Critical Care Medicine

Changes in the Plethysmographic Perfusion Index During an End-Expiratory Occlusion Detect a Positive Passive Leg Raising Test Objectives: The end-expiratory occlusion test for assessing preload responsiveness consists in interrupting mechanical ventilation for 15 seconds at end-expiration and measuring the cardiac index changes. The perfusion index is the ratio between the pulsatile and the nonpulsatile portions of the plethysmography signal and is, in part, determined by stroke volume. We tested whether the end-expiratory occlusion-induced changes in perfusion index could detect a positive passive leg raising test, suggesting preload responsiveness. Design: Observational study. Setting: Medical ICU. Patients: Thirty-one ventilated patients without atrial fibrillation. Interventions: We measured perfusion index (Radical-7 device; Masimo Corp., Irvine, CA) and cardiac index (PiCCO2; Pulsion Medical Systems, Feldkirchen, Germany) before and during a passive leg raising test and a 15-second end-expiratory occlusion. Measurements and Main Results: In 19 patients with a positive passive leg raising test (increase in cardiac index ≥ 10%), compared to the baseline value and expressed as a relative change, passive leg raising increased cardiac index and perfusion index by 17% ± 7% and 49% ± 23%, respectively, In these patients, end-expiratory occlusion increased cardiac index and perfusion index by 6% ± 2% and 11% ± 8%, respectively. In the 12 patients with a negative passive leg raising test, perfusion index did not significantly change during passive leg raising and end-expiratory occlusion. Relative changes in perfusion index and cardiac index observed during all interventions were significantly correlated (r = 0.83). An end-expiratory occlusion-induced relative increase in perfusion index greater than or equal to 2.5% ([perfusion index during end-expiratory occlusion–perfusion index at baseline]/perfusion index at baseline × 100) detected a positive passive leg raising test with an area under the receiver operating characteristic curve of 0.95 ± 0.03. This threshold is larger than the least significant change observed for perfusion index (1.62% ± 0.80%). Conclusions: Perfusion index could be used as a reliable surrogate of cardiac index for performing the end-expiratory occlusion test. Confirming previous results, the relative changes in perfusion index also reliably detected a positive passive leg raising test. 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. Beurton collected the data, performed data analysis, drafted the article, and approved its final version. Dr. Teboul conceived the study, participated in analyzing the data and to writing the article, and approved its final version. Drs. Gavelli and De Vita contributed to data recording and approved the final version of the article. Dr. Monnet conceived the study, supervised data analysis, drafted the article, and approved its final version. All authors read and approved the final article. Dr. Teboul received funding from Getinge/Pulsion. Dr. Monnet received funding from Pulsion Medical Systems, and he received support for article research from Assistance publique-Hôpitaux de Paris. Drs. Teboul and Monnet are members of the Medical Advisory Board of Pulsion Medical Systems and have given lectures for Masimo Corp. The remaining authors have disclosed that they do not have any potential conflicts of interest. Information and consent obtained for each patient. Name of the ethics committee that approved the study and the committee's reference number: Comité pour la Protection des Personnes, Ile-de-France VII. Trial registration ID RCB: 2016-A00959-42. Registered June 27, 2016. The patients were included prospectively. Information and consent obtained for each patient. For information regarding this article, E-mail: alexandra.beurton@aphp.fr Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

