, Kosin University – 262, Gamcheon-ro, 49267, Busan, South Korea

Received 26 December 2018, Revised 12 March 2019, Accepted 14 August 2019, Available online 15 August 2019. DOI:



  • HPeV meningitis was found in 11.1% of sepsis-like children less than 12 months.
  • CSF findings were significantly different between HPeV and enteroviral meningitis.
  • CSF cytokine profiles noticeably differed between HPeV and enteroviral meningitis.


{1} Su Eun Park and Duyeal Song were equally responsible for the work described in this paper.

© 2019 Elsevier B.V. All rights reserved.

Keywords: Parechovirus; Enterovirus; Sepsis; Pediatrics.


#Shock and Early #Death in #Hematologic Patients with Febrile #Neutropenia (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Shock and Early Death in Hematologic Patients with Febrile Neutropenia

Mariana Guarana, Marcio Nucci, Simone A. Nouér

DOI: 10.1128/AAC.01250-19



Empiric antibiotic therapy with a betalactam is standard of care in febrile neutropenia (FN), and is given to prevent early death. The addition of vancomycin is recommended in certain circumstances but the quality of evidence is low, reflecting the lack of clinical data. In order to characterize the epidemiology of early death and shock in FN, we reviewed all episodes of FN from 2003 to 2017 at University Hospital, Federal University of Rio de Janeiro, and looked at factors associated with shock at first fever and early death (within 3 days from first fever) by univariate and multivariate analyses. Among 1305 episodes of FN, shock occurred in 42 episodes (3.2%) and early death in 15 (1.1%). Predictors of shock were bacteremia due to Escherichia coli (odds ratio [OR] 8.47, 95% confidence interval [95% CI] 4.08 – 17.55, p<0.001), Enterobacter sp. (OR 7.53, 95% CI 1.60 – 35.33, p=0.01), and Acinetobacter sp. (OR 6.95, 95% CI 1.49 – 32.36, p=0.01). Factors associated with early death were non-Hodgkin lymphoma (OR 3.57, 95% CI 1.18-10.73, p=0.02), pneumonia (OR 21.36, 95% CI 5.72-79.72, p<0.001), shock (OR 11.64, 95% CI 2.77-48.86, p=0.01) and bacteremia due to Klebsiella pneumoniae (OR 5.91, 95% CI 1.11-31.47, p=0.03). Adequate empiric antibiotic therapy was protective (OR 0.23, 95% CI 0.07 – 0.81, p=0.02). Shock or early death was not associated with Gram-positive bacteremia, catheter-related, skin or soft tissue infection, or inadequate Gram-positive coverage. These data challenge guidelines recommendations for the empiric use of vancomycin at first fever in neutropenic patients.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Vancomycin; Sepsis; Bacteremia; Enterobacteriaceae.


In vitro #synergy and in vivo activity of #tigecycline plus #ciprofloxacin combination #therapy against #Vibrio vulnificus #sepsis (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

In vitro synergy and in vivo activity of tigecycline plus ciprofloxacin combination therapy against Vibrio vulnificus sepsis

Seong Eun Kim, Hee Kyung Kim, Su-Mi Choi, Yohan Yu, Uh Jin Kim, Kalifa Sanneh Darboe, Seung-Ji Kang, Kyung-Hwa Park, Gaeun Kang, Young Ran Kim, Joon Haeng Rhee, Sook-In Jung,Hee-Chang Jang

DOI: 10.1128/AAC.00310-19



The mortality rate associated with Vibrio vulnificus sepsis remains high. An in vitro time-kill assay revealed synergism between tigecycline and ciprofloxacin. The survival rate was significantly higher in mice treated with tigecycline plus ciprofloxacin than in mice treated with cefotaxime plus minocycline. Thus, combination treatment with tigecycline plus ciprofloxacin can be an effective novel antibiotic regimen for V. vulnificus sepsis.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Vibrio vulnificus; Sepsis; Ciprofloxacin; Tigecycline.


#Simvastatin Improves #Neutrophil Function and Clinical #Outcomes in #Pneumonia: a Pilot #RCT (Am J Respir Crit Care Med., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Am J Respir Crit Care Med. 2019 Jun 17. doi: 10.1164/rccm.201812-2328OC. [Epub ahead of print]

Simvastatin Improves Neutrophil Function and Clinical Outcomes in Pneumonia: a Pilot Randomised Controlled Trial.

