Which Multicenter Randomized Controlled Trials in Critical Care Medicine Have Shown Reduced Mortality? A Systematic Review Objectives: To determine which multicenter randomized controlled trials in critically ill patients have shown that the study intervention was associated with a statistically significant reduction in mortality. Our analysis provides an update to a report published 10 years ago. Data Sources: MEDLINE database and PubMed interface from inception until April 30, 2019. Study Selection: All adult multicenter randomized controlled trials that evaluated the effects of any intervention or monitoring system in critically ill patients and reported mortality as a primary or secondary outcome were included. Data Extraction: Numbers of centers and patients, type of intervention, reported mortality outcome, and rate and level of significance were extracted into predefined tables. Included randomized controlled trials were classified as reporting reduced, increased, or no effect of the intervention on mortality. Methodologic quality of trials was evaluated using the updated Consolidated Standards of Reporting Trials statement. Data Synthesis: A total of 212 trials met the inclusion criteria: 27 (13%) reported a significant reduction in mortality, 16 (7%) an increase in mortality, and 170 (80%) no difference in mortality (one study was reported in 2 groups). Of the 27 trials reporting reduced mortality, six had assessed interventions likely to decrease ventilator-induced lung injury, including low tidal volume, prone position, and neuromuscular blockers, demonstrating the negative effects of mechanical ventilation strategies or improved process of care rather than positive effects of new therapies. Seven of the 27 trials reported beneficial effects of noninvasive ventilation. Results from some positive randomized controlled trials, for example, studies of recombinant activated protein C, talactoferrin, interleukin-1 receptor antagonist in sepsis, and muscle relaxants in severe acute respiratory distress syndrome were not replicated in subsequent randomized controlled trials. Other interventions, for example, gastric tonometry, have been abandoned. Conclusions: A systematic literature search provided no conclusive evidence of any pharmacologic intervention that has consistently reduced mortality in critically ill patients. Strategies associated with improved or noninvasive mechanical ventilation were associated with reduced mortality. Drs. Santacruz and Vincent designed the study. Drs. Santacruz and Pereira performed the literature search and extracted the data. Dr. Santacruz wrote the first draft of the article. Drs. Pereira, Celis, and Vincent reviewed the article for critical content. All authors read and approved the final text. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: jlvincent@intensive.org Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Lung Purinoceptor Activation Triggers Ventilator-Induced Brain Injury Objectives: Mechanical ventilation can cause ventilator-induced brain injury via afferent vagal signaling and hippocampal neurotransmitter imbalances. The triggering mechanisms for vagal signaling during mechanical ventilation are unknown. The objective of this study was to assess whether pulmonary transient receptor potential vanilloid type-4 (TRPV4) mechanoreceptors and vagal afferent purinergic receptors (P2X) act as triggers of ventilator-induced brain injury. Design: Controlled, human in vitro and ex vivo studies, as well as murine in vivo laboratory studies. Setting: Research laboratory. Subjects: Wild-type, TRPV4-deficient C57BL/6J mice, 8–10 weeks old. Human postmortem lung tissue and human lung epithelial cell line BEAS-2B. Intervention: Mice subjected to mechanical ventilation were studied using functional MRI to assess hippocampal activity. The effects of lidocaine (a nonselective ion-channel inhibitor), P2X-purinoceptor antagonist (iso-PPADS), or genetic TRPV4 deficiency on hippocampal dopamine-dependent pro-apoptotic signaling were studied in mechanically ventilated mice. Human lung epithelial cells (BEAS-2B) were used to study the effects of mechanical stretch on TRPV4 and P2X expression and activation. TRPV4 levels were measured in postmortem lung tissue from ventilated and nonventilated patients. Measurements and Main Results: Hippocampus functional MRI analysis revealed considerable changes in response to the increase in tidal volume during mechanical ventilation. Intratracheal lidocaine, iso-PPADS, and TRPV4 genetic deficiency protected mice against ventilationinduced hippocampal pro-apoptotic signaling. Mechanical stretch in both, BEAS-2B