Time to Recognition of Sepsis in the Emergency Department Using Electronic Health Record Data: A Comparative Analysis of Systemic Inflammatory Response Syndrome, Sequential Organ Failure Assessment, and Quick Sequential Organ Failure Assessment Objectives: Early identification of sepsis is critical to improving patient outcomes. Impact of the new sepsis definition (Sepsis-3) on timing of recognition in the emergency department has not been evaluated. Our study objective was to compare time to meeting systemic inflammatory response syndrome (Sepsis-2) criteria, Sequential Organ Failure Assessment (Sepsis-3) criteria, and quick Sequential Organ Failure Assessment criteria using electronic health record data. Design: Retrospective, observational study. Setting: The emergency department at the University of California, San Francisco. Patients: Emergency department encounters between June 2012 and December 2016 for patients greater than or equal to 18 years old with blood cultures ordered, IV antibiotic receipt, and identification with sepsis via systemic inflammatory response syndrome or Sequential Organ Failure Assessment within 72 hours of emergency department presentation. Interventions: None. Measurements and Main Results: We analyzed timestamped electronic health record data from 16,612 encounters identified as sepsis by greater than or equal to 2 systemic inflammatory response syndrome criteria or a Sequential Organ Failure Assessment score greater than or equal to 2. The primary outcome was time from emergency department presentation to meeting greater than or equal to 2 systemic inflammatory response syndrome criteria, Sequential Organ Failure Assessment greater than or equal to 2, and/or greater than or equal to 2 quick Sequential Organ Failure Assessment criteria. There were 9,087 patients (54.7%) that met systemic inflammatory response syndrome-first a median of 26 minutes post-emergency department presentation (interquartile range, 0–109 min), with 83.1% meeting Sequential Organ Failure Assessment criteria a median of 118 minutes later (interquartile range, 44–401 min). There were 7,037 patients (42.3%) that met Sequential Organ Failure Assessment-first, a median of 113 minutes post-emergency department presentation (interquartile range, 60–251 min). Quick Sequential Organ Failure Assessment was met in 46.4% of patients a median of 351 minutes post-emergency department presentation (interquartile range, 67–1,165 min). Adjusted odds of in-hospital mortality were 39% greater in patients who met systemic inflammatory response syndrome-first compared with those who met Sequential Organ Failure Assessment-first (odds ratio, 1.39; 95% CI, 1.20–1.61). Conclusions: Systemic inflammatory response syndrome and Sequential Organ Failure Assessment initially identified distinct populations. Using systemic inflammatory response syndrome resulted in earlier electronic health record sepsis identification in greater than 50% of patients. Using Sequential Organ Failure Assessment alone may delay identification. Using systemic inflammatory response syndrome alone may lead to missed sepsis presenting as acute organ dysfunction. Thus, a combination of inflammatory (systemic inflammatory response syndrome) and organ dysfunction (Sequential Organ Failure Assessment) criteria may enhance timely electronic health record-based sepsis identification. The contents are solely the responsibility of the authors and do not necessarily represent the official views of University of California San Francisco or the National Institutes of Health. 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. Prasad’s institution received funding from National Center for Advancing Translational Sciences, National Institutes of Health (NIH), through University of California San Francisco (UCSF)-Clinical & Translational Science Institute (CTSI) grant number #A127552, and she received funding as an epidemiologist for EpiExcellence, LLC (consultant). Drs. Prasad, Fang, Abe-Jones, Matthay, and Kangelaris received support for article research from the NIH. Dr. Fang’s institution received funding from the National Heart, Lung, and Blood Institute (NHLBI) K24HL141354 and Patient-Centered Outcomes Research Institute. Dr. Abe-Jones disclosed that data acquisition for this publication was supported by UCSF Academic Research Systems and by the National Center for Advancing Translational Sciences, NIH, through UCSF-CTSI Grant Number UL1 TR001872. Dr. Calfee’s institution received funding from the NHLBI HL140026, GlaxoSmithKline, and Bayer, and she received funding from Bayer, CSL Behring, Prometic, Roche/Genentech, and Quark Pharmaceuticals. Dr. Matthay’s institution received funding from the NIH/NHLBI, GlaxoSmithKline, Bayer, and a Department of Defense grant. Dr. Kangelaris’s institution received funding from NHLBI 1K23HL116800. For information regarding this article, E-mail: Priya.Prasad@ucsf.