Publications by authors named "Timothy D Girard"

154 Publications

Haloperidol in the ICU: A Hammer Looking for a Nail?

Crit Care Med 2021 Aug;49(8):1363-1365

The Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Center, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA.

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http://dx.doi.org/10.1097/CCM.0000000000004995DOI Listing
August 2021

Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial.

Intensive Care Med 2021 Aug 12;47(8):867-886. Epub 2021 Jul 12.

Medical Research Institute of New Zealand, Wellington, New Zealand.

Purpose: To study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19).

Methods: Critically ill adults with COVID-19 were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or no antiviral therapy (control). The primary endpoint was an ordinal scale of organ support-free days. Analyses used a Bayesian cumulative logistic model and expressed treatment effects as an adjusted odds ratio (OR) where an OR > 1 is favorable.

Results: We randomized 694 patients to receive lopinavir-ritonavir (n = 255), hydroxychloroquine (n = 50), combination therapy (n = 27) or control (n = 362). The median organ support-free days among patients in lopinavir-ritonavir, hydroxychloroquine, and combination therapy groups was 4 (- 1 to 15), 0 (- 1 to 9) and-1 (- 1 to 7), respectively, compared to 6 (- 1 to 16) in the control group with in-hospital mortality of 88/249 (35%), 17/49 (35%), 13/26 (50%), respectively, compared to 106/353 (30%) in the control group. The three interventions decreased organ support-free days compared to control (OR [95% credible interval]: 0.73 [0.55, 0.99], 0.57 [0.35, 0.83] 0.41 [0.24, 0.72]), yielding posterior probabilities that reached the threshold futility (≥ 99.0%), and high probabilities of harm (98.0%, 99.9% and > 99.9%, respectively). The three interventions reduced hospital survival compared with control (OR [95% CrI]: 0.65 [0.45, 0.95], 0.56 [0.30, 0.89], and 0.36 [0.17, 0.73]), yielding high probabilities of harm (98.5% and 99.4% and 99.8%, respectively).

Conclusion: Among critically ill patients with COVID-19, lopinavir-ritonavir, hydroxychloroquine, or combination therapy worsened outcomes compared to no antiviral therapy.
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http://dx.doi.org/10.1007/s00134-021-06448-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274471PMC
August 2021

Nutritional Risk at intensive care unit admission and outcomes in survivors of critical illness.

Clin Nutr 2021 Jun 11;40(6):3868-3874. Epub 2021 May 11.

Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center, Nashville, TN, USA; Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University College of Medicine, Columbus OH, USA; Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA. Electronic address:

Background And Aims: Risk factors for poor outcomes after critical illness are incompletely understood. While nutritional risk is associated with mortality in critically ill patients, its association with disability, cognitive, and health-related quality of life is unclear in survivors of critical illness. This study's objective was to determine whether greater nutritional risk at ICU admission is associated with greater disability, worse cognition, and worse HRQOL at 3 and 12-month follow-up.

Methods: We enrolled adults (≥18 years of age) with respiratory failure or shock treated in medical and surgical intensive care units from two U.S. centers. We measured nutritional risk using the modified Nutrition Risk in Critically Ill (mNUTRIC) score (range 0-9 [highest risk]) at intensive care unit admission. We measured associations between mNUTRIC scores and discharge destination, disability in basic activities of daily living (ADLs) using the Katz ADL, instrumental ADLs using the Functional Activities Questionnaire (FAQ), global cognition using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), executive function using the Trail Making Test Part B (Trails B), and health-related quality of life using the SF-36, adjusting for sex, education, BMI, baseline frailty, disability, and cognition, severity of illness, days of delirium, coma, and mechanical ventilation.

Results: Of the 821 patients enrolled in the ICU, 636 patients survived to hospital discharge. We assessed outcomes in 448 of 535 survivors (84%) at 3 months and 382 of 476 survivors (80%) at 12 months. Higher mNUTRIC scores predicted greater odds of discharge to an institution (OR 2.0, 95% CI: 1.6 to 2.6; P < 0.01). Higher mNUTRIC scores were associated with a trend towards greater disability in basic activities of daily living (IRR 1.3, 95% CI 1.0 to 1.7) at 3 months that did not reach significance (p = 0.09) with no association demonstrated at 12 months. There were no associations between mNUTRIC scores and FAQ, RBANS, or Trails B scores. mNUTRIC scores were inconsistently associated with SF-36 physical and mental component scale scores.

Conclusions: Greater nutritional risk at ICU admission is associated with disability in survivors of critical illness. Future studies should evaluate interventions in those at high nutritional risk as a means to speed recovery.
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http://dx.doi.org/10.1016/j.clnu.2021.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243837PMC
June 2021

Reply to: No Strong Evidence for Ruling out the Role of Coagulation in Long-Term Disability after Critical Illness.

Am J Respir Crit Care Med 2021 Jun 10. Epub 2021 Jun 10.

University of Pittsburgh, 6614, Department of Critical Care Medicine, Pittsburgh, Pennsylvania, United States;

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http://dx.doi.org/10.1164/rccm.202105-1133LEDOI Listing
June 2021

Delirium and long term cognition in critically ill patients.

BMJ 2021 06 8;373:n1007. Epub 2021 Jun 8.

Division of Pulmonary and Critical Care Medicine, Oregon Health & Science University, Portland, OR, USA.

Delirium, a form of acute brain dysfunction, is very common in the critically ill adult patient population. Although its pathophysiology is poorly understood, multiple factors associated with delirium have been identified, many of which are coincident with critical illness. To date, no drug or non-drug treatments have been shown to improve outcomes in patients with delirium. Clinical trials have provided a limited understanding of the contributions of multiple triggers and processes of intensive care unit (ICU) acquired delirium, making identification of therapies difficult. Delirium is independently associated with poor long term outcomes, including persistent cognitive impairment. A longer duration of delirium is associated with worse long term cognition after adjustment for age, education, pre-existing cognitive function, severity of illness, and exposure to sedatives. Interestingly, differences in prevalence are seen between ICU survivor populations, with survivors of acute respiratory distress syndrome experiencing higher rates of cognitive impairment at early follow-up compared with mixed ICU survivor populations. Although cognitive performance improves over time for some ICU survivors, impairment is persistent in others. Studies have so far been unable to identify patients at higher risk of long term cognitive impairment; this is an active area of scientific investigation.
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http://dx.doi.org/10.1136/bmj.n1007DOI Listing
June 2021

Advancing Telehealth-Based Screening for Postintensive Care Syndrome: A Coronavirus Disease 2019 Paradigm Shift.

