Magnesium and Hemorrhage Volume in Patients With Aneurysmal Subarachnoid Hemorrhage Objectives: We tested the hypothesis that admission serum magnesium levels are associated with extent of hemorrhage in patients with aneurysmal subarachnoid hemorrhage. Design: Single-center prospective observational study. Setting: Tertiary hospital neurologic ICU. Patients: Patients with aneurysmal subarachnoid hemorrhage. Interventions: Clinically indicated CT scans and serum laboratory studies. Measurements and Main Results: Demographic, clinical, laboratory, and radiographic data were analyzed. Extent of initial hemorrhage was graded semi-quantitatively on admission CT scans using the modified Fisher scale (grades: 0, no radiographic hemorrhage; 1, thin [< 1 mm in depth] subarachnoid hemorrhage; 2, thin subarachnoid hemorrhage with intraventricular hemorrhage; 3, thick [≥ 1 mm] subarachnoid hemorrhage; 4, thick subarachnoid hemorrhage with intraventricular hemorrhage). We used both ordinal (modified Fisher scale) and dichotomized (thick vs thin subarachnoid hemorrhage) univariate and adjusted logistic regression models to assess associations between serum magnesium and radiographic subarachnoid hemorrhage severity. Data from 354 patients (mean age 55 ± 14 yr, 28.5% male, median admission Glasgow Coma Scale 14 [10–15]) were analyzed. Mean magnesium was lower in patients with thick versus thin subarachnoid hemorrhage (1.92 vs 1.99 mg/dL; p = 0.022). A monotonic trend across categories of modified Fisher scale was found using analysis of variance and Spearman rank correlation (p = 0.015 and p = 0.008, respectively). In adjusted ordinal and binary regression models, lower magnesium levels were associated with higher modified Fisher scale (odds ratio 0.33 per 1 mg/dL increase; 95% CI, 0.14–0.77; p = 0.011) and with thick subarachnoid hemorrhage (odds ratio 0.29 per 1 mg/dL increase; 95% CI, 0.10–0.78; p = 0.015). Conclusions: These data support the hypothesis that magnesium influences hemorrhage severity in patients with aneurysmal subarachnoid hemorrhage, potentially through a hemostatic mechanism. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Agency for Healthcare Research and Quality. Dr. Liotta originated the idea for the study, designed and conceptualized the study, analyzed and interpreted the data, collected study data, and drafted and revised the article for important intellectual content. Drs. Karmarkar, Batra, and Kim revised the article for important intellectual content. Dr. Prabhakaran collected study data and revised the article for important intellectual content. Dr. Naidech designed and conceptualized the study, collected study data, and revised the article for important intellectual content. Dr. Maas designed and conceptualized the study, analyzed and interpreted the data, collected study data, and drafted and revised the article for important intellectual content. Statistical analyses were performed jointly by Drs. Liotta and Maas. Dr. Maas holds a masters of science in biostatistics from Northwestern University and Dr. Liotta has completed post-graduate coursework in biostatistics at Northwestern University. Dr. Liotta’s institution received funding from the National Institutes of Health (NIH) National Center for Advancing Translational Sciences (NCATS) grant KL2TR001424 and NIH grants K23 NS092975, and he received funding from NIH medical school student loan repayment grant L30 NS098427. Drs. Liotta and Maas received support for article research from the NIH. Dr. Naidech’s institution received funding from the Agency for Healthcare Research and Quality grant K18 HS023437. Research reported in this publication was supported, in part, by the NIH NCATS grant UL1 TR000150. Dr. Maas’ institution received funding from the NIH grants K23 NS092975. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: eric.liotta@northwestern.