CNS Complications in Adult Patients Treated With Extracorporeal Membrane Oxygenation Objectives: To describe the incidence and outcomes of radiologically confirmed acute CNS complications in extracorporeal membrane oxygenation patients at an Australian extracorporeal membrane oxygenation referral center and identify associated patient characteristics. Design: Retrospective cohort study. Setting: Single-center tertiary institution. Patients: Four-hundred twelve consecutive adult patients supported with extracorporeal membrane oxygenation from 2009 to 2017. Results: Fifty-five patients (13.3%) had a CNS complication confirmed by CT or MRI, including ischemic stroke (7.0%), intracerebral hemorrhage (3.4%), hypoxic ischemic encephalopathy (3.6%), and spinal cord injury (1.2%). CNS complication rates in the venoarterial, venovenous, and veno-pulmonary artery extracorporeal membrane oxygenation subgroups were 18.0%, 4.6%, and 13.6%, respectively. Neurologic complications were independently associated with the use of venoarterial extracorporeal membrane oxygenation (p = 0.002) and renal replacement therapy (p = 0.04). Sixty-five percent of patients with a neurologic complication died during their hospital admission compared with 32% of patients without this complication (p < 0.001). Venoarterial extracorporeal membrane oxygenation, renal replacement therapy, and days of extracorporeal membrane oxygenation support were also associated with hospital mortality and remained so after adjustment in a multivariable regression model (p = 0.01, p < 0.001, and p = 0.003, respectively). Conclusions: CNS complications appear to occur more frequently in patients requiring circulatory as opposed to respiratory support on extracorporeal membrane oxygenation and are independently associated with mortality. It remains unclear if these complications are causative of a poor outcome or a marker of severity of the underlying condition. Further research is required to better elucidate modifiable or preventable aspects through better patient selection and change in ongoing care. 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. Kerr disclosed work for hire. The remaining authors have disclosed that they do not have any potential conflicts of interest. This work was performed at Department of Intensive Care Medicine, St Vincent's Hospital, Darlinghurst, NSW, Australia. For information regarding this article, E-mail: Hergen.Buscher@svha.org.au Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Mortality of Older Patients Admitted to an ICU: A Systematic Review Objectives: To conduct a systematic review of mortality and factors independently associated with mortality in older patients admitted to ICU. Data Sources: MEDLINE via PubMed, EMBASE, the Cochrane Library, and references of included studies. Study Selection: Two reviewers independently selected studies conducted after 2000 evaluating mortality of older patients (≥ 75 yr old) admitted to ICU. Data Extraction: General characteristics, mortality rate, and factors independently associated with mortality were extracted independently by two reviewers. Disagreements were solved by discussion within the study team. Data Synthesis: Because of expected heterogeneity, no meta-analysis was performed. We selected 129 studies (median year of publication, 2015; interquartile range, 2012–2017) including 17 based on a national registry. Most were conducted in Europe and North America. The median number of included patients was 278 (interquartile range, 124–1,068). ICU and in-hospital mortality were most frequently reported with considerable heterogeneity observed across studies that was not explained by study design or location. ICU mortality ranged from 1% to 51%, in-hospital mortality from 10% to 76%, 6-month mortality from 21% to 58%, and 1-year mortality from 33% to 72%. Factors addressed in multivariate analyses were also heterogeneous across studies. Severity score, diagnosis at admission, and use of mechanical ventilation were the independent factors most frequently associated with ICU mortality, whereas age, comorbidities, functional status, and severity score at admission were the independent factors most frequently associated with 3– 6 and 12 months mortality. Conclusions: In this systematic review of older patients admitted to intensive care, we have documented substantial variation in short- and long-term mortality as well as in prognostic factors evaluated. To better understand this variation, we need consistent, high-quality data on pre-ICU conditions, ICU physiology and treatments, structure and system factors, and post-ICU trajectories. These data could inform geriatric care bundles as well as a core data set of prognostic factors to inform patient-centered decision-making. 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 institutional sources. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: helene.vallet@aphp.fr Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Surrogate Humane Endpoints in Small Animal Models of Acute Lung Injury: A Modified Delphi Consensus Study of Researchers and Laboratory Animal Veterinarians Objectives: In many jurisdictions, ethical concerns require surrogate humane endpoints to replace death in small animal models of acute lung injury. Heterogenous selection and reporting of surrogate endpoints render interpretation and generalizability of findings between studies difficult. We aimed to establish expert-guided consensus among preclinical scientists and laboratory animal veterinarians on selection and reporting of surrogate endpoints, monitoring of these models, and the use of analgesia. Design: A three-round consensus process, using modified Delphi methodology, with researchers who use small animal models of acute lung injury and laboratory animal veterinarians who provide care for these animals. Statements on the selection and reporting of surrogate endpoints, monitoring, and analgesia were generated through a systematic search of MEDLINE and Embase. Participants were asked to suggest any additional potential statements for evaluation. Setting: A web-based survey of participants representing the two stakeholder groups (researchers, laboratory animal veterinarians). Statements were rated on level of evidence and strength of support by participants. A final face-to-face meeting was then held to discuss results. Subjects: None. Interventions: None. Measurements and Main Results: Forty-two statements were evaluated, and 29 were rated as important, with varying strength of evidence. The majority of evidence was based on rodent models of acute lung injury. Endpoints with strong support and evidence included temperature changes and body weight loss. Behavioral signs and respiratory distress also received support but were associated with lower levels of evidence. Participants strongly agreed that analgesia affects outcomes in these models and that none may be necessary following nonsurgical induction of acute lung injury. Finally, participants strongly supported transparent reporting of surrogate endpoints. A prototype composite score was also developed based on participant feedback. Conclusions: We provide a preliminary framework that researchers and animal welfare committees may adapt for their needs. We have identified knowledge gaps that future research should address. 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. Fergusson, Stewart, McIntyre, and Lalu contributed to conceptualization. Drs. Fergusson, Stewart, McIntyre, Stacey, and Lalu contributed to methodology. Drs. McGinn, MacNeil, and Lalu contributed to formal analysis. Drs. McGinn, Fergusson, Stewart, MacNeil, and Lalu contributed to investigation. Drs. McGinn and Lalu contributed to data curation. Drs. McGinn, Barron, and Lalu contributed to writing—original draft. Drs. McGinn, MacNeil, and Lalu contributed to visualization. Drs. Fergusson, Stewart, and Lalu contributed to supervision. Drs. McGinn, Barron, MacNeil, and Lalu contributed to project administration. Drs. Fergusson, Stewart, McIntyre, and Lalu contributed to funding acquisition. All coauthors contributed to writing, review, and editing. Supported, in part, by a planning and dissemination grant from the Canadian Institutes for Health Research (no 345325), a New Ideas Grant from the Ontario Institutes for Regenerative Medicine, and a Grant-in-Aid from the Ontario Lung Association (Drs. Stewart, McIntyre, and Lalu). Drs. McGinn, Fergusson, Barron, Liu, and Lalu institutions received funding from Canadian Institutes of Health Research (CIHR). Dr. Kristof received funding from Ottawa Hospital Research Institute (travel costs). Dr. Downey received support for article research from the National Institutes of Health. Dr. Brown received support for article research from CIHR. Dr. dos Santos disclosed that she is funded by CIHR. Dr. Lalu is supported by The Ottawa Hospital Anesthesia Alternate Funds Association and the University of Ottawa Junior Research Chair in Innovative Translational Research. All of work was completed at the Ottawa Hospital Research Institute in Ottawa, ON, Canada. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: mlalu@toh.ca or manojlalu@gmail.com Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Effectiveness of Bundle Interventions on ICU Delirium: A Meta-Analysis Objective: To evaluate the impact of bundle interventions on ICU delirium prevalence, duration, and other patients' adverse outcomes. Data Sources: The Cochrane Library, PubMed, CINAHL, EMBASE, PsychINFO, and MEDLINE from January 2000 to July 2020. The protocol of the study was registered in International prospective register of systematic reviews (CRD42020163147). Study Selection: Randomized clinical trials or cohort studies that examined the following outcomes were included in the current study: ICU delirium prevalence and