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Brain Hypoxia Secondary to Diffusion Limitation in Hypoxic Ischemic Brain Injury Postcardiac Arrest Objectives: We sought to characterize 1) the difference in the diffusion gradient of cellular oxygen delivery and 2) the presence of diffusion limitation physiology in hypoxic-ischemic brain injury patients with brain hypoxia, as defined by parenchymal brain tissue oxygen tension less than 20 mm Hg versus normoxia (brain tissue oxygen tension > 20 mm Hg). Design: Post hoc subanalysis of a prospective study in hypoxic-ischemic brain injury patients dichotomized into those with brain hypoxia versus normoxia. Setting: Quaternary ICU. Patients: Fourteen adult hypoxic-ischemic brain injury patients after cardiac arrest. Interventions: Patients underwent monitoring with brain oxygen tension, intracranial pressure, cerebral perfusion pressure, mean arterial pressure, and jugular venous bulb oxygen saturation. Data were recorded in real time at 300Hz into the ICM+ monitoring software (Cambridge University Enterprises, Cambridge, United Kingdom). Simultaneous arterial and jugular venous bulb blood gas samples were recorded prospectively. Measurements and Main Results: Both the normoxia and hypoxia groups consisted of seven patients. In the normoxia group, the mean brain tissue oxygen tension, jugular venous bulb oxygen tension, and cerebral perfusion pressure were 29 mm Hg (SD, 9), 45 mm Hg (SD, 9), and 80 mm Hg (SD, 7), respectively. In the hypoxia group, the mean brain tissue oxygen tension, jugular venous bulb oxygen to brain tissue oxygen tension gradient, and cerebral perfusion pressure were 14 mm Hg (SD, 4), 53 mm Hg (SD, 8), and 72 mm Hg (SD, 6), respectively. There were significant differences in the jugular venous bulb oxygen tension–brain oxygen tension gradient (16 mm Hg [sd, 6] vs 39 mm Hg SD, 11]; p < 0.001) and in the relationship of jugular venous bulb oxygen tension–brain oxygen tension gradient to cerebral perfusion pressure (p = 0.004) when comparing normoxia to hypoxia. Each 1 mm Hg increase in cerebral perfusion pressure led to a decrease in the jugular venous bulb oxygen tension–brain oxygen tension gradient by 0.36 mm Hg (95% CI, –0.54 to 0.18; p < 0.001) in the normoxia group, but no such relation was demonstrable in the hypoxia group. Conclusions: In hypoxic-ischemic brain injury patients with brain hypoxia, there is an elevation in the jugular venous bulb oxygen tension–brain oxygen tension gradient, which is not modulated by changes in cerebral perfusion pressure. 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 Laerdal Foundation. Dr. Sekhon’s institution received funding from Laerdal Foundation; he received funding from the Clinician Scientist Award from Vancouver Coastal Health Research Institute. Dr. Menon received support for article research from National Institute for Health Research, United Kingdom. Dr. Gooderham received funding from consulting for Stryker Canada and Baxter Canada, and research grants from Brain Aneurysm Foundation and Rare Diseases Foundation (research into Moyamoya disease). Dr. Griesdale is funded through a Health-Professional Investigator Award from the Michael Smith Foundation for Health Research. The remaining authors have disclosed that they do not have any potential conflicts of interest. Trial Registration: NCT03609333—ClinicalTrials.gov. For information regarding this article, E-mail: mypindersekhon@gmail.com Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Evaluation of Serotonin Release Assay and Enzyme-Linked Immunosorbent Assay Optical Density Thresholds for Heparin-Induced Thrombocytopenia in Patients on Extracorporeal Membrane Oxygenation Objectives: Heparin-induced thrombocytopenia is a recognized concern in patients on extracorporeal life support. The purpose of this study was to evaluate the applicability of an enzyme-linked immunosorbent assay optical density threshold less than 1 to rule out heparin-induced thrombocytopenia in patients on extracorporeal membrane oxygenation. Design: Retrospective, single-center study. Setting: Patients were recruited from a prospectively maintained database of all patients on extracorporeal membrane oxygenation from 2012 to 