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Online Learning and Residents’ Acquisition of Mechanical Ventilation Knowledge: Sequencing Matters Objective: Rapid advancements in medicine and changing standards in medical education require new, efficient educational strategies. We investigated whether an online intervention could increase residents’ knowledge and improve knowledge retention in mechanical ventilation when compared with a clinical rotation and whether the timing of intervention had an impact on overall knowledge gains. Design: A prospective, interventional crossover study conducted from October 2015 to December 2017. Setting: Multicenter study conducted in 33 PICUs across eight countries. Subjects: Pediatric categorical residents rotating through the PICU for the first time. We allocated 483 residents into two arms based on rotation date to use an online intervention either before or after the clinical rotation. Interventions: Residents completed an online virtual mechanical ventilation simulator either before or after a 1-month clinical rotation with a 2-month period between interventions. Measurements and Main Results: Performance on case-based, multiple-choice question tests before and after each intervention was used to quantify knowledge gains and knowledge retention. Initial knowledge gains in residents who completed the online intervention (average knowledge gain, 6.9%; SD, 18.2) were noninferior compared with those who completed 1 month of a clinical rotation (average knowledge gain, 6.1%; SD, 18.9; difference, 0.8%; 95% CI, –5.05 to 6.47; p = 0.81). Knowledge retention was greater following completion of the online intervention when compared with the clinical rotation when controlling for time (difference, 7.6%; 95% CI, 0.7–14.5; p = 0.03). When the online intervention was sequenced before (average knowledge gain, 14.6%; SD, 15.4) rather than after (average knowledge gain, 7.0%; SD, 19.1) the clinical rotation, residents had superior overall knowledge acquisition (difference, 7.6%; 95% CI, 2.01–12.97;p = 0.008). Conclusions: Incorporating an interactive online educational intervention prior to a clinical rotation may offer a strategy to prime learners for the upcoming rotation, augmenting clinical learning in graduate medical education. 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 Department of Anesthesiology, Critical Care and Pain Management at Boston Children’s Hospital. Dr. Boyer received funding from University of Pennsylvania Graduate School of Education (MedEd Master’s Program leadership and teaching). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: traci.wolbrink@childrens.harvard.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

A Novel Patient-Specific Model for Predicting Severe Oliguria; Development and Comparison With Kidney Disease: Improving Global Outcomes Acute Kidney Injury Classification Objectives: The Kidney Disease: Improving Global Outcomes urine output criteria for acute kidney injury lack specificity for identifying patients at risk of adverse renal outcomes. The objective was to develop a model that analyses hourly urine output values in real time to identify those at risk of developing severe oliguria. Design: This was a retrospective cohort study utilizing prospectively collected data. Setting: A cardiac ICU in the United Kingdom. Patients: Patients undergoing cardiac surgery between January 2013 and November 2017. Interventions: None. Measurement and Main Results: Patients were randomly assigned to development (n = 981) and validation (n = 2,389) datasets. A patient-specific, dynamic Bayesian model was developed to predict future urine output on an hourly basis. Model discrimination and calibration for predicting severe oliguria (< 0.3 mL/kg/hr for 6 hr) occurring within the next 12 hours were tested in the validation dataset at multiple time points. Patients with a high risk of severe oliguria (p > 0.8) were identified and their outcomes were compared with those for low-risk patients and for patients who met the Kidney Disease: Improving Global Outcomes urine output criterion for acute kidney injury. Model discrimination was excellent at all time points (area under the curve > 0.9 for all). Calibration of the model’s predictions was also excellent. After adjustment using multivariable logistic regression, patients in the high-risk group were more likely to require renal replacement therapy (odds ratio, 10.4; 95% CI, 5.9–18.1), suffer prolonged hospital stay (odds ratio, 4.4; 95% CI, 3.0–6.4), and die in hospital (odds ratio, 6.4; 95% CI, 2.8–14.0) (p < 0.001 for all). Outcomes for those identified as high risk by the model were significantly worse than for patients who met the Kidney Disease: Improving Global Outcomes urine output criterion. Conclusions: This novel, patient-specific model identifies patients at increased risk of severe oliguria. Classification according to model predictions outperformed the Kidney Disease: Improving Global Outcomes urine output criterion. As the new model identifies patients at risk before severe oliguria develops it could potentially facilitate intervention to improve patient outcomes. This study was undertaken at Wythenshawe Hospital, Manchester University Hospital Foundation Trust, Manchester, United Kingdom. 