Crit Care Med 2021 May 25. Epub 2021 May 25.

Division of Geriatric Medicine and Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA Clinical Research, Investigation, and Systems Modeling of Acute illness (CRISMA) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA.

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http://dx.doi.org/10.1097/CCM.0000000000005092DOI Listing
May 2021

Design of Clinical Trials Evaluating Sedation in Critically Ill Adults Undergoing Mechanical Ventilation: Recommendations From Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research (SCEPTER) Recommendation III.

Crit Care Med 2021 Apr 28. Epub 2021 Apr 28.

1 Department of Anesthesiology and Perioperative Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY. 2 University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 3School of Health Sciences, University of London, London, United Kingdom. 4 School of Nursing and Midwifery, Griffith University, Brisbane, QLD, Australia. 5 Center of Healthy Aging, Self-Management, and Complex Care, The Ohio State University, College of Nursing, Columbus, OH. 6 Clear Consults, LLC, Hayward, WI. 7 Leslie Dan Faculty of Pharmacy, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada. 8 Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University School of Medicine, Baltimore, MD. 9 Departments of Anesthesiology and Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI. 10 School of Pharmacy, Northeastern University, Boston, MA 11 Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA. 12 Department of Anesthesia, University of Iowa, Iowa City, IA. 13 Department of Anesthesiology and Perioperative Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY. 14 Department of Anesthesiology, University of Utah, Salt Lake City, UT. 15 Faculty of Health, University of Technology Sydney, Sydney, NSW, Australia. 16 Intensive Care Unit, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 17 Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Palo Alto, CA. 18 Department of Medicine, Tufts University School of Medicine, Maine Medical Center, Portland, ME. 9 Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA. 20 Division of Anesthesiology and CCM, Hadassah Medical Center, The Hebrew University School of Medicine, Jerusalem, Israel. 21 Psychology Department and Neuroscience Center, Brigham Young University, Provo, UT. 22 Center for Humanizing Critical Care, Intermountain Medical Center, Murray, UT. 23 Department of Medicine, Section of Pulmonary and Critical Care, The University of Chicago, Chicago, IL. 24 Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA. 25 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, Baltimore, MD. 26 Department of Anesthesiology and the Critical Illness, Vanderbilt University Medical Center, Nashville, TN. 27 Department of Critical Care Services, Maine Medical Center, Portland, ME. 28 Department of Outcomes Research, Cleveland Clinic, Cleveland, OH. 29 Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Palo Alto, CA. 30 Monash Health School of Clinical Sciences - Department of Intensive Care Medicine - Critical Care Research, Melbourne, VIC, Australia. 31 Department of Anesthesiology and Operative Intensive Care Medicine, Charité - Universitätsmedizin Berlin, Campus Charité Mitte & Campus Virchow-Klinikum, Berlin, Germany. 32 Department of Anesthesiology, Columbia University Medical Center, New York, NY. 33 Department of Anesthesia and Critical Care, The University of Chicago, Chicago, IL. 34 Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Objectives: Clinical trials evaluating the safety and effectiveness of sedative medication use in critically ill adults undergoing mechanical ventilation differ considerably in their methodological approach. This heterogeneity impedes the ability to compare results across studies. The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research Recommendations convened a meeting of multidisciplinary experts to develop recommendations for key methodologic elements of sedation trials in the ICU to help guide academic and industry clinical investigators.

Design: A 2-day in-person meeting was held in Washington, DC, on March 28-29, 2019, followed by a three-round, online modified Delphi consensus process.

Participants: Thirty-six participants from academia, industry, and the Food and Drug Administration with expertise in relevant content areas, including two former ICU patients attended the in-person meeting, and the majority completed an online follow-up survey and participated in the modified Delphi process.

Measurements And Main Results: The final recommendations were iteratively refined based on the survey results, participants' reactions to those results, summaries written by panel moderators, and a review of the meeting transcripts made from audio recordings. Fifteen recommendations were developed for study design and conduct, subject enrollment, outcomes, and measurement instruments. Consensus recommendations included obtaining input from ICU survivors and/or their families, ensuring adequate training for personnel using validated instruments for assessments of sedation, pain, and delirium in the ICU environment, and the need for methodological standardization.

Conclusions: These recommendations are intended to assist researchers in the design, conduct, selection of endpoints, and reporting of clinical trials involving sedative medications and/or sedation protocols for adult ICU patients who require mechanical ventilation. These recommendations should be viewed as a starting point to improve clinical trials and help reduce methodological heterogeneity in future clinical trials.
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http://dx.doi.org/10.1097/CCM.0000000000005049DOI Listing
April 2021

Association of Delirium during Critical Illness With Mortality: Multicenter Prospective Cohort Study.

Anesth Analg 2021 Apr 30. Epub 2021 Apr 30.

Department of Anesthesiology, Nashville Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, Tennessee.

Background: The temporal association of delirium during critical illness with mortality is unclear, along with the associations of hypoactive and hyperactive motoric subtypes of delirium with mortality. We aimed to evaluate the relationship of delirium during critical illness, including hypoactive and hyperactive motoric subtypes, with mortality in the hospital and after discharge up to 1 year.

Methods: We analyzed a prospective cohort study of adults with respiratory failure and/or shock admitted to university, community, and Veterans Affairs hospitals. We assessed patients using the Richmond Agitation-Sedation Scale and the Confusion Assessment Method for the intensive care unit (ICU) and defined the motoric subtype according to the corresponding Richmond Agitation-Sedation Scale if delirium was present. We used Cox proportional hazard models, adjusted for baseline characteristics, coma, and daily hospital events, to determine whether delirium on a given day predicted mortality the following day in patients in the hospital and also to determine whether delirium presence and duration predicted mortality after discharge up to 1 year in patients who survived to hospital discharge. We performed similar analyses for hypoactive and hyperactive subtypes of delirium.

