Publications by authors named "Rameela Chandrasekhar"

80 Publications

Spatial and temporal clustering of patients hospitalized with laboratory-confirmed influenza in the United States.

Epidemics 2020 06 10;31:100387. Epub 2020 Feb 10.

Vanderbilt University School of Medicine, Nashville, TN, USA. Electronic address:

Background: Timing of influenza spread across the United States is dependent on factors including local and national travel patterns and climate. Local epidemic intensity may be influenced by social, economic and demographic patterns. Data are needed to better explain how local socioeconomic factors influence both the timing and intensity of influenza seasons to result in national patterns.

Methods: To determine the spatial and temporal impacts of socioeconomics on influenza hospitalization burden and timing, we used population-based laboratory-confirmed influenza hospitalization surveillance data from the CDC-sponsored Influenza Hospitalization Surveillance Network (FluSurv-NET) at up to 14 sites from the 2009/2010 through 2013/2014 seasons (n = 35,493 hospitalizations). We used a spatial scan statistic and spatiotemporal wavelet analysis, to compare temporal patterns of influenza spread between counties and across the country.

Results: There were 56 spatial clusters identified in the unadjusted scan statistic analysis using data from the 2010/2011 through the 2013/2014 seasons, with relative risks (RRs) ranging from 0.09 to 4.20. After adjustment for socioeconomic factors, there were five clusters identified with RRs ranging from 0.21 to 1.20. In the wavelet analysis, most sites were in phase synchrony with one another for most years, except for the H1N1 pandemic year (2009-2010), wherein most sites had differential epidemic timing from the referent site in Georgia.

Conclusions: Socioeconomic factors strongly impact local influenza hospitalization burden. Influenza phase synchrony varies by year and by socioeconomics, but is less influenced by socioeconomics than is disease burden.
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http://dx.doi.org/10.1016/j.epidem.2020.100387DOI Listing
June 2020

Association of Hypoactive and Hyperactive Delirium With Cognitive Function After Critical Illness.

Crit Care Med 2020 Jun;48(6):e480-e488

Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center and the Center for Health Services Research, Vanderbilt University Medical Center, Nashville, TN.

Objectives: Delirium, a heterogenous syndrome, is associated with worse long-term cognition after critical illness. We sought to determine if duration of motoric subtypes of delirium are associated with worse cognition.

Design: Secondary analysis of prospective multicenter cohort study.

Setting: Academic, community, and Veteran Affairs hospitals.

Patients: Five-hundred eighty-two survivors of respiratory failure or shock.

Interventions: We assessed delirium and level of consciousness using the Confusion Assessment Method-ICU and Richmond Agitation Sedation Scale daily during hospitalization. We defined a day with hypoactive delirium as a day with positive Confusion Assessment Method-ICU and corresponding Richmond Agitation Sedation Scale score less than or equal to 0 and a day with hyperactive delirium as a day with positive Confusion Assessment Method-ICU and corresponding Richmond Agitation Sedation Scale score greater than 0. At 3 and 12 months, we assessed global cognition with the Repeatable Battery for the Assessment of Neurologic Status and executive function with the Trail Making Test Part B. We used multivariable regression to examine the associations between days of hypoactive and hyperactive delirium with cognition outcomes. We allowed for interaction between days of hypoactive and hyperactive delirium and adjusted for baseline and in-hospital covariates.

Measurements And Results: Hypoactive delirium was more common and persistent than hyperactive delirium (71% vs 17%; median 3 vs 1 d). Longer duration of hypoactive delirium was associated with worse global cognition at 3 (-5.13 [-8.75 to -1.51]; p = 0.03) but not 12 (-5.76 [-9.99 to -1.53]; p = 0.08) months and with worse executive functioning at 3 (-3.61 [-7.48 to 0.26]; p = 0.03) and 12 (-6.22 [-10.12 to -2.33]; p = 0.004) months; these associations were not modified by hyperactive delirium. Hyperactive delirium was not associated with global cognition or executive function in this cohort.

Conclusions: Longer duration of hypoactive delirium was independently associated with worse long-term cognition. Assessing motoric subtypes of delirium in the ICU might aid in prognosis and intervention allocation. Future studies should consider delineating motoric subtypes of delirium.
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http://dx.doi.org/10.1097/CCM.0000000000004313DOI Listing
June 2020

Moving Otology Beyond p < 0.05.

Otol Neurotol 2020 06;41(5):578-579

Department of Otolaryngology, Vanderbilt University School of Medicine, Nashville, Tennessee.

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http://dx.doi.org/10.1097/MAO.0000000000002662DOI Listing
June 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

Statistical analysis plan for the Maximizing the Efficacy of Sedation and Reducing Neurological Dysfunction and Mortality in Septic Patients with Acute Respiratory Failure trial.

Crit Care Resusc 2020 Mar;22(1):63-71

Critical Illness, Brain Dysfunction, and Survivorship Center, Vanderbilt University Medical Center, Nashville, TN, USA.

Background: The best sedative medication to reduce delirium, mortality and long term brain dysfunction in mechanically ventilated septic patients is unclear. This multicentre, double-blind, randomised trial investigates the short term and long term effects of dexmedetomidine versus propofol for sedation in mechanically ventilated severely septic patients.

Objectives: To describe the statistical analysis plan for this randomised clinical trial comprehensively and place it in the public domain before unblinding.

Methods: To ensure that analyses are not selectively reported, we developed a comprehensive statistical analysis plan before unblinding. This trial has an enrolment target of 420 severely septic and mechanically ventilated adult patients, randomly assigned to dexmedetomidine or propofol in a 1:1 ratio. Enrolment was completed in January 2019, and the study was estimated to be completed in September 2019. The primary endpoint is days alive without delirium or coma during first 14 study days. Secondary outcomes include 28-day ventilator-free days, 90-day all-cause mortality and cognitive function at 180 days. Time frames all begin on the day of randomisation. All analyses will be conducted on an intention-to-treat basis.

Conclusion: This study will compare the effects of two sedatives in mechanically ventilated severely septic patients. In keeping with the guidance on statistical principles for clinical trials, we have developed a comprehensive statistical analysis plan by which we will adhere, as this will avoid bias and support transparency and reproducibility.

Trial Registration: ClinicalTrials.gov (NCT01739933).
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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

Plasma biomarkers of inflammation, coagulation, and brain injury as predictors of delirium duration in older hospitalized patients.

PLoS One 2019 19;14(12):e0226412. Epub 2019 Dec 19.

The Critical Illness, Brain Dysfunction and Survivorship (CIBS) Center, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.

