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Longitudinal correlation of biomarkers of cardiac injury, inflammation, and coagulation to outcome in hospitalized COVID-19 patients.
Li C, Jiang J, Wang F, Zhou N, Veronese G, Moslehi JJ, Ammirati E, Wang DW
(2020) J Mol Cell Cardiol 147: 74-87
MeSH Terms: Aged, Betacoronavirus, Biomarkers, Blood Coagulation, Coronavirus Infections, Critical Illness, Cytokines, Female, Heart Injuries, Humans, Inflammation, Longitudinal Studies, Male, Middle Aged, Pandemics, Pneumonia, Viral, Prognosis, Retrospective Studies, Troponin I
Show Abstract · Added September 29, 2020
BACKGROUND - Cardiac injury, as measured by troponin elevation, has been reported among hospitalized coronavirus disease 2019 (COVID-19) patients and portends a poor prognosis. However, how the dynamics of troponin elevation interplay with inflammation and coagulation biomarkers over time is unknown. We assessed longitudinal follow-up of cardiac injury, inflammation and coagulation markers in relation to disease severity and outcome.
METHODS - We retrospectively assessed 2068 patients with laboratory-confirmed COVID-19 between January 29 and April 1, 2020 at Tongji Hospital in Wuhan, China. We defined cardiac injury as an increase in high sensitivity cardiac troponin-I (hs-cTnI) above the 99th of the upper reference limit. We explored the dynamics of elevation in hs-cTnI and the relationship with inflammation (interleukin [IL]-6, IL-8, IL-10, IL-2 receptor, tumor necrosis factor-α, C-reactive protein) and coagulation (d-dimer, fibrinogen, international normalized ratio) markers in non-critically ill versus critically ill patients longitudinally and further correlated these markers to survivors and non-survivors.
RESULTS - Median age was 63 years (first to third quartile 51-70 years), 51.4% of whom were women. When compared to non-critically ill patients (N = 1592, 77.0%), critically ill (defined as requiring mechanical ventilation, in shock or multiorgan failure) patients (N = 476, 23.0%), had more frequent cardiac injury on admission (30.3% vs. 2.3%, p < 0.001), with increased mortality during hospitalization (38.4% vs. 0%, p < 0.001). Among critically ill patients, non-survivors (N = 183) had a continuous increase in hs-cTnI levels during hospitalization, while survivors (N = 293) showed a decrease in hs-cTnI level between day 4 and 7 after admission. Specifically, cardiac injury is an independent marker of mortality among critically ill patients at admission, day 4-7 and 8-14. Consistent positive correlations between hs-cTnI and interleukin (IL)-6 on admission (r = 0.59), day 4-7 (r = 0.66) and day 8-14 (r = 0.61; all p < 0.001) and d-dimer (at the same timepoints r = 0.54; 0.65; 0.61, all p < 0.001) were observed. A similar behavior was observed between hs-cTnI and most of other biomarkers of inflammation and coagulation.
CONCLUSIONS - Cardiac injury commonly occurs in critically ill COVID-19 patients, with increased levels of hs-cTnI beyond day 3 since admission portending a poor prognosis. A consistent positive correlation of hs-cTnI with IL-6 and d-dimer at several timepoints along hospitalization could suggest nonspecific cytokine-mediated cardiotoxicity.
Copyright © 2020. Published by Elsevier Ltd.
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Mitochondrial DNA Haplogroups and Delirium During Sepsis.
Samuels DC, Hulgan T, Fessel JP, Billings FT, Thompson JL, Chandrasekhar R, Girard TD
(2019) Crit Care Med 47: 1065-1071
MeSH Terms: Adult, African Americans, Critical Illness, DNA, Mitochondrial, European Continental Ancestry Group, Female, Haplotypes, Humans, Male, Middle Aged, Polymerase Chain Reaction, Retrospective Studies, Sepsis-Associated Encephalopathy, Sequence Analysis, DNA
Show Abstract · Added December 11, 2019
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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Antimicrobial exposure and the risk of delirium in critically ill patients.