cells and ventilated wild-type mice, resulted in TRPV4 activation and reduced Trpv4 and P2x expression. Intratracheal replenishment of adenosine triphosphate in Trpv4–/– mice abrogated the protective effect of TRPV4 deficiency. Autopsy lung tissue from ventilated patients showed decreased lung TRPV4 levels compared with nonventilated patients. Conclusions: TRPV4 mechanosensors and purinergic receptors are involved in the mechanisms of ventilator-induced brain injury. Inhibition of this neural signaling, either using nonspecific or specific inhibitors targeting the TRPV4/adenosine triphosphate/P2X signaling axis, may represent a novel strategy to prevent or treat ventilator-induced brain injury. Drs. González-López, Pickerodt, Muniz Albaiceta, Francis, and Spies helped with delineation of hypotheses, and conception and design of the study; González-López, López-Alonso, von Haefen, Amado-Rodríguez, Reimann, and Niendorf helped with acquisition, analysis, and interpretation of data; and Drs. González-López, Kuebler, Muniz Albaiceta, and Francis helped with writing the article or substantial involvement in its revision before submission. 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. Francis and Spies contributed equally. Drs. González-López, Pickerodt, Albaiceta, Francis, and Spies helped with delineation of hypotheses, and conception and design of the study. Drs. González-López, López-Alonso, von Haefen, Amado-Rodríguez, Reimann, and Niendorf helped with acquisition, analysis, and interpretation of data. Drs. González-López, Kuebler, Albaiceta, and Francis helped with writing the article or substantial involvement in its revision before submis Supported by a grant from the Deutsche Forschungsgemeinschaft (DFG GO2666/2; to Drs. González-López and Francis). Presented, in part, at the annual conference of the American Thoracic Association, May 23, 2018 (7448–“Transient Receptor Potential Vanilloid 4 [TRPV4] Channels as Trigger Mechanisms of Ventilator Induced Brain Injury [VIBI],” B22 session “Critical Care: Microbiome, Genetics, and Other Biomarkers in Acute Critical Illness”) in San Diego, CA Dr. González-López’s institution received funding from Deutsche Forschungsgemeinschaft (DFG GO2666/2). Dr. Pickerodt disclosed government work. Dr. Amado-Rodríguez was supported with a grant from Instituto de Salud Carlos III (Rio Hortega, CM16/00128). Drs. López-Alonso, Amado-Rodríguez, and Albaiceta received funding from Instituto de Salud Carlos III (PI16/01614 European Regional Development Funds, FEDER funds) and Centro de Investigacion Biomedica en Red, CIBER-Enfermedades Respiratorias (CB17/06/00021). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: adrian.gonzales-lopez@charite.de This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Ramelteon for Prevention of Postoperative Delirium: A Randomized Controlled Trial in Patients Undergoing Elective Pulmonary Thromboendarterectomy Objectives: To assess the efficacy of ramelteon in preventing delirium, an acute neuropsychiatric condition associated with increased morbidity and mortality, in the perioperative, ICU setting. Design: Parallel-arm, randomized, double-blinded, placebo-controlled trial. Setting: Academic medical center in La Jolla, California. Patients: Patients greater than or equal to 18 years undergoing elective pulmonary thromboendarterectomy. Interventions: Ramelteon 8 mg or matching placebo starting the night prior to surgery and for a maximum of six nights while in the ICU. Measurements and Main Results: Incident delirium was measured twice daily using the Confusion Assessment Method-ICU. The safety outcome was coma-free days assessed by the Richmond Agitation-Sedation Scale. One-hundred twenty participants were enrolled and analysis completed in 117. Delirium occurred in 22 of 58 patients allocated to placebo versus 19 of 59 allocated to ramelteon (relative risk, 0.8; 95% CI, 0.5–1.4; p = 0.516). Delirium duration, as assessed by the number of delirium-free days was also similar in both groups (placebo median 2 d [interquartile range, 2–3 d] vs ramelteon 3 d [2–5 d]; p = 0.181). Coma-free days was also similar between groups (placebo median 2 d [interquartile range, 1–3 d] vs ramelteon 3 d [2–4 d]; p = 0.210). We found no difference in ICU length of stay (median 4 d [interquartile range, 3–5 d] vs 4 d [3–6 d]; p = 0.349), or in-hospital mortality (four vs three deaths; relative risk ratio, 0.7; 95% CI, 0.2–3.2; p = 0.717), all placebo versus ramelteon, respectively. Conclusions: Ramelteon 8 mg did not prevent postoperative delirium in patients admitted for elective cardiac surgery. All of the above authors