Thyroid Storm in the ICU: A Retrospective Multicenter Study Objectives: Thyroid storm represents a rare but life-threatening endocrine emergency. Only rare data are available on its management and the outcome of the most severe forms requiring ICU admission. We aimed to describe the clinical manifestations, management and in-ICU and 6-month survival rates of patients with those most severe thyroid storm forms requiring ICU admission. Design: Retrospective, multicenter, national study over an 18-year period (2000–2017). Setting: Thirty-one French ICUs. Patients: The local medical records of patients from each participating ICU were screened using the International Classification of Diseases, 10th Revision. Inclusion criteria were “definite thyroid storm,” as defined by the Japanese Thyroid Association criteria, and at least one thyroid storm-related organ failure. Measurements and Main Results: Ninety-two patients were included in the study. Amiodarone-associated thyrotoxicosis and Graves’ disease represented the main thyroid storm etiologies (30 [33%] and 24 [26%] patients, respectively), while hyperthyroidism was unknown in 29 patients (32%) before ICU admission. Amiodarone use (24 patients [26%]) and antithyroid-drug discontinuation (13 patients [14%]) were the main thyroid storm-triggering factors. No triggering factor was identified for 30 patients (33%). Thirty-five patients (38%) developed cardiogenic shock within the first 48 hours after ICU admission. In-ICU and 6-month postadmission mortality rates were 17% and 22%, respectively. ICU nonsurvivors more frequently required vasopressors, extracorporeal membrane of oxygenation, renal replacement therapy, mechanical ventilation, and/or therapeutic plasmapheresis. Multivariable analyses retained Sequential Organ Failure Assessment score without cardiovascular component (odds ratio, 1.22; 95% CI, 1.03–1.46; p = 0.025) and cardiogenic shock within 48 hours post-ICU admission (odds ratio, 9.43; 1.77–50.12; p = 0.008) as being independently associated with in-ICU mortality. Conclusions: Thyroid storm requiring ICU admission causes high in-ICU mortality. Multiple organ failure and early cardiogenic shock seem to markedly impact the prognosis, suggesting a prompt identification and an aggressive management. 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. Kimmoun received funding from lecturing for MSD, Gilead, and Baxter. Further relationships with industry can be found on https://www.transparence.sante.gouv.fr. Dr. Azoulay’s institution received funding from Fisher & Paykel and Gilead, and he received funding from Pfizer, Baxter, MSD, Alexion, and Ablynx. 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 Réanimation Médicale, 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.

Development of an Undergraduate Medical Education Critical Care Content Outline Utilizing the Delphi Method Objectives: No consensus exists on a standardized critical care content outline for medical student education. The aim of this research is to develop a national undergraduate medical education critical care content outline. Design: The authors used a Delphi process to reach expert consensus on a content outline that identified the core critical care knowledge topics and procedural skills that medical students should learn prior to entering residency. Over three iterative rounds, the expert panel reached consensus on a critical care content outline. Setting: An electronic survey of critical care medical educators, residency program directors, and residents in the United States. Subjects: The expert panel included three groups as follows: 1) undergraduate medical education critical care educators, 2) residency program directors representing all core specialties, and 3) residents representing their core specialties. Interventions: None. Measurements and Main Results: The expert panel included 28 members. Experts represented the following medical specialties: anesthesiology, emergency medicine, internal medicine, obstetrics and gynecology, pediatrics, and surgery. Seventeen experts had subspecialty training in critical care. The expert panel identified 19 highly recommended critical care knowledge topics and procedural skills. These topics and procedural skills were grouped into five broad categories as follows: 1) neurologic, 2) respiratory, 3) cardiovascular, 4) renal and electrolytes, and 5) supplemental ICU topics. Bag-mask ventilation was the only procedural skill identified as highly recommended. Conclusions: This study provides a national consensus undergraduate medical education critical care content outline. By including experts from multiple specialties, this content outline is meaningful for medical student education, independent of medical specialty. The content outline represents a first step in the development of a national undergraduate medical education critical care curriculum. Dr. Campbell’s institution received funding from Robert Wood Johnson Foundation, Substance Abuse and Mental Health Administration, State of Utah, Primary Children’s Hospital Foundation, and from expert testimony provided for clinical cases. The remaining authors have disclosed that they do not have any potential conflicts of interest. This research was conducted at the University of Utah School of Medicine. For information regarding this article, E-mail: Andrew.Gerald.Smith@hsc.utah.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Serum Protein Changes in Pediatric Sepsis Patients Identified With an Aptamer-Based Multiplexed Proteomic Approach Objectives: Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, is a leading cause of death and disability among children worldwide. Identifying sepsis in pediatric patients is difficult and can lead to treatment delay. Our objective was to assess the host proteomic response to infection utilizing an aptamer-based multiplexed proteomics approach to identify novel serum protein changes that might help distinguish between pediatric sepsis and infection-negative systemic inflammation and hence can potentially improve sensitivity and specificity of the diagnosis of sepsis over current clinical criteria approaches. Design: Retrospective, observational cohort study. Setting: PICU and cardiac ICU, Seattle Children’s Hospital, Seattle, WA. Patients: A cohort of 40 children with clinically overt sepsis and 30 children immediately postcardiopulmonary bypass surgery (infection-negative systemic inflammation control subjects) was recruited. Children with sepsis had a confirmed or suspected infection, two or more systemic inflammatory response syndrome criteria, and at least cardiovascular and/or pulmonary organ dysfunction. Interventions: None. Measurements and Main Results: Serum samples from 35 of the sepsis and 28 of the bypass surgery subjects were available for screening with an aptamer-based proteomic platform that measures 1,305 proteins to search for large-scale serum protein expression pattern changes in sepsis. A total of 111 proteins were significantly differentially expressed between the sepsis and control groups, using the linear models for microarray data (linear modeling) and Boruta (decision trees) R packages, with 55 being previously identified in sepsis patients. Weighted gene correlation network analysis helped identify 76 proteins that correlated highly with clinical sepsis traits, 27 of which had not been previously reported in sepsis. Conclusions: The serum protein changes identified with the aptamer-based multiplexed proteomics approach used in this study can be useful to distinguish between sepsis and noninfectious systemic inflammation. Drs. Shubin and Navalkar contributed equally to this work. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Drs. Navalkar, Sampson, Yager, Cermelli, and Seldon disclosed that they are present or past employees and/or shareholders in Immunexpress. Dr. Navalkar received funding from Immunexpress and the University of Washington, and she received support for article research from the Seattle Children’s Hospital. Drs. Navalkar, Yager, and Cermelli disclosed that Seattle Children’s Hospital paid Somalogic directly to conduct screening. Dr. Yager received funding from ORC International and Foundation for Innovative New Diagnostics (Geneva) for consulting. Dr. Seldon received funding from Immunexpress. Dr. Zimmerman disclosed that he received funding from the Society of Critical Care Medicine (travel reimbursement to attend board meetings) and Elsevier Publishing (royalties for the textbook, Pediatric Critical Care), and that his institution (Seattle Children’s Hospital) received research grant funding from the National Institutes of Health (NIH)/National Institute of Child Health and Human Development. Dr. Zimmerman and Ms. Sullivan disclosed that their institution (Seattle Children’s Hospital) received funding from the Seattle Children’s Research Institute and from Immunexpress for the present study. Dr. Piliponsky’s institution received funding from NIH/National Heart, Lung, and Blood Institute and NIH/National Institute of Child Health and Human Development. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: adrian.piliponsky@seattlechildrens.org Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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.