duration, proportion of patient-days with coma, ventilator-free days, mechanical ventilation days, ICU or hospital length of stay, and ICU or inhospital or 28-day mortality. Data Extraction: Using a standardized data-collection form, two authors screened the studies and extracted the data independently, and assessed the studies' quality using the Modified Jadad Score Scale for randomized clinical trials and the Newcastle-Ottawa Scale for cohort studies. Data Synthesis: Eleven studies with a total of 26,384 adult participants were included in the meta-analysis. Five studies (three randomized clinical trials and two cohort studies) involving 18,638 patients demonstrated that ICU delirium prevalence was not reduced (risk ratio = 0.92; 95% CI, 0.68–1.24). Meta-analysis showed that the use of bundle interventions was not associated with shortening the duration of ICU delirium (mean difference = –1.42 d; 95% CI, –3.06 to 0.22; two randomized clinical trials and one cohort study), increasing ventilator-free days (mean difference = 1.56 d; 95% CI, –1.56 to 4.68; three randomized clinical trials), decreasing mechanical ventilation days (mean difference = –0.83 d; 95% CI, –1.80 to 0.14; four randomized clinical trials and two cohort studies), ICU length of stay (mean difference = –1.08 d; 95% CI, –2.16 to 0.00; seven randomized clinical trials and two cohort studies), and inhospital mortality (risk ratio = 0.86; 95% CI, 0.70–1.06; five randomized clinical trials and four cohort studies). However, bundle interventions are effective in reducing the proportion of patient-days experiencing coma (risk ratio = 0.47; 95% CI, 0.39–0.57; two cohort studies), hospital length of stay (mean difference = –1.47 d; 95% CI, –2.80 to –0.15; four randomized clinical trials and one cohort study), and 28-day mortality by 18% (risk ratio = 0.82; 95% CI, 0.69–0.99; three randomized clinical trials). Conclusions: This meta-analysis fails to support that bundle interventions are effective in reducing ICU delirium prevalence and duration, but supports that bundle interventions are effective in reducing the proportion of patient-days with coma, hospital length of stay, and 28-day mortality. Larger randomized clinical trials are needed to evaluate the impact of bundle interventions on ICU delirium and other clinical outcomes. 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 source had no role in the study design, data collection, data analysis, data explanation, or article writing. Dr. Wu is receiving a grant (#71661167008) from "the National Natural Science Foundation of China." The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: helenywu@vip.163.com 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 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Inspiratory Muscle Training With an Electronic Resistive Loading Device Improves Prolonged Weaning Outcomes in a Randomized Controlled Trial Objectives: To test if the use of an inspiratory muscle training program with an electronic resistive loading device is associated with benefits as to muscle strength, weaning, and survival in the ICU. Design: Prospective randomized controlled trial. Settings: Study conducted at the ICU of a Navy's hospital, Rio de Janeiro, Brazil, from January 2016 to September 2018. Patients: Tracheostomized patients (18–86 yr) on prolonged weaning. Interventions: Participants were assigned to inspiratory muscle training (intervention group) or a traditional T-piece protocol (control group). In the inspiratory muscle training group, participants underwent training with an electronic inspiratory training device (POWERbreathe K-5; Technologies Ltd, Birmingham, United Kingdom). MEASUREMENTS AND MAIN RESULTS: Changes in respiratory muscle strength and rates of ICU survival and weaning success were compared between groups. Forty-eight participants in the inspiratory muscle training group and 53 ones in the control group were included in the final analysis. The inspiratory muscle training was associated with a substantially higher gain on muscle strength as assessed by the maximal inspiratory pressure (70.5 [51.0–82.5] vs –48.0 cm H2O [36.0–72.0 cm H2O]; p = 0.003) and the timed inspiratory effort index (1.56 [1.25–2.08] vs 0.99 cm H2O/s [0.65–1.71 cm H2O/s]; p = 0.001). Outcomes at the 60th day of ICU were significantly better in the intervention group regarding both survival (71.1% vs 48.9%; p = 0.030) and weaning success (74.8% vs 44.5%; p = 0.001). Conclusions: The use of an inspiratory muscle training program with an electronic resistive loading device was associated with substantial muscle strength gain and positive impacts in two very relevant clinical outcomes: the rates of ICU survival and successful weaning. This work was performed at Hospital Naval Marcilio Dias, Rio de Janiero, Brazil (Brazil's Navy). This study was approved by the local Research Ethics Committee and was registered in a publicly accessible clinical trial database (ClinicalTrials.gov ID: NCT02932189). Approved by the institution's ethics committee under the number 45060215.3.0000.0065. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. All authors contributed substantially to the study design, data analysis and interpretation, and the writing of the article. All authors read and approved the final 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. de Souza disclosed that this study was partially supported by Universidade Estácio de Sá by a research productivity program and disclosed off-label product use of the digital vacuometer MVD 300 (Globalmed, Porto Alegre, Brazil) and the device POWERbreathe K-5 and the software (BreatheLink; Power Breathe International, Warwickshire, United Kingdom). Dr. Alvim disclosed government work. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: brunoguimaraespneumo@yahoo.com.br Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Timing, Outcome, and Risk Factors of Intracranial Hemorrhage in Acute Respiratory Distress Syndrome Patients During Venovenous Extracorporeal Membrane Oxygenation Objectives: Intracranial hemorrhage is a serious complication in patients receiving venovenous extracorporeal membrane oxygenation during treatment of the acute respiratory distress syndrome. We analyzed timing, outcome, and risk factors of intracranial hemorrhage in patients on venovenous extracorporeal membrane oxygenation. Design: Retrospective cohort study. Setting: Single acute respiratory distress syndrome referral center. Patients: Patients receiving venovenous extracorporeal membrane oxygenation were identified from a cohort of 1,044 patients with acute respiratory distress syndrome. Patients developing an intracranial hemorrhage during venovenous extracorporeal membrane oxygenation therapy were compared with patients without evidence for intracranial hemorrhage. The primary objective was to assess the association of intracranial hemorrhage with 60-day mortality. Further objectives included the identification of risk factors for intracranial hemorrhage and the evaluation of clinical cutoff values. Interventions: None. Measurements and Main Results: Among 444 patients treated with venovenous extracorporeal membrane oxygenation, 49 patients (11.0% [95% CI, 8.3–14.4%]) developed an intracranial hemorrhage. The median time to intracranial hemorrhage occurrence was 4 days (95% CI, 2–7 d). Patients who developed an intracranial hemorrhage had a higher 60-day mortality compared with patients without intracranial hemorrhage (69.4% [54.4–81.3%] vs 44.6% [39.6–49.6%]; odds ratio 3.05 [95% CI, 1.54–6.32%]; p = 0.001). A low platelet count, a high positive end expiratory pressure, and a major initial decrease of PaCO2 were identified as independent risk factors for the occurrence of intracranial hemorrhage. A platelet count greater than 100/nL and a positive end expiratory pressure less than or equal to 14 cm H2O during the first 7 days of venovenous extracorporeal membrane oxygenation therapy as well as a decrease of PaCO2 less than 24 mm Hg during venovenous extracorporeal membrane oxygenation initiation were identified as clinical cutoff values to prevent intracranial hemorrhage (sensitivity 91% [95% CI, 82–99%], 94% [85–99%], and 67% [48–81%], respectively). Conclusions: Intracranial hemorrhage occurs early during venovenous extracorporeal membrane oxygenation and is a determinant for 60-day mortality. Appropriate adjustment of identified modifiable risk factors might lower the prevalence of intracranial hemorrhage during venovenous extracorporeal membrane oxygenation therapy. The study was approved by the Medical Ethics Committee of Charité-Universitätsmedizin Berlin (No. EA1/007/19). Data are available from the corresponding author. Drs. Graw and Menk are co-senior authors. Dr. Menk contributed to conception and design and study supervision. Drs. Hunsicker, Beck, Graw, and Menk contributed to acquisition of data. Drs. Hunsicker, Beck, Weber-Carstens, Graw, and Menk contributed to interpretation of data. Drs. Hunsicker, Krannich, and Menk contributed to statistical analysis. Drs. Hunsicker, Graw, and Menk contributed to drafting of the article. All authors contributed to critical revision of the