Ultra-Protective Ventilation Reduces Biotrauma in Patients on Venovenous Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome Introduction: Ventilator settings for patients with severe acute respiratory distress syndrome supported by venovenous extracorporeal membrane oxygenation are currently set arbitrarily. The impact on serum and pulmonary biotrauma markers of the transition to ultra-protective ventilation settings following extracorporeal membrane oxygenation implantation, and different mechanical ventilation strategies while on extracorporeal membrane oxygenation were investigated. Design: Randomized clinical trial. Settings: Nine-month monocentric study. Patients: Severe acute respiratory distress syndrome patients on venovenous extracorporeal membrane oxygenation. Interventions: After starting extracorporeal membrane oxygenation, patients were switched to the bi-level positive airway pressure mode with 1 second of 24 cm H2O high pressure and 2 seconds of 12 cm H2O low pressure for 24 hours. A computer-generated allocation sequence randomized patients to receive each of the following three experimental steps: 1) high pressure 24 cm H2O and low pressure 20 cm H2O (very high positive end-expiratory pressure–very low driving pressure); 2) high pressure 24 cm H2O and low pressure 5 cm H2O (low positive end-expiratory pressure–high driving pressure); and 3) high pressure 17 cm H2O and low pressure 5 cm H2O (low positive end-expiratory pressure–low driving pressure). Plasma and bronchoalveolar lavage soluble receptor for advanced glycation end-products, plasma interleukin-6, and monocyte chemotactic protein-1 were sampled preextracorporeal membrane oxygenation and after 12 hours at each step. Measurements and Main Results: Sixteen patients on ECMO after 7 days (1–11 d) of mechanical ventilation were included. “Ultra-protective” mechanical ventilation settings following ECMO initiation were associated with significantly lower plasma sRAGE, interleukin-6, and monocyte chemotactic protein-1 concentrations. Plasma sRAGE and cytokines were comparable within each on-ECMO experimental step, but the lowest bronchoalveolar lavage sRAGE levels were obtained at minimal driving pressure. Conclusions: ECMO allows ultra- protective ventilation, which combines significantly lower plateau pressure, tidalvolume, and driving pressure. This ventilation strategy significantly limited pulmonary biotrauma, which couldtherefore decrease ventilator-induced lung injury. However, the optimal ultra-protective ventilation strategy once ECMO is initiated remains undetermined and warrants further investigations. 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. Luyt received funding from MSD, Bayer Healthcare, Thermofischer Brahms, Carmot, and Faron. Dr. Combes received lecture fees from Getinge and Baxter. Dr. Schmidt received lectures fees from Getinge, Dräger, and Xenios. The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Matthieu Schmidt, MD, PhD, Service de Réanimation Médicale, iCAN, Institute of Cardiometabolism and Nutrition, Hôpital de la Pitié–Salpêtrière, 47, bd de l’Hôpital, 75651 Paris Cedex 13, France. E-mail: matthieu.schmidt@aphp.fr Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Randomized Clinical Trial of an ICU Recovery Pilot Program for Survivors of Critical Illness Objectives: To examine the effect of an interdisciplinary ICU recovery program on process measures and clinical outcomes. Design: A prospective, single-center, randomized pilot trial. Setting: Academic, tertiary-care medical center. Patients: Adult patients admitted to the medical ICU for at least 48 hours with a predicted risk of 30-day same-hospital readmission of at least 15%. Interventions: Patients randomized to the ICU recovery program group were offered a structured 10-intervention program, including an inpatient visit by a nurse practitioner, an informational pamphlet, a 24 hours a day, 7 days a week phone number for the recovery team, and an outpatient ICU recovery clinic visit with a critical care physician, nurse practitioner, pharmacist, psychologist, and case manager. For patients randomized to the usual care group, all aspects of care were determined by treating clinicians. Measurements and Main Results: Among the primary analysis of enrolled patients who survived to hospital discharge, patients randomized to the ICU recovery program (n = 111) and usual care (n = 121) were similar at baseline. Patients in the ICU recovery program group received a median of two interventions compared with one intervention in the usual care group (p < 0.001). A total of 16 patients (14.4%) in the ICU recovery program group and 26 patients (21.5%) in the usual care group were readmitted to the study hospital within 30 days of discharge (p = 