2018 at a tertiary referral center. Patients: Forty-seven patients on extracorporeal membrane oxygenation support. Interventions: The primary objective was to evaluate the application of enzyme-linked immunosorbent assay optical density thresholds and the serotonin release assay in patients on extracorporeal membrane oxygenation. Patients were divided into two cohorts, serotonin release assay negative and serotonin release assay positive. In order to perform a sensitivity and specificity analysis of enzyme-linked immunosorbent assay optical density thresholds, heparin-induced thrombocytopenia negative was defined as an optical density less than 1.0 and heparin-induced thrombocytopenia positive as an optical density greater than or equal to 1.0. Measurements and Main Results: Utilizing the prespecified optical density thresholds, a specificity and negative predictive value of 89% and 95% were achieved, respectively. Conclusions: This assessment has helped to identify optical density thresholds for patients undergoing extracorporeal membrane oxygenation. Our data suggest that an optical density threshold of 1.0 may aid clinicians in objectively ruling out heparin-induced thrombocytopenia without sending a confirmatory serotonin release assay. Increasing the optical density threshold to 1.0 resulted in a high specificity and negative predictive value. Dr. Kataria is the guarantor of the content of the article, including the data and analysis. Drs. Moore, Harrison, Hernandez, Vaughan, and Schwartz served as co-investigators. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: Vivek.Kataria@BSWHealth.org Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Systematic Review and Meta-Analysis of Effects of Transfusion on Hemodynamic and Oxygenation Variables Objectives: RBC transfusions can increase oxygen availability to the tissues, but studies have provided conflicting results. The objectives of this study were, therefore, to evaluate, using systematic review and meta-analysis, the effects of transfusion on hemodynamic/oxygenation variables in patients without acute bleeding. Data Sources: PubMed, Scopus, Cochrane Database of Systematic Reviews, and Embase from inception until June 30, 2019. Study Selection: All articles that reported values of prespecified hemodynamic or oxygenation variables before and after RBC transfusion. Data Extraction: Publication year, number of patients, number of transfusions and the type of population studied, hemodynamic and oxygenation data (heart rate, cardiac index, mixed venous oxygen saturation or central venous oxygen saturation, oxygen delivery index, oxygen consumption index, oxygen extraction ratio, arteriovenous oxygen difference and arterial blood lactate) before and after transfusion. We performed a meta-analysis for each variable for which there were sufficient data to estimate mean differences. We also performed subgroup analyses comparing septic with nonseptic patients. Data Synthesis: We retrieved 6,420 studies; 33 met the inclusion criteria, 14 of which were in patients with sepsis. In the meta-analysis, the estimated mean differences and 95% CIs comparing the periods before and after transfusion were –0.0 L/min/m2 (–0.1 to 0.1 L/min/m2) (p = 0.86) for cardiac index; –1.8 beats/min (–3.7 to 0.1 beats/min) (p = 0.06) for heart rate; 96.8 mL/min/m2 (71.1–122.5 mL/min/m2) (p < 0.01) for oxygen delivery index; 2.9% (2.2–3.5%) (p < 0.01) for mixed venous oxygen saturation or central venous oxygen saturation; –3.7% (–4.4% to –3.0%) (p < 0.01) for oxygen extraction ratio; and 4.9 mL/min/m2 (0.9–9.0 mL/min/m2) (p = 0.02) for oxygen consumption index. The estimated mean difference for oxygen consumption index in the patients with sepsis was 8.4 mL/min/m2 (2.3–14.5 mL/min/m2; p = 0.01). Conclusions: Transfusion was not associated with a decrease in mean cardiac output or mean heart rate. The increase in mean oxygen delivery following transfusion was associated with an increase in mean oxygen consumption after transfusion, especially in patients with sepsis. Dr. Cavalcante dos Santos helped design the study, performed the literature review, extracted the data, analyzed data, drafted the article, and read and approved the final version. Dr. Orbegozo helped design the study, performed the literature review, extracted the data, revised the article for intellectual content, and read and approved the final version. Drs. Mongkolpun, Galfo, Nan, and Bogossian performed the literature review, extracted the data, revised the article for intellectual content, and read and approved the final version. Dr. Taccone revised the article for intellectual content, read and approved the final version. Dr. Vallet provided data, revised the article for intellectual content, and read and approved the final version. Dr. Creteur revised the article for intellectual content, read and approved the final version. Dr. Vincent helped design the study, helped interpret the data, revised the article for intellectual content, and read and approved the final version. 