Sapey E1, Patel JM2, Greenwood H3, Walton GM4, Grudzinska F4, Parekh D5, Mahida RY2, Dancer RC3, Lugg ST4, Howells PA6, Hazeldine J2, Newby P4, Scott A3, Nightingale P7, Hill AT8, Thickett DR9.

Author information: 1 University of Birmingham, Institute of Inflammation and Ageing, Birmingham, United Kingdom of Great Britain and Northern Ireland ; 2 University of Birmingham, 1724, Institute of Inflammation and Ageing, Birmingham, West Midlands, United Kingdom of Great Britain and Northern Ireland. 3 University of Birmingham, Institute of Inflammation and Aging, Birmingham, United Kingdom of Great Britain and Northern Ireland. 4 University of Birmingham, Institute of Inflammation and Ageing, Birmingham, West Midlands, United Kingdom of Great Britain and Northern Ireland. 5 University of Birmingham, Critical Care and Pain Perioperative, Critical Care and Trauma Trials Group, School of Clinical and Experimental Medicine,, Birmingham, United Kingdom of Great Britain and Northern Ireland. 6 University of Birmingham, Centre for Translational Inflammation Research, Birmingham, United Kingdom of Great Britain and Northern Ireland. 7 University Hospital Birmingham NHS Foundation Trust, Statistics, Birmingham, United Kingdom of Great Britain and Northern Ireland. 8 Royal Infirmary of Edinburgh, Respiratory Medicine, Scotland, Edinburgh, United Kingdom of Great Britain and Northern Ireland. 9 University of Birmingham, Lung Injury and Fibrosis Treatment Programme, Birmingham, United Kingdom of Great Britain and Northern Ireland.




Population studies suggest improved sepsis outcomes with statins but randomized controlled trials in patients with sepsis and organ dysfunction in critical care settings have broadly been negative. In vitro data suggest statins modulate age-related neutrophil functions improving neutrophil responses to infection, but only in older patients and at high dose.


To determine if high dose simvastatin improved neutrophil functions and clinical outcomes in hospitalized older adults with community acquired pneumonia with sepsis (CAP+S) not admitted to critical care.


A randomized, double-blinded, placebo-controlled pilot study of simvastatin 80mg or placebo for 7 days for CAP+S patients aged >55 years admitted to a secondary care hospital. Day 4 primary endpoint was change in neutrophil NETosis. Day 4 secondary endpoints included neutrophil chemotaxis, safety and tolerability, Sequential Organ Failure Assessment(SOFA) score, mortality, readmission and markers of tissue degradation/inflammation.


Four days of simvastatin adjuvant therapy in CAP+S was associated with improvements in systemic neutrophil function (NETosis and chemotaxis), a reduction in systemic neutrophil elastase burden and improved SOFA scores compared with placebo. A post-hoc analysis demonstrated simvastatin therapy was associated with improved hospital-free survival compared to placebo. Simvastatin was well tolerated in this elderly and multi-morbid patient group with common co-prescription of macrolide antibiotics.


This pilot study supports high-dose simvastatin as an adjuvant therapy in CAP+S in an older and milder disease cohort than assessed previously. A definitive multi-centred study is now warranted in this population to assess the likelihood of benefit and harm. Clinical trial registration available at, ID: 2012-003343-29.

KEYWORDS: elderly care; innate immunity; pneumonia; sepsis; statin

PMID: 31206313 DOI: 10.1164/rccm.201812-2328OC

Keywords: Pneumonia; Sepsis; Statins.


#Lactate normalization within 6 hours of bundle therapy and 24 hours of delayed achievement were associated with 28-day #mortality in #septic shock patients (PLoS One, abstract)

[Source: PLoS One, full page: (LINK). Abstract, edited.]