Grahl JJ, Stollings JL, Rakhit S, Person AK, Wang L, Thompson JL, Pandharipande PP, Ely EW, Patel MB
(2018) Crit Care 22: 337
MeSH Terms: Adult, Aged, Anti-Infective Agents, Cohort Studies, Critical Illness, Cross-Sectional Studies, Delirium, Female, Humans, Intensive Care Units, Length of Stay, Male, Middle Aged, Multivariate Analysis, Retrospective Studies
Show Abstract · Added December 16, 2018
BACKGROUND - Prior retrospective cross-sectional work has associated antimicrobials with a non-specific phrase: encephalopathy without seizures. The purpose of this study is to determine whether different classes of antimicrobials have differential associations with the daily risk of delirium after critical illness is adjusted for.
METHODS - Our study was a nested cohort that enrolled non-neurological critically ill adults from a medical or surgical intensive care unit (ICU) with daily follow-up to 30 days. Our independent variable was exposure to previous-day antimicrobial class: beta-lactams (subclasses: penicillins, first- to third-generation cephalosporins, fourth-generation cephalosporins, and carbapenems), macrolides, fluoroquinolones, and other. We adjusted for baseline covariates (age, comorbidities, cognition scores, sepsis, and mechanical ventilation), previous-day covariates (delirium, doses of analgesics/sedatives, and antipsychotic use), and same-day covariates (illness severity). Our primary outcome of delirium was measured by using the Confusion Assessment Method for the ICU. A daily delirium logistic regression model was used with an ICU time-restricted sensitivity analysis including daily adjustment for sepsis and mechanical ventilation.
RESULTS - Of 418 ICU patients, delirium occurred in 308 (74%) with a median of 3 days (interquartile range 2-6) among those affected and 318 (76%) were exposed to antimicrobials. When covariates and ICU type were adjusted for, only first- to third-generation cephalosporins were associated with delirium (logistic regression model odds ratio (OR) = 2.2, 95% confidence interval (CI) 1.28-3.79, P = 0.004; sensitivity analysis OR = 2.13, 95% CI 1.10-4.10, P = 0.024).
CONCLUSIONS - First-, second-, and third-generation cephalosporins doubled the odds of delirium after baseline co-morbidities, ICU type, the course of critical care, and other competing antimicrobial and psychotropic medication risks were adjusted for. We did not find an association between delirium and cefepime, penicillins, carbapenems, fluoroquinolones, or macrolides.
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Deficits in Self-Reported Initiation Are AssociatedWith Subsequent Disability in ICU Survivors.
Wilson JE, Duggan MC, Chandrasekhar R, Brummel NE, Dittus RS, Ely EW, Patel MB, Jackson JC
(2019) Psychosomatics 60: 376-384
MeSH Terms: Activities of Daily Living, Aged, Cohort Studies, Critical Illness, Disabled Persons, Executive Function, Female, Humans, Intensive Care Units, Male, Middle Aged, Prospective Studies, Self Report, Survivors
Show Abstract · Added October 28, 2018
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.
Copyright © 2018 Academy of Consultation-Liaison Psychiatry. All rights reserved.
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14 MeSH Terms
Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness.
Girard TD, Exline MC, Carson SS, Hough CL, Rock P, Gong MN, Douglas IS, Malhotra A, Owens RL, Feinstein DJ, Khan B, Pisani MA, Hyzy RC, Schmidt GA, Schweickert WD, Hite RD, Bowton DL, Masica AL, Thompson JL, Chandrasekhar R, Pun BT, Strength C, Boehm LM, Jackson JC, Pandharipande PP, Brummel NE, Hughes CG, Patel MB, Stollings JL, Bernard GR, Dittus RS, Ely EW, MIND-USA Investigators
(2018) N Engl J Med 379: 2506-2516
MeSH Terms: Aged, Antipsychotic Agents, Critical Illness, Delirium, Dopamine Antagonists, Double-Blind Method, Female, Haloperidol, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Piperazines, Respiratory Insufficiency, Shock, Thiazoles, Treatment Failure
Show Abstract · Added October 23, 2018
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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The Cost of ICU Delirium and Coma in the Intensive Care Unit Patient.
Vasilevskis EE, Chandrasekhar R, Holtze CH, Graves J, Speroff T, Girard TD, Patel MB, Hughes CG, Cao A, Pandharipande PP, Ely EW
(2018) Med Care 56: 890-897
MeSH Terms: Adult, Aged, Coma, Comorbidity, Costs and Cost Analysis, Critical Illness, Delirium, Dialysis, Female, Humans, Intensive Care Units, Male, Middle Aged, Prospective Studies, Respiration, Artificial, Risk Factors
Show Abstract · Added September 5, 2018
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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16 MeSH Terms
Delirium Monitoring in Neurocritically Ill Patients: A Systematic Review.