Background: Delirium's pathophysiology is poorly understood. We sought to determine if plasma biomarkers of inflammation, coagulation, endothelial activation, and blood brain barrier (BBB) injury were associated with emergency department (ED) delirium duration.

Methods: We enrolled hospitalized patients who were 65 years or older from the ED. Plasma biomarkers of inflammation (interleukin-6 [IL-6], IL-8, soluble tumor necrosis factor receptor I [sTNFRI]), coagulation (Protein C), endothelial activation (plasminogen activating inhibitor-1 [PAI-1]), and BBB injury (S100B) at were measured using blood obtained at enrollment. The dependent variable was ED delirium duration which was determined by the Brief Confusion Assessment Method assessed in the ED and hospitalization. Proportional odds logistic regression analyses were performed adjusted for relevant confounders and allowing for interaction by baseline dementia status.

Results: A total of 156 patients were enrolled. IL-6 (POR = 1.59, 95%CI: 1.09-2.32) and PAI-1 (POR = 2.96, 95%CI: 1.48 to 6.85) were independently associated with more prominent ED delirium duration in subjects without dementia only. No significant associations between IL-8, Protein C, sTNRFI, and S100B and ED delirium duration were observed.

Conclusions: Plasma Biomarkers of systemic inflammation and endothelial activation are associated with ED delirium duration in older ED patients without dementia.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226412PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6922408PMC
March 2020

A randomized trial of a specialist palliative care intervention for patients undergoing surgery for cancer: rationale and design of the Surgery for Cancer with Option of Palliative Care Expert (SCOPE) Trial.

Trials 2019 Dec 11;20(1):713. Epub 2019 Dec 11.

Critical Illness, Brain Dysfunction, and Survivorship Center, Nashville, TN, USA.

Background: In medical oncology settings, early specialist palliative care interventions have demonstrated improvements in patient quality of life and survival compared with usual oncologic care. However, the effect of early specialist palliative care interventions in surgical oncology settings is not well studied.

Methods: The Surgery for Cancer with Option for Palliative Care Expert (SCOPE) Trial is a single-center, prospective, single-blind, randomized controlled trial of a specialist palliative care intervention for cancer patients undergoing non-palliative surgery. It will enroll 236 patients scheduled for major abdominal operations for malignancy, who will be randomized 1:1 at enrollment to receive usual care (control arm) or specialist palliative care consultation (intervention arm). Intervention arm patients will receive consultations from a palliative care specialist (physician or nurse practitioner) preoperatively and postoperatively. The primary outcome is physical and functional wellbeing at 90 days postoperatively. Secondary outcomes are quality of life at 90 days postoperatively, posttraumatic stress disorder symptoms at 180 days postoperatively, days alive at home without an emergency room visit in the first 90 postoperative days, and overall survival at 1 year postoperatively. Participants will be followed for 3 years after surgery for exploratory analyses of their ongoing quality of life, healthcare utilization, and mortality.

Discussion: SCOPE is an ongoing randomized controlled trial evaluating specialist palliative care interventions for cancer patients undergoing non-palliative oncologic surgery. Findings from the study will inform ways to identify and improve care of surgical patients who will likely benefit from specialist palliative care services.

Trial Registration: ClinicalTrials.gov Identifier: NCT03436290 First Registered: 16 February 2018 Enrollment Began: 1 March 2018 Last Update: 20 December 2018.
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http://dx.doi.org/10.1186/s13063-019-3754-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907134PMC
December 2019

Vitamin D Deficiency and Long-Term Cognitive Impairment Among Older Adult Emergency Department Patients.

West J Emerg Med 2019 Oct 16;20(6):926-930. Epub 2019 Oct 16.

Vanderbilt University Medical Center, Department of Emergency Medicine and Geriatric Research, Education, and Clinical Center, Tennessee Valley Healthcare System, Nashville, Tennessee.

Introduction: Approximately 16% of acutely ill older adults develop new, long-term cognitive impairment (LTCI), many of whom initially seek care in the emergency department (ED). Currently, no effective interventions exist to prevent LTCI after an acute illness. Identifying early and modifiable risk factors for LTCI is the first step toward effective therapy. We hypothesized that Vitamin D deficiency at ED presentation was associated with LTCI in older adults.

Methods: This was an observational analysis of a prospective cohort study that enrolled ED patients ≥ 65 years old who were admitted to the hospital for an acute illness. All patients were enrolled within four hours of ED presentation. Serum Vitamin D was measured at enrollment and Vitamin D deficiency was defined as serum concentrations <20 mg/dL. We measured pre-illness and six-month cognition using the short form Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), which ranges from 1 to 5 (severe cognitive impairment). Multiple linear regression was performed to determine whether Vitamin D deficiency was associated with poorer six-month cognition adjusted for pre-illness IQCODE and other confounders. We incorporated a two-factor interaction into the regression model to determine whether the relationship between Vitamin D deficiency and six-month cognition was modified by pre-illness cognition.

Results: We included a total of 134 older ED patients; the median (interquartile range [IQR]) age was 74 (69, 81) years old, 61 (46%) were female, and 14 (10%) were nonwhite race. The median (IQR) vitamin D level at enrollment was 25 (18, 33) milligrams per deciliter and 41 (31%) of enrolled patients met criteria for vitamin D deficiency. Seventy-seven patients survived and had a six-month IQCODE. In patients with intact pre-illness cognition (IQCODE of 3.13), Vitamin D deficiency was significantly associated with worsening six-month cognition (β-coefficient: 0.43, 95% CI, 0.07 to 0.78, p = 0.02) after adjusting for pre-illness IQCODE and other confounders. Among patients with pre-illness dementia (IQCODE of 4.31), no association with Vitamin D deficiency was observed (β-coefficient: -0.1;, 95% CI, [-0.50-0.27], p = 0.56).

Conclusion: Vitamin D deficiency was associated with poorer six-month cognition in acutely ill older adult ED patients who were cognitively intact at baseline. Future studies should determine whether early Vitamin D repletion in the ED improves cognitive outcomes in acutely ill older patients.
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http://dx.doi.org/10.5811/westjem.2019.8.43312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6860383PMC
October 2019

Supratherapeutic Psychotropic Drug Levels in the Emergency Department and Their Association with Delirium Duration: A Preliminary Study.

J Am Geriatr Soc 2019 11 10;67(11):2387-2392. Epub 2019 Sep 10.

Center for Quality Aging, Vanderbilt University Medical Center, Nashville, Tennessee.