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). A grant from the British Heart Foundation (grant number PG/16/80/32411) was used to support this research. Drs. Howitt’s, Oakley’s, Caiado's, Goldstein's, Malagon's, McCollum’s, and Grant’s institutions received funding from the British Health Foundation. Dr. Grant received funding from Rinicare. Dr. Malagon disclosed that he does not have any potential conflicts of interest. For information regarding this article, E-mail: samuel.howitt@manchester.ac.uk Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Very Low Density Lipoprotein Receptor Sequesters Lipopolysaccharide Into Adipose Tissue During Sepsis Objectives: Obese patients have lower sepsis mortality termed the “obesity paradox.” We hypothesized that lipopolysaccharide, known to be carried within lipoproteins such as very low density lipoprotein, could be sequestered in adipose tissue during sepsis; potentially contributing a survival benefit. Design: Retrospective analysis. Setting: University research laboratory. Subjects and Patients: Vldlr knockout mice to decrease very low density lipoprotein receptors, Pcsk9 knockout mice to increase very low density lipoprotein receptor, and Ldlr knockout mice to decrease low density lipoprotein receptors. Differentiated 3T3-L1 adipocytes. Caucasian septic shock patients. Interventions: We measured lipopolysaccharide uptake into adipose tissue 6 hours after injection of fluorescent lipopolysaccharide into mice. Lipopolysaccharide uptake and very low density lipoprotein receptor protein expression were measured in adipocytes. To determine relevance to humans, we genotyped the VLDLR rs7852409 G/C single-nucleotide polymorphism in 519 patients and examined the association of 28-day survival with genotype. Measurements and Main Results: Lipopolysaccharide injected into mice was found in adipose tissue within 6 hours and was dependent on very low density lipoprotein receptor but not low density lipoprotein receptors. In an adipocyte cell line decreased very low density lipoprotein receptor expression resulted in decreased lipopolysaccharide uptake. In septic shock patients, the minor C allele of VLDLR rs7852409 was associated with increased survival (p = 0.010). Previously published data indicate that the C allele is a gain-of-function variant of VLDLR which may increase sequestration of very low density lipoprotein (and lipopolysaccharide within very low density lipoprotein) into adipose tissue. When body mass index less than 25 this survival effect was accentuated and when body mass index greater than or equal to 25 this effect was diminished suggesting that the effect of variation in very low density lipoprotein receptor function is overwhelmed when copious adipose tissue is present. Conclusions: Lipopolysaccharide may be sequestered in adipose tissue via the very low density lipoprotein receptor and this sequestration may contribute to improved sepsis survival. Drs. Shimada, Topchiy, and Leung, Ms. Kong, and Dr. Nakada performed the experiments. Drs. Shimada, Topchiy, and Leung, Ms. Kong, and Drs. Genga, Oda, Nakada, and Hirasawa analyzed the data. Drs. Shimada and Walley wrote the article. The guarantors are Drs. Shimada and Walley. All authors reviewed the results and approved final version of the article. 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. Russell received funding from Asahi Kasei Pharmaceuticals of America, La Jolla Pharmaceuticals (he chaired the Data Safety and Monitoring Board of a trial of angiotensin II from 2015 to 2017), Ferring Pharmaceuticals, Cubist Pharmaceuticals, Leading Biosciences (share options), Grifols (investigator-initiated grant to his institution), and CytoVale. Dr. Russell reports patents owned by the University of British Columbia (UBC) that are related to proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor(s) and sepsis and related to the use of vasopressin in septic shock; he is an inventor on these patents. Dr. Russell is a founder, Director, and shareholder in Cyon Therapeutics, and he is a shareholder in Molecular You Corp. Dr. Walley disclosed that he is supported by an operating grant (FDN 154311) from the Canadian Institutes of Health Research and an inventor on a patent filed by the UBC related to PCSK9 in sepsis. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: Keith.Walley@hli.ubc.ca Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Host-Response Subphenotypes Offer Prognostic Enrichment in Patients With or at Risk for Acute Respiratory Distress Syndrome Objectives: Classification of patients with acute respiratory distress syndrome into hyper- and hypoinflammatory subphenotypes using plasma biomarkers may facilitate more effective targeted therapy. We examined whether established subphenotypes are present not only in patients with acute respiratory distress syndrome but also in patients at risk for acute respiratory distress syndrome (ARFA) and then assessed the prognostic information of baseline subphenotyping on the evolution of host-response biomarkers and clinical outcomes. Design: Prospective, observational cohort study. Setting: Medical ICU at a tertiary academic medical center. Patients: Mechanically ventilated patients with acute respiratory distress syndrome or ARFA. Interventions: None. Measurements and Main Results: We performed longitudinal measurements of 10 plasma biomarkers of host injury and inflammation. We applied unsupervised latent class analysis methods utilizing baseline clinical and biomarker variables and demonstrated that two-class models (hyper- vs hypoinflammatory subphenotypes) offered improved fit compared with one-class models in both patients with acute respiratory distress syndrome and ARFA. Baseline assignment to the hyperinflammatory subphenotype (39/104 [38%] acute respiratory distress syndrome and 30/108 [28%] ARFA patients) was associated with higher severity of illness by Sequential Organ Failure Assessment scores and incidence of acute kidney injury in patients with acute respiratory distress syndrome, as well as higher 30-day mortality and longer duration of mechanical ventilation in ARFA patients (p < 0.0001). Hyperinflammatory patients exhibited persistent elevation of biomarkers of innate immunity for up to 2 weeks postintubation. Conclusions: Our results suggest that two distinct subphenotypes are present not only in patients with established acute respiratory distress syndrome but also in patients at risk for its development. Hyperinflammatory classification at baseline is associated with higher severity of illness, worse clinical outcomes, and trajectories of persistently elevated biomarkers of host injury and inflammation during acute critical illness compared with hypoinflammatory patients. Our findings provide strong rationale for examining treatment effect modifications by subphenotypes in randomized clinical trials to inform precision therapeutic approaches in critical care. Drs. Kitsios, Morris, and McVerry involved in conception and design. Dr.Kitsios, Ms. Yang, and Drs. Manatakis, Evankovich, Bain, Dunlap, Shah, and Barbash, Ms. Rapport, Drs. Zhang and Nouraie, Ms. DeSensi, and Drs. Weathington, Benos, Lee, Morris, and McVerry involved in acquisition, analysis, or interpretation of data. Drs. Kitsios, Evankovich, Bain, Dunlap, Shah, and Barbash, Ms. Rapport, and Drs. Weathington, Lee, Morris, and McVerry involved in clinical cohort phenotyping. Drs. Kitsios, Yang, Manatakis, Evankovich, Bain, Dunlap, Shah, and Barbash, Ms. Rapport, Drs. Zhang and Nouraie, Ms. DeSensi, and Drs. Weathington, Chen, Ray, Mallampalli, Benos, Lee, Morris, and McVerry involved in drafting of work and/or revising for important intellectual content. Dr. Kitsios, Ms. Yang, and Drs. Manatakis, Evankovich, Bain, Dunlap, Shah, and Barbash, Ms. Rapport, Drs. Zhang and Nouraie, Ms. DeSensi, and Drs. Weathington, Chen, Ray, Mallampalli, Benos, Lee, Morris, and McVerry involved in final approval of version to be published, and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by grants from National Institutes of Health (NIH) (K23 HL139987 [to Dr. Kitsios]; U01 HL098962 [to Dr. Morris]; P01 HL114453 [to Drs. Ray, Mallampalli, and McVerry]; R01 HL097376 [to Drs. Mallampalli and McVerry]; R01 HL116472 [to Dr. Chen]; K24 HL123342 [to Dr. Morris]; U01 HL137159 [to Drs. Manatakis and Benos]; R01 LM012087 [to Drs. Manatakis and Benos]; R01 HL142084 [to Dr. Lee]; R01 HL136143 [to Dr. Lee]; F32 HL137258 [to Dr. Evankovich]; F32 HL142172 [to Dr. Bain]; K08 HS025455 [to Dr. Barbash]; K23 GM122069 [to Dr. Shah]; R35 HL139860 [to Dr. Chen]; and R01 HL133184 [to Dr. Chen]). Dr. Kitsios receives research funding from Karius. Drs. Kitsios, Nouraie, Evankovich, Bain, Shah, Barbash, Zhang, Weathington, Chen, Ray, Mallampalli, Benos, Lee, Morris, and McVerry received support for article research from the NIH. Drs. Chen and Mallampalli are consultants for Koutif Pharmaceuticals, and they received funding from Koutif Pharmaceuticals (consulting). Dr. Morris’s institution received funding from Gilead. Dr. McVerry received funding from Vapotherm (consulting) and Bayer Pharmaceuticals (research support). The remaining authors have disclosed that they do not have any potential conflicts of interest. All de-identified datasets as well as the statistical code in R used for analyses for this study are provided in https://github.com/MicrobiomeALIR. For information regarding this article, E-mail: kitsiosg@upmc.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