0.16). For these patients, the median time to readmission was 21.5 days (interquartile range, 11.5–26.2 d) in the ICU recovery program group and 7 days (interquartile range, 4–21.2 d) in the usual care group (p = 0.03). Four patients (3.6%) in the ICU recovery program and 14 patients (11.6%) in the usual care group were readmitted within 7 days of hospital discharge (p = 0.02). The composite outcome of death or readmission within 30 days of hospital discharge occurred in 20 patients (18%) in the ICU recovery program group and 36 patients (29.8%) in usual care group (p = 0.04). Conclusions: This randomized pilot trial found that a multidisciplinary ICU recovery program could deliver more interventions for post ICU recovery than usual care. The finding of longer time-to-readmission with an ICU recovery program should be examined in future trials. Ms. Bloom and Ms. Stollings contributed equally to this work. Ms. Bloom, Ms. Stollings, Ms. Kirkpatrick, and Drs. Sevin and Semler contributed to study concept and design. Ms. Bloom, Ms. Stollings, Ms. Kirkpatrick, and Dr. Sevin acquired data. Ms. Bloom and Ms. Stollings drafted the article. Ms. Wang and Mr. Byrne performed statistical analysis. Mr. Byrne and Drs. Sevin and Semler supervised the study. Ms. Bloom, Ms. Stollings, Ms. Kirkpatrick, and Ms. Wang had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Ms. Wang and Mr. Byrne conducted and are responsible for the data analysis. All authors performed analysis and interpreted the data. All authors performed the critical revision of 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 Vanderbilt Institute for Clinical and Translational Research Learning Healthcare System Platform (UL1 TR000445 and Clinical Translational Science Award award number UL1TR002243 from National Center for Advancing Translational Sciences/National Institutes of Health). Ms. Bloom’s and Ms. Stollings’s institutions received funding from Vanderbilt Institute for Clinical and Translational Research. Ms. Bloom, Mr. Byrne, and Dr. Semler received support for article research from the National Institutes of Health. Ms. Stollings received funding from the Society of Critical Care Medicine (SCCM) and Intermountain Health (lecture on postintensive care syndrome). Dr. Sevin’s institution received funding from SCCM. Dr. Semler’s institution received funding from National Heart Lung and Blood Institute (HL087738-09 and K12HL133117). The remaining authors have disclosed that they do not have any potential conflicts of interest. The contents are solely the responsibility of the authors and do not represent official views of the National Center for Advancing Translational Science or the National Institutes of Health. For information regarding this article, E-mail: sarah.l.bloom@vumc.org Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Persistent Mitochondrial Dysfunction Linked to Prolonged Organ Dysfunction in Pediatric Sepsis Objectives: Limited data exist about the timing and significance of mitochondrial alterations in children with sepsis. We therefore sought to determine if alterations in mitochondrial respiration and content within circulating peripheral blood mononuclear cells were associated with organ dysfunction in pediatric sepsis. Design: Prospective observational study Setting: Single academic PICU. Patients: One-hundred sixty-seven children with sepsis/septic shock and 19 PICU controls without sepsis, infection, or organ dysfunction. Interventions: None. Measurements and Main Results: Mitochondrial respiration and content were measured in peripheral blood mononuclear cells on days 1–2, 3–5, and 8–14 after sepsis recognition or once for controls. Severity and duration of organ dysfunction were determined using the Pediatric Logistic Organ Dysfunction score and organ failure-free days through day 28. Day 1–2 maximal uncoupled respiration (9.7 ± 7.7 vs 13.7 ± 4.1 pmol O2/s/106 cells; p = 0.02) and spare respiratory capacity (an index of bioenergetic reserve: 6.2 ± 4.3 vs 9.6 ± 3.1; p = 0.005) were lower in sepsis than controls. Mitochondrial content, measured by mitochondrial DNA/nuclear DNA, was higher in sepsis on day 1–2 than controls (p = 0.04) and increased in sepsis patients who had improving spare respiratory capacity over time (p = 0.005). Mitochondrial respiration and content were not associated with day 1–2 Pediatric Logistic Organ Dysfunction score, but low spare respiratory capacity was associated with higher Pediatric Logistic Organ Dysfunction score on day 3–5. Persistently low spare respiratory capacity was predictive of residual organ dysfunction on day 14 (area under the receiver operating characteristic, 0.72; 95% CI, 0.61–0.84) and trended toward fewer organ failure-free days although day 28 (β coefficient, –0.64; 95% CI, –1.35 to 0.06; p = 0.08). Conclusions: Mitochondrial respiration was acutely decreased in peripheral blood mononuclear cells in pediatric sepsis despite an increase in mitochondrial content. Over time, a rise in mitochondrial DNA tracked with improved respiration. Although initial mitochondrial alterations in peripheral blood mononuclear cells were unrelated to organ dysfunction, persistently low respiration was associated with slower recovery from organ dysfunction. 