Results: Among 1040 critically ill patients, 214 (21%) died in the hospital and 204 (20%) died out-of-hospital by 1 year. Delirium was common, occurring in 740 (71%) patients for a median (interquartile range [IQR]) of 4 (2-7) days. Hypoactive delirium occurred in 733 (70%) patients, and hyperactive occurred in 185 (18%) patients, with a median (IQR) of 3 (2-7) days and 1 (1-2) days, respectively. Delirium on a given day (hazard ratio [HR], 2.87; 95% confidence interval [CI], 1.32-6.21; P = .008), in particular the hypoactive subtype (HR, 3.35; 95% CI, 1.51-7.46; P = .003), was independently associated with an increased risk of death the following day in the hospital. Hyperactive delirium was not associated with an increased risk of death in the hospital (HR, 4.00; 95% CI, 0.49-32.51; P = .19). Among hospital survivors, neither delirium presence (HR, 1.01; 95% CI, 0.82-1.24; P = .95) nor duration (HR, 0.99; 95% CI, 0.97-1.01; P = .56), regardless of motoric subtype, was associated with mortality after hospital discharge up to 1 year.

Conclusions: Delirium during critical illness is associated with nearly a 3-fold increased risk of death the following day for patients in the hospital but is not associated with mortality after hospital discharge. This finding appears primarily driven by the hypoactive motoric subtype. The independent relationship between delirium and mortality occurs early during critical illness but does not persist after hospital discharge.
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http://dx.doi.org/10.1213/ANE.0000000000005544DOI Listing
April 2021

A structured methodology review showed analyses of functional outcomes are frequently limited to "survivors only" in trials enrolling patients at high risk of death.

J Clin Epidemiol 2021 Apr 7;137:126-132. Epub 2021 Apr 7.

Outcomes After Critical Illness and Surgery (OACIS) Group, Johns Hopkins University, Baltimore, Maryland, USA; Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Objective: This structured methodology review evaluated statistical approaches used in randomized controlled trials (RCTs) enrolling patients at high risk of death and makes recommendations for reporting future RCTs.

Study Design And Setting: Using PubMed, we searched for RCTs published in five general medicine journals from January 2014 to August 2019 wherein mortality was ≥10% in at least one randomized group. We abstracted primary and secondary outcomes, statistical analysis methods, and patient samples evaluated (all randomized patients vs. "survivors only").

Results: Of 1947 RCTs identified, 434 met eligibility criteria. Of the eligible RCTs, 91 (21%) and 351 (81%) had a primary or secondary functional outcome, respectively, of which 36 (40%) and 263 (75%) evaluated treatment effects among "survivors only". In RCTs that analyzed all randomized patients, the most common methods included use of ordinal outcomes (e.g., modified Rankin Scale) or creating composite outcomes (primary: 41 of 91 [45%]; secondary: 57 of 351 [16%]).

Conclusion: In RCTs enrolling patients at high risk of death, statistical analyses of functional outcomes are frequently conducted among "survivors only," for which conclusions might be misleading. Given the growing number of RCTs conducted among patients hospitalized with COVID-19 and other critical illnesses, standards for reporting should be created.
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http://dx.doi.org/10.1016/j.jclinepi.2021.03.027DOI Listing
April 2021

The Use of Near-Infrared Spectroscopy and/or Transcranial Doppler as Non-Invasive Markers of Cerebral Perfusion in Adult Sepsis Patients With Delirium: A Systematic Review.

J Intensive Care Med 2021 Mar 9:885066621997090. Epub 2021 Mar 9.

Department of Anesthesiology, Pharmacology and Therapeutics, 8166University of British Columbia, Vancouver, British Columbia, Canada.

Background: Several studies have previously reported the presence of altered cerebral perfusion during sepsis. However, the role of non-invasive neuromonitoring, and the impact of altered cerebral perfusion, in sepsis patients with delirium remains unclear.

Methods: We performed a systematic review of studies that used near-infrared spectroscopy (NIRS) and/or transcranial Doppler (TCD) to assess adults (≥18 years) with sepsis and delirium. From study inception to July 28, 2020, we searched the following databases: Ovid MedLine, Embase, Cochrane Library, and Web of Science.

Results: Of 1546 articles identified, 10 met our inclusion criteria. Although NIRS-derived regional cerebral oxygenation was consistently lower, this difference was only statistically significant in one study. TCD-derived cerebral blood flow velocity was inconsistent across studies. Importantly, both impaired cerebral autoregulation during sepsis and increased cerebrovascular resistance were associated with delirium during sepsis. However, the heterogeneity in NIRS and TCD devices, duration of recording (from 10 seconds to 72 hours), and delirium assessment methods (e.g., electronic medical records, confusion assessment method for the intensive care unit), precluded meta-analysis.

Conclusion: The available literature demonstrates that cerebral perfusion disturbances may be associated with delirium in sepsis. However, future investigations will require consistent definitions of delirium, delirium assessment training, harmonized NIRS and TCD assessments (e.g., consistent measurement site and length of recording), as well as the quantification of secondary and tertiary variables (i.e., Cox, Mxa, MAP), in order to fully assess the relationship between cerebral perfusion and delirium in patients with sepsis.
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http://dx.doi.org/10.1177/0885066621997090DOI Listing
March 2021

Dexmedetomidine or Propofol for Sedation in Mechanically Ventilated Adults with Sepsis.

N Engl J Med 2021 04 2;384(15):1424-1436. Epub 2021 Feb 2.

From the Critical Illness, Brain Dysfunction, and Survivorship Center (C.G.H., J.C.J., A.S.H., B.T.P., O.M.O., R.R., J.L.S., A.L.K, M.B.P., N.E.B., T.D.G., R.S.D., G.R.B., E.W.E., P.P.P.), the Center for Health Services Research (C.G.H., J.C.J., R.R., M.B.P., T.D.G., R.S.D., E.W.E., P.P.P.), the Division of Anesthesiology Critical Care Medicine, Department of Anesthesiology (C.G.H., P.P.P.), the Division of Allergy, Pulmonary, and Critical Care Medicine (J.C.J., B.T.P., G.R.B., E.W.E.), and the Division of General Internal Medicine and Public Health (R.S.D.), Department of Medicine, the Departments of Biostatistics (O.M.O., R.R.) and Pharmaceutical Services (J.L.S.), and Division of Trauma and Surgical Critical Care, Department of Surgery (M.B.P.), Vanderbilt University Medical Center, and the Anesthesia Service (C.G.H., P.P.P.), Research Service (J.C.J.), Surgical Service (M.B.P.), and Geriatric Research, Education and Clinical Center (R.S.D., E.W.E.), Department of Veterans Affairs Medical Center, Tennessee Valley Healthcare System - both in Nashville; the Neuroscience Institute and Department of Critical Care Medicine, Maine Medical Center, Portland (P.T.M.); the Department of Pharmacy and Health Systems Sciences, Bouve College of Health Sciences, Northeastern University, Boston (J.W.D., M.S.D.); the Departments of Pharmacy (J.T.S., L.N.B.) and Surgery (J.T.S.) and the Center for Outcomes Research (J.T.S.), Houston Methodist, and the Pulmonary, Critical Care and Sleep Medicine Section, Ben Taub Hospital, Baylor College of Medicine (K.K.G.), Houston; the Division of Pulmonary/Critical Care Medicine, University of Texas Health, and the South Texas Veterans Health Care System, San Antonio (A.A.); and Texas Health Harris Methodist Hospital Fort Worth, Fort Worth (A.S.) - all in Texas; the University of Sydney, and the Department of Anaesthetics, Royal Prince Alfred Hospital, Sydney, and the Department of Anesthesiology, University of Wisconsin, Madison (R.D.S.); Pulmonary and Critical Care Medicine, Baton Rouge General Medical Center and Our Lady of the Lake Regional Medical Center, Baton Rouge, LA (H.R.O.); the Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco (M.A.G.); Pulmonary and Critical Care, Mission Hospital, Asheville, NC (G.J.S.); the Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus (N.E.B.); and Clinical Research, Investigation, and Systems Modeling of Acute Illness Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh (T.D.G.).