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: jlvincent@intensive.org Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Comparative Performance of Pulmonary Ultrasound, Chest Radiograph, and CT Among Patients With Acute Respiratory Failure Objectives: The study goal was to concurrently evaluate agreement of a 9-point pulmonary ultrasound protocol and portable chest radiograph with chest CT for localization of pathology to the correct lung and also to specific anatomic lobes among a diverse group of intubated patients with acute respiratory failure. Design: Prospective cohort study. Setting: Medical, surgical, and neurologic ICUs at a 670-bed urban teaching hospital. Patients: Intubated adults with acute respiratory failure having chest CT and portable chest radiograph performed within 24 hours of intubation. Interventions: A 9-point pulmonary ultrasound examination performed at the time of intubation. Measurements and Main Results: Sixty-seven patients had pulmonary ultrasound, portable chest radiograph, and chest CT performed within 24 hours of intubation. Overall agreement of pulmonary ultrasound and portable chest radiograph findings with correlating lobe (“lobe-specific” agreement) on CT was 87% versus 62% (p < 0.001), respectively. Relaxing the agreement definition to a matching CT finding being present anywhere within the correct lung (“lung-specific” agreement), not necessarily the specific mapped lobe, showed improved agreement for both pulmonary ultrasound and portable chest radiograph respectively (right lung: 92.5% vs 65.7%; p < 0.001 and left lung: 83.6% vs 71.6%; p = 0.097). The highest lobe-specific agreement was for the finding of atelectasis/consolidation for both pulmonary ultrasound and portable chest radiograph (96% and 73%, respectively). The lowest lobe-specific agreement for pulmonary ultrasound was normal lung (79%) and interstitial process for portable chest radiograph (29%). Lobe-specific agreement differed most between pulmonary ultrasound and portable chest radiograph for interstitial findings (86% vs 29%, respectively). Pulmonary ultrasound had the lowest agreement with CT for findings in the left lower lobe (82.1%). Pleural effusion agreement also differed between pulmonary ultrasound and portable chest radiograph (right: 99% vs 87%; p = 0.009 and left: 99% vs 85%; p = 0.004). Conclusions: A clinical, 9-point pulmonary ultrasound protocol strongly agreed with specific CT findings when analyzed by both lung- and lobe-specific location among a diverse population of mechanically ventilated patients with acute respiratory failure; in this regard, pulmonary ultrasound significantly outperformed portable chest radiograph. 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. Tierney received funding from personally purchased stock options and disclosed he is a member of Medical Advisory Boards for Echonous and Bay Labs. The remaining authors have disclosed that they do not have any potential conflicts of interest. This work was performed at Abbott Northwestern Hospital, Minneapolis, MN. For information regarding this article, E-mail: david.tierney@allina.com Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Epinephrine for Out-of-Hospital Cardiac Arrest: An Updated Systematic Review and Meta-Analysis Objectives: To perform an updated systematic review and meta-analysis of clinical trials evaluating epinephrine for adult out-of-hospital cardiac arrest resuscitation. Data Sources: The search included MEDLINE, EMBASE, and Ovid Evidence-Based Medicine, clinical trial registries, and bibliographies. Study Selection: Randomized and quasi-randomized controlled trials that compared the current standard dose of epinephrine to placebo, high or low dose epinephrine, any other vasopressor alone or in combination were screened by three independent reviewers. Data Extraction: Randomized and quasi-randomized controlled trials that compared the current standard dose of epinephrine to placebo, high or low dose epinephrine, any other vasopressor alone or in combination were screened by three independent reviewers. Data Synthesis: A total