Objectives: Polypharmacy is associated with delirium, but the mechanisms for this connection are unclear. Our goal was to determine the frequency of supratherapeutic psychotropic drug levels (SPDLs) in older hospitalized patients and if it is associated with the duration of emergency department (ED) delirium.

Design: Secondary analysis of a prospective cohort study.

Setting: Tertiary care academic medical center.

Participants: ED patients 65 years or older who were admitted to the hospital.

Measurements: Delirium was assessed in the ED and during the first 7 days of hospitalization using the modified Brief Confusion Assessment Method. Drug concentrations were determined in serum samples collected at enrollment via a novel platform based on liquid chromatography-tandem mass spectrometry capable of identifying and quantitating 78 clinically approved medications including opioids, benzodiazepines, antidepressants, antipsychotics, and amphetamines. Patients with serum psychotropic drug concentrations above established reference ranges were considered supratherapeutic and have a SPDL. We performed proportional odds logistic regression to determine if SPDLs were associated with ED delirium duration adjusted for confounders. Medical record review was performed to determine if the doses of medications associated with SPDLs were adjusted at hospital discharge.

Results: A total of 158 patients were enrolled; of these, 66 were delirious in the ED. SPDLs were present in 11 (17%) of the delirious and 4 (4%) of the non-delirious ED patients. SPDLs were significantly associated with longer ED delirium duration (adjusted proportional odds ratio = 6.0; 95% confidence interval = 2.1-17.3) after adjusting for confounders. Of the 15 medications associated with SPDLs, 9 (60%) were prescribed at the same or higher doses at the time of hospital discharge.

Conclusion: SPDLs significantly increased the odds of prolonged ED delirium episodes. Approximately half of the medications associated with SPDLs were continued after hospital discharge at the same or higher doses. J Am Geriatr Soc 67:2387-2392, 2019.
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http://dx.doi.org/10.1111/jgs.16156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029781PMC
November 2019

Mitochondrial DNA Haplogroups and Delirium During Sepsis.

Crit Care Med 2019 08;47(8):1065-1071

Clinical Research, Investigation, and Systems Modeling of Acute illness (CRISMA) Center in the Department of Critical Care Medicine, University of Pittsburgh School of Medicine.

Objectives: Studies suggest that mitochondrial dysfunction underlies some forms of sepsis-induced organ failure. We sought to test the hypothesis that variations in mitochondrial DNA haplogroup affect susceptibility to sepsis-associated delirium, a common manifestation of acute brain dysfunction during sepsis.

Design: Retrospective cohort study.

Setting: Medical and surgical ICUs at a large tertiary care center.

Patients: Caucasian and African American adults with sepsis.

Measurements And Main Results: We determined each patient's mitochondrial DNA haplogroup using single-nucleotide polymorphisms genotyping data in a DNA databank and extracted outcomes from linked electronic medical records. We then used zero-inflated negative binomial regression to analyze age-adjusted associations between mitochondrial DNA haplogroups and duration of delirium, identified using the Confusion Assessment Method for the ICU. Eight-hundred ten patients accounted for 958 sepsis admissions, with 802 (84%) by Caucasians and 156 (16%) by African Americans. In total, 795 patient admissions (83%) involved one or more days of delirium. The 7% of Caucasians belonging to mitochondrial DNA haplogroup clade IWX experienced more delirium than the 49% in haplogroup H, the most common Caucasian haplogroup (age-adjusted rate ratio for delirium 1.36; 95% CI, 1.13-1.64; p = 0.001). Alternatively, among African Americans the 24% in haplogroup L2 experienced less delirium than those in haplogroup L3, the most common African haplogroup (adjusted rate ratio for delirium 0.60; 95% CI, 0.38-0.94; p = 0.03).

Conclusions: Variations in mitochondrial DNA are associated with development of and protection from delirium in Caucasians and African Americans during sepsis. Future studies are now required to determine whether mitochondrial DNA and mitochondrial dysfunction contribute to the pathogenesis of delirium during sepsis so that targeted treatments can be developed.
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http://dx.doi.org/10.1097/CCM.0000000000003810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012366PMC
August 2019

Challenges With Postoperative Cognitive Impairment Research.

JAMA Surg 2019 04;154(4):334-335

Critical Illness, Brain Dysfunction, and Survivorship Center, 2525 West End Avenue, 4th Floor, Nashville, Tennessee.

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http://dx.doi.org/10.1001/jamasurg.2018.5110DOI Listing
April 2019

Socioeconomic Disparities and Health Outcomes.

Am J Respir Crit Care Med 2019 03;199(6):807-808

1 Vanderbilt University School of Medicine Nashville, Tennessee.

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http://dx.doi.org/10.1164/rccm.201811-2073LEDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423093PMC
March 2019

Deficits in Self-Reported Initiation Are AssociatedWith Subsequent Disability in ICU Survivors.

Psychosomatics 2019 Jul - Aug;60(4):376-384. Epub 2018 Sep 29.

Department of Medicine, Division of General Internal Medicine and Public Health, Vanderbilt University School of Medicine, Nashville, TN.

Objective: To determine whether deficits in a key aspect of executive functioning, namely, initiation, were associated with current and future functional disabilities in intensive care unit survivors.

Methods: A nested substudy within a 2-center prospective observational cohort. We used 3 tests of initiation at 3 and 12 months: the Ruff Total Unique Design, Controlled Oral Word Association, and Behavior Rating Inventory of Executive Function initiation. Disability in instrumental activities of daily living (IADL) was measured with the Functional Activities Questionnaire. We used a proportional odds logistic regression model to evaluate the association between initiation and disability. Covariates in the model included age, education, baseline Functional Activities Questionnaire, pre-existing cognitive impairment, comorbidities, admission severity of illness, episodes of hypoxia, and days of severe sepsis.

Results: In 195 patients, after adjusting for covariates, only the Behavior Rating Inventory of Executive Function initiation was associated with disability at any time point. Comparing the 25th vs the 75th percentile scores (95% confidence interval) of the Behavior Rating Inventory of Executive Function initiation at 3 months, patients with worse initiation scores had 5.062 times the odds (95% confidence interval: 2.539, 10.092) of disability according to the Functional Activities Questionnaire at 3 months, with similar odds at 12 months (odds ratio: 3.476, 95% confidence interval: 1.943, 6.216). Worse Behavior Rating Inventory of Executive Function initiation scores at 3 months were associated with future disability at 12 months odds ratio (95% confidence interval) 5.079 (2.579, 10.000).