High-Frequency Oscillatory Ventilation and Ventilator-Induced Lung Injury: Size Does Matter Objectives: The theoretical basis for minimizing tidal volume during high-frequency oscillatory ventilation may not be appropriate when lung tissue stretch occurs heterogeneously and/or rapidly. The objective of this study was to assess the extent to which increased ventilation heterogeneity may contribute to ventilator-induced lung injury during high-frequency oscillatory ventilation in adults compared with neonates on the basis of lung size, using a computational model of human lungs. Design: Computational modeling study. Setting: Research laboratory. Subjects: High-fidelity, 3D computational models of human lungs, scaled to various sizes representative of neonates, children, and adults, with varying injury severity. All models were generated from one thoracic CT image of a healthy adult male. Interventions: Oscillatory ventilation was simulated in each lung model at frequencies ranging from 0.2 to 40 Hz. Sinusoidal flow oscillations were delivered at the airway opening of each model and distributed through the lungs according to regional parenchymal mechanics. Measurements and Main Results: Acinar flow heterogeneity was assessed by the coefficient of variation in flow magnitudes across all acini in each model. High-frequency oscillatory ventilation simulations demonstrated increasing heterogeneity of regional parenchymal flow with increasing lung size, with decreasing ratio of deadspace to total acinar volume, and with increasing frequency above lung corner frequency and resonant frequency. Potential for resonant amplification was greatest in injured adult-sized lungs with higher regional quality factors indicating the presence of underdamped lung regions. Conclusions: The potential for ventilator-induced lung injury during high-frequency oscillatory ventilation is enhanced at frequencies above lung corner frequency or resonant frequency despite reduced tidal volumes, especially in adults, due to regional amplification of heterogeneous flow. Measurements of corner frequency and resonant frequency should be considered during high-frequency oscillatory ventilation management. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the U.S. Department of Defense or National Institutes of Health. Drs. Herrmann and Tawhai performed experiments. Drs. Herrmann and Kaczka prepared figures and drafted article. Drs. Herrmann, Tawhai, and Kaczka conceived and designed research; analyzed data. All authors interpreted results of experiments; edited and revised article; and approved the final version of the article. 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 Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program under Award number W81XWH-16-1-0434, the University of Iowa Hospitals and Clinics Department of Anesthesia, the National Heart, Lung, and Blood Institute Grants R01-HL-112986 and R01-HL-126838, and the University of Auckland Medical Technologies Centre of Research Excellence. Drs. Herrmann and Kaczka are cofounders and shareholders of OscillaVent, Inc. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: david-kaczka@uiowa.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Acute Respiratory Distress Syndrome Following Pediatric Trauma: Application of Pediatric Acute Lung Injury Consensus Conference Criteria Objectives: To assess the incidence, severity, and outcomes of pediatric acute respiratory distress syndrome following trauma using Pediatric Acute Lung Injury Consensus Conference criteria. Design: Retrospective cohort study. Setting: Level 1 pediatric trauma center. Patients: Trauma patients less than or equal to 17 years admitted to the ICU from 2009 to 2017. Interventions: None. Measurements and Main Results: We queried electronic health records to identify patients meeting pediatric acute respiratory distress syndrome oxygenation criteria for greater than or equal to 6 hours and determined whether patients met complete pediatric acute respiratory distress