Bioactive Adrenomedullin, Organ Support Therapies, and Survival in the Critically Ill: Results from the French and European Outcome Registry in ICU Study Objectives: Adrenomedullin has vascular properties and elevated plasma adrenomedullin levels were detected in sepsis. We assessed, in septic and nonseptic ICU patients, the relation between circulating adrenomedullin, the need for organ support and mortality, using an assay of bioactive adrenomedullin. Design: Prospective multicenter observational cohort study. Setting: Data from the French and euRopean Outcome reGistry in ICUs study. Patients: Consecutive patients admitted to intensive care with a requirement for invasive mechanical ventilation and/or vasoactive drug support for more than 24 hours following ICU admission and discharged from ICU were included. Interventions: Clinical and biological parameters were collected at baseline, including bioactive-adrenomedullin. Status of ICU survivors was assess until 1 year after discharge. The main outcome was the need for organ support, including renal replacement therapy and/or for inotrope(s) and/or vasopressor(s). Secondary endpoints were the ICU length of stay and the 28-day all-cause mortality. Measurements and Main Results: Median plasma bioactive adrenomedullin (n = 2,003) was 66.6 pg/mL (34.6–136.4 pg/mL) and the median Simplified Acute Physiology Score II score 49 (36–63). Renal replacement therapy was needed in 23% and inotropes(s) and/or vasopressor(s) in 77% of studied patients. ICU length of stay was 13 days (7–21 d) and mortality at 28 days was 22 %. Elevated bioactive adrenomedullin independently predicted 1) the need for organ support (odds ratio, 4.02; 95% CI, 3.08–5.25) in ICU patients whether admitted for septic or nonseptic causes and 2) the need for renal replacement therapy (odds ratio, 4.89; 3.83–6.28), and for inotrope(s) and/or vasopressor(s) (odds ratio, 3.64; 2.84–4.69), even in patients who were not on those supports at baseline. Elevated bioactive adrenomedullin was also associated with a prolonged length of stay (odds ratio, 1.85; 1.49–2.29) and, after adjustment for Simplified Acute Physiology Score II, with mortality (odds ratio, 2.31; 1.83–2.92). Conclusions: Early measurement of bioactive adrenomedullin is a strong predictor of the need of organ support and of short-term mortality in critically ill patients. This work was performed at Department of Anesthesia, Burn and Critical Care, University Hospitals Saint-Louis - Lariboisière, AP-HP, Paris, France. Drs. Lemasle and Blet 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). Dr. Geven and his institution have received funding from Adrenomed AG. Dr. Monnet received support for article research from Assistance publique hôpitaux de Paris. Drs. Struck and Hartmann received funding from sphingotec GmbH (employees). Dr. Hartmann disclosed off-label product use of biomarker assay for adrenomedullin. Dr. Bergmann disclosed he is a member of the Adrenomed Board (but he receives no financial compensation). Dr. Mebazaa’s institution received funding from Adrenomed (paid to ship the samples), and he received funding from the Steering Committee of Adrenoss-2 (member). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: etienne.gayat@aphp.fr Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Perceptions of Ethical Decision-Making Climate Among Clinicians Working in European and U.S. ICUs: Differences Between Nurses and Physicians Objectives: To examine perceptions of nurses and physicians in regard to ethical decision-making climate in the ICU and to test the hypothesis that the worse the ethical decision-making climate, the greater the discordance between nurses’ and physicians’ rating of ethical decision-making climate with physicians hypothesized to rate the climate better than the nurses. Design: Prospective observational study. Setting: A total of 68 adult ICUs in 13 European countries and the United States. Subjects: ICU physicians and nurses. Interventions: None. Measurements and Main Results: Perceptions of ethical decision-making climate among clinicians were measured in April-May 2014, using a 35-items self-assessment questionnaire that evaluated seven factors (empowering leadership by physicians, interdisciplinary reflection, not avoiding end-of-life decisions, mutual respect within the interdisciplinary team, involvement of nurses in end-of-life care and decision-making, active decision-making by physicians, and ethical awareness). A total of 2,275 nurses and 717 physicians participated (response rate of 63%). Using cluster analysis, ICUs were categorized according to four ethical decision-making climates: good, average with nurses’ involvement at end-of-life, average without nurses’ involvement at end-of-life, and poor. Overall, physicians rated ethical decision-making climate more positively than nurses (p < 0.001 for all seven factors). Physicians had more positive perceptions of ethical decision-making climate than nurses in all 13 