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. Weiss’ institution received funding from Eunice Kennedy Shriver National Institute of Child Health and Human Development K12HD047349, National Institute of General Medical Sciences K23GM110496, Society of Critical Care Medicine (SCCM) Weil Research Grant; he disclosed that the study was also supported by the Center for Mitochondrial and Epigenomic Medicine (although grants awarded to Dr. Wallace including National Institutes of Health (NIH) NS021328, MH108592, OD010944 and U.S. Department of Defense grant W81XWH-16-1-0401) and Department of Anesthesiology and Critical Care at the Children’s Hospital of Philadelphia; and he received funding from Bristol-Myers Squibb (Advisory Panel Member). Drs. Weiss, Zhang, Starr, Henrickson, and Kilbaugh received support for article research from the NIH. Dr. Deutschman received funding from SCCM (Scientific Editor for Critical Care Medicine); Department of Anesthesiology, NYU; St. Johns University; Western Ireland Critical Care Society; and International Society of Thrombosis and Hemostasis. Dr. McGowan’s institution received funding from Merck and the NIH. Dr. Becker’s institution received funding from Nihon Kohden, the NIH, and United Therapeutics, and he received other funding from Northwell Health, Philips, and Zoll. The remaining authors have disclosed that they do not have any potential conflicts of interest. This study was performed at the Children’s Hospital of Philadelphia. For information regarding this article, E-mail: WeissS@email.chop.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

U.K. Intensivists’ Preferences for Patient Admission to ICU: Evidence From a Choice Experiment Objectives: Deciding whether to admit a patient to the ICU requires considering several clinical and nonclinical factors. Studies have investigated factors associated with the decision but have not explored the relative importance of different factors, nor the interaction between factors on decision-making. We examined how ICU consultants prioritize specific factors when deciding whether to admit a patient to ICU. Design: Informed by a literature review and data from observation and interviews with ICU clinicians, we designed a choice experiment. Senior intensive care doctors (consultants) were presented with pairs of patient profiles and asked to prioritize one of the patients in each task for admission to ICU. A multinomial logit and a latent class logit model was used for the data analyses. Setting: Online survey across U.K. intensive care. Subjects: Intensive care consultants working in NHS hospitals. Measurements and Main Results: Of the factors investigated, patient’s age had the largest impact at admission followed by the views of their family, and severity of their main comorbidity. Physiologic measures indicating severity of illness had less impact than the gestalt assessment by the ICU registrar. We identified four distinct decision-making patterns, defined by the relative importance given to different factors. Conclusions: ICU consultants vary in the importance they give to different factors in deciding who to prioritize for ICU admission. Transparency regarding which factors have been considered in the decision-making process could reduce variability and potential inequity for patients. The views expressed in this publication are those of the authors and not necessarily those of the National Institute for Health Research or the Department of Health and Social 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). This article presents independent research funded by the National Institute for Health Research (NIHR) under the Health Services and Delivery Research Programme (reference 13/10/14). Further information available at: www.journalslibrary.nihr.ac.uk/programmes/hsdr/131014. The University of Aberdeen and the Chief Scientist Office of the Scottish Government Health and Social Care Directorates fund the Health Economics Research Unit. The research team acknowledges the support of the NIHR Clinical Research Network. Drs. Bassford’s, Krucien’s, Griffiths’s, Fritz’s, Perkins’s, Quinton’s, and Slowther’s institutions received funding from National Institute for Health Research (NIHR) (United Kingdom). Drs. Bassford, Krucien, Ryan, Griffiths, Quinton, and