Lactate normalization within 6 hours of bundle therapy and 24 hours of delayed achievement were associated with 28-day mortality in septic shock patients

Seung Mok Ryoo , Ryeok Ahn , Tae Gun Shin, You Hwan Jo, Sung Phil Chung, Jin Ho Beom, Sung-Hyuk Choi, Young -Hoon Yoon, Byuk Sung Ko, Hui Jai Lee, Gil Joon Suh, Won Young Kim , for the Korean Shock Society (KoSS) Investigators

Published: June 3, 2019 / DOI:



This study evaluated the prognostic ability of lactate normalization achieved within 6 and 24 h from septic shock recognition. Data from a septic shock registry from October 2015 to February 2017 were reviewed. The study included 2,102 eligible septic shock patients to analyze the prognostic ability of lactate normalization, defined as a follow-up lactate level <2 mmol/L within six hours of bundle therapy and within 24 hours of delayed normalization. The primary outcome was 28-day mortality. The overall 28-day mortality rate was 21.4%. The rates of lactate normalization within 6 and 24 h were significantly higher in the survivor groups than in the non-survivor group (42.4% vs. 23.4% and 60.2% vs. 31.2%; P<0.001, respectively). Multivariate logistic regression analysis showed that both 6- and 24-h lactate normalization were independent predictors (odds ratio [OR] 0.58, 95% confidence interval [CI] 0.45–0.75, p<0.001 and OR 0.42, 95% CI 0.33–0.54, p<0.001, respectively). When we could not achieve the lactate normalization, the sensitivity, specificity, positive, and negative predictive value to predict mortality were 76.6%, 42.4%, 26.5% and 87.0% respectively for 6-h normalization, and 68.8%, 60.2%, 32.0% and 87.7% respectively for 24-h normalization. Besides 6-h lactate normalization, 24-h delayed lactate normalization was associated with decreasing mortality in septic shock patients. Lactate normalization may have a role in early risk stratification and as a therapeutic target.


Citation: Ryoo SM, Ahn R, Shin TG, Jo YH, Chung SP, Beom JH, et al. (2019) Lactate normalization within 6 hours of bundle therapy and 24 hours of delayed achievement were associated with 28-day mortality in septic shock patients. PLoS ONE 14(6): e0217857.

Editor: Chiara Lazzeri, Azienda Ospedaliero Universitaria Careggi, ITALY

Received: March 18, 2019; Accepted: May 20, 2019; Published: June 3, 2019

Copyright: © 2019 Ryoo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: This study was supported by a grant (2018-0409) from the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea []. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Keywords: Sepsis; Septic shock.


#Derivation, #Validation, and Potential #Treatment Implications of Novel #Clinical #Phenotypes for #Sepsis (JAMA, abstract)

[Source: JAMA, full page: (LINK). Abstract, edited.]

Original Investigation  / Caring for the Critically Ill Patient / May 19, 2019

Derivation, Validation, and Potential Treatment Implications of Novel Clinical Phenotypes for Sepsis

Christopher W. Seymour, MD, MSc1,2,3; Jason N. Kennedy, MS1,3; Shu Wang, MS4; et al., Chung-Chou H. Chang, PhD3,4,5; Corrine F. Elliott, MS 6; Zhongying Xu, MS 4; Scott Berry, PhD 6; Gilles Clermont, MD, MSc 1,3; Gregory Cooper, MD, PhD 7; Hernando Gomez, MD, MPH 1,2,3; David T. Huang, MD, MPH 1,2,3; John A. Kellum, MD, FACP, MCCM 1,3; Qi Mi, PhD 8; Steven M. Opal, MD 9; Victor Talisa, MS 4; Tom van der Poll, MD, PhD 10; Shyam Visweswaran, MD, PhD 7; Yoram Vodovotz, PhD 11; Jeremy C. Weiss, MD, PhD 12; Donald M. Yealy, MD, FACEP 2; Sachin Yende, MD, MS 1,3,13; Derek C. Angus, MD, MPH 1,3,5

Author Affiliations: 1 Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; 2 Department of Emergency Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; 3 Clinical Research, Investigation, and Systems Modeling of Acute Illness Center, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; 4 Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania; 5 Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; 6 Berry Consultants, Austin, Texas; 7 Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania; 8 Department of Sports Medicine and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania; 9 Department of Medicine, Infectious Disease Division, Rhode Island Hospital, Providence; 10 Center of Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands; 11 Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania; 12 Machine Learning Department, Carnegie Mellon University, Pittsburgh, Pennsylvania; 13 Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania

JAMA. 2019;321(20):2003-2017. doi:10.1001/jama.2019.5791


Key Points

  • Question  – Are clinical sepsis phenotypes identifiable at hospital presentation correlated with the biomarkers of host response and clinical outcomes and relevant for understanding the heterogeneity of treatment effects?
  • Findings  – In this retrospective analysis using data from 63 858 patients in 3 observational cohorts, 4 novel sepsis phenotypes (α, β, γ, and δ) with different demographics, laboratory values, and patterns of organ dysfunction were derived, validated, and shown to correlate with biomarkers and mortality. In the simulations using data from 3 randomized clinical trials involving 4737 patients, the outcomes related to the treatments were sensitive to changes in the distribution of these phenotypes.
  • Meaning  – Four novel clinical phenotypes of sepsis were identified that correlated with host-response patterns and clinical outcomes and may help inform the design and interpretation of clinical trials.




Sepsis is a heterogeneous syndrome. Identification of distinct clinical phenotypes may allow more precise therapy and improve care.


To derive sepsis phenotypes from clinical data, determine their reproducibility and correlation with host-response biomarkers and clinical outcomes, and assess the potential causal relationship with results from randomized clinical trials (RCTs).

Design, Settings, and Participants  

Retrospective analysis of data sets using statistical, machine learning, and simulation tools. Phenotypes were derived among 20 189 total patients (16 552 unique patients) who met Sepsis-3 criteria within 6 hours of hospital presentation at 12 Pennsylvania hospitals (2010-2012) using consensus kmeans clustering applied to 29 variables. Reproducibility and correlation with biological parameters and clinical outcomes were assessed in a second database (2013-2014; n = 43 086 total patients and n = 31 160 unique patients), in a prospective cohort study of sepsis due to pneumonia (n = 583), and in 3 sepsis RCTs (n = 4737).


All clinical and laboratory variables in the electronic health record.

Main Outcomes and Measures  

Derived phenotype (α, β, γ, and δ) frequency, host-response biomarkers, 28-day and 365-day mortality, and RCT simulation outputs.


The derivation cohort included 20 189 patients with sepsis (mean age, 64 [SD, 17] years; 10 022 [50%] male; mean maximum 24-hour Sequential Organ Failure Assessment [SOFA] score, 3.9 [SD, 2.4]). The validation cohort included 43 086 patients (mean age, 67 [SD, 17] years; 21 993 [51%] male; mean maximum 24-hour SOFA score, 3.6 [SD, 2.0]). Of the 4 derived phenotypes, the α phenotype was the most common (n = 6625; 33%) and included patients with the lowest administration of a vasopressor; in the β phenotype (n = 5512; 27%), patients were older and had more chronic illness and renal dysfunction; in the γ phenotype (n = 5385; 27%), patients had more inflammation and pulmonary dysfunction; and in the δ phenotype (n = 2667; 13%), patients had more liver dysfunction and septic shock. Phenotype distributions were similar in the validation cohort. There were consistent differences in biomarker patterns by phenotype. In the derivation cohort, cumulative 28-day mortality was 287 deaths of 5691 unique patients (5%) for the α phenotype; 561 of 4420 (13%) for the β phenotype; 1031 of 4318 (24%) for the γ phenotype; and 897 of 2223 (40%) for the δ phenotype. Across all cohorts and trials, 28-day and 365-day mortality were highest among the δ phenotype vs the other 3 phenotypes (P < .001). In simulation models, the proportion of RCTs reporting benefit, harm, or no effect changed considerably (eg, varying the phenotype frequencies within an RCT of early goal-directed therapy changed the results from >33% chance of benefit to >60% chance of harm).

Conclusions and Relevance  

In this retrospective analysis of data sets from patients with sepsis, 4 clinical phenotypes were identified that correlated with host-response patterns and clinical outcomes, and simulations suggested these phenotypes may help in understanding heterogeneity of treatment effects. Further research is needed to determine the utility of these phenotypes in clinical care and for informing trial design and interpretation.

Keywords: Sepsis; Critical care.