Conclusions: Executive function deficits acquired after a critical illness in the domain of initiation are common in intensive care unit survivors, and when they are identified via self-report tools, they are associated with current and future disability in instrumental activities of daily living.
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http://dx.doi.org/10.1016/j.psym.2018.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583673PMC
May 2020

Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness.

N Engl J Med 2018 12 22;379(26):2506-2516. Epub 2018 Oct 22.

From the 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.); the Pulmonary, Critical Care, and Sleep Medicine Division, Department of Medicine, Ohio State University Wexner Medical Center, Columbus (M.C.E.), and the Department of Critical Care Medicine, Respiratory Institute, Cleveland Clinic Foundation, Cleveland (R.D.H.) - both in Ohio; the Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill (S.S.C.), the Section on Critical Care, Department of Anesthesiology, Wake Forest Baptist Health, Winston-Salem (D.L.B.), and Cone Health System, Greensboro (D.J.F.) - all in North Carolina; the Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington School of Medicine, Seattle (C.L.H.); the Department of Anesthesiology, University of Maryland School of Medicine, Baltimore (P.R.); the Division of Critical Care Medicine, Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, New York (M.N.G.); the Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, Denver Health Medical Center, Denver (I.S.D.); the Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of California at San Diego, San Diego (A.M., R.L.O.); the Division of Pulmonary, Critical Care, Sleep, and Occupational Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis (B.K.); the Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University School of Medicine, New Haven, CT (M.A.P.); the Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor (R.C.H.); the Division of Pulmonary, Critical Care, and Occupational Medicine, Department of Medicine, University of Iowa Hospitals and Clinics, Iowa City (G.A.S.); , and the Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia (W.D.S.); the Center for Clinical Effectiveness, Baylor Scott and White Health, Dallas (A.L.M.); and the Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center (J.L.T., R.C., B.T.P., C.S., L.M.B., J.C.J., P.P.P., N.E.B., C.G.H., M.B.P., J.L.S., G.R.B., R.S.D., E.W.E.), the Center for Health Services Research (R.C., J.C.J., C.S., N.E.B., R.S.D., E.W.E.), the Center for Quality Aging (N.E.B., E.W.E.), the Division of Allergy, Pulmonary, and Critical Care Medicine (J.C.J., C.S., N.E.B., G.R.B., E.W.E.), the Division of General Internal Medicine and Public Health (R.S.D.), Department of Medicine, the Department of Biostatistics (J.L.T., R.C.), the Department of Psychiatry (J.C.J.), the Division of Anesthesiology Critical Care Medicine, Department of Anesthesiology (P.P.P., C.G.H.), the Division of Trauma and Surgical Critical Care, Department of Surgery (M.B.P.), and the Department of Pharmaceutical Services (J.L.S.), Vanderbilt University School of Medicine, Vanderbilt University School of Nursing (L.M.B.), and the Anesthesia Service (P.P.P., C.G.H.), Research Service (J.C.J.), Surgical Service (M.B.P.), and Geriatric Research, Education, and Clinical Center Service (R.S.D., E.W.E.), Department of Veterans Affairs Medical Center, Tennessee Valley Healthcare System - all in Nashville.

Background: There are conflicting data on the effects of antipsychotic medications on delirium in patients in the intensive care unit (ICU).

Methods: In a randomized, double-blind, placebo-controlled trial, we assigned patients with acute respiratory failure or shock and hypoactive or hyperactive delirium to receive intravenous boluses of haloperidol (maximum dose, 20 mg daily), ziprasidone (maximum dose, 40 mg daily), or placebo. The volume and dose of a trial drug or placebo was halved or doubled at 12-hour intervals on the basis of the presence or absence of delirium, as detected with the use of the Confusion Assessment Method for the ICU, and of side effects of the intervention. The primary end point was the number of days alive without delirium or coma during the 14-day intervention period. Secondary end points included 30-day and 90-day survival, time to freedom from mechanical ventilation, and time to ICU and hospital discharge. Safety end points included extrapyramidal symptoms and excessive sedation.

Results: Written informed consent was obtained from 1183 patients or their authorized representatives. Delirium developed in 566 patients (48%), of whom 89% had hypoactive delirium and 11% had hyperactive delirium. Of the 566 patients, 184 were randomly assigned to receive placebo, 192 to receive haloperidol, and 190 to receive ziprasidone. The median duration of exposure to a trial drug or placebo was 4 days (interquartile range, 3 to 7). The median number of days alive without delirium or coma was 8.5 (95% confidence interval [CI], 5.6 to 9.9) in the placebo group, 7.9 (95% CI, 4.4 to 9.6) in the haloperidol group, and 8.7 (95% CI, 5.9 to 10.0) in the ziprasidone group (P=0.26 for overall effect across trial groups). The use of haloperidol or ziprasidone, as compared with placebo, had no significant effect on the primary end point (odds ratios, 0.88 [95% CI, 0.64 to 1.21] and 1.04 [95% CI, 0.73 to 1.48], respectively). There were no significant between-group differences with respect to the secondary end points or the frequency of extrapyramidal symptoms.

Conclusions: The use of haloperidol or ziprasidone, as compared with placebo, in patients with acute respiratory failure or shock and hypoactive or hyperactive delirium in the ICU did not significantly alter the duration of delirium. (Funded by the National Institutes of Health and the VA Geriatric Research Education and Clinical Center; MIND-USA ClinicalTrials.gov number, NCT01211522 .).
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http://dx.doi.org/10.1056/NEJMoa1808217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6364999PMC
December 2018

The Cost of ICU Delirium and Coma in the Intensive Care Unit Patient.

Med Care 2018 10;56(10):890-897

Geriatric Research, Education and Clinical Center (GRECC), Department of Veterans Affairs Medical.

Rationale: Intensive care unit (ICU) delirium is highly prevalent and a potentially avoidable hospital complication. The current cost of ICU delirium is unknown.

Objectives: To specify the association between the daily occurrence of delirium in the ICU with costs of ICU care accounting for time-varying illness severity and death.

Research Design: We performed a prospective cohort study within medical and surgical ICUs in a large academic medical center.

Subjects: We analyzed critically ill patients (N=479) with respiratory failure and/or shock.

Measures: Covariates included baseline factors (age, insurance, cognitive impairment, comorbidities, Acute Physiology and Chronic Health Evaluation II Score) and time-varying factors (sequential organ failure assessment score, mechanical ventilation, and severe sepsis). The primary analysis used a novel 3-stage regression method: first, estimation of the cumulative cost of delirium over 30 ICU days and then costs separated into those attributable to increased resource utilization among survivors and those that were avoided on the account of delirium's association with early mortality in the ICU.