Background: Guidelines currently recommend targeting light sedation with dexmedetomidine or propofol for adults receiving mechanical ventilation. Differences exist between these sedatives in arousability, immunity, and inflammation. Whether they affect outcomes differentially in mechanically ventilated adults with sepsis undergoing light sedation is unknown.

Methods: In a multicenter, double-blind trial, we randomly assigned mechanically ventilated adults with sepsis to receive dexmedetomidine (0.2 to 1.5 μg per kilogram of body weight per hour) or propofol (5 to 50 μg per kilogram per minute), with doses adjusted by bedside nurses to achieve target sedation goals set by clinicians according to the Richmond Agitation-Sedation Scale (RASS, on which scores range from -5 [unresponsive] to +4 [combative]). The primary end point was days alive without delirium or coma during the 14-day intervention period. Secondary end points were ventilator-free days at 28 days, death at 90 days, and age-adjusted total score on the Telephone Interview for Cognitive Status questionnaire (TICS-T; scores range from 0 to 100, with a mean of 50±10 and lower scores indicating worse cognition) at 6 months.

Results: Of 432 patients who underwent randomization, 422 were assigned to receive a trial drug and were included in the analyses - 214 patients received dexmedetomidine at a median dose of 0.27 μg per kilogram per hour, and 208 received propofol at a median dose of 10.21 μg per kilogram per minute. The median duration of receipt of the trial drugs was 3.0 days (interquartile range, 2.0 to 6.0), and the median RASS score was -2.0 (interquartile range, -3.0 to -1.0). We found no difference between dexmedetomidine and propofol in the number of days alive without delirium or coma (adjusted median, 10.7 vs. 10.8 days; odds ratio, 0.96; 95% confidence interval [CI], 0.74 to 1.26), ventilator-free days (adjusted median, 23.7 vs. 24.0 days; odds ratio, 0.98; 95% CI, 0.63 to 1.51), death at 90 days (38% vs. 39%; hazard ratio, 1.06; 95% CI, 0.74 to 1.52), or TICS-T score at 6 months (adjusted median score, 40.9 vs. 41.4; odds ratio, 0.94; 95% CI, 0.66 to 1.33). Safety end points were similar in the two groups.

Conclusions: Among mechanically ventilated adults with sepsis who were being treated with recommended light-sedation approaches, outcomes in patients who received dexmedetomidine did not differ from outcomes in those who received propofol. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01739933.).
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http://dx.doi.org/10.1056/NEJMoa2024922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162695PMC
April 2021

Epidemiological Conceptual Models and Health Justice for Critically Ill Older Adults.

Crit Care Med 2021 02;49(2):375-379

Department of Occupational Therapy, University of Pittsburgh, Pittsburgh, PA.

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http://dx.doi.org/10.1097/CCM.0000000000004793DOI Listing
February 2021

Prevalence and risk factors for delirium in critically ill patients with COVID-19 (COVID-D): a multicentre cohort study.

Lancet Respir Med 2021 03 8;9(3):239-250. Epub 2021 Jan 8.

Critical Illness, Brain Dysfunction, and Survivorship Center, Vanderbilt University Medical Center, Nashville, TN, USA; Center for Health Services Research, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Anesthesiology, Division of Anesthesiology Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Background: To date, 750 000 patients with COVID-19 worldwide have required mechanical ventilation and thus are at high risk of acute brain dysfunction (coma and delirium). We aimed to investigate the prevalence of delirium and coma, and risk factors for delirium in critically ill patients with COVID-19, to aid the development of strategies to mitigate delirium and associated sequelae.

Methods: This multicentre cohort study included 69 adult intensive care units (ICUs), across 14 countries. We included all patients (aged ≥18 years) admitted to participating ICUs with severe acute respiratory syndrome coronavirus 2 infection before April 28, 2020. Patients who were moribund or had life-support measures withdrawn within 24 h of ICU admission, prisoners, patients with pre-existing mental illness, neurodegenerative disorders, congenital or acquired brain damage, hepatic coma, drug overdose, suicide attempt, or those who were blind or deaf were excluded. We collected de-identified data from electronic health records on patient demographics, delirium and coma assessments, and management strategies for a 21-day period. Additional data on ventilator support, ICU length of stay, and vital status was collected for a 28-day period. The primary outcome was to determine the prevalence of delirium and coma and to investigate any associated risk factors associated with development of delirium the next day. We also investigated predictors of number of days alive without delirium or coma. These outcomes were investigated using multivariable regression.