participating countries and in each individual participating ICU. Compared to ICUs with good or average ethical decision-making climates, ICUs with poor ethical decision-making climates had the greatest discordance between physicians and nurses. Although nurse/physician differences were found in all seven factors of ethical decision-making climate measurement, the factors with greatest discordance were regarding physician leadership, interdisciplinary reflection, and not avoiding end-of-life decisions. Conclusions: Physicians consistently perceived ICU ethical decision-making climate more positively than nurses. ICUs with poor ethical decision-making climates had the largest discrepancies. This work was carried out 68 adult ICUs in 13 European countries and the United States. Please see the Acknowledgments section at the end of the article for details. 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. Benoit received funding from the Research Foundation Flanders (1800513N and 1800518N) and from ESICM/European Critical Care Research Network clinical research award. Dr. Piers received funding from Fund Marie-Thérèse De Lava, King Baudouin Foundation, Belgium. Dr. Hartog received funding from the German Federal Ministry of Education and Research via the Center for Sepsis Control and Care (FKZ 01EO1002) and a grant from the Innovation Funds of the German Federal Joint Committee (FKZ 91VSF17010). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: hanne.irene.jensen@rsyd.dk Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Bioelectrical Impedance Measurements for Assessment of Kidney Function in Critically Ill Patients Objectives: To evaluate the use of multifrequency bioelectrical impedance analysis to predict creatinine/urea clearance based on 24 hours urine collection. A practical formula was developed, and its performance was compared with that of established formulas such as Cockcroft-Gault, Modification of Diet in Renal Disease, and Jelliffe’s. Design: An open-label prospective observational cohort study. Setting: A 12-bed ICU at a nonuniversity major teaching hospital (Gelre ziekenhuizen Apeldoorn/Zutphen, The Netherlands). Patients: Adult critical care patients with an expected ICU length of stay at admission of at least 48 hours. Interventions: Each patient’s body composition was assessed using a validated Quadscan 4000 analyzer (Bodystat, Isle of Man, British Isles). Twenty-four hours urine was collected, and laboratory variables in serum including creatinine, urea, and albumin were obtained at the beginning and end of the collection period. Measurements and Main Results: A total of 151 patients, stratified to an acute and nonacute ICU-group, were enrolled in the study over a 2-year period. A formula to predict creatinine/urea clearance based on 24 hours urine collection was developed using stepwise linear regression using a training data set of 75 patients. This formula was subsequently tested and compared with other relevant predictive equations using a validation data set of 76 patients. Serum creatinine values ranged from 40 to 446 µmol/L. With the predictive model based on estimated body cell mass and a “prediction marker” more than 71% of the observed variance in creatinine/urea clearance based on 24 hours urine collection could be explained. Predictive performance was superior to the other eight evaluated models (R2 = 0.39–0.55) and demonstrated to be constant over the whole range of creatinine/urea clearance based on 24 hours urine collection values. Conclusions: Multifrequency bioelectrical impedance analysis measurements can be used to predict creatinine/urea clearance based on 24 hours urine collection with superior performance than currently established prediction models. This rapid, noninvasive method enables correction for influences of a patient’s actual body composition and may prove valuable in daily clinical practice. 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: l.van.gendt@gelre.nl Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Preoperative Diaphragm Function Is Associated With Postoperative Pulmonary Complications After Cardiac Surgery Objectives: Postoperative pulmonary complications increase mortality, length, and cost of hospitalization. A better diaphragmatic strength may help face an increased work of breathing postoperatively. We, therefore, sought to determine if a low preoperative diaphragm thickening fraction (TFdi) determined by ultrasonography helped predict the occurrence of postoperative pulmonary complications after cardiac surgery independently of indicators of frailty, sarcopenia, and pulmonary function. Design: Prospective observational cohort study. Setting: Montreal Heart Institute, an academic cardiac surgery center in Canada. Patients: Adults undergoing nonemergency cardiac surgery. Interventions: We measured the preoperative thickness of the right and left hemidiaphragms at their zone of apposition at end-expiration (Tdi,ee) and peak-inspiration (Tdi,ei) with