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.

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?…

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).

Kollef M, Burnham J.

Klompas, Michael; Rhee, Chanu

No abstract available…

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.

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.

Greg S. Martin

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

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. …

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.

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.

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.

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.

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.

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.…

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.

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.

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.