Findings: Between Jan 20 and April 28, 2020, 4530 patients with COVID-19 were admitted to 69 ICUs, of whom 2088 patients were included in the study cohort. The median age of patients was 64 years (IQR 54 to 71) with a median Simplified Acute Physiology Score (SAPS) II of 40·0 (30·0 to 53·0). 1397 (66·9%) of 2088 patients were invasively mechanically ventilated on the day of ICU admission and 1827 (87·5%) were invasively mechanical ventilated at some point during hospitalisation. Infusion with sedatives while on mechanical ventilation was common: 1337 (64·0%) of 2088 patients were given benzodiazepines for a median of 7·0 days (4·0 to 12·0) and 1481 (70·9%) were given propofol for a median of 7·0 days (4·0 to 11·0). Median Richmond Agitation-Sedation Scale score while on invasive mechanical ventilation was -4 (-5 to -3). 1704 (81·6%) of 2088 patients were comatose for a median of 10·0 days (6·0 to 15·0) and 1147 (54·9%) were delirious for a median of 3·0 days (2·0 to 6·0). Mechanical ventilation, use of restraints, and benzodiazepine, opioid, and vasopressor infusions, and antipsychotics were each associated with a higher risk of delirium the next day (all p≤0·04), whereas family visitation (in person or virtual) was associated with a lower risk of delirium (p<0·0001). During the 21-day study period, patients were alive without delirium or coma for a median of 5·0 days (0·0 to 14·0). At baseline, older age, higher SAPS II scores, male sex, smoking or alcohol abuse, use of vasopressors on day 1, and invasive mechanical ventilation on day 1 were independently associated with fewer days alive and free of delirium and coma (all p<0·01). 601 (28·8%) of 2088 patients died within 28 days of admission, with most of those deaths occurring in the ICU.

Interpretation: Acute brain dysfunction was highly prevalent and prolonged in critically ill patients with COVID-19. Benzodiazepine use and lack of family visitation were identified as modifiable risk factors for delirium, and thus these data present an opportunity to reduce acute brain dysfunction in patients with COVID-19.

Funding: None.

Translations: For the French and Spanish translations of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S2213-2600(20)30552-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832119PMC
March 2021

Perceptions of Hyperoxemia and Conservative Oxygen Therapy in the Management of Acute Respiratory Failure.

Ann Am Thorac Soc 2021 Aug;18(8):1369-1379

Clinical Research, Investigation, and Systems Modeling of Acute Illness Center, Department of Critical Care Medicine.

Mechanically ventilated patients in the intensive care unit (ICU) are often managed to maximize oxygenation, yet hyperoxemia may be deleterious to some. Little is known about how ICU providers weigh tradeoffs between hypoxemia and hyperoxemia when managing acute respiratory failure. To define ICU providers' mental models for managing oxygenation for patients with acute respiratory failure and identify barriers and facilitators to conservative oxygen therapy. In two large U.S. tertiary care hospitals, we performed semistructured interviews with a purposive sample of ICU nurses, respiratory therapists, and physicians. We assessed perceptions of oxygenation management, hyperoxemia, and conservative oxygen therapies through interviews, which we audio recorded and transcribed verbatim. We analyzed transcripts for representative themes using an iterative thematic-analysis approach. We interviewed 10 nurses, 10 respiratory therapists, 4 fellows, and 5 attending physicians before reaching thematic saturation. Major themes included perceptions of hyperoxemia, attitudes toward conservative oxygen therapy, and aspects of titrated-oxygen-therapy implementation. Many providers did not recognize the term "hyperoxemia," whereas others described a poor understanding; several stated they never encounter hyperoxemia clinically. Concerns about hyperoxemia varied: some providers believed that typical ventilation strategies emphasizing progressive lowering of the fraction of inspired oxygen mitigated worries about excess oxygen administration, whereas others maintained that hyperoxemia is harmful only to patients with chronic lung disease. Almost all interviewees expressed familiarity with lower oxygen saturations in chronic obstructive pulmonary disease. Cited barriers to conservative oxygen therapy included concerns about hypoxemia, particularly among nurses and respiratory therapists; perceptions that hyperoxemia is not harmful; and a lack of clear evidence supporting conservative oxygen therapy. Interviewees suggested that interprofessional education and convincing clinical trial evidence could facilitate uptake of conservative oxygenation. This study describes attitudes toward hyperoxemia and conservative oxygen therapy. These preferences and uncertain benefits and risks of conservative oxygen therapy should be considered during future implementation efforts. Successful oxygen therapy implementation most likely will require ) improving awareness of hyperoxemia's effects, ) normalizing lower saturations in patients without chronic lung disease, ) addressing ingrained beliefs regarding oxygen management and oxygen's safety, and ) using interprofessional education to obtain buy-in across providers and inform the ICU team.
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http://dx.doi.org/10.1513/AnnalsATS.202007-802OCDOI Listing
August 2021

Publisher Correction: Delirium.

Nat Rev Dis Primers 2020 Dec 1;6(1):94. Epub 2020 Dec 1.

Center for Critical Illness, Brain Dysfunction, and Survivorship (CIBS), Vanderbilt University Medical Center, Nashville, TN, USA.

An Erratum to this paper has been published: https://doi.org/10.1038/s41572-020-00236-z.
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December 2020

Delirium.

Nat Rev Dis Primers 2020 11 12;6(1):90. Epub 2020 Nov 12.

Center for Critical Illness, Brain Dysfunction, and Survivorship (CIBS), Vanderbilt University Medical Center, Nashville, TN, USA.

Delirium, a syndrome characterized by an acute change in attention, awareness and cognition, is caused by a medical condition that cannot be better explained by a pre-existing neurocognitive disorder. Multiple predisposing factors (for example, pre-existing cognitive impairment) and precipitating factors (for example, urinary tract infection) for delirium have been described, with most patients having both types. Because multiple factors are implicated in the aetiology of delirium, there are likely several neurobiological processes that contribute to delirium pathogenesis, including neuroinflammation, brain vascular dysfunction, altered brain metabolism, neurotransmitter imbalance and impaired neuronal network connectivity. The Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) is the most commonly used diagnostic system upon which a reference standard diagnosis is made, although many other delirium screening tools have been developed given the impracticality of using the DSM-5 in many settings. Pharmacological treatments for delirium (such as antipsychotic drugs) are not effective, reflecting substantial gaps in our understanding of its pathophysiology. Currently, the best management strategies are multidomain interventions that focus on treating precipitating conditions, medication review, managing distress, mitigating complications and maintaining engagement to environmental issues. The effective implementation of delirium detection, treatment and prevention strategies remains a major challenge for health-care organizations globally.
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http://dx.doi.org/10.1038/s41572-020-00223-4DOI Listing
November 2020

Analgesia and sedation in patients with ARDS.

Intensive Care Med 2020 12 10;46(12):2342-2356. Epub 2020 Nov 10.

Department of Medicine, Section of Pulmonary and Critical Care, University of Chicago, Chicago, IL, USA.