contributed to this article by participation in the research and preparation of the article. Additionally, all authors had access to the data and a role in writing 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 National Institutes of Health/National Center for Advancing Translational Sciences flagship Clinical and Translational Science Award Grant (KL2 TR001112 and UL1 TR001114). Drs. Jaiswal and Maholtra received support for article research from the National Institutes of Health. Drs. Jaiswal, Fernandes, and Owens disclosed off-label product use of ramelteon for delirium prevention. Dr. Owens received funding from ResMed (consulting), Novartis, and expert testimony. The remaining authors have disclosed that they do not have any potential conflicts of interest. Trial Registration: Registered at ClinicalTrials.gov: NCT02691013. Registered on February 24, 2016, by principal investigator, Dr. Owens. Data Statement: The protocol and de-identified data for this study are available upon reasonable request to the authors via email to rowens@ucsd.edu. For information regarding this article, E-mail: stuti@scripps.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Phosphorylated Hexa-Acyl Disaccharides Augment Host Resistance Against Common Nosocomial Pathogens Objectives: To determine whether synthetic phosphorylated hexa-acyl disaccharides provide antimicrobial protection in clinically relevant models of bacterial infection. Design: Laboratory study. Setting: University laboratory. Subjects: BALB/c, C57BL/10J, and C57BL/10ScNJ mice. Interventions: Mice were treated with lactated Ringer’s (vehicle) solution, monophosphoryl lipid A, or phosphorylated hexa-acyl disaccharides at 48 and 24 hours prior to intraperitoneal Pseudomonas aeruginosa or IV Staphylococcus aureus infection. Leukocyte recruitment, cytokine production, and bacterial clearance were measured 6 hours after P. aeruginosa infection. In the systemic S. aureus infection model, one group of mice was monitored for 14-day survival and another for S. aureus tissue burden at 3 days postinfection. Duration of action for 3-deacyl 6-Acyl phosphorylated hexa-acyl disaccharide was determined at 3, 10, and 14 days using a model of intraperitoneal P. aeruginosa infection. Effect of 3-deacyl 6-Acyl phosphorylated hexa-acyl disaccharide on in vivo leukocyte phagocytosis and respiratory burst was examined. Leukocyte recruitment, cytokine production, and bacterial clearance were measured after P. aeruginosa infection in wild-type and toll-like receptor 4 knockout mice treated with 3-deacyl 6-Acyl phosphorylated hexa-acyl disaccharide or vehicle to assess receptor specificity. Measurements and Main Results: During intraperitoneal P. aeruginosa infection, phosphorylated hexa-acyl disaccharides significantly attenuated infection-induced hypothermia, augmented leukocyte recruitment and bacterial clearance, and decreased cytokine production. At 3 days post S. aureus infection, bacterial burden in lungs, spleen, and kidneys was significantly decreased in mice treated with monophosphoryl lipid A or phosphorylated hexa-acyl disaccharides, which was associated with improved survival. Leukocyte phagocytosis and respiratory burst functions were enhanced after treatment with monophosphoryl lipid A or phosphorylated hexa-acyl disaccharides. A time course study showed that monophosphoryl lipid A– and 3-deacyl 6-Acyl phosphorylated hexa-acyl disaccharide–mediated protection against P. aeruginosa lasts for up to 10 days. Partial loss of augmented innate antimicrobial responses was observed in toll-like receptor 4 knockout mice treated with 3-deacyl 6-Acyl phosphorylated hexa-acyl disaccharide. Conclusions: Phosphorylated hexa-acyl disaccharides significantly augment resistance against clinically relevant Gram-negative and Gram-positive infections via enhanced leukocyte recruitment, phagocytosis, and respiratory burst functions of innate leukocytes. Improved antimicrobial protection persists for up to 10 days and is partially mediated through toll-like receptor 4. Drs. Hernandez, Sherwood, and Bohannon designed and supervised the experiments. Drs. Hernandez and Luan, Ms. Fults, and Dr. Fensterheim performed the experiments. Drs. Hernandez, Sherwood, and Bohannon analyzed the data. Mr. Stothers, Dr. Guo, and Ms. Wang performed experiments. Drs. Hernandez and Luan, Mr. Stothers, and Drs. Patil, Guo, Sherwood, and Bohannon critically revised the article for important intellectual content. Drs. Hernandez and Bohannon wrote 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 U.S. National Institutes of Health, Institute of General Medicine Grants K08 GM123345 (to Dr. Hernandez), R01 GM121711 (to Dr. Bohannon), R01 GM104306 (to Dr. Sherwood), and T32 grant, 5T32GM108554-05 (to Dr. Delpire). Drs. Hernandez and Luan, Mr. Stothers, and Drs. Patil, Fensterheim, Guo, Sherwood, and Bohannon received support for article research from the National Institutes of Health (NIH). Dr. Sherwood’s institution received funding 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: antonio.hernandez@vanderbilt.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