Results: The patient-level 30-day cumulative cost of ICU delirium attributable to increased resource utilization was $17,838 (95% confidence interval, $11,132-$23,497). A combination of professional, dialysis, and bed costs accounted for the largest percentage of the incremental costs associated with ICU delirium. The 30-day cumulative incremental costs of ICU delirium that were avoided due to delirium-associated early mortality was $4654 (95% confidence interval, $2056-7869).

Conclusions: Delirium is associated with substantial costs after accounting for time-varying illness severity and could be 20% higher (∼$22,500) if not for its association with early ICU mortality.
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http://dx.doi.org/10.1097/MLR.0000000000000975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200340PMC
October 2018

Delirium etiology subtypes and their effect on six-month function and cognition in older emergency department patients.

Int Psychogeriatr 2019 02 19;31(2):267-276. Epub 2018 Jul 19.

Department of Emergency Medicine,Vanderbilt University Medical Center,Nashville,Tennessee,USA.

ABSTRACTBackground:Delirium is heterogeneous and can vary by etiology.

Objectives: We sought to determine how delirium subtyped by etiology affected six-month function and cognition.

Design: Prospective cohort study.

Setting: Tertiary care, academic medical center.

Participants: A total of 228 hospitalized patients > 65 years old were admitted from the emergency department (ED).

Measurements: The modified Brief Confusion Assessment Method was used to determine delirium in the ED. Delirium etiology was determined by three trained physician reviewers using a Delirium Etiology checklist. Pre-illness and six-month function and cognition were determined using the Older American Resources and Services Activities of Daily Living (OARS ADL) questionnaire and the short-form Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Multiple linear regression was performed to determine if delirium etiology subtypes were associated with six-month function and cognition adjusted for baseline OARS ADL and IQCODE. Two-factor interactions were incorporated to determine pre-illness function or cognition-modified relationships between delirium subtypes and six-month function and cognition.

Results: In patients with poorer pre-illness function only, delirium secondary to metabolic disturbance (β coefficient = -2.9 points, 95%CI: -0.3 to -5.6) and organ dysfunction (β coefficient = -4.3 points, 95%CI: -7.2 to -1.4) was significantly associated with poorer six-month function. In patients with intact cognition only, delirium secondary to central nervous system insults was significantly associated with poorer cognition (β coefficient = 0.69, 95%CI: 0.19 to 1.20).

Conclusions: Delirium is heterogeneous and different etiologies may have different prognostic implications. Furthermore, the effect of these delirium etiologies on outcome may be dependent on the patient's pre-illness functional status and cognition.
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http://dx.doi.org/10.1017/S1041610218000777DOI Listing
February 2019

Delirium's Arousal Subtypes and Their Relationship with 6-Month Functional Status and Cognition.

Psychosomatics 2019 Jan - Feb;60(1):27-36. Epub 2018 May 17.

Center for Quality Aging, Vanderbilt University Medical Center, Nashville, TN; Center for Health Services Research, Vanderbilt University Medical Center, Nashville, TN; Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN; Geriatric Research, Education, and Clinical Center, Department of Veterans Affairs Medical Center, Tennessee Valley Health Care Center, Nashville, TN.

Objective: We sought to determine how delirium subtyped by arousal affected 6-month function and cognition in acutely ill older patients.

Methods: This was secondary analysis of a prospective cohort study which enrolled hospitalized patients ≥65 years old. Delirium and arousal were ascertained daily in the emergency department and the first 7 days of hospitalization using the modified Brief Confusion Assessment Method and Richmond Agitation Sedation Scale, respectively. For each day, patients were categorized as having no delirium, delirium with normal arousal, delirium with decreased arousal, or delirium with increased arousal. Preillness and 6-month functional status were determined using the Older American Resources and Services activities of daily living scale which ranges from 0 (completely dependent) to 28 (completely independent). Preillness and 6-month cognition were determined using the Informant Questionnaire on Cognitive Decline in the Elderly which ranges from 1 (markedly improved cognition) to 5 (severe cognitive impairment). Multiple linear regression was performed adjusted for preillness Older American Resources and Services activities of daily living and Informant Questionnaire on Cognitive Decline in the Elderly and other relevant confounders.

Results: In 228 older patients, delirium with normal arousal was the only subtype independently associated with poorer 6-month function and cognition. For every day spent in this subtype, the 6-month Older American Resources and Services activities of daily living decreased by 0.84 points (95% confidence interval: -1.59 to -0.09) and the patient's 6-month Informant Questionnaire on Cognitive Decline in the Elderly significantly increased by 0.14 points (95% confidence interval: 0.06-0.23).

Conclusions: Delirium with normal arousal, as opposed to delirium with decreased or increased arousal, was the only arousal subtype significantly associated with worsening 6-month function and cognition. Subtyping delirium by arousal may have important prognostic value.
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http://dx.doi.org/10.1016/j.psym.2018.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296894PMC
August 2019

Co-Occurrence of Post-Intensive Care Syndrome Problems Among 406 Survivors of Critical Illness.

Crit Care Med 2018 09;46(9):1393-1401

Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.

Objectives: To describe the frequency of co-occurring newly acquired cognitive impairment, disability in activities of daily livings, and depression among survivors of a critical illness and to evaluate predictors of being free of post-intensive care syndrome problems.

Design: Prospective cohort study.

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

Patients: Patients with respiratory failure or shock, excluding those with preexisting cognitive impairment or disability in activities of daily livings.

Interventions: None.

Measurements And Main Results: At 3 and 12 months after hospital discharge, we assessed patients for cognitive impairment, disability, and depression. We categorized patients into eight groups reflecting combinations of cognitive, disability, and mental health problems. Using multivariable logistic regression, we modeled the association between age, education, frailty, durations of mechanical ventilation, delirium, and severe sepsis with the odds of being post-intensive care syndrome free. We analyzed 406 patients with a median age of 61 years and an Acute Physiology and Chronic Health Evaluation II of 23. At 3 and 12 months, one or more post-intensive care syndrome problems were present in 64% and 56%, respectively. Nevertheless, co-occurring post-intensive care syndrome problems (i.e., in two or more domains) were present in 25% at 3 months and 21% at 12 months. Post-intensive care syndrome problems in all three domains were present in only 6% at 3 months and 4% at 12 months. More years of education was associated with greater odds of being post-intensive care syndrome free (p < 0.001 at 3 and 12 mo). More severe frailty was associated with lower odds of being post-intensive care syndrome free (p = 0.005 at 3 mo and p = 0.048 at 12 mo).