of 17 trials (21,510 patients) were included; seven were judged to be at high risk of bias. Compared to placebo, pooled results from two trials showed that standard dose of epinephrine increased return of spontaneous circulation (risk ratio, 3.09; 95% CI, 2.82–3.89), survival to hospital admission (risk ratio, 2.50; 95% CI, 1.68–3.72), and survival to discharge (risk ratio, 1.44; 95% CI, 1.11–1.86). The largest placebo-controlled trial showed that standard dose of epinephrine also improved survival at 30 days and 3 months but not neurologic outcomes, standard dose of epinephrine decreased return of spontaneous circulation (risk ratio, 0.87; 95% CI, 0.77–0.98) and survival to admission (risk ratio, 0.88; 95% CI, 0.78–0.99) when compared with high dose epinephrine. There were no differences in outcomes between standard dose of epinephrine and vasopressin alone or in combination with epinephrine. Conclusions: Largely based on one randomized controlled trial, standard dose of epinephrine improved overall survival but not neurologic outcomes in out-of-hospital cardiac arrest patients compared with placebo. There is a paucity of trials with meaningful patient outcomes; future epinephrine trials should evaluate dose and method of delivery on long-term survival, neurologic function, and quality of life after cardiac arrest. 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. Lin is an Investigator of the Cardiac Arrhythmia Network of Canada as part of the Networks of Centres of Excellence and is the Co-Principal Investigator of a Canadian Institutes of Health Research Project Grant for a clinical trial to evaluate low-dose epinephrine during cardiac arrest resuscitation, and he was an Evidence Reviewer for the C2015 International Liaison Committee on Resuscitation advanced life support Taskforce. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: steve.lin@unityhealth.to Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Effect of Continuous Epinephrine Infusion on Survival in Critically Ill Patients. A Meta-Analysis of Randomized Trials Objectives: Epinephrine is frequently used as an inotropic and vasopressor agent in critically ill patients requiring hemodynamic support. Data from observational trials suggested that epinephrine use is associated with a worse outcome as compared with other adrenergic and nonadrenergic vasoactive drugs. We performed a systematic review and meta-analysis of randomized controlled trials to investigate the effect of epinephrine administration on outcome of critically ill patients. Data Sources: PubMed, EMBASE, and Cochrane central register were searched by two independent investigators up to March 2019. Study Selection: Inclusion criteria were: administration of epinephrine as IV continuous infusion, patients admitted to an ICU or undergoing major surgery, and randomized controlled trials. Studies on epinephrine administration as bolus (e.g., during cardiopulmonary resuscitation), were excluded. The primary outcome was mortality at the longest follow-up available. Data Extraction: Two independent investigators examined and extracted data from eligible trials. Data Synthesis: A total of 5,249 studies were assessed, with a total of 12 studies (1,227 patients) finally included in the meta-analysis. The majority of the trials were performed in the setting of septic shock, and the most frequent comparator was a combination of norepinephrine plus dobutamine. We found no difference in all-cause mortality at the longest follow-up available (197/579 [34.0%] in the epinephrine group vs 219/648 [33.8%] in the control group; risk ratio = 0.95; 95% CI, 0.82–1.10; p = 0.49; I2 = 0%). No differences in the need for renal replacement therapy, occurrence rate of myocardial ischemia, occurrence rate of arrhythmias, and length of ICU stay were observed. Conclusions: Current randomized evidence showed that continuous IV administration of epinephrine as inotropic/vasopressor agent is not associated with a worse outcome in critically ill patients. 