The Nursing Activities Score per Nurse Ratio Is Associated With In-Hospital Mortality, Whereas the Patients Per Nurse Ratio Is Not Objectives: Studies have shown contradicting results on the association of nursing workload and mortality. Most of these studies expressed workload as patients per nurse ratios; however, this does not take into account that some patients require more nursing time than others. Nursing time can be quantified by tools like the Nursing Activities Score. We investigated the association of the Nursing Activities Score per nurse ratio, respectively, the patients per nurse ratio with in-hospital mortality in ICUs. Design: Retrospective analysis of the National Intensive Care Evaluation database. Setting: Fifteen Dutch ICUs. Patients: All ICU patients admitted to and registered ICU nurses working at 15 Dutch ICUs between January 1, 2016, and January 1, 2018, were included. The association of mean or day 1 patients per nurse ratio and Nursing Activities Score per nurse ratio with in-hospital mortality was analyzed using logistic regression models. Interventions: None. Measurements and Main Results: Nursing Activities Score per nurse ratio greater than 41 for both mean Nursing Activities Score per nurse ratio as well as Nursing Activities Score per nurse ratio on day 1 were associated with a higher in-hospital mortality (odds ratios, 1.19 and 1.17, respectively). After case-mix adjustment the association between a Nursing Activities Score per nurse ratio greater than 61 for both mean Nursing Activities Score per nurse ratio as well as Nursing Activities Score per nurse ratio on day 1 and in-hospital mortality remained significant (odds ratios, 1.29 and 1.26, respectively). Patients per nurse ratio was not associated with in-hospital mortality. Conclusions: A higher Nursing Activities Score per nurse ratio was associated with higher in-hospital mortality. In contrast, no association was found between patients per nurse ratios and in-hospital mortality in the Netherlands. Therefore, we conclude that it is more important to focus on the nursing workload that the patients generate rather than on the number of patients the nurse has to take care of in the ICU. 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 funding by the National Intensive Care Evaluation foundation does not alter the authors’ adherence to all Intensive Care Medicine policies on sharing data and materials. Prof. Dr. de Keizer, Dr. Brinkman and Drs. Margadant’s department of Medical Informatics received funding from the National Intensive Care Evaluation (NICE) foundation to process and analyse data for the registry. Drs. Hoogendoorn, Bosman, and Spijkstra, and Prof. Dr. de Keizer are members of the board of NICE. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: c.c.margadant@amc.uva.nl Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Occupational Therapy in the ICU: A Scoping Review of 221 Documents Objectives: Occupational therapists have specialized expertise to enable people to perform meaningful “occupations” that support health, well-being, and participation in life roles. Given the physical, cognitive, and psychologic disability experienced by ICU survivors, occupational therapists could play an important role in their recovery. We conducted a scoping review to determine the state of knowledge of interventions delivered by occupational therapists in adult ICU patients. Data Sources: Eight electronic databases from inception to 05/2018. Study Selection: We included reports of adult patients receiving direct patient care from an occupational therapist in the ICU, all study designs, and quantitative and qualitative traditions. Data Extraction: Independently in duplicate, interprofessional team members screened titles, abstracts, and full texts and extracted report and intervention characteristics. From original research articles, we also extracted study design, number of patients, and primary outcomes. We resolved disagreements by consensus. Data Synthesis: Of 50,700 citations, 221 reports met inclusion criteria, 74 (79%) published after 2010, and 125 (56%) appeared in critical care journals. The