Slowther received support for article research from the NIHR. Dr. Bassford received funding from Intensive Care Society (United Kingdom) and disclosed he is a member of the Faculty of Intensive Care Medicine (United Kingdom) standards committee. Dr. Svantesson received support for article research from the National Institutes of Health (NIH). Dr. Fritz received funding from Wellcome; she disclosed that she is an executive member for the Resuscitation Council UK and chair the subcommittee for the Recommended Summary Plan for Emergency Care and Treatment process; and she received support for article research from the NIH and Wellcome Trust/Charity Open Access Fund. Dr. Perkins is also supported by the NIHR as a senior investigator. Dr. Quinton’s institution received funding from Warwick University (delivers the MSc Advanced Critical Care Practice pathway), and she disclosed she is currently on the Executive Board of the National Outreach Forum (Treasurer and past-Chair). Dr. Slowther’s institution received funding from NIHR Health Service and Delivery Research stream (United Kingdom), NIHR Health Technology Assessment program (coinvestigator), and NIHR Health Service and Delivery Research program (coinvestigator); she received funding from Dutch Clinical ethics network 2017 (travel and accommodations); and she disclosed she is a member of the Board of Trustees of the Institute of Medical Ethics (United Kingdom) and the UK Clinical Ethics Network, and her husband is a medical researcher who receives grant funding (through his institution) from the NIHR who also funded this study. Dr. Slowther’s spouse is a Director of Clinvivo. This work was conducted at the University of Warwick and the University of Aberdeen, United Kingdom. Ethical approval: The project was approved by the Coventry and Warwickshire research ethics committee (reference 15/WM/0025). For information regarding this article, E-mail: chris.bassford@uhcw.nhs.uk Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Ventilation Rates and Pediatric In-Hospital Cardiac Arrest Survival Outcomes Objectives: The objective of this study was to associate ventilation rates during in-hospital cardiopulmonary resuscitation with 1) arterial blood pressure during cardiopulmonary resuscitation and 2) survival outcomes. Design: Prospective, multicenter observational study. Setting: Pediatric and pediatric cardiac ICUs of the Collaborative Pediatric Critical Care Research Network. Patients: Intubated children (≥ 37 wk gestation and < 19 yr old) who received at least 1 minute of cardiopulmonary resuscitation. Interventions: None. Measurements and Main Results: Arterial blood pressure and ventilation rate (breaths/min) were manually extracted from arterial line and capnogram waveforms. Guideline rate was defined as 10 ± 2 breaths/min; high ventilation rate as greater than or equal to 30 breaths/min in children less than 1 year old, and greater than or equal to 25 breaths/min in older children. The primary outcome was survival to hospital discharge. Regression models using Firth penalized likelihood assessed the association between ventilation rates and outcomes. Ventilation rates were available for 52 events (47 patients). More than half of patients (30/47; 64%) were less than 1 year old. Eighteen patients (38%) survived to discharge. Median event-level average ventilation rate was 29.8 breaths/min (interquartile range, 23.8–35.7). No event-level average ventilation rate was within guidelines; 30 events (58%) had high ventilation rates. The only significant association between ventilation rate and arterial blood pressure occurred in children 1 year old or older and was present for systolic blood pressure only (–17.8 mm Hg/10 breaths/min; 95% CI, –27.6 to –8.1; p < 0.01). High ventilation rates were associated with a higher odds of survival to discharge (odds ratio, 4.73; p = 0.029). This association was stable after individually controlling for location (adjusted odds ratio, 5.97; p = 0.022), initial rhythm (adjusted odds ratio, 3.87; p = 0.066), and time of day (adjusted odds ratio, 4.12; p = 0.049). Conclusions: In this multicenter cohort, ventilation rates exceeding guidelines were common. Among the range of rates delivered, higher rates were associated with improved survival to hospital discharge. 