ultrasonography. Maximal thickening fraction of the diaphragm during inspiration (TFdi,max) was calculated using the following formula: TFdi,max = (Tdi,ei–Tdi,ee)/Tdi,ee. We also evaluated other potential risk factors including demographic parameters, comorbidities, Clinical Frailty Scale, grip strength, 5-meter walk test, and pulmonary function tests. We repeated TFdi,max measurements within 24 hours of extubation. The primary composite outcome of this study was the occurrence of postoperative pulmonary complications, defined as pneumonia, clinically significant atelectasis, or prolonged mechanical ventilation (> 24 hr). Measurement and Main Results: Of the 115 patients included, 34 (29.6%) developed postoperative pulmonary complications, including two with pneumonia, four with prolonged mechanical ventilation, and 32 with clinically significant atelectasis. Those with postoperative pulmonary complications had prolonged ICU and hospital length of stays. They had a lower TFdi,max (37% [interquartile range, 31–45%] vs 44% [interquartile range, 33–58%]; p = 0.03). In multiple logistic regression, a TFdi,max less than 38.1% was associated with postoperative pulmonary complications (odds ratio, 4.9; 95% CI, 1.81–13.50; p = 0.002). All patients who developed pneumonia or prolonged mechanical ventilation had a TFdi,max less than 38.1%. Respiratory rate and diabetes were also independently associated with postoperative pulmonary complications, while pulmonary function tests and the assessed indicators of frailty and sarcopenia were not. Conclusions: A low preoperative TFdi,max can help to identify patients at increased risk of postoperative pulmonary complications after cardiac surgery. Clinical Trial Registration: ClinicalTrials.gov NCT02658006. Dr. Denault takes responsibility for the content of the article, including the data and analysis. Dr. Denault had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs. Cavayas, Eljaiek, Rodrigue, Levesque, and Denault contributed to study design and data collection. Drs. Cavayas, Eljaiek, Rodrigue, Lamarche, Girard, Wang, Levesque, and Denault contributed to data analysis and interpretation, and the writing of the article. All authors approved 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. Girard received funding from GE Healthcare (consulting). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: andre.denault@gmail.com Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Early Palliative Care Consultation in the Medical ICU: A Cluster Randomized Crossover Trial Objectives: To assess the impact of early triggered palliative care consultation on the outcomes of high-risk ICU patients. Design: Single-center cluster randomized crossover trial. Setting: Two medical ICUs at Barnes Jewish Hospital. Patients: Patients (n = 199) admitted to the medical ICUs from August 2017 to May 2018 with a positive palliative care screen indicating high risk for morbidity or mortality. Interventions: The medical ICUs were randomized to intervention or usual care followed by washout and crossover, with independent assignment of patients to each ICU at admission. Intervention arm patients received a palliative care consultation from an interprofessional team led by board-certified palliative care providers within 48 hours of ICU admission. Measurements and Main Results: Ninety-seven patients (48.7%) were assigned to the intervention and 102 (51.3%) to usual care. Transition to do-not-resuscitate/do-not-intubate occurred earlier and significantly more often in the intervention group than the control group (50.5% vs 23.4%; p < 0.0001). The intervention group had significantly more transfers to hospice care (18.6% vs 4.9%; p < 0.01) with fewer ventilator days (median 4 vs 6 d; p < 0.05), tracheostomies performed (1% vs 7.8%; p < 0.05), and postdischarge emergency department visits and/or readmissions (17.3% vs 38.9%; p < 0.01). Although total operating cost was not significantly different, medical ICU (p < 0.01) and pharmacy (p < 0.05) operating costs were significantly lower in the intervention group. There was no significant difference in ICU length of stay (median 5 vs 5.5 d), hospital length of stay (median 10 vs 11 d), in-hospital mortality (22.6% vs 29.4%), or 30-day mortality between groups (35.1% vs 36.3%) (p > 0.05). Conclusions: Early triggered palliative care consultation was associated with greater transition to do-not-resuscitate/do-not-intubate and to hospice care, as well as decreased ICU and post-ICU healthcare resource utilization. Our study suggests that routine palliative care consultation may positively impact the care of high risk, critically ill patients. Trial Registration: ClinicalTrials.gov Identifier: NCT03263143. Drs. Ma, Chi, Buettner, Pollard, Muir, Kolekar, Kollef, and Dans were involved in substantial contributions to conception or design of the work, drafting of the work or revising it critically for important intellectual content. All authors were involved in substantial