three most commonly reported types of interventions were mobility (81%), physical rehabilitation (61%), and activities of daily living (31%). We identified 46 unique original research studies of occupational therapy interventions; the most common study research design was before-after studies (33%). Conclusions: The role of occupational therapists in ICU rehabilitation is not currently well established. Current interventions in the ICU are dominated by physical rehabilitation with a growing role in communication and delirium prevention and care. Given the diverse needs of ICU patients and the scope of occupational therapy, there could be an opportunities for occupational therapists to expand their role and spearhead original research investigating an enriched breadth of ICU interventions. 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 Knowledge Synthesis Grant from the Canadian Frailty Network (formerly Technology Evaluation in the Elderly Network) funded this study (KS 2013-13). Dr. Harris’s institution received funding from the Canadian Institutes of Health Research (CIHR). Dr. Baptiste disclosed that they received Research Knowledge Synthesis Grants in 2015 that provided the foundational funds to complete this study; the funds were held at McMaster University, Faculty of Health Sciences. Dr. Duffett was funded by a Fellowship from the CIHR and Hamilton Health Sciences Early Career Award during this project. Dr. Kho’s institution received funding from Canadian Frailty Network (formerly Technology Evaluation in the Elderly Network). Dr. Kho holds a Canada Research Chair in Critical Care Rehabilitation and Knowledge Translation from the CIHR. Dr. Costigan has disclosed that she does not have any potential conflicts of interest. For information regarding this article, E-mail: khome@mcmaster.ca Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Frequency, Risk Factors, Causes, and Consequences of Diagnostic Errors in Critically Ill Medical Patients: A Retrospective Cohort Study Objective: Diagnostic errors are a source of significant morbidity and mortality but understudied in the critically ill. We sought to characterize the frequency, causes, consequences, and risk factors of diagnostic errors among unplanned ICU admissions. Design: We conducted a retrospective cohort study of randomly selected nonsurgical ICU admissions between July 2015 and June 2016. Setting: Medical ICU at a tertiary academic medical center. Subjects: Critically ill adults with unplanned admission to the medical ICU. Measurements and Main Results: The primary investigator reviewed patient records using a modified version of the Safer Dx instrument, a validated instrument for detecting diagnostic error. Two intensivists performed secondary reviews of possible errors, and reviewers met periodically to adjudicate errors by consensus. For each confirmed error, we judged harm on a 1–6 rating scale. We also collected detailed demographic and clinical data for each patient. We analyzed 256 unplanned ICU admissions and identified 18 diagnostic errors (7% of admissions). All errors were associated with harm, and only six errors (33%) were recognized by the ICU team within the first 24 hours. More women than men experienced a diagnostic error (11.7% vs 2.7%; p = 0.015, χ2 test). On multivariable logistic regression analysis, female sex remained independently associated with risk of diagnostic error both at admission (odds ratio, 5.18; 95% CI, 1.34–20.08) and at 24 hours (odds ratio, 11.6; 95% CI, 1.37–98.6). Similarly, Quick Sequential Organ Failure Assessment score greater than or equal to 2 at admission was independently associated with diagnostic error (odds ratio, 5.73; 95% CI, 1.72—19.01). Conclusions: Diagnostic errors may be an underappreciated source of ICU-related harm. Women and higher acuity patients appear to be at increased risk for such errors. Further research is merited to define the scope of error-associated harm and to clarify risk factors for diagnostic errors among the critically ill. The content is solely the responsibility of the author(s) and does not necessarily represent the official views of the National Institutes of Health or any other funding agency. Dr. Bergl initiated this project, prepared the study protocol, collected and analyzed the data, and drafted the article. Dr. Taneja contributed to the protocol design and participated in data collection, analysis, and interpretation. Drs. El-Kareh and Singh provided critical input into the study design and appropriate analytical methods and aided in interpretation of the results. Dr. Nanchal also partook in protocol design, collected and analyzed the data, performed sample size calculations and statistical analyses, and aided in the drafting of the article. All authors contributed important intellectual content and made critical revisions to the article, and all authors read and approved this submission. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by the National Center for Advancing Translational Sciences, National Institutes of Health, Award Number UL1TR001436. Dr. Singh disclosed government work. He is partly supported by the VA Health Services Research and Development Service Center for Innovations in Quality, Effectiveness and Safety (CIN13-413). The remaining authors have disclosed that they do not have any potential conflicts of interest. This study was reviewed by the institutional review board at the Medical College of Wisconsin and was deemed exempt from oversight. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For information regarding this article, E-mail: pbergl@mcw.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Impact of Critical Illness on Resource Utilization: A Comparison of Use in the Year Before and After ICU Admission* Objectives: Increasingly, patients admitted to an ICU survive to hospital discharge; many with ongoing medical needs. The full impact of an ICU admission on an individual’s resource utilization and survivorship trajectory in the United States is not clear. We sought to compare healthcare utilization among ICU survivors in each year surrounding an ICU admission. Design: Retrospective cohort of patients admitted to an ICU during one calendar year (2012) in a multipayer healthcare system. We assessed mortality, hospital readmissions (categorized by ambulatory care sensitive conditions and emergency department), and outpatient visits. We compared the proportion of patients with visits during the pre-ICU year versus the post-ICU year. Patients: People admitted to an Intermountain healthcare ICU for greater than 48 hours in the year 2012 Interventions: None. Measurements and Main Results: Among 4,074 ICU survivors, 45% had increased resource utilization. Readmission rates at 30-day, 90-day, and 1-year were 15%, 26%, and 43%. The proportion of patients with a hospital admission increased significantly in the post-ICU period (43% vs 29%; p < 0.001). Of patients with a readmission in the post-ICU period, 24% were ambulatory care sensitive condition. Patients with increased utilization differed by socioeconomic status, insurance type, and severity of illness. Sixteen percent of patients had either an emergency department or inpatient admission, but no outpatient visits during the post-ICU period. Conclusions: An ICU admission is associated with increased resource utilization including hospital readmissions, with many due to an ambulatory care sensitive condition. Lower socioeconomic status and higher severity of illness are associated with increased resource utilization. After an ICU visit patients seem to use hospital resources over outpatient resources. Interventions to improve and coordinate care after ICU discharge are needed. Drs. Hirshberg, Hopkins, and Brown and Ms. Wilson conceptualize the article. Drs. Hirshberg, Kuttler, and Brown, Ms. Wilson, and Ms. Stanfield acquire the data. Drs. Hirshberg, Majercik, Beesley, Orme, and Brown and Ms. Wilson analyze the data. Drs. Hirshberg, Majercik, Beesley, Orme, Hopkins, and Brown write the article. All authors approve the final copy and revise 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). Supported, in part, by grant from the departmental funds. Dr. Hopkins’ institution received funding from Intermountain Research and Medical Foundation to study outcomes of family caregivers of ICU patients. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: Ellie.hirshberg@imail.org; ellie.hirshberg@hsc.utah.edu This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Clinical Practice Guidelines and Consensus Statements About Pain Management in Critically Ill End-of-Life Patients: A Systematic Review Objectives: To identify and synthesize available recommendations from scientific societies and experts on pain management at the end-of-life in the ICU. Data Sources: We conducted a systematic review of PubMed, EMBASE, the Cochrane Database of Systematic Reviews, and Biblioteca Virtual en Salud from their inception until March 28, 2019. Study Selection: We included all clinical practice guidelines, consensus statements, and benchmarks for quality. Data Extraction: Study selection, methodological quality, and data extraction were performed independently by two investigators. A quality assessment was performed by four investigators