article for important intellectual content. Drs. Hunsicker, Weber-Carstens, Spies, Graw, and Menk contributed to final revision of 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 institutional sources only. Dr. Graw received funding from CSL Behring, and he is a participant in the BIH-Charité Clinician Scientist Program funded by the Charité – Universitätsmedizin Berlin and the Berlin Institute of Health. The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Mario Menk, MD, PhD, Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail: mario.menk@charite.de Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Procalcitonin Is Useful for Antibiotic Deescalation in Sepsis No abstract available

Determining Thresholds for Three Indices of Autoregulation to Identify the Lower Limit of Autoregulation During Cardiac Surgery Objectives: Monitoring cerebral autoregulation may help identify the lower limit of autoregulation in individual patients. Mean arterial blood pressure below lower limit of autoregulation appears to be a risk factor for postoperative acute kidney injury. Cerebral autoregulation can be monitored in real time using correlation approaches. However, the precise thresholds for different cerebral autoregulation indexes that identify the lower limit of autoregulation are unknown. We identified thresholds for intact autoregulation in patients during cardiopulmonary bypass surgery and examined the relevance of these thresholds to postoperative acute kidney injury. Design: A single-center retrospective analysis. Setting: Tertiary academic medical center. Patients: Data from 59 patients was used to determine precise cerebral autoregulation thresholds for identification of the lower limit of autoregulation. These thresholds were validated in a larger cohort of 226 patients. Methods and Main Results: Invasive mean arterial blood pressure, cerebral blood flow velocities, regional cortical oxygen saturation, and total hemoglobin were recorded simultaneously. Three cerebral autoregulation indices were calculated, including mean flow index, cerebral oximetry index, and hemoglobin volume index. Cerebral autoregulation curves for the three indices were plotted, and thresholds for each index were used to generate threshold- and index-specific lower limit of autoregulations. A reference lower limit of autoregulation could be identified in 59 patients by plotting cerebral blood flow velocity against mean arterial blood pressure to generate gold-standard Lassen curves. The lower limit of autoregulations defined at each threshold were compared with the gold-standard lower limit of autoregulation determined from Lassen curves. The results identified the following thresholds: mean flow index (0.45), cerebral oximetry index (0.35), and hemoglobin volume index (0.3). We then calculated the product of magnitude and duration of mean arterial blood pressure less than lower limit of autoregulation in a larger cohort of 226 patients. When using the lower limit of autoregulations identified by the optimal thresholds above, mean arterial blood pressure less than lower limit of autoregulation was greater in patients with acute kidney injury than in those without acute kidney injury. Conclusions: This study identified thresholds of intact and impaired cerebral autoregulation for three indices and showed that mean arterial blood pressure below lower limit of autoregulation is a risk factor for acute kidney injury after cardiac surgery. 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 Institutes of Health (NIH) K76 AG057020 (to Dr. Brown) and by NIH R01 NS107417 and the American Heart Association Transformational Project Award (cofunded by the Lawrence J. and Florence A. DeGeorge Charitable Trust) (to Dr. Lee). Drs. Lee, Hogue, and Brown received support for article research from the National Institutes of Health (NIH). Dr. Lee has received support from and been a paid consultant for Medtronic, and she received research support from Edwards Life Sciences. Dr. Lee's arrangements have been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. Some methods used to measure and monitor autoregulation as described in this article were patented by The Johns Hopkins University, listing Dr. Brady as a coinventor. These patents are exclusively licensed to Medtronic. Dr. Brown reported receiving grants from the NIH during the conduct of the study, and consulting for and participating in a data share with Medtronic. Dr. Brady is listed as inventor on patents awarded and assigned to the Johns Hopkins University. These patents are related to the monitoring