contributions to the acquisition, analysis, and interpretation of data for the work. They also had final approval of the version to be published and agreed 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 were 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). This publication in part was supported by The Foundation for Barnes-Jewish Hospital and their generous donors, and the Washington University Institute of Clinical and Translational Sciences which is, in part, supported by the National Institutes of Health/National Center for Advancing Translational Sciences, Clinical Translational Sciences Award grant UL1TR002345. Drs. Ma and Chi disclosed that the study is supported by The Foundation for Barnes-Jewish Hospital and Washington University Institute of Clinical and Translational Sciences (ICTS) which is, in part, supported by the National Institutes of Health (NIH)/National Center for Advancing Translational Sciences, Clinical Translational Sciences Award grant UL1TR002345. Drs. Chi, Buettner, Al-Hammadi, and Kollef received support for article research from the NIH. Dr. Buettner’s institution received funding from ICTS Just In Time award. Drs. Buettner’s and Dans’s institutions received funding from Barnes-Jewish Hospital Foundation. Dr. Chen disclosed work for hire. Dr. Kollef’s effort was supported by the Barnes-Jewish Hospital Foundation. Dr. Dans’ institution also received funding from ICTS at Washington University School of Medicine and Barnes Jewish Hospital Foundation, and she received funding from National Comprehensive Cancer Network (NCCN) (Guidelines Panel Chair for the Palliative Care Guidelines. The NCCN reimburses travel & accommodation expenses for attending their annual conference). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: kollefm@wustl.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Enteral Acetaminophen Bioavailability in Pediatric Intensive Care Patients Determined With an Oral Microtracer and Pharmacokinetic Modeling to Optimize Dosing Objectives: Decreasing morbidity and mortality by rationalizing drug treatment in the critically ill is of paramount importance but challenging as the underlying clinical condition may lead to large variation in drug disposition and response. New microtracer methodology is now available to gain knowledge on drug disposition in the intensive care. On the basis of studies in healthy adults, physicians tend to assume that oral doses of acetaminophen will be completely absorbed and therefore prescribe the same dose per kilogram for oral and IV administration. As the oral bioavailability of acetaminophen in critically ill children is unknown, we designed a microtracer study to shed a light on this issue. Design: An innovative microtracer study design with population pharmacokinetics. Setting: A tertiary referral PICU. Patients: Stable critically ill children, 0–6 years old, and already receiving IV acetaminophen. Interventions: Concomitant administration of an oral 14C radiolabeled acetaminophen microtracer (3 ng/kg) with IV acetaminophen treatment (15 mg/kg every 6 hr). Measurements: Blood was drawn from an indwelling arterial or central venous catheter up to 24 hours after 14C acetaminophen microtracer administration. Acetaminophen concentrations were measured by liquid chromatography-mass spectrometry and 14C concentrations by accelerated mass spectrometry. Main Results: In 47 patients (median age of 6.1 mo; Q1–Q3, 1.8–20 mo) the mean enteral bioavailability was 72% (range, 11–91%). With a standard dose (15 mg/kg 4 times daily), therapeutic steady-state concentrations were 2.5 times more likely to be reached with IV than with oral administration. Conclusions: Microtracer studies present a new opportunity to gain knowledge on drug disposition in the intensive care. Using this modality in children in the pediatric intensive care, we showed that enteral administration of acetaminophen results in less predictable exposure and higher likelihood of subtherapeutic blood concentration than does IV administration. IV dosing may be preferable to ensure adequate pain relief. Drs. Kleiber and Calvier contributed equally to this work. Drs. Knibbe and de Wildt 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). Supported, in part, by grant from The Netherlands Organization for Health Research and Development research grant (113202007). Drs. Krekels and de Wildt disclosed work for hire. Drs. Vaes’s and de Wildt’s institutions received funding from The Netherlands Organization for Health Research and Development (ZonMw). Dr. de Wildt’s institution also received funding from TNO Zeist (consulting); she disclosed she is Director of the Dutch Knowledge Center for Pharmacotherapy in Children and as such is responsible for the dosing guidelines of paracetamol in the Dutch Pediatric Formulary; and she disclosed off-label product of paracetamol. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: s.dewildt@erasmusmc.nl Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Vasopressin Versus Norepinephrine for the Management of Septic Shock in Cancer Patients: The VANCS II Randomized Clinical Trial Objectives: Previous trials suggest that vasopressin may improve outcomes in patients with vasodilatory shock. The aim of this study was to evaluate whether vasopressin could be superior to norepinephrine to improve outcomes in cancer patients with septic shock. Design: Single-center, randomized, double-blind clinical trial, and meta-analysis of randomized trials. Setting: ICU of a tertiary care hospital. Patients: Two-hundred fifty patients 18 years old or older with cancer and septic shock. Interventions: Patients were assigned to either vasopressin or norepinephrine as first-line vasopressor therapy. An updated meta-analysis was also conducted including randomized trials published until October 2018. Measurements and Main Results: The primary outcome was all-cause mortality at 28 days after randomization. Prespecified secondary outcomes included 90-days all-cause mortality rate; number of days alive and free of advanced organ support at day 28; and Sequential Organ Failure Assessment score 24 hours and 96 hours after randomization. We also measure the prevalence of adverse effects in 28 days. A total of 250 patients were randomized. The primary outcome was observed in 71 patients (56.8%) in the vasopressin group and 66 patients (52.8%) in the norepinephrine group (p = 0.52). There were no significant differences in 90-day mortality (90 patients [72.0%] and 94 patients [75.2%], respectively; p = 0.56), number of days alive and free of advanced organ support, adverse events, or Sequential Organ Failure Assessment score. Conclusions: In cancer patients with septic shock, vasopressin as first-line vasopressor therapy was not superior to norepinephrine in reducing 28-day mortality rate. The views expressed are those of the author(s) and not necessarily those of the National Health Service, the National Institutes of Health Research, or the Department 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). This trial was performed at the Instituto do Câncer do Estado de São Paulo da Faculdade de Medicina da Universidade de São Paulo. This study was sponsored by University of São Paulo and supported by departmental funds only. Dr. Gordon’s institution received funding from the National Institutes of Health Research (NIHR) Research Professorship award (RP-2015-06-018) and the NIHR Comprehensive Biomedical Research Centre based at Imperial College Healthcare National Health Service Trust and Imperial College London, and, outside of the submitted work, he has received speaker fees from Orion Corporation, Orion Pharma, and Amomed Pharma. He has consulted for Ferring Pharmaceuticals, Tenax Therapeutics, Baxter Healthcare, Bristol-Myers Squibb, and GlaxoSmithKline, and received grant support from Orion Corporation, Orion Pharma, Tenax Therapeutics, and Hospital Corporation of America International with funds paid to his institution. The remaining authors have disclosed that they do not have any potential conflicts of interest. Trial registration number: ClinicalTrials.gov NCT01718613. For information regarding this article, E-mail: landoni.giovanni@hsr.it Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Early and Late Mortality Following Discharge From the ICU: A Multicenter Prospective Cohort Study Objectives: To identify the frequency, causes, and risk factors of early and late mortality among general adult patients discharged from ICUs. Design: Multicenter, prospective cohort study. Setting: ICUs of 10 tertiary hospitals in Brazil. Patients: One-thousand five-hundred fifty-four adult ICU survivors with an ICU stay greater than 72 hours for medical and emergency surgical admissions or greater than 120 hours for elective surgical admissions. Interventions: None. Measurements and Main Results: The main outcomes were early (30 d) and late (31 to 365 d) mortality. Causes of death were extracted from death certificates and medical records. Twelve-month cumulative mortality was 28.2% (439 deaths). The frequency of early mortality was 7.9% (123 deaths), and the frequency of late mortality was 22.3% (316 deaths). Infections were the leading cause of death in both early (47.2%) and late (36.4%) periods. Multivariable analysis identified age greater than or equal to 65 years (hazard ratio, 1.65; p = 0.01), pre-ICU high comorbidity (hazard ratio, 1.59; p = 0.02), pre-ICU physical dependence (hazard ratio, 2.29; p < 0.001), risk of death at ICU admission (hazard ratio per 1% increase, 1.008; p = 0.03), ICU-acquired infections (hazard ratio, 2.25; p < 0.001), and ICU readmission (hazard ratio, 3.76; p < 0.001) as risk factors for early mortality. Age greater than or equal to 65 years (hazard ratio, 1.30; p = 0.03), pre-ICU high comorbidity (hazard ratio, 2.28; p < 0.001), pre-ICU physical dependence (hazard ratio, 2.00; p < 0.001), risk of death at ICU admission (hazard ratio per 1% increase, 1.010; p < 0.001), and