Conclusions: In this multicenter cohort study, one or more post-intensive care syndrome problems were present in the majority of survivors, but co-occurring problems were present in only one out of four. Education was protective from post-intensive care syndrome problems and frailty predictive of the development of post-intensive care syndrome problems. Future studies are needed to understand better the heterogeneous subtypes of post-intensive care syndrome and to identify modifiable risk factors.
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http://dx.doi.org/10.1097/CCM.0000000000003218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6095801PMC
September 2018

Pain and Its Long-term Interference of Daily Life After Critical Illness.

Anesth Analg 2018 09;127(3):690-697

Division of Anesthesiology Critical Care Medicine and Center for Health Services Research, Vanderbilt University School of Medicine, Nashville, Tennessee.

Background: Persistent pain likely interferes with quality of life in survivors of critical illness, but data are limited on its prevalence and risk factors. We sought to determine the prevalence of persistent pain after critical illness and its interference with daily life. Additionally, we sought to determine if intensive care unit (ICU) opioid exposure is a risk factor for its development.

Methods: In a cohort of adult medical and surgical ICU survivors, we used the brief pain inventory (BPI) to assess pain intensity and pain interference of daily life at 3 and 12 months after hospital discharge. We used proportional odds logistic regression with Bonferroni correction to evaluate the independent association of ICU opioid exposure with BPI scores, adjusting for potential confounders including age, preadmission opioid use, frailty, surgery, severity of illness, and durations of delirium and sepsis while in the ICU.

Results: We obtained BPI outcomes in 295 patients overall. At 3 and 12 months, 77% and 74% of patients reported persistent pain symptoms, respectively. The median (interquartile range) pain intensity score was 3 (1, 5) at both 3 and 12 months. Pain interference with daily life was reported in 59% and 62% of patients at 3 and 12 months, respectively. The median overall pain interference score was 2 (0, 5) at both 3 and 12 months. ICU opioid exposure was not associated with increased pain intensity at 3 months (odds ratio [OR; 95% confidence interval], 2.12 [0.92-4.93]; P = .18) or 12 months (OR, 2.58 [1.26-5.29]; P = .04). ICU opioid exposure was not associated with increased pain interference of daily life at 3 months (OR, 1.48 [0.65-3.38]; P = .64) or 12 months (OR, 1.46 [0.72-2.96]; P = .58).

Conclusions: Persistent pain is prevalent after critical illness and frequently interferes with daily life. Increased ICU opioid exposure was not associated with worse pain symptoms. Further studies are needed to identify modifiable risk factors for persistent pain in the critically ill and the effects of ICU opioids on patients with and without chronic pain.
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http://dx.doi.org/10.1213/ANE.0000000000003358DOI Listing
September 2018

Acute Brain Dysfunction: Development and Validation of a Daily Prediction Model.

Chest 2018 08 24;154(2):293-301. Epub 2018 Mar 24.

Department of Medicine, Division of General Internal Medicine and Public Health, Vanderbilt University Medical Center, Nashville, TN; Geriatric Research, Education and Clinical Center (GRECC) of the VA Tennessee Valley Healthcare System, Nashville, TN; Center for Health Services Research, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN; Center for Quality Aging, Vanderbilt University Medical Center, Nashville, TN. Electronic address:

Background: The goal of this study was to develop and validate a dynamic risk model to predict daily changes in acute brain dysfunction (ie, delirium and coma), discharge, and mortality in ICU patients.

Methods: Using data from a multicenter prospective ICU cohort, a daily acute brain dysfunction-prediction model (ABD-pm) was developed by using multinomial logistic regression that estimated 15 transition probabilities (from one of three brain function states [normal, delirious, or comatose] to one of five possible outcomes [normal, delirious, comatose, ICU discharge, or died]) using baseline and daily risk factors. Model discrimination was assessed by using predictive characteristics such as negative predictive value (NPV). Calibration was assessed by plotting empirical vs model-estimated probabilities. Internal validation was performed by using a bootstrap procedure.

Results: Data were analyzed from 810 patients (6,711 daily transitions). The ABD-pm included individual risk factors: mental status, age, preexisting cognitive impairment, baseline and daily severity of illness, and daily administration of sedatives. The model yielded very high NPVs for "next day" delirium (NPV: 0.823), coma (NPV: 0.892), normal cognitive state (NPV: 0.875), ICU discharge (NPV: 0.905), and mortality (NPV: 0.981). The model demonstrated outstanding calibration when predicting the total number of patients expected to be in any given state across predicted risk.

Conclusions: We developed and internally validated a dynamic risk model that predicts the daily risk for one of three cognitive states, ICU discharge, or mortality. The ABD-pm may be useful for predicting the proportion of patients for each outcome state across entire ICU populations to guide quality, safety, and care delivery activities.
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http://dx.doi.org/10.1016/j.chest.2018.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113630PMC
August 2018

Psychometric Properties of the FACIT-Pal 14 Administered in an Outpatient Palliative Care Clinic.

Am J Hosp Palliat Care 2018 Oct 12;35(10):1292-1294. Epub 2018 Mar 12.

1 Section of Palliative Care, Vanderbilt University Medical Center, Nashville, TN, USA.

Background: The Functional Assessment of Chronic Illness Therapy-Palliative (FACIT-Pal) 14 instrument measures the quality of life in palliative care patients but its psychometric properties are not well characterized.

Objectives: To establish the reliability and validity of the FACIT-Pal 14 in an outpatient palliative care clinic population.

Methods: The FACIT-Pal 14 was administered to 227 patients in an outpatient palliative care clinic at a large, urban academic medical center. Internal consistency reliability was assessed with Crohnbach's α, and principal component analysis was used to investigate for multiple underlying latent variables. Construct validity was tested by comparing mean scores in various subgroups.

Results: The FACIT-Pal 14 has Crohnbach's α of 0.76, which increases to 0.79 if 2 items are removed. Principal component analysis supports a single latent variable underlying the instrument. Significantly lower mean scores were found in patients with Eastern Cooperative Oncology Group (ECOG) functional status 3 to 4 compared with patients with ECOG functional status 1-2 ( P = .007), in patients with life expectancy under 6 months compared to those with 6 months or greater ( P = .003), and in patients referred to clinic for pain and symptom management compared with patients referred for other reasons ( P = .038). Instrument scores did not significantly differ between men and women or between white and nonwhite patients ( P = .525 and P = .263, respectively).