syndrome criteria via chart review. We estimated associations between pediatric acute respiratory distress syndrome and outcome using generalized linear Poisson regression adjusted for age, injury mechanism, Injury Severity Score, and serious brain and chest injuries. Of 2,470 critically injured children, 103 (4.2%) met pediatric acute respiratory distress syndrome criteria. Mortality was 34.0% among pediatric acute respiratory distress syndrome patients versus 1.7% among patients without pediatric acute respiratory distress syndrome (adjusted relative risk, 3.7; 95% CI, 2.0–6.9). Mortality was 50.0% for severe pediatric acute respiratory distress syndrome at onset, 33.3% for moderate, and 30.5% for mild. Cause of death was neurologic in 60.0% and multiple organ failure in 34.3% of pediatric acute respiratory distress syndrome nonsurvivors versus neurologic in 85.4% of nonsurvivors without pediatric acute respiratory distress syndrome (p = 0.001). Among survivors, 77.1% of pediatric acute respiratory distress syndrome patients had functional disability at discharge versus 30.7% of patients without pediatric acute respiratory distress syndrome patients (p < 0.001), and only 17.5% of pediatric acute respiratory distress syndrome patients discharged home without ongoing care versus 86.4% of patients without pediatric acute respiratory distress syndrome (adjusted relative risk, 1.5; 1.1–2.1). Conclusions: Incidence and mortality associated with pediatric acute respiratory distress syndrome following traumatic injury are substantially higher than previously recognized, and pediatric acute respiratory distress syndrome development is associated with high risk of poor outcome even after adjustment for underlying injury type and severity. This work performed at Harborview Injury Prevention and Research Center, University of Washington, Seattle, WA. 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 Institute of Child Health and Human Development grant 5 T32 HD057822-08. Drs. Killien’s and Rivara’s institutions received funding from the National Institutes of Health (NIH). Drs. Killien, Vavilala, and Rivara 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: elizabeth.killien@seattlechildrens.org Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Agmatine Protects Against the Progression of Sepsis Through the Imidazoline I2 Receptor-Ribosomal S6 Kinase 2-Nuclear Factor-κB Signaling Pathway Objectives: The knowledge that agmatine is found in the human body has existed for several years; however, its role in sepsis has not yet been studied. In the present study, we investigate the role of agmatine in the progression and treatment of sepsis. Design: Clinical/laboratory investigations. Setting: Medical centers/University-based research laboratory. Subjects: Elective ICU patients with severe sepsis and healthy volunteers; C57BL/6 mice weighing 18–22 g. Interventions: Serum agmatine level and its associations with inflammatory markers were assessed in patients with sepsis. Agmatine was administered intraperitoneally to mice before a lipopolysaccharide challenge. Human peripheral blood mononuclear cells and murine macrophages were pretreated with agmatine followed by lipopolysaccharide stimulation. Measurements and Main Results: Serum agmatine levels were significantly decreased in patients with sepsis and lipopolysaccharide-induced mice, and correlated with Acute Physiology and Chronic Health Evaluation II score, procalcitonin, tumor necrosis factor-α, and interleukin-6 levels. In a therapeutic experiment, exogenous agmatine attenuated the cytokine production of peripheral blood mononuclear cells from patients with sepsis and healthy controls. Agmatine also exerted a significant beneficial effect in the inflammatory response and organ damage and reduced the death rate in lipopolysaccharide-induced mice. Imidazoline I2 receptor agonist 2-benzofuran-2-yl blocked the pharmacological action of agmatine; whereas, other imidazoline receptor ligands did not. Furthermore, agmatine significantly impaired the inflammatory response by inactivating nuclear factor-κB, but not protein 38 mitogen-activated protein kinase, c-Jun N-terminal kinase, extracellular signal-regulated kinase, and inducible nitric oxide synthase signaling in macrophages. Activation of imidazoline I2 receptor or knockdown of ribosomal S6 kinase 2 counteracted the effects of agmatine on phosphorylation and degradation of inhibitor of nuclear factor-κBα. Conclusions: Endogenous agmatine metabolism correlated with the progression