technology described in this article and are exclusively licensed to Medtronic, and Dr. Brady received a portion of the licensing fee. Dr. Venkataraman received funding from Vixiar Medical (consulting) and from universities for speaker honorariums, and she was supported by the National Science Foundation CAREER award 1845430. Dr. Hogue reported receiving grants and personal fees for being a consultant and providing lectures for Medtronic/Covidien, being a consultant to Merck, and receiving grants from the NIH outside of the submitted work, and he disclosed off-label product use of autoregulation monitoring is investigational. Drs. Czosnyka and Smielewski received funding from licensing ICM+ through Cambridge Enterprise Ltd, United Kingdom. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: liuxiuyun1@gmail.com Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Stability of Do-Not-Resuscitate Orders in Hospitalized Adults: A Population-Based Cohort Study Objectives: Prior work has shown substantial between-hospital variation in do-not-resuscitate orders, but stability of do-not-resuscitate preferences between hospitalizations and the institutional influence on do-not-resuscitate reversals are unclear. We determined the extent of do-not-resuscitate reversals between hospitalizations and the association of the readmission hospital with do-not-resuscitate reversal. Design: Retrospective cohort study. Setting: California Patient Discharge Database, 2016–2018. Patients: Nonsurgical patients admitted to an acute care hospital with an early do-not-resuscitate order (within 24 hr of admission). Interventions: None. Measurements and Main Results: We identified nonsurgical adult patients who survived an initial hospitalization with an early-do-not-resuscitate order and were readmitted within 30 days. The primary outcome was the association of do-not-resuscitate reversal with readmission to the same or different hospital from the initial hospital. Secondary outcomes included association of readmission to a low versus high do-not-resuscitate-rate hospital with do-not-resuscitate reversal. Among 49,336 patients readmitted within 30 days following a first do-not-resuscitate hospitalization, 22,251 (45.1%) experienced do-not-resuscitate reversal upon readmission. Patients readmitted to a different hospital versus the same hospital were at higher risk of do-not-resuscitate reversal (59.5% vs 38.5%; p < 0.001; adjusted odds ratio = 2.4; 95% CI, 2.3–2.5). Patients readmitted to low versus high do-not-resuscitate-rate hospitals were more likely to have do-not-resuscitate reversals (do-not-resuscitate-rate quartile 1 77.0% vs quartile 4 27.2%; p < 0.001; adjusted odds ratio = 11.9; 95% CI, 10.7–13.2). When readmitted to a different versus the same hospital, patients with do-not-resuscitate reversal had higher rates of mechanical ventilation (adjusted odds ratio = 1.9; 95% CI, 1.6–2.1) and hospital death (adjusted odds ratio = 1.2; 95% CI, 1.1–1.3). Conclusions: Do-not-resuscitate reversals at the time of readmission are more common than previously reported. Although changes in patient preferences may partially explain between-hospital differences, we observed a strong hospital effect contributing to high do-not-resuscitate-reversal rates with significant implications for patient outcomes and resource. Drs. Mehta, Walkey, and Douglas conceived the study. Dr. Mehta was responsible for data collection. Drs. Mehta, Walkey, Curran-Everett, and Douglas were responsible for data analysis and interpretation. Drs. Mehta drafted the article. All the authors were responsible for critical revisions of article and provided final approval for the manuscript. Dr. Mehta had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr. Mehta conducted all aspects of data analysis. 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 Institutes of Health (NIH) K23HL141704 (to Dr. Mehta; primary funding source), NIH R01HL136660 and R01HL139751 (to Dr. Walkey), NIH R01HL136403 (to Dr. Matlock), and NIH R01NR016459 (to Dr. Douglas). Drs. Mehta and Walkey's institutions received funding from the National Institutes of Health (NIH). Drs. Mehta and Matlock received support for article research from the NIH. Dr. Walkey received funding from UptoDate. The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Anuj B. Mehta, MD, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, National Jewish Health, 1400 Jackson Street J209, Denver, CO. E-mail: mehtaa@njhealth.org Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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