Conclusions: In an outpatient palliative care clinic population, the FACIT-Pal 14 has good internal consistency, but removal of 2 items would improve consistency. One latent variable underlies the instrument and there is evidence of construct validity.
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http://dx.doi.org/10.1177/1049909118763793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026571PMC
October 2018

Relationships between markers of neurologic and endothelial injury during critical illness and long-term cognitive impairment and disability.

Intensive Care Med 2018 03 9;44(3):345-355. Epub 2018 Mar 9.

Department of Critical Care Medicine and Clinical Research, Investigation and Systems Modeling of Acute Illnesses Center, University of Pittsburgh, Pittsburgh, USA.

Purpose: Neurologic and endothelial injury biomarkers are associated with prolonged delirium during critical illness and may reflect injury pathways that lead to poor long-term outcomes. We hypothesized that blood-brain barrier (BBB), neuronal, and endothelial injury biomarkers measured during critical illness are associated with cognitive impairment and disability after discharge.

Methods: We enrolled adults with respiratory failure and/or shock and measured plasma concentrations of BBB (S100B), neuronal (UCHL1, BDNF), and endothelial (E-selectin, PAI-1) injury markers within 72 h of ICU admission. At 3 and 12 months post-discharge, we assessed participants' global cognition, executive function, and activities of daily living (ADL). We used multivariable regression to determine whether biomarkers were associated with outcomes after adjusting for relevant demographic and acute illness covariates.

Results: Our study included 419 survivors of critical illness with median age 59 years and APACHE II score 25. Higher S100B was associated with worse global cognition at 3 and 12 months (P = 0.008; P = 0.01). UCHL1 was nonlinearly associated with global cognition at 3 months (P = 0.02). Higher E-selectin was associated with worse global cognition (P = 0.006 at 3 months; P = 0.06 at 12 months). BDNF and PAI-1 were not associated with global cognition. No biomarkers were associated with executive function. Higher S100B (P = 0.05) and E-selectin (P = 0.02) were associated with increased disability in ADLs at 3 months.

Conclusions: S100B, a marker of BBB and/or astrocyte injury, and E-selectin, an adhesion molecule and marker of endothelial injury, are associated with long-term cognitive impairment after critical illness, findings that may reflect mechanisms of critical illness brain injury.
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http://dx.doi.org/10.1007/s00134-018-5120-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870884PMC
March 2018

Clinical phenotypes of delirium during critical illness and severity of subsequent long-term cognitive impairment: a prospective cohort study.

Lancet Respir Med 2018 03;6(3):213-222

ICU Delirium and Cognitive Impairment Study Group at the Vanderbilt University School of Medicine, Nashville, Tennessee, USA; Center for Health Services Research, Vanderbilt University School of Medicine, Nashville, TN, USA; Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA; Center for Quality Aging, Vanderbilt University School of Medicine, Nashville, TN, USA; Geriatric Research, Education and Clinical Center (GRECC) Service, Department of Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, TN, USA.

Background: Delirium during critical illness results from numerous insults, which might be interconnected and yet individually contribute to long-term cognitive impairment. We sought to describe the prevalence and duration of clinical phenotypes of delirium (ie, phenotypes defined by clinical risk factors) and to understand associations between these clinical phenotypes and severity of subsequent long-term cognitive impairment.

Methods: In this multicentre, prospective cohort study, we included adult (≥18 years) medical or surgical ICU patients with respiratory failure, shock, or both as part of two parallel studies: the Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunction in ICU Survivors (BRAIN-ICU) study, and the Delirium and Dementia in Veterans Surviving ICU Care (MIND-ICU) study. We assessed patients at least once a day for delirium using the Confusion Assessment Method-ICU and identified a priori-defined, non-mutually exclusive phenotypes of delirium per the presence of hypoxia, sepsis, sedative exposure, or metabolic (eg, renal or hepatic) dysfunction. We considered delirium in the absence of hypoxia, sepsis, sedation, and metabolic dysfunction to be unclassified. 3 and 12 months after discharge, we assessed cognition with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). We used multiple linear regression to separately analyse associations between the duration of each phenotype of delirium and RBANS global cognition scores at 3-month and 12-month follow-up, adjusting for potential confounders.

Findings: Between March 14, 2007, and May 27, 2010, 1048 participants were enrolled, eight of whom could not be analysed. Of 1040 participants, 708 survived to 3 months of follow-up and 628 to 12 months. Delirium was common, affecting 740 (71%) of 1040 participants at some point during the study and occurring on 4187 (31%) of all 13 434 participant-days. A single delirium phenotype was present on only 1355 (32%) of all 4187 participant-delirium days, whereas two or more phenotypes were present during 2832 (68%) delirium days. Sedative-associated delirium was most common (present during 2634 [63%] delirium days), and a longer duration of sedative-associated delirium predicted a worse RBANS global cognition score 12 months later, after adjusting for covariates (difference in score comparing 3 days vs 0 days: -4·03, 95% CI -7·80 to -0·26). Similarly, longer durations of hypoxic delirium (-3·76, 95% CI -7·16 to -0·37), septic delirium (-3·67, -7·13 to -0·22), and unclassified delirium (-4·70, -7·16 to -2·25) also predicted worse cognitive function at 12 months, whereas duration of metabolic delirium did not (1·14, -0·12 to 3·01).

Interpretation: Our findings suggest that clinicians should consider sedative-associated, hypoxic, and septic delirium, which often co-occur, as distinct indicators of acute brain injury and seek to identify all potential risk factors that may impact on long-term cognitive impairment, especially those that are iatrogenic and potentially modifiable such as sedation.

Funding: National Institutes of Health and the Department of Veterans Affairs.
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http://dx.doi.org/10.1016/S2213-2600(18)30062-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709878PMC
March 2018

Antioxidant supplementation and atrial arrhythmias in critically ill trauma patients.

J Surg Res 2018 02 31;222:10-16. Epub 2017 Oct 31.

Vanderbilt University Medical Center, Section of Surgical Sciences, Department of Surgery, Division of Trauma, Emergency General Surgery, and Surgical Critical Care, Nashville, Tennessee; Vanderbilt University Medical Center, Departments of Neurosurgery, and Speech & Hearing Sciences, Vanderbilt Brain Institute, Center for Health Services Research; Vanderbilt University School of Medicine; Geriatric Research, Education and Clinical Center Service, Surgical Services, Nashville Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, Tennessee. Electronic address:

Background: The purpose of this study is to determine if antioxidant supplementation influences the incidence of atrial arrhythmias in trauma intensive care unit (ICU) patients.