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 following cooperative agreements from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, and Department of Health and Human Services: UG1HD050096, UG1HD049981, UG1HD049983, UG1HD063108, UG1HD083171, UG1HD083166, UG1HD083170, U10HD050012, U10HD063106, U10HD063114, and U01HD049934. All authors received support for article research from the National Institutes of Health (NIH). Dr. Sutton, Dr. Reeder, Mr. Landis, Dr. Meert, Dr. Yates, Dr. Berger, Dr. Harrison, Dr. Moler, Dr. Pollack, Dr. Holubkov, and Dr. Berg’s institutions received funding from the NIH. Dr. Sutton received funding from Zoll Medical (speaking honoraria), and he disclosed that he is the Chair Elect of the Pediatric Research Task Force of the American Heart Association’s (AHA’s) Get with the Guidelines Resuscitation registry, a 2015 and 2018 Pediatric Advanced Life Support Guidelines Author, and a member of the AHA’s Emergency Cardiovascular Care Committee’s Pediatric Emphasis Group. He reports grant funding from the NIH. Dr. Berger’s institution also received funding from Association for Pediatric Pulmonary Hypertension and Actelion. Drs. Newth, Carcillo, McQuillen, Notterman, and Dean’s institutions received funding from the National Institute of Child Health and Human Development. Dr. Newth received funding from Philips Research North America. He reports consulting services for both Philips Research of North America and Medtronics. Dr. Moler reports NIH funding paid to his institution. Dr. Pollack reports grant funding from the NIH and the Department of Defense, collaborative projects with Cerner, and philanthropy from Mallinckrodt Pharmaceuticals. Dr. Holubkov received funding from Pfizer (DSMB member), MedImmune (DSMB), Physicians Committee for Responsible Medicine (Biostatistical Consulting), DURECT (Biostatistical Consulting), American Burn Association (DSMB), Armaron Bio (DSMB), and St. Jude Medical (Biostatistical Consulting). For information regarding this article, E-mail: suttonr@email.chop.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Physician Judgment and Circulating Biomarkers Predict 28-Day Mortality in Emergency Department Patients Objectives: To determine whether biomarkers of endothelial activation and inflammation provide added value for prediction of in-hospital mortality within 28 days when combined with physician judgment in critically ill emergency department patients. Design: Prospective, observational study. Setting: Two urban, academic emergency departments, with ≈80,000 combined annual visits, between June 2016 and December 2017. Patients: Admitted patients, greater than 17 years old, with two systemic inflammatory response syndrome criteria and organ dysfunction, systolic blood pressure less than 90 mm Hg, or lactate greater than 4.0 mmol/L. Patients with trauma, intracranial hemorrhage known prior to arrival, or without available blood samples were excluded. Interventions: Emergency department physicians reported likelihood of in-hospital mortality (0–100%) by survey at hospital admission. Remnant EDTA blood samples, drawn during the emergency department stay, were used to measure angiopoietin-1, angiopoietin-2, tumor necrosis factor receptor-1, interleukin-6, and interleukin-8. Measurements and Main Results: We screened 421 patients and enrolled 314. The primary outcome of in-hospital mortality within 28 days occurred in 31 (9.9%). When predicting the primary outcome, the best biomarker model included angiopoietin-2 and interleukin-6 and performed moderately well (area under the curve, 0.72; 95% CI, 0.69–0.75), as did physician judgment (area under the curve, 0.78; 95% CI, 0.74–0.82). Combining physician judgment and biomarker models improved performance (area under the curve, 0.85; 95% CI, 0.82–0.87), with area under the curve change of 0.06 (95% CI, 0.04–0.09; p < 0.01) compared with physician judgment alone. Conclusions: Predicting in-hospital mortality within 28 days among critically ill emergency department patients may be improved by including biomarkers of endothelial activation and inflammation in combination with emergency department physician judgment. Drs. Henning, Liles, and Wurfel contributed in study concept and design. Dr. Henning contributed in drafting of the article. Drs. Henning and Zelnick contributed in statistical analysis. Drs. Henning, Liles, and Wurfel contributed in obtained funding. Dr. Kosamo contributed in administrative, technical, or material support. Drs. Liles and Wurfel contributed in supervision. All authors contributed in acquisition, analysis, or interpretation of data, and critical revision of 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). Primary funding for this study was provided by the Medic One Foundation Research Grant. Supported, in part, by an unrestricted fund from the Northwest Kidney Centers. Dr. Bhatraju received support for article research from the National Institutes of Health (NIH). Dr. Johnson’s institution received funding from the NIH and Medic One Foundation. Dr. Liles disclosed that he is an inventor on U.S. Patent Application Numbers US61/603,765 and US14/019,447, both of which pertain to the use of angiopoietin-1 and angiopoietin-2 as prognostic biomarkers in critical illness. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: henning2@uw.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Antibiotic- and Fluid-Focused Bundles Potentially Improve Sepsis Management, but High-Quality Evidence Is Lacking for the Specificity Required in the Centers for Medicare and Medicaid Service's Sepsis Bundle (SEP-1) Objective: To address three controversial components in the Centers for Medicare and Medicaid Service’s sepsis bundle for performance measure (SEP-1): antibiotics within 3 hours, a 30 mL/kg fluid infusion for all hypotensive patients, and repeat lactate measurements within 6 hours if initially elevated. We hypothesized that antibiotic- and fluid-focused bundles like SEP-1 would probably show benefit, but evidence supporting specific antibiotic timing, fluid dosing, or serial lactate requirements would not be concordant. Therefore, we performed a meta-analysis of studies of sepsis bundles like SEP-1. Data Sources: PubMed, Embase, ClinicalTrials.gov through March 15, 2018. Study Selection: Studies comparing survival in septic adults receiving versus not receiving antibiotic- and fluid-focused bundles. Data Extraction: Two investigators (D.J.P., P.Q.E.). Data Synthesis: Seventeen observational studies (11,303 controls and 4,977 bundle subjects) met inclusion criteria. Bundles were associated with increased odds ratios of survival (odds ratio [95% CI]) in 15 studies with substantial heterogeneity (I2 = 61%; p < 0.01). Survival benefits were consistent in the five largest (1,697–12,486 patients per study) (1.20 [1.11–1.30]; I2 = 0%) and six medium-sized studies (167–1,029) (2.03 [1.52–2.71]; I2 = 8%) but not the six smallest (64–137) (1.25 [0.42–3.66]; I2 = 57%). Bundles were associated with similarly increased survival benefits whether requiring antibiotics within 1 hour (n = 7 studies) versus 3 hours (n = 8) versus no specified time (n = 2); or 30 mL/kg fluid (n = 7) versus another volume (≥ 2 L, n = 1; ≥ 20 mL/kg, n = 2; 1.5–2 L or 500 mL, n = 1 each; none specified, n = 4) (p = 0.19 for each comparison). In the only study employing serial lactate measurements, survival was not increased versus others. No study had a low risk of bias or assessed potential adverse bundle effects. Conclusions: Available studies support the notion that antibiotic- and fluid-focused sepsis bundles like SEP-1 improve survival but do not demonstrate the superiority of any specific antibiotic time or fluid volume or of serial lactate measurements. Until strong reproducible evidence demonstrates the safety and benefit of any fixed requirement for these interventions, the present findings support the revision of SEP-1 to allow flexibility in treatment according to physician judgment. The National Institutes of Health had no role in study design or data collection, analysis, or interpretation. Drs. Pepper and Eichacker had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis, including and especially any adverse effects, and drafted the article. Dr. Pepper, Dr. Sun, Ms. Welsh, and Drs. Cui, Natanson, and Eichacker contributed substantially to the study design, data analysis, and interpretation, and approve the final version to be published. Dr. Sun, Ms. Welsh, and Drs. Cui and Natanson revised the article critically 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 National Institutes of Health intramural funding. Drs. Pepper, Sun, Cui, Natanson, and Eichacker received support for article research from the National Institutes of Health. Drs. Pepper, Sun, and Cui, Ms. Welsh, and Dr. Eichacker disclosed government work. Clinical Trial Registration numbers: International Prospective Register of Systematic Reviews (PROSPERO) 2017: CRD42017080258. For information regarding this article, E-mail: peichacker@cc.nih.gov Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Continuous Renal Replacement Therapy in Pediatric Severe Sepsis: A Propensity Score-Matched Prospective Multicenter Cohort Study in the PICU Objectives: Continuous renal replacement therapy becomes available utilization for pediatric critically ill, but the impact of mortality rate in severe sepsis remains no consistent conclusion. The aim of the study is to assess the effect of continuous renal replacement therapy in pediatric patients with severe sepsis and the impact this therapy may have on their mortality. Design: Propensity score-matched cohort study analyzing data prospectively collected by the PICUs over 2 years (2016–2018). Setting: Four PICUs of tertiary university children’s hospital in China. Patients: The consecutive patients with severe sepsis admitted to study PICUs were enrolled from July 2016 to June 2018. Interventions: The patients were divided into the continuous renal replacement therapy group and the