using the Appraisal of Guidelines for Research and Evaluation II instrument. The recommendations were then synthesized and categorized. Data Synthesis: Ten publications were included. The Appraisal of Guidelines for Research and Evaluation II statement showed low scores in various quality domains, especially in the applicability and rigor of development. Most documents were in agreement on five topics: 1) using a quantitative tool for pain assessment; 2) administering narcotics for pain relief and benzodiazepines for anxiety relief; 3) against prescribing neuromuscular blockers during withdrawal of life support to assess pain; 4) endorsing the use of high doses of opioids and sedatives for pain control, regardless of the risk that they will hasten death; and 5) using quality indicators to improve pain management during end-of-life in the ICU. Conclusions: In spite of the lack of high-quality evidence, recommendations for pain management at the end-of-life in the ICU are homogeneous and are justified by ethical principles and agreement among experts. Considering the growing demand for the involvement of palliative care teams in the management of the dying patients in the ICU, there is a need to clearly define their early involvement and to further develop comprehensive evidence-based pain management strategies. Based on the study findings, we propose a management algorithm to improve the overall care of dying critically ill patients. Drs. Durán-Crane and Laserna contributed equally. 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. Durán-Crane disclosed he was previously employed by Fundacion Santa Fe de Bogotá, Colombia. Dr. Lopez-Olivo’s work is supported by a career award from the Rheumatology Research Foundation. Dr. Nates’ institution received funding from the George Sweeney Fellowship grant of the MD Anderson resources grant. The remaining authors have disclosed that they do not have any potential conflicts of interest. Systematic Review Registration: PROSPERO Number CRD42018089489. For information regarding this article, E-mail: jlnates@mdanderson.org Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Circuit Hemodynamics and Circuit Failure During Continuous Renal Replacement Therapy Objectives: To study hemodynamic changes within continuous renal replacement therapy circuits and evaluate their relationship with continuous renal replacement therapy longevity. Design: Analysis of downloaded variables recorded by continuous renal replacement therapy machines during multiple episodes of clinical care. Setting: Tertiary ICU in Melbourne, Australia. Patients: Cohort of 149 ICU patients: 428 episodes of continuous renal replacement therapy. Interventions: None. Measurements and Main Results: Indices of continuous renal replacement therapy function representing 554,991 minutes were assessed including blood flow, access pressure, effluent pressure, prefilter pressure, and return pressure. We defined three patterns of artificial kidney failure: early (≤ 12 hr), intermediate (> 12–24 hr), and late (> 24 hr) in 35%, 31%, and 34% of circuits, respectively. Mean access pressure in late artificial kidney failure was 7.5 mm Hg (7.1–7.9 mm Hg) less negative than early failing circuits and pressures demonstrated lower variability in such late failing circuits. Access dysfunction, defined as access pressure less than or equal to –200 mm Hg occurred in the first 4 hours in 118 circuits (27%) which had a shorter (median [interquartile range]) life at 12.9 hr [5.5–21.3 hr]) hours than access dysfunction-free circuits (18.8 hr [10.1–33.4 hr]; p < 0.0001). Multivariate analysis found the first occurrence of access dysfunction (as a time-varying covariate) was independently associated with increased hazard of subsequent failure (hazard ratio, 1.75; 1.36–2.26). Classification and regression tree analysis of summary pressure indices in the first 2 hours confirmed minimum access pressure to be a significant predictor, as well as indices of transmembrane pressure and return pressure. A pressure-based predictor correctly identified early and late failing circuits (86.2% and 93.6% specificity, respectively). Conclusions: Access dysfunction is a predictor of continuous renal replacement therapy circuit failure. Future monitoring of continuous renal replacement therapy hemodynamics may facilitate remedial actions to improve circuit function. 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. Sansom receives a research scholarship from the University of Melbourne. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: rinaldo.bellomo@mh.org.au Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.