Materials And Methods: In this retrospective pre-post study, critically ill injured patients aged ≥18 years, admitted to a single-center trauma ICU for ≥48 hours were eligible for inclusion. The control group consists of patients admitted from January 2000 to September 2005, before routine antioxidant supplementation in our ICU. The antioxidant group consists of patients admitted from October 2005 to June 2011 who received an antioxidant protocol for ≥48 hours. The primary outcome is the incidence of atrial arrhythmias in the first 2 weeks of hospitalization or before discharge.

Results: Of the 4699 patients, 1622 patients were in the antioxidant group and 2414 patients were in the control group. Adjusted for age, sex, year, injury severity, past medical history, and medication administration, the unadjusted incidence of atrial arrhythmias was 3.02% in the antioxidant group versus 3.31% in the control group, with no adjusted difference in atrial arrhythmias among those exposed to antioxidants (odds ratio: 1.31 [95% confidence interval: 0.46, 3.75], P = 0.62). Although there was no change in overall mortality, the expected adjusted survival of patients in those without antioxidant therapy was lower (odds ratio: 0.65 [95% confidence interval: 0.43, 0.97], P = 0.04).

Conclusions: ICU antioxidant supplementation did not decrease the incidence of atrial arrhythmias, nor alter the time from admission to development of arrhythmia. A longer expected survival time was observed in the antioxidant group compared with the control group but without a change in overall mortality between groups.
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http://dx.doi.org/10.1016/j.jss.2017.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745045PMC
February 2018

Subsyndromal Delirium and Institutionalization Among Patients With Critical Illness.

Am J Crit Care 2017 Nov;26(6):447-455

Nathan E. Brummel is an assistant professor and E. Wesley Ely is a professor, Department of Medicine, Center for Quality Aging and the Center for Health Services Research, Vanderbilt University Medical Center, Nashville, Tennessee. Dr Ely is also the associate director for research for the Geriatric Research, Education, and Clinical Center Service (GRECC), Department of Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, Tennessee. Leanne M. Boehm is a postdoctoral fellow, Vanderbilt University School of Nursing, a quality scholar, GRECC, Department of Veterans Affairs Medical Center, Tennessee Valley Healthcare System, and a research nurse, Department of Medicine, Center for Health Services Research, Vanderbilt University Medical Center. Timothy D. Girard is an associate professor, Clinical Research, Investigation, and Systems Modeling of Acute Illness Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Pratik P. Pandharipande is a professor and Christopher G. Hughes is an associate professor, Department of Anesthesiology, Vanderbilt University Medical Center. James C. Jackson is a research associate professor, Department of Medicine, Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, and Mayur B. Patel is an assistant professor, Department of Surgery, Vanderbilt University Medical Center. Jin H. Han is an associate professor, Department of Emergency Medicine and Center for Quality Aging, Vanderbilt University Medical Center. Eduard E. Vasilevskis is a staff physician, GRECC, Department of Veterans Affairs Medical Center, VA Tennessee Valley Healthcare System, and an assistant professor, Department of Medicine and Center for Health Services Research, Vanderbilt University Medical Center. Jennifer L. Thompson is a biostatistician and Rameela Chandrasekhar is an assistant professor, Department of Biostatistics, Vanderbilt University School of Medicine. Gordon R. Bernard is associate vice-chancellor for research and a professor, Department of Medicine, Vanderbilt University Medical Center. Robert S. Dittus is director, GRECC, Department of Veterans Affairs Medical Center, VA Tennessee Valley Healthcare System, and a professor, Department of Medicine, Vanderbilt University Medical Center.

Background: The prognostic importance of subsyndromal delirium is unknown.

Objective: To test whether duration of subsyndromal delirium is independently associated with institutionalization.

Methods: The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) was used twice daily to assess for subsyndromal delirium in patients with respiratory failure or shock. Delirium was considered present if the assessment was positive. Subsyndromal delirium was considered present if the assessment was negative but the patient exhibited any CAM-ICU features. Multivariable regression was used to determine the association between duration of subsyndromal delirium and institutionalization, adjusting for age, education, baseline cognition and disability, comorbidities, severity of illness, delirium, coma, sepsis, and doses of sedatives and opiates.

Results: Subsyndromal delirium, lasting a median of 3 days, developed in 702 of 821 patients (86%). After adjusting for covariates, duration of subsyndromal delirium was an independent predictor of increased odds of institutionalization ( = .007). This association was greatest in patients with less delirium ( for interaction = .01). Specifically, of patients who were never delirious, those with 5 days of subsyndromal delirium (upper interquartile range [IQR]) were 4.2 times more likely to be institutionalized than those with 1.5 days of subsyndromal delirium (lower IQR).

Conclusions: Subsyndromal delirium occurred in most critically ill patients, and its duration was an independent predictor of institutionalization. Routine monitoring of all delirium symptoms may enable detection of full and subsyndromal forms of delirium.
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http://dx.doi.org/10.4037/ajcc2017263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831547PMC
November 2017

Social determinants of influenza hospitalization in the United States.

Influenza Other Respir Viruses 2017 11 6;11(6):479-488. Epub 2017 Oct 6.

Vanderbilt University School of Medicine, Nashville, TN, USA.

Background: Influenza hospitalizations result in substantial morbidity and mortality each year. Little is known about the association between influenza hospitalization and census tract-based socioeconomic determinants beyond the effect of individual factors.

Objective: To evaluate whether census tract-based determinants such as poverty and household crowding would contribute significantly to the risk of influenza hospitalization above and beyond individual-level determinants.

Methods: We analyzed 33 515 laboratory-confirmed influenza-associated hospitalizations that occurred during the 2009-2010 through 2013-2014 influenza seasons using a population-based surveillance system at 14 sites across the United States.

Results: Using a multilevel regression model, we found that individual factors were associated with influenza hospitalization with the highest adjusted odds ratio (AOR) of 9.20 (95% CI 8.72-9.70) for those ≥65 vs 5-17 years old. African Americans had an AOR of 1.67 (95% CI 1.60-1.73) compared to Whites, and Hispanics had an AOR of 1.21 (95% CI 1.16-1.26) compared to non-Hispanics. Among census tract-based determinants, those living in a tract with ≥20% vs <5% of persons living below poverty had an AOR of 1.31 (95% CI 1.16-1.47), those living in a tract with ≥5% vs <5% of persons living in crowded conditions had an AOR of 1.17 (95% CI 1.11-1.23), and those living in a tract with ≥40% vs <5% female heads of household had an AOR of 1.32 (95% CI 1.25-1.40).

Conclusion: Census tract-based determinants account for 11% of the variability in influenza hospitalization.
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http://dx.doi.org/10.1111/irv.12483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5720587PMC
November 2017