conventional (noncontinuous renal replacement therapy) group. Measurements and Main Results: A total of 324 patients with severe sepsis were enrolled. The hospital mortality rate was 35.6% (64/180) in the continuous renal replacement therapy group and 47.9% (69/144) in the noncontinuous renal replacement therapy group. After propensity score adjustment, the hospital mortality rate was 21.3% (29/136) in the continuous renal replacement therapy group and 32.4% (44/136) in the noncontinuous renal replacement therapy group. In subgroup analysis, the relative risk of dying was 0.447 (95% CI, 0.208–0.961) only in patients complicated by acute respiratory distress syndrome (p = 0.037), but not in patients with shock, acute kidney injury, acute liver dysfunction, encephalopathy, and fluid overload greater than 10%. The mean duration of continuous renal replacement therapy was 45 hours (26–83 hr) with an ultrafiltration rate of 50 mL/kg/hr. The level of interleukin-6 was decreased, and the percent of natural killer cells (%) was improved in the continuous renal replacement therapy group compared with the noncontinuous renal replacement therapy group. Furthermore, continuous renal replacement therapy was an independently significant risk factor for hospital mortality in pediatric patients with severe sepsis, and the interval between continuous renal replacement therapy initiation and PICU admission was an independent risk factor for hospital mortality in patients receiving continuous renal replacement therapy. Conclusions: Continuous renal replacement therapy with an ultrafiltration rate of 50 mL/kg/hr decreases hospital mortality rate in pediatric severe sepsis, especially in patients with acute respiratory distress syndrome. Drs. Miao and Shi 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 grants from the Science and Technology Commission of Shanghai Municipality (16411970300,18411951000), funded by Clinical Multicenter Study supported by Clinical Research Center of Shanghai Jiao Tong University School of Medicine (DLY201618, 20171928), New Advanced Technology Project at the Shanghai City Hospital Development Center (SHDC12014116). Drs. Wang and Zhang received funding from Clinical Multicenter Study supported by Clinical Research Center of Shanghai Jiao Tong University School of Medicine (DLY201618, 20171928). Dr. Zhang received funding from Science and Technology Commission of Shanghai Municipality (16411970300); Science and Technology Commission of Shanghai Municipality (18411951000). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: zyucai2018@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 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Optimizing Mean Arterial Pressure in Acutely Comatose Patients Using Cerebral Autoregulation Multimodal Monitoring With Near-Infrared Spectroscopy Objectives: This study investigated whether comatose patients with greater duration and magnitude of clinically observed mean arterial pressure outside optimal mean arterial blood pressure have worse outcomes than those with mean arterial blood pressure closer to optimal mean arterial blood pressure calculated by bedside multimodal cerebral autoregulation monitoring using near-infrared spectroscopy. Design: Prospective observational study. Setting: Neurocritical Care Unit of the Johns Hopkins Hospital. Subjects: Acutely comatose patients secondary to brain injury. Interventions: None. Measurements and Main Results: The cerebral oximetry index was continuously monitored with near-infrared spectroscopy for up to 3 days. Optimal mean arterial blood pressure was defined as that mean arterial blood pressure at the lowest cerebral oximetry index (nadir index) for each 24-hour period of monitoring. Kaplan-Meier analysis and proportional hazard regression models were used to determine if survival at 3 months was associated with a shorter duration of mean arterial blood pressure outside optimal mean arterial blood pressure and the absolute difference between clinically observed mean arterial blood pressure and optimal mean arterial blood pressure. A total 91 comatose patients were enrolled in the study. The most common etiology was intracerebral hemorrhage. Optimal mean arterial blood pressure could be calculated in 89 patients (97%), and the median optimal mean arterial blood pressure was 89.7 mm Hg (84.6–100 mm Hg). In multivariate proportional hazard analysis, duration outside optimal mean arterial blood pressure of greater than 80% of monitoring time (adjusted hazard ratio, 2.13; 95% CI, 1.04–4.41; p = 0.04) and absolute difference between clinically observed mean arterial blood pressure and optimal mean arterial blood pressure of more than 10 mm Hg (adjusted hazard ratio, 2.44; 95% CI, 1.21–4.92; p = 0.013) were independently