Patel MB, Bednarik J, Lee P, Shehabi Y, Salluh JI, Slooter AJ, Klein KE, Skrobik Y, Morandi A, Spronk PE, Naidech AM, Pun BT, Bozza FA, Marra A, John S, Pandharipande PP, Ely EW
(2018) Crit Care Med 46: 1832-1841
MeSH Terms: Critical Care, Critical Illness, Delirium, Female, Humans, Intensive Care Units, Male, Nervous System Diseases, Prospective Studies, Risk Assessment
Show Abstract · Added August 25, 2018
OBJECTIVES - The Society of Critical Care Medicine recommends routine delirium monitoring, based on data in critically ill patients without primary neurologic injury. We sought to answer whether there are valid and reliable tools to monitor delirium in neurocritically ill patients and whether delirium is associated with relevant clinical outcomes (e.g., survival, length of stay, functional independence, cognition) in this population.
DATA SOURCES - We systematically reviewed Cumulative Index to Nursing and Allied Health Literature, Web of Science, and PubMed.
STUDY SELECTION AND DATA EXTRACTION - Inclusion criteria allowed any study design investigating delirium monitoring in neurocritically ill patients (e.g., neurotrauma, ischemic, and/or hemorrhagic stroke) of any age. We extracted data relevant to delirium tool sensitivity, specificity, negative predictive value, positive predictive value, interrater reliability, and associated clinical outcomes.
DATA SYNTHESIS - Among seven prospective cohort studies and a total of 1,173 patients, delirium was assessed in neurocritically patients using validated delirium tools after considering primary neurologic diagnoses and associated complications, finding a pooled prevalence rate of 12-43%. When able to compare against a common reference standard, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, the test characteristics showed a sensitivity of 62-76%, specificity of 74-98%, positive predictive value of 63-91%, negative predictive value of 70-94%, and reliability kappa of 0.64-0.94. Among four studies reporting multivariable analyses, delirium in neurocritically patients was associated with increased hospital length of stay (n = 3) and ICU length of stay (n = 1), as well as worse functional independence (n = 1) and cognition (n = 2), but not survival.
CONCLUSIONS - These data from studies of neurocritically ill patients demonstrate that patients with primary neurologic diagnoses can meet diagnostic criteria for delirium and that delirious features may predict relevant untoward clinical outcomes. There is a need for ongoing investigations regarding delirium in these complicated neurocritically ill patients.
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10 MeSH Terms
The authors reply.
Wilson JE, Heckers S, Ely EW, Delirium and Catatonia (DeCat) Prospective Cohort Investigation
(2018) Crit Care Med 46: e722-e723
MeSH Terms: Catatonia, Cohort Studies, Critical Illness, Delirium, Humans, Prospective Studies
Added March 30, 2020
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Co-Occurrence of Post-Intensive Care Syndrome Problems Among 406 Survivors of Critical Illness.
Marra A, Pandharipande PP, Girard TD, Patel MB, Hughes CG, Jackson JC, Thompson JL, Chandrasekhar R, Ely EW, Brummel NE
(2018) Crit Care Med 46: 1393-1401
MeSH Terms: Activities of Daily Living, Aged, Cognitive Dysfunction, Critical Care, Critical Illness, Depression, Disability Evaluation, Female, Humans, Male, Middle Aged, Prospective Studies, Respiratory Insufficiency, Shock, Syndrome
Show Abstract · Added June 26, 2018
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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Relationships between markers of neurologic and endothelial injury during critical illness and long-term cognitive impairment and disability.
Hughes CG, Patel MB, Brummel NE, Thompson JL, McNeil JB, Pandharipande PP, Jackson JC, Chandrasekhar R, Ware LB, Ely EW, Girard TD
(2018) Intensive Care Med 44: 345-355
MeSH Terms: Activities of Daily Living, Adult, Aged, Biomarkers, Cognition Disorders, Cognitive Dysfunction, Critical Illness, Delirium, E-Selectin, Endothelium, Humans, Male, Middle Aged, Prospective Studies, S100 Calcium Binding Protein beta Subunit
Show Abstract · Added March 14, 2018
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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15 MeSH Terms