Acute Respiratory Distress Syndrome (ARDS) is one of the most demanding conditions in an Intensive Care Unit (ICU). Management of analgesia and sedation in ARDS is particularly challenging. An expert panel was convened to produce a "state-of-the-art" article to support clinicians in the optimal management of analgesia/sedation in mechanically ventilated adults with ARDS, including those with COVID-19. Current ICU analgesia/sedation guidelines promote analgesia first and minimization of sedation, wakefulness, delirium prevention and early rehabilitation to facilitate ventilator and ICU liberation. However, these strategies cannot always be applied to patients with ARDS who sometimes require deep sedation and/or paralysis. Patients with severe ARDS may be under-represented in analgesia/sedation studies and currently recommended strategies may not be feasible. With lightened sedation, distress-related symptoms (e.g., pain and discomfort, anxiety, dyspnea) and patient-ventilator asynchrony should be systematically assessed and managed through interprofessional collaboration, prioritizing analgesia and anxiolysis. Adaptation of ventilator settings (e.g., use of a pressure-set mode, spontaneous breathing, sensitive inspiratory trigger) should be systematically considered before additional medications are administered. Managing the mechanical ventilator is of paramount importance to avoid the unnecessary use of deep sedation and/or paralysis. Therefore, applying an "ABCDEF-R" bundle (R = Respiratory-drive-control) may be beneficial in ARDS patients. Further studies are needed, especially regarding the use and long-term effects of fast-offset drugs (e.g., remifentanil, volatile anesthetics) and the electrophysiological assessment of analgesia/sedation (e.g., electroencephalogram devices, heart-rate variability, and video pupillometry). This review is particularly relevant during the COVID-19 pandemic given drug shortages and limited ICU-bed capacity.
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http://dx.doi.org/10.1007/s00134-020-06307-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653978PMC
December 2020

Risk, Results, and Costs: Optimizing Clinical Trial Efficiency through Prognostic Enrichment.

Am J Respir Crit Care Med 2021 03;203(6):671-672

Department of Critical Care Medicine University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania.

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http://dx.doi.org/10.1164/rccm.202009-3649EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958522PMC
March 2021

Inflammation and Coagulation during Critical Illness and Long-Term Cognitive Impairment and Disability.

Am J Respir Crit Care Med 2021 03;203(6):699-706

Critical Illness, Brain Dysfunction, and Survivorship Center, Nashville, Tennessee.

The biological mechanisms of long-term cognitive impairment and disability after critical illness are unclear. To test the hypothesis that markers of acute inflammation and coagulation are associated with subsequent long-term cognitive impairment and disability. We obtained plasma samples from adults with respiratory failure or shock on Study Days 1, 3, and 5 and measured concentrations of CRP (C-reactive protein), IFN-γ, IL-1β, IL-6, IL-8, IL-10, IL-12, MMP-9 (matrix metalloproteinase-9), TNF-α (tumor necrosis factor-α), soluble TNF receptor 1, and protein C. At 3 and 12 months after discharge, we assessed global cognition, executive function, and activities of daily living. We analyzed associations between markers and outcomes using multivariable regression, adjusting for age, sex, education, comorbidities, baseline cognition, doses of sedatives and opioids, stroke risk (in cognitive models), and baseline disability scores (in disability models). We included 548 participants who were a median (interquartile range) of 62 (53-72) years old, 88% of whom were mechanically ventilated, and who had an enrollment Sequential Organ Failure Assessment score of 9 (7-11). After adjusting for covariates, no markers were associated with long-term cognitive function. Two markers, CRP and MMP-9, were associated with greater disability in basic and instrumental activities of daily living at 3 and 12 months. No other markers were consistently associated with disability outcomes. Markers of systemic inflammation and coagulation measured early during critical illness are not associated with long-term cognitive outcomes and demonstrate inconsistent associations with disability outcomes. Future studies that pair longitudinal measurement of inflammation and related pathways throughout the course of critical illness and during recovery with long-term outcomes are needed.
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http://dx.doi.org/10.1164/rccm.201912-2449OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958515PMC
March 2021

Strategies to Promote ResiliencY (SPRY): a randomised embedded multifactorial adaptative platform (REMAP) clinical trial protocol to study interventions to improve recovery after surgery in high-risk patients.

BMJ Open 2020 09 29;10(9):e037690. Epub 2020 Sep 29.

Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Introduction: As the population ages, there is interest in strategies to promote resiliency, especially for frail patients at risk of its complications. The physiological stress of surgery in high-risk individuals has been proposed both as an important cause of accelerated age-related decline in health and as a model testing the effectiveness of strategies to improve resiliency to age-related health decline. We describe a randomised, embedded, multifactorial, adaptative platform (REMAP) trial to investigate multiple perioperative interventions, the first of which is metformin and selected for its anti-inflammatory and anti-ageing properties beyond its traditional blood glucose control features.

Methods And Analysis: Within a multihospital, single healthcare system, the Core Protocol for Strategies to Promote ResiliencY (SPRY) will be embedded within both the electronic health record (EHR) and the healthcare culture generating a continuously self-learning healthcare system. Embedding reduces the administrative burden of a traditional trial while accessing and rapidly analysing routine patient care EHR data. SPRY-Metformin is a placebo-controlled trial and is the first SPRY domain evaluating the effectiveness of three metformin dosages across three preoperative durations within a heterogeneous set of major surgical procedures. The primary outcome is 90-day hospital-free days. Bayesian posterior probabilities guide interim decision-making with predefined rules to determine stopping for futility or superior dosing selection. Using response adaptative randomisation, a maximum of 2500 patients allows 77%-92% power, detecting >15% primary outcome improvement. Secondary outcomes include mortality, readmission and postoperative complications. A subset of patients will be selected for substudies evaluating the microbiome, cognition, postoperative delirium and strength.

Ethics And Dissemination: The Core Protocol of SPRY REMAP and associated SPRY-Metformin Domain-Specific Appendix have been ethically approved by the Institutional Review Board and are publicly registered. Results will be publicly available to healthcare providers, patients and trial participants following achieving predetermined platform conclusions.

Trial Registration Number: NCT03861767.
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http://dx.doi.org/10.1136/bmjopen-2020-037690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526307PMC
September 2020

Socioeconomic Factors and Intensive Care Unit-Related Cognitive Impairment.

Ann Surg 2020 10;272(4):596-602

Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, TN.

Objective: We aimed to identify socioeconomic and clinical risk factors for post-intensive care unit (ICU)-related long-term cognitive impairment (LTCI).

Summary Background Data: After delirium during ICU stay, LTCI has been increasingly recognized, but without attention to socioeconomic factors.