ICU readmission (hazard ratios, 4.10, 4.17, and 1.82 for death between 31 and 60 days, 61 and 90 days, and greater than 90 days after ICU discharge, respectively; p < 0.001 for all comparisons) were associated with late mortality. Conclusions: Infections are the main cause of death after ICU discharge. Older age, pre-ICU comorbidities, pre-ICU physical dependence, severity of illness at ICU admission, and ICU readmission are associated with increased risk of early and late mortality, while ICU-acquired infections are associated with increased risk of early mortality. The complete list of board members of The Quality of Life After ICU Study Group Investigators and BRICNet is provided in the electronic supplemental material (Supplemental Digital Content 1, http://links.lww.com/CCM/E958). The study was carried out at Critical Care Department of Hospital Moinhos de Vento (Porto Alegre, Brazil), Critical Care Department of Hospital de Clínicas de Porto Alegre (Porto Alegre, Brazil), Critical Care Department of Hospital Santa Clara (Porto Alegre, Brazil), Critical Care Department of Pavilhão Pereira Filho (Porto Alegre, Brazil), Critical Care Department of Hospital Ernesto Dornelles (Porto Alegre, Brazil), Critical Care Department of Hospital Nossa Senhora da Conceição (Porto Alegre, Brazil), Critical Care Department of Hospital de Urgências de Goiânia (Goiânia, Brazil), Critical Care Department of Hospital Regional do Baixo Amazonas (Santarém, Brazil), Critical Care Department of Hospital Geral Clériston Andrade (Feira de Santana, Brazil), and Critical Care Department of Hospital do Coração (São Paulo, Brazil). 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 present study was funded by the Brazilian Ministry of Health through the Brazilian Unified Health System Institutional Development Program. Drs. Rosa’s, Falavigna’s, Robinson’s, Sanchez’s, Kochhann’s, Schneider’s, Sganzerla’s, Dietrich’s, Barbosa’s, de Souza’s, Rech’s, and dos Santos’s institutions received funding from Brazilian Ministry of Health through the Brazilian Unified Health System Institutional Development Program. Dr Falavigna is manager partner of HTAnalyze, a consulting and training firm in health technology assessment topics. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: regis.rosa@hmv.org.br Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Clinical and Genetic Contributors to New-Onset Atrial Fibrillation in Critically Ill Adults Objectives: New-onset atrial fibrillation during critical illness is an independent risk factor for mortality. The ability to identify patients at high risk for new-onset atrial fibrillation is limited. We hypothesized that genetic susceptibility contributes to risk of new-onset atrial fibrillation in the ICU. Design: Retrospective sub-study of a prospective observational cohort study. Setting: Medical and general surgical ICUs in a tertiary academic medical center. Patients: One-thousand three-hundred sixty-nine critically ill patients admitted to the ICU for at least 2 days with no known history of atrial fibrillation who had DNA available for genotyping. Interventions: None. Measurements and Main Results: We genotyped 21 single-nucleotide polymorphisms associated with atrial fibrillation in ambulatory studies using a Sequenom platform (San Diego, CA). We collected demographics, medical history, and development of new-onset atrial fibrillation during the first four days of ICU admission. New-onset atrial fibrillation occurred in 98 patients (7.2%) and was associated with age, male sex, coronary artery disease, and vasopressor use. Single-nucleotide polymorphisms associated with new-onset atrial fibrillation were rs3853445 (near PITX2, p = 0.0002), rs6838973 (near PITX2, p = 0.01), and rs12415501 (in NEURL, p = 0.03) on univariate testing. When controlling for clinical factors, rs3853445 (odds ratio, 0.47; 95% CI, 0.30–0.73; p = 0.001) and rs12415501 (odds ratio, 1.72; 95% CI, 1.27–2.59; p = 0.01) remained significantly associated with new-onset atrial fibrillation. The addition of genetic variables to clinical factors improved new-onset atrial fibrillation discrimination in a multivariable logistic regression model (C-statistic 0.82 vs 0.78; p = 0.0009). Conclusions: We identified several single-nucleotide polymorphisms associated with new-onset atrial fibrillation in a large cohort of critically ill ICU patients, suggesting there is genetic susceptibility underlying this common clinical condition. This finding may provide new targets for future mechanistic studies and additional insight into the application of genomic information to identify patients at elevated risk for a common and important condition in the ICU. The contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences 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). Supported, in part, by grants from the National Institutes of Health (NIH) T32 GM108554 (to Dr. Kerchberger), NIH HL 138737 (to Dr. Darbar), NIH HL 135849 (to Drs. Bastarache and Ware), NIH