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. This trial was performed at the IRCCS San Raffaele Scientific Institute, Milan, Italy. For information regarding this article, E-mail: mucchetti.marta@hsr.it Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Bacterial and Fungal Etiology of Sepsis in Children in the United States: Reconsidering Empiric Therapy Objectives: Timely empiric antimicrobial therapy is associated with improved outcomes in pediatric sepsis, but minimal data exist to guide empiric therapy. We sought to describe the prevalence of four pathogens that are not part of routine empiric coverage (e.g., Staphylococcus aureus, Pseudomonas aeruginosa, Clostridium difficile, and fungal infections) in pediatric sepsis patients in a contemporary nationally representative sample. Design: This was a retrospective cohort study using administrative data. Setting: We used the Nationwide Readmissions Database from 2014, which is a nationally representative dataset that contains data from nearly half of all discharges from nonfederal hospitals in the United States. Patients: Discharges of patients who were less than 19 years old at discharge and were not neonatal with a discharge diagnosis of sepsis. Interventions: None. Measurements and Main Results: Of the 19,113 pediatric admissions with sepsis (6,300 [33%] previously healthy and 12,813 [67%] with a chronic disease), 31% received mechanical ventilation, 19% had shock, and 588 (3.1%) died during their hospitalization. Among all admissions, 8,204 (42.9%) had a bacterial or fungal pathogen identified. S. aureus was the most common pathogen identified in previously healthy patients (n = 593, 9.4%) and those with any chronic disease (n = 1,430, 11.1%). Methicillin-resistant S. aureus, P. aeruginosa, C. difficile, and fungal infections all had high prevalence in specific chronic diseases associated with frequent contact with the healthcare system, early surgery, indwelling devices, or immunosuppression. Conclusions: In this nationally representative administrative database, the most common identified pathogen was S. aureus in previously healthy and chronically ill children. In addition, a high proportion of children with sepsis and select chronic diseases had infections with methicillin-resistant S. aureus, fungal infections, Pseudomonas infections, and C. difficile. Clinicians caring for pediatric patients should consider coverage of these organisms when administering empiric antimicrobials for sepsis. 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). Drs. Prout’s (T32HL007820) and Yende’s institutions received funding from National Heart, Lung and Blood Institute of the National Institutes of Health (NIH). Drs. Prout, Carcillo, and Yende received support for article research from the NIH. Dr. Carcillo’s institution received funding from the National Institute of Child Health and Human Development and National Institute of General Medical Sciences. Dr. Decker disclosed government work. Dr. Talisa disclosed that she does not have any potential conflicts of interest. For information regarding this article, E-mail: yendes@upmc.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Biomarkers of Delirium Duration and Delirium Severity in the ICU Objectives: Both delirium duration and delirium severity are associated with adverse patient outcomes. Serum biomarkers associated with delirium duration and delirium severity in ICU patients have not been reliably identified. We conducted our study to identify peripheral biomarkers representing systemic inflammation, impaired neuroprotection, and astrocyte activation associated with delirium duration, delirium severity, and in-hospital mortality. Design: Observational study. Setting: Three Indianapolis hospitals. Patients: Three-hundred twenty-one critically ill delirious patients. Interventions: None. Measurements and Main Results: We analyzed the associations between biomarkers collected at delirium onset and delirium-/coma-free days assessed through Richmond Agitation-Sedation Scale/Confusion Assessment Method for the ICU, delirium severity assessed through Confusion Assessment Method for the ICU-7, and in-hospital mortality. After adjusting for age, gender, Acute Physiology and Chronic Health Evaluation II score, Charlson comorbidity score, sepsis diagnosis and study intervention group, interleukin-6, -8, and -10, tumor necrosis factor-α, C-reactive protein, and S-100β levels in quartile 4 were negatively associated with delirium-/coma-free days by 1 week and 30 days post enrollment. Insulin-like growth factor-1 levels in quartile 4 were not associated with delirium-/coma-free days at both time points. Interleukin-6, -8, and -10, tumor necrosis factor-α, C-reactive protein, and S-100β levels in quartile 4 were also associated with delirium severity by 1 week. At hospital discharge, interleukin-6, -8, and -10 retained the association but tumor necrosis factor-α, C-reactive protein, and S-100β lost their associations with delirium severity. Insulin-like growth factor-1 levels in quartile 4 were not associated with delirium severity at both time points. Interleukin-8 and S-100β levels in quartile 4 were also associated with higher in-hospital mortality. Interleukin-6 and -10, tumor necrosis factor-α, and insulin-like growth factor-1 were not found to be associated with in-hospital mortality. Conclusions: Biomarkers of systemic inflammation and those for astrocyte and glial activation were associated with longer delirium duration, higher delirium severity, and in-hospital mortality. Utility of these biomarkers early in delirium onset to identify patients at a higher risk of severe and prolonged delirium, and delirium related complications during hospitalization needs to be explored in future studies. 