Methods: We enrolled a prospective, multicenter cohort of ICU survivors with shock or respiratory failure from surgical and medical ICUs across 5 civilian and Veteran Affairs (VA) hospitals from 2010 to 2016. Our primary outcome was LTCI at 3- and 12 months post-hospital discharge defined by the Repeatable Battery for Assessment of Neuropsychological Symptoms (RBANS) global score. Covariates adjusted using multivariable linear regression included age, sex, race, AHRQ socioeconomic index, Charlson comorbidity, Framingham stroke risk, Sequential Organ Failure Assessment, duration of coma, delirium, hypoxemia, sepsis, education level, hospital type, insurance status, discharge disposition, and ICU drug exposures.

Results: Of 1040 patients, 71% experienced delirium, and 47% and 41% of survivors had RBANS scores >1 standard deviation below normal at 3- and 12 months, respectively. Adjusted analysis indicated that delirium, non-White race, lower education, and civilian hospitals (as opposed to VA), were associated with at least a half standard deviation lower RBANS scores at 3- and 12 months (P ≤ 0.03). Sex, AHRQ socioeconomic index, insurance status, and discharge disposition were not associated with RBANS scores.

Conclusions: Socioeconomic and clinical risk factors, such as race, education, hospital type, and delirium duration, were linked to worse PICS ICU-related, LTCI. Further efforts may focus on improved identification of higher-risk groups to promote survivorship through emerging improvements in cognitive rehabilitation.
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http://dx.doi.org/10.1097/SLA.0000000000004377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739516PMC
October 2020

Recovery From Severe COVID-19: Leveraging the Lessons of Survival From Sepsis.

JAMA 2020 Aug;324(8):739-740

Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Center, Pittsburgh, Pennsylvania.

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http://dx.doi.org/10.1001/jama.2020.14103DOI Listing
August 2020

Prevalence and Course of Frailty in Survivors of Critical Illness.

Crit Care Med 2020 10;48(10):1419-1426

Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center, Vanderbilt University Medical Center, Nashville, TN.

Objectives: Little is known about frailty that develops following critical illness. We sought to describe the prevalence of newly acquired frailty, its clinical course, and the co-occurrence of frailty with disability and cognitive impairment in survivors of critical illness.

Design: Longitudinal prospective cohort study.

Setting: Medical and surgical ICUs at five U.S. centers.

Patients: Adult patients treated for respiratory failure and/or shock.

Measurements And Main Results: We measured frailty with the Clinical Frailty Scale at baseline (i.e., study enrollment) and at 3 and 12 months postdischarge. We constructed alluvial diagrams to describe the course of frailty and Venn diagrams to describe the overlap of frailty with disability in activities of daily living and cognitive impairment. We included 567 participants a median (interquartile range) of 61 years old (51-70 yr old) with a high severity of illness (Acute Physiology and Chronic Health Evaluation II of 23). Frailty (Clinical Frailty Scale scores ≥ 5) was present in 135 of 567 (24%) at baseline, 239 of 530 (45%) at 3 months, and 163 of 445 (37%) at 12 months. Of those with frailty at 3- or 12-month follow-up, 61% were not frail at baseline. Transition to a worse frailty state occurred in 242 of 530 of patients (46%) between baseline and 3 months and in 179 of 445 of patients (40%) between baseline and 12 months. There were 376 patients with frailty, disability, or cognitive impairment at 3-month follow-up. Of these, 53 (14%) had frailty alone. At 12 months, 276 patients had frailty, disability, or cognitive impairment, 37 (13%) of whom had frailty alone.

Conclusions: Frailty is common among survivors of critical illness. In the majority, frailty is newly acquired. Roughly one in seven had frailty without co-occurring disability or cognitive impairment. Studies to understand outcomes of frailty that develops as the result of a critical illness and to identify modifiable risk factors for this potentially reversible syndrome are needed.
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http://dx.doi.org/10.1097/CCM.0000000000004444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941759PMC
October 2020

A multisite study of nurse-reported perceptions and practice of ABCDEF bundle components.

Intensive Crit Care Nurs 2020 Oct 8;60:102872. Epub 2020 May 8.

VA Tennessee Valley Healthcare System, Geriatric Research, Education and Clinical Center (GRECC), Nashville, TN, United States; Vanderbilt University, Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Nashville, TN, United States; Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center at Vanderbilt, Nashville, TN, United States. Electronic address:

Objectives: ABCDEF bundle implementation in the Intensive Care Unit (ICU) is associated with dose dependent improvements in patient outcomes. The objective was to compare nurse attitudes about the ABCDEF bundle to self-reported adherence to bundle components.

Research Methodology/design: Cross-sectional study.

Setting: Nurses providing direct patient care in 28 ICUs within 18 hospitals across the United States.

Main Outcome Measures: 53-item survey of attitudes and practice of the ABCDEF bundle components was administered between November 2011 and August 2015 (n = 1661).

Results: We did not find clinically significant correlations between nurse attitudes and adherence to Awakening trials, Breathing trials, and sedation protocol adherence (r = 0.05-0.28) or sedation plan discussion during rounds and Awakening and Breathing trial Coordination (r = 0.19). Delirium is more likely to be discussed during rounds when ICU physicians and nurse managers facilitate delirium reduction (r = 0.27-0.36). Early mobilization is more likely to occur when ICU physicians, nurse managers, staffing, equipment, and the ICU environment facilitate early mobility (r = 0.36-0.47). Physician leadership had the strongest correlation with reporting an ICU environment that facilitates ABCDEF bundle implementation (r = 0.63-0.74).

Conclusions: Nurse attitudes about bundle implementation did not predict bundle adherence. Nurse manager and physician leadership played a large role in creating a supportive ICU environment.
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http://dx.doi.org/10.1016/j.iccn.2020.102872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011280PMC
October 2020

A Brief Informant Screening Instrument for Dementia in the ICU: The Diagnostic Accuracy of the AD8 in Critically Ill Adults Suspected of Having Pre-Existing Dementia.

Dement Geriatr Cogn Disord 2019 7;48(5-6):241-249. Epub 2020 Apr 7.

Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

Background/aim: The diagnostic accuracy of brief informant screening instruments to detect dementia in critically ill adults is unknown. We sought to determine the diagnostic accuracy of the 2- to 3-min Ascertain Dementia 8 (AD8) completed by surrogates in detecting dementia among critically ill adults suspected of having pre-existing dementia by comparing it to the Clinical Dementia Rating Scale (CDR).