HL 103836 (to Dr. Ware), NIH HL 136888 (to Dr. Shaver), Parker B. Francis Foundation (to Dr. Shaver), and Vanderbilt Faculty Research Scholars (to Dr. Shaver). The project publication described was supported by Clinical and Translational Science Award award number UL1 TR002243 from the National Center for Advancing Translational Sciences. Drs. Kerchberger, Koyama, Shoemaker, Darbar, Ware, and Shaver received support for article research from the National Institutes of Health (NIH). Dr. Darbar’s institution received funding from NIH R01 HL138737. Dr. Ware’s institution received funding from Boehringer Ingelheim and Global Blood Therapeutics (research grants). Dr. Shaver’s institution received funding from NIH (K08), Parker B Francis Foundation, and Vanderbilt Faculty Research Scholars. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: vern.e.kerchberger@vumc.org Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Allergic Immune Diseases and the Risk of Mortality Among Patients Hospitalized for Acute Infection Objectives: The immune response during sepsis remains poorly understood and is likely influenced by the host’s preexisting immunologic comorbidities. Although more than 20% of the U.S. population has an allergic-atopic disease, the type 2 immune response that is overactive in these diseases can also mediate beneficial pro-resolving, tissue-repair functions. Thus, the presence of allergic immunologic comorbidities may be advantageous for patients suffering from sepsis. The objective of this study was to test the hypothesis that comorbid type 2 immune diseases confer protection against morbidity and mortality due to acute infection. Design: Retrospective cohort study of patients hospitalized with an acute infection between November 2008 and January 2016 using electronic health record data. Setting: Single tertiary-care academic medical center. Patients: Admissions to the hospital through the emergency department with likely infection at the time of admission who may or may not have had a type 2 immune-mediated disease, defined as asthma, allergic rhinitis, atopic dermatitis, or food allergy, as determined by International Classification of Diseases, 9th Revision, Clinical Modification codes. Interventions: None. Measurements and Main Results: Of 10,789 admissions for infection, 2,578 (24%) had a type 2 disease; these patients were more likely to be female, black, and younger than patients without type 2 diseases. In unadjusted analyses, type 2 patients had decreased odds of dying during the hospitalization (0.47; 95% CI, 0.38–0.59, p < 0.001), while having more than one type 2 disease conferred a dose-dependent reduction in the risk of mortality (p < 0.001). When adjusting for demographics, medications, types of infection, and illness severity, the presence of a type 2 disease remained protective (odds ratio, 0.55; 95% CI, 0.43–0.70; p < 0.001). Similar results were found using a propensity score analysis (odds ratio, 0.57; 95% CI, 0.45–0.71; p < 0.001). Conclusions: Patients with type 2 diseases admitted with acute infections have reduced mortality, implying that the type 2 immune response is protective in sepsis. Drs. Verhoef and Churpek were involved in study concept and design, obtained funding, and supervised the study. Dr. Churpek was involved in acquisition of data. Dr. Verhoef was involved in the first drafting of the article, had full access to all the data in the study, and took responsibility for the integrity of the data and the accuracy of the data analysis. Drs. Carey and Churpek were involved in administrative, technical, and material support. All authors were involved in critical revision of the article for important intellectual content and statistical analysis; analysis and interpretation of data. 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. Verhoef is supported by a career development award from the National Heart, Lung, and Blood Institute (NHLBI) (K08 HL132109) and was also supported by the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) under award number UL1TR002389 that funds the Institute for Translational Medicine. Dr. Bhavani is supported by the Research Training in Respiratory Biology award from NHLBI (T32HL007605). Dr. Churpek is supported by a career development award from the NHLBI (K08 HL121080) and an R01 from National Institute of General Medical Sciences (R01 GM123193). Dr. Churpek has a patent pending (ARCD. P0535US.P2) for risk stratification algorithms for hospitalized patients, and he received research support from EarlySense (Tel Aviv, Israel). Drs. Verhoef and Churpek received support for article research from the NIH. Mr. Carey has disclosed that he does not have any potential conflicts of interest. Address requests for reprints to: Philip A. Verhoef, MD, PhD, FACP, FAAP, Kaiser Permanente Internal Medicine Residency Program, Room 3D04, 2828 Pa'a Street, Honolulu, HI 96819. E-mail: Philip.verhoef@gmail.com Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.