of sepsis. Supplemental exogenous agmatine could ameliorate the lipopolysaccharide-induced systemic inflammatory responses and multiple organ injuries through the imidazoline I2 receptor-ribosomal S6 kinase 2-nuclear factor-κB pathway. Agmatine could be used as both a clinical biomarker and a promising pharmaconutrient in patients with severe sepsis. Drs. Li, Zhu, and Tian contributed equally. This work was performed at Army Medical Center (Daping Hospital), Army Medical University (Third Military Medical University), Chongqing, People’s Republic of China. Drs. Li, Xu, and Liang involved in conception and design. Drs. Li, Zhu, Tian, X. Ma, Fan, Luo, Yu, Sun, Yang, Tang, and W. Ma involved in experiments. Dr. Li involved in analysis and interpretation. Drs. Li, Xu, and Liang involved in drafting the article. 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 Nature Science Foundation of China (numbers 81671906, 81871612, and 81902018), the Fund of Basic Science and Frontier Technology Research of Chongqing (number cstc2017jcyjAX0159), Hubei Provincial Natural Science Foundation of China (number 2019CFB109), the Fund of State Key Laboratory of Trauma, Burn and Combined Injury (number SKLKF201601), and the Fund for Transformation of Scientific and Technological Achievements from Third military medical university (number 2016XZH11). Drs. Li, Zhu, Tian, X. Ma, Fan, Yu, Yang, Tang, W. Ma, and Yan received support for article research from National Nature Science Foundation of China (NSFC). Dr. Liang received support for article research from the NSFC (numbers 81671906 and 81871612), the Fund of Basic Science and Frontier Technology Research of Chongqing (number cstc2017jcyjAX0159), the Fund of State Key Laboratory of Trauma, Burn and Combined Injury (number SKLKF201601), and the Fund for Transformation of Scientific and Technological Achievements from Third military medical university (number 2016XZH11). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: (Xiang Xu, PhD); 13638356728@163.com (Huaping Liang, PhD). Drs. Xu and Liang are corresponding author. Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Microcirculation Evolution in Patients on Venoarterial Extracorporeal Membrane Oxygenation for Refractory Cardiogenic Shock Objectives: Despite the increasing use of venoarterial extracorporeal membrane oxygenation to treat severe cardiogenic shock patients, microcirculation data in this context are scarce. We evaluated the venoarterial extracorporeal membrane oxygenation impact on macrocirculatory hemodynamics and microcirculation in patients with refractory cardiogenic shock and compared the evolutions of those parameters between patients successfully weaned-off extracorporeal membrane oxygenation and those who died on extracorporeal membrane oxygenation. Design: Prospective study. Setting: Academic medical ICU. Patients: Consecutive patients with refractory cardiogenic shock (cardiac arrest excluded) who required venoarterial extracorporeal membrane oxygenation and for whom sublingual microcirculation measurements before cannulation were possible. Interventions: All patients were followed until death or venoarterial extracorporeal membrane oxygenation removal. Microcirculatory and macrocirculatory evaluations were made before, and 2, 4, 12, 24, and 48 hours after extracorporeal membrane oxygenation initiation, respectively. Patients weaned-off extracorporeal membrane oxygenation were also evaluated 6 hours before and after venoarterial extracorporeal membrane oxygenation removal. Measurements and Main Results: Fourteen patients (median age, 58 yr [interquartile range, 56–62 yr]; Sequential Organ Failure Assessment score, 14 [12–18]) were included. Acute myocardial infarction (50%) was the main cause of cardiogenic shock. Six patients (33%) were successfully weaned-off extracorporeal membrane oxygenation. Profound microcirculation parameter changes found before venoarterial extracorporeal membrane oxygenation implantation regressed within 12 hours after extracorporeal membrane oxygenation onset. Pre-extracorporeal membrane oxygenation macrocirculation, echocardiography, arterial blood gases, and microcirculation parameters did not differ between patients who died on extracorporeal membrane oxygenation and those successfully weaned. However, perfused small-vessel density, small-vessel density, and percent perfused vessels were consistently higher and then stabilized 48 hours postcannulation for patients successfully weaned-off extracorporeal membrane oxygenation. Conclusions: Microcirculation is severely impaired in patients with refractory cardiogenic shock requiring venoarterial extracorporeal membrane oxygenation. Inability to rapidly restore microcirculation during the first 24 hours, despite normal global/macrocirculatory hemodynamics, was associated with death on extracorporeal membrane oxygenation. Further studies are now warranted to better determine the relevant microcirculation determinants during venoarterial extracorporeal membrane oxygenation support, before future routine use of this promising tool in clinical practice. Drs. Chommeloux, Montero, Franchineau, Nieszkowska, and Schmidt helped with conception and design; Drs. Chommeloux, Montero, Franchineau, Combes, and Schmidt helped with analysis and interpretation; and all authors helped with drafting the 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). Dr. Montero received funding from European Society of Cardiology. Dr. Luyt received funding from lecturing for Merck Sharp & Dohme, Thermofischer Brahms, Biomerieux, and from consulting for Bayer and Carmat. Dr. Combes received lecture fees from Getinge and Baxter. Dr. Schmidt received lectures fees from Getinge, Dräger, and Xenios. The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Matthieu Schmidt, MD, PhD, Service de Ledecine Intensive Reanimation, iCAN, Institute of Cardiometabolism and Nutrition, Hôpital de la Pitié–Salpêtrière, 47, bd de l’Hôpital, 75651 Paris Cedex 13, France. E-mail: matthieu.schmidt@aphp.fr Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Incidence and Outcomes of Acute Laryngeal Injury After Prolonged Mechanical Ventilation Objectives: Upper airway injury is a recognized complication of prolonged endotracheal intubation, yet little attention has been paid to the consequences of laryngeal injury and functional impact. The purpose of our study was to prospectively define the incidence of acute laryngeal injury and investigate the impact of injury on breathing and voice outcomes. Design: Prospective cohort study. Setting: Tertiary referral critical care center. Patients: Consecutive adult patients intubated greater than 12 hours in the medical ICU from August 2017 to May 2018 who underwent laryngoscopy within 36 hours of extubation. Interventions: Laryngoscopy following endotracheal intubation. Measurements and Main Results: One hundred consecutive patients (62% male; median age, 58.5 yr) underwent endoscopic examination after extubation. Acute laryngeal injury (i.e., mucosal ulceration or granulation tissue in the larynx) was present in 57 patients (57%). Patients with laryngeal injury had significantly worse patient-reported breathing (Clinical Chronic Obstructive Pulmonary Disease Questionnaire: median, 1.05; interquartile range, 0.48–2.10) and vocal symptoms (Voice Handicap Index-10: median, 2; interquartile range, 0–6) compared with patients without injury (Clinical Chronic Obstructive Pulmonary Disease Questionnaire: median, 0.20; interquartile range, 0–0.80; p < 0.001; and Voice Handicap Index-10: median, 0; interquartile range, 0–1; p = 0.005). Multivariable logistic regression independently associated diabetes, body habitus, and endotracheal tube size greater than 7.0 with the development of laryngeal injury. Conclusions: Acute laryngeal injury occurs in more than half of patients who receive mechanical ventilation and is associated with significantly worse breathing and voicing 10 weeks after extubation. An endotracheal tube greater than size 7.0, diabetes, and larger body habitus may predispose to injury. Our results suggest that acute laryngeal injury impacts functional recovery from critical illness. This work was performed at the Vanderbilt University Medical Center. Drs. Shinn, Kimura, and Campbell, Ms. Lowery, and Dr. Gelbard had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs. Shinn, Du, and Gelbard were involved with statistical analysis. All authors provided revisions and approved the final article. Trial Registration: Clinical Trials ID# NCT03250975. 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 websites (http://journals.lww.com/ccmjournal). Supported, in part, by a Vanderbilt Institute for Clinical and Translational Research grant to purchase video laryngoscopy recording capabilities. Dr. Shinn received funding from Vanderbilt Institute for Clinical and Translational Research grant (to purchase video laryngoscopy recording capabilities). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: alexander.gelbard@vumc.org Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.