Methods: This substudy of BRAIN-ICU included a subgroup of 75 critically ill medical/surgical patients determined to be at medium risk of having pre-existing dementia (Informant Questionnaire on Cognitive Decline in the Elderly [IQCODE] score ≥3.3). We calculated the sensitivity, specificity, positive and negative predictive values (PPV and NPV), and AUC for the standard AD8 cutoff of ≥2 versus the reference standard CDR score of ≥1 for mild dementia.

Results: By the CDR, 38 patients had very mild or no dementia and 37 had mild dementia or greater. For diagnosing mild dementia, the AD8 had a sensitivity of 97% (95% CI 86-100), a specificity of 16% (6-31), a PPV of 53% (40-65), an NPV of 86% (42-100), and an AUC of 0.738 (0.626-0.850).

Conclusions: Among critically ill patients judged at risk for pre-existing dementia, the 2- to 3-min AD8 is highly sensitive and has a high NPV. These data indicate that the brief tool can serve to rule out dementia in a specific patient population.
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http://dx.doi.org/10.1159/000490379DOI Listing
July 2020

On the Road to a Delirium Assay.

Crit Care Med 2020 03;48(3):431-432

Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA The Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Center, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA.

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http://dx.doi.org/10.1097/CCM.0000000000004208DOI Listing
March 2020

Association of neuronal repair biomarkers with delirium among survivors of critical illness.

J Crit Care 2020 04 16;56:94-99. Epub 2019 Dec 16.

Department of Anesthesiology, Division of Anesthesiology Critical Care Medicine, Center for Health Services Research, Vanderbilt University Medical Center, Nashville, TN, United States.

Purpose: Delirium is prevalent but with unclear pathogenesis. Neuronal injury repair pathways may be protective. We hypothesized that higher concentrations of neuronal repair biomarkers would be associated with decreased delirium in critically ill patients.

Materials And Methods: We performed a nested study of hospital survivors within a prospective cohort that enrolled patients within 72 h of respiratory failure or shock. We measured plasma concentrations of ubiquitin carboxyl-terminal-esterase-L1 (UCHL1) and brain-derived neurotrophic factor (BDNF) from blood collected at enrollment. Delirium was assessed twice daily using the CAM-ICU. Multivariable regression was used to examine the associations between biomarkers and delirium prevalence/duration, adjusting for covariates and interactions with age and IL-6 plasma concentration.

Results: We included 427 patients with a median age of 59 years (IQR 48-69) and APACHE II score of 25 (IQR 19-30). Higher plasma concentration of UCHL1 on admission was independently associated with lower prevalence of delirium (p = .04) but not associated with duration of delirium (p = .06). BDNF plasma concentration was not associated with prevalence (p = .26) or duration of delirium (p = .36).

Conclusions: During critical illness, higher UCHL1 plasma concentration is associated with lower prevalence of delirium; BDNF plasma concentration is not associated with delirium. Clinical trial number: NCT00392795; https://clinicaltrials.gov/ct2/show/NCT00392795.
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http://dx.doi.org/10.1016/j.jcrc.2019.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080575PMC
April 2020

Delirium in the critically ill patient.

Handb Clin Neurol 2019 ;167:357-375

Department of Critical Care Medicine, Clinical Research, Investigation, and Systems Modeling of Acute Illness Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States. Electronic address:

Delirium is an acute and transient brain dysfunction that is characterized by disturbances in consciousness, affecting both its content (i.e., attention) and level (i.e., arousal). It affects as many as 50% of those admitted to an intensive care unit (ICU). Once believed to be an inconsequential outcome of critical illness, it is now recognized that delirium is harmful in both the short- and long-term. Despite occurring frequently in critically ill patients, delirium often goes unrecognized. Well-validated delirium screening tools, designed for use in the ICU, should be used to reliably detect delirium. The first step in delirium treatment is to identify and address potentially modifiable risk factors. Multiple trials have shown that benzodiazepines are a risk factor for delirium in a dose-dependent manner. Sedation with nonbenzodiazepine-based strategies are an effective means by which to reduce delirium. Nonpharmacologic strategies such as those which seek to reduce sensory impairment, sleep deprivation, and immobility are effective. Pharmacologic treatment with antipsychotics, though commonly used, is not supported by findings from placebo-controlled trials. Recent data support from multiple trials support the use of the "ABCDEF bundle" as a means by which to reduce delirium.
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http://dx.doi.org/10.1016/B978-0-12-804766-8.00019-4DOI Listing
April 2020

Association between hospital mortality and inspiratory airway pressures in mechanically ventilated patients without acute respiratory distress syndrome: a prospective cohort study.

Crit Care 2019 11 21;23(1):367. Epub 2019 Nov 21.

Division of Pulmonary and Critical Care, Johns Hopkins University, 1830 E Monument St Room 555, Baltimore, MD, 21287, USA.

Background: Higher inspiratory airway pressures are associated with worse outcomes in mechanically ventilated patients with the acute respiratory distress syndrome (ARDS). This relationship, however, has not been well investigated in patients without ARDS. We hypothesized that higher driving pressures (ΔP) and plateau pressures (Pplat) are associated with worse patient-centered outcomes in mechanically ventilated patients without ARDS as well as those with ARDS.

Methods: Using data collected during a prospective, observational cohort study of 6179 critically ill participants enrolled in 59 ICUs across the USA, we used multivariable logistic regression to determine whether ΔP and Pplat at enrollment were associated with hospital mortality among 1132 mechanically ventilated participants. We stratified analyses by ARDS status.

Results: Participants without ARDS (n = 822) had lower average severity of illness scores and lower hospital mortality (27.3% vs. 38.7%; p <  0.001) than those with ARDS (n = 310). Average Pplat (20.6 vs. 23.9 cm HO; p <  0.001), ΔP (14.3 vs. 16.0 cm HO; p <  0.001), and positive end-expiratory pressure (6.3 vs. 7.9 cm HO; p <  0.001) were lower in participants without ARDS, whereas average tidal volumes (7.2 vs. 6.8 mL/kg PBW; p <  0.001) were higher. Among those without ARDS, higher ΔP (adjusted OR = 1.36 per 7 cm HO, 95% CI 1.14-1.62) and Pplat (adjusted OR = 1.42 per 8 cm HO, 95% CI 1.17-1.73) were associated with higher mortality. We found similar relationships with mortality among those participants with ARDS.

Conclusions: Higher ΔP and Pplat are associated with increased mortality for participants without ARDS. ΔP may be a viable target for lung-protective ventilation in all mechanically ventilated patients.
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http://dx.doi.org/10.1186/s13054-019-2635-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868689PMC
November 2019
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