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. Khan’s institution received funding from the National Institutes of Health (NIH)/National Institute on Aging (NIA) (K23AG043476). Dr. Perkins’ institution received funding from the NIH and the Centers for Medicare and Medicaid Services. Dr. Prasad disclosed that he is currently employed at Eli Lilly, which has no direct or indirect role or influence on the research findings presented here. Dr. Shekhar received research grants from the NIH, Department of Defense, Eli Lilly, Johnson & Johnson, and Astra Zeneca for unrelated research. Dr. Gao’s institution received funding from the NIH. Dr. Wang received funding from American Psychiatric Publishing (royalties). Dr. Marcantonio’s effort was supported by grants R01AG044518 and K24AG035075 from the NIA. Dr. Boustani received funding from NIA (R01AG034205) and disclosed that he has ownership equity in two for profit companies, Preferred Population Health Management and RestUp; the products and services of the two companies are not related to the research activities of the published papers. Drs. Khan, Perkins, Shekhar, Gao, Wang, Marcantonio, and Boustani received support for article research from the NIH. The remaining authors have disclosed that they do not have any potential conflicts of interest. This work was performed at Indiana University School of Medicine, Indianapolis, IN. For information regarding this article, E-mail: bakhan@iu.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Timing of Tracheostomy in Pediatric Patients: A Systematic Review and Meta-Analysis Objectives: Tracheostomy is a very common clinical intervention in critically ill adult patients. The indications for tracheostomy procedures in pediatric patients with complex conditions have increased dramatically in recent years, but there are currently no guidelines on the optimal timing of tracheostomy in pediatric patients undergoing prolonged ventilation. Data Sources: We performed a systematic search of the existing literature in MEDLINE via PubMed and Embase databases and the Cochrane Library to identify clinical trials, observational studies, and cohort studies that compare early and late tracheostomy in children. The date of the last search was August 27, 2018. Included articles were subjected to manual searching. Study Selection: Studies in mechanically ventilated children that compared early with late tracheostomy were included. Data Extraction: Data were extracted into a spreadsheet and copied into Review Manager 5.3 (The Cochrane Collaboration, Copenhagen, Denmark). Data Synthesis: Data were meta-analyzed using an inverse variance, random effects model. Continuous outcomes were calculated as mean differences with 95% CIs, and dichotomous outcomes were calculated as Mantel-Haenszel risk ratios with 95% CIs. We included eight studies (10 study arms). These studies were all retrospective cohort studies. Early tracheostomy was associated with significant reductions in mortality, days on mechanical ventilation, and length of intensive care and total hospital stay, although the lack of randomized, controlled trials limits the validity of these findings. Although variance was imputed for some studies, these conclusions did not change after removing these studies from the analysis. Conclusions: In children on mechanical ventilation, early tracheostomy may improve important medical outcomes. However, our data demonstrate the urgent need for high-quality, randomized controlled trials in the pediatric population. 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. Reeves received funding from Ahmed Mahmoud. The remaining authors have disclosed that they do not have any potential conflicts of interest. ORCID ID: 0000-0002-0473-9764. For information regarding this article, E-mail: carnitin7@yahoo.com; dr.ahmedabdelaalmahmoud@gmail.com; ahmed.alkhatip@nhs.net Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.