associated with mortality at 3 months, after adjusting for brain herniation, admission Glasgow Coma Scale, duration on vasopressors and midline shift at septum. Conclusions: Comatose neurocritically ill adults with an absolute difference between clinically observed mean arterial blood pressure and optimal mean arterial blood pressure greater than 10 mm Hg and duration outside optimal mean arterial blood pressure greater than 80% had increased mortality at 3 months. Noninvasive near-infrared spectroscopy-based bedside calculation of optimal mean arterial blood pressure is feasible and might be a promising tool for cerebral autoregulation oriented-therapy in neurocritical care patients. Drs. Hogue and Ziai are senior authors. 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 American Academy of Neurology/American Brain Foundation. Dr. Rivera-Lara’s institution received funding from American Academy of Neurology/American Brain Foundation and equipment from a Covidien/Medtronic grant. Dr. Brown’s institution received funding from National Institutes of Health (NIH)/National Institute on Aging and Medtronic. Drs. Brown and Hogue received support for article research from the NIH. Dr. Hogue is the PI on an NIH-sponsored clinical study (R01 HL 92259); he received funding from Medtronic/Covidien, Dublin, IR (advisor and lecturer), Merck (Data Safety and Monitoring Board for unrelated drug trial); he serves as a consultant to Medtronic/Covidien and Ornim Medical, Foxborough, MA; he received other support from Medtronic in the form of a near-infrared spectroscopy sensor; and he disclosed off-label product use of autoregulation monitoring. Dr. Ziai received funding form HeadSense. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: lriver14@jhmi.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Are Peripherally Inserted Central Catheters Suitable for Cardiac Output Assessment With Transpulmonary Thermodilution? Objectives: Peripherally inserted central catheters are increasingly used in ICU as an alternative to centrally inserted central catheters for IV infusion. However, their reliability for hemodynamic measurements with transpulmonary thermodilution is currently unknown. We investigated the agreement between transpulmonary thermodilution measurements obtained with bolus injection through peripherally inserted central catheter and centrally inserted central catheter (reference standard) using a transpulmonary thermodilution–calibrated Pulse Contour hemodynamic monitoring system (VolumeView/EV1000). Design: Prospective method-comparison study. Setting: Twenty-bed medical-surgical ICU of a teaching hospital. Patients: Twenty adult ICU patients who required hemodynamic monitoring because of hemodynamic instability and had both peripherally inserted central catheter and centrally inserted central catheter in place. Intervention: The hemodynamic measurements obtained by transpulmonary thermodilution after injection of a cold saline bolus via both centrally inserted central catheter and either a single-lumen 4F or a double-lumen 5F peripherally inserted central catheter using were compared. In order to rule out bias related to manual injection, measurements were repeated using an automated rapid injection system. Measurements and Main Results: A total of 320 measurements were made. Cardiac index was significantly higher when measured with double-lumen 5F peripherally inserted central catheter than with centrally inserted central catheter (mean, 4.5 vs 3.3 L/min/m2; p < 0.0001; bias, 1.24 L/min/m2 [0.27, 2.22 L/min/m2]; bias percentage, 31%). Global end-diastolic index, extravascular lung water index, and stroke volume index were also overestimated (853 ± 240 vs 688 ± 175 mL/m2, 12.2 ± 4.2 vs 9.4 ± 2.9 mL/kg, and 49.6 ± 14.9 vs 39.5 ± 9.6 mL/m2, respectively; p < 0.0001). Lower, albeit significant differences were found using single-lumen 4F peripherally inserted central catheter (mean cardiac index, 4.2 vs 3.7 L/min/m2; p = 0.043; bias, 0.51 L/min/m2 [–0.53, 1.55 L/min/m2]; bias percentage, 12.7%). All differences were confirmed, even after standardization of bolus speed with automated injection. Conclusions: Bolus injection through peripherally inserted central catheter for transpulmonary thermodilution using EV1000 led to a significant overestimation of cardiac index, global end-diastolic index, extravascular lung water index, and stroke volume index, especially when double-lumen 5F peripherally inserted central catheter was used (ClinicalTrial.gov NCT03834675). Drs. D’Arrigo and Sandroni 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). The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: sonia.darrigo@virgilio.it; sonia.darrigo@policlinicogemelli.it Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.