Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness.

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 .).

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

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.

Mitochondrial DNA Haplogroups and Delirium During Sepsis.

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.

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.

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.

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

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.

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

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.

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

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 (ß coefficient = -2.9 points, 95%CI: -0.3 to -5.6) and organ dysfunction (ß 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 (ß 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.

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

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.

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

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.

Antioxidant supplementation and atrial arrhythmias in critically ill trauma patients.

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.

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

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.

Frailty and Subsequent Disability and Mortality among Patients with Critical Illness.

RATIONALE: The prevalence of frailty (diminished physiologic reserve) and its effect on outcomes for those aged 18 years and older with critical illness is unclear. OBJECTIVES: We hypothesized greater frailty would be associated with subsequent mortality, disability, and cognitive impairment, regardless of age. METHODS: At enrollment, we measured frailty using the Clinical Frailty Scale (range, 1 [very fit] to 7 [severely frail]). At 3 and 12 months post-discharge, we assessed vital status, instrumental activities of daily living, basic activities of daily living, and cognition. We used multivariable regression to analyze associations between Clinical Frailty Scale scores and outcomes, adjusting for age, sex, education, comorbidities, baseline disability, baseline cognition, severity of illness, delirium, coma, sepsis, mechanical ventilation, and sedatives/opiates. MEASUREMENTS AND MAIN RESULTS: We enrolled 1,040 patients who were a median (interquartile range) of 62 (53-72) years old and who had a median Clinical Frailty Scale score of 3 (3-5). Half of those with clinical frailty (i.e., Clinical Frailty Scale score ≥5) were younger than 65 years old. Greater Clinical Frailty Scale scores were independently associated with greater mortality (P = 0.01 at 3 mo and P < 0.001 at 12 mo) and with greater odds of disability in instrumental activities of daily living (P = 0.04 at 3 mo and P = 0.002 at 12 mo). Clinical Frailty Scale scores were not associated with disability in basic activities of daily living or with cognition. CONCLUSIONS: Frailty is common in critically ill adults aged 18 years and older and is independently associated with increased mortality and greater disability. Future studies should explore routine screening for clinical frailty in critically ill patients of all ages. Interventions to reduce mortality and disability among patients with heightened vulnerability should be developed and tested. Clinical trial registered with www.clinicaltrials.gov (NCT 00392795 and NCT 00400062).

Surgery and Anesthesia Exposure Is Not a Risk Factor for Cognitive Impairment After Major Noncardiac Surgery and Critical Illness.

OBJECTIVE: The aim of this study was to determine whether surgery and anesthesia exposure is an independent risk factor for cognitive impairment after major noncardiac surgery associated with critical illness. SUMMARY OF BACKGROUND DATA: Postoperative cognitive impairment is a prevalent individual and public health problem. Data are inconclusive as to whether this impairment is attributable to surgery and anesthesia exposure versus patients' baseline factors and hospital course. METHODS: In a multicenter prospective cohort study, we enrolled ICU patients with major noncardiac surgery during hospital admission and with nonsurgical medical illness. At 3 and 12 months, we assessed survivors' global cognitive function with the Repeatable Battery for the Assessment of Neuropsychological Status and executive function with the Trail Making Test, Part B. We performed multivariable linear regression to study the independent association of surgery/anesthesia exposure with cognitive outcomes, adjusting initially for baseline covariates and subsequently for in-hospital covariates. RESULTS: We enrolled 1040 patients, 402 (39%) with surgery/anesthesia exposure. Median global cognition scores were similar in patients with surgery/anesthesia exposure compared with those without exposure at 3 months (79 vs 80) and 12 months (82 vs 82). Median executive function scores were also similar at 3 months (41 vs 40) and 12 months (43 vs 42). Surgery/anesthesia exposure was not associated with worse global cognition or executive function at 3 or 12 months in models incorporating baseline or in-hospital covariates (P > 0.2). Higher baseline education level was associated with better global cognition at 3 and 12 months (P < 0.001), and longer in-hospital delirium duration was associated with worse global cognition (P < 0.02) and executive function (P < 0.01) at 3 and 12 months. CONCLUSIONS: Cognitive impairment after major noncardiac surgery and critical illness is not associated with the surgery and anesthesia exposure but is predicted by baseline education level and in-hospital delirium.

Delirium and Catatonia in Critically Ill Patients: The Delirium and Catatonia Prospective Cohort Investigation.

OBJECTIVES: Catatonia, a condition characterized by motor, behavioral, and emotional changes, can occur during critical illness and appear as clinically similar to delirium, yet its management differs from delirium. Traditional criteria for medical catatonia preclude its diagnosis in delirium. Our objective in this investigation was to understand the overlap and relationship between delirium and catatonia in ICU patients and determine diagnostic thresholds for catatonia. DESIGN: Convenience cohort, nested within two ongoing randomized trials. SETTING: Single academic medical center in Nashville, TN. PATIENTS: We enrolled 136 critically ill patients on mechanical ventilation and/or vasopressors, randomized to two usual care sedation regimens. MEASUREMENTS AND MAIN RESULTS: Patients were assessed for delirium and catatonia by independent and masked personnel using Confusion Assessment Method for the ICU and the Bush Francis Catatonia Rating Scale mapped to Diagnostic Statistical Manual 5 criterion A for catatonia. Of 136 patients, 58 patients (43%) had only delirium, four (3%) had only catatonia, 42 (31%) had both, and 32 (24%) had neither. In a logistic regression model, more catatonia signs were associated with greater odds of having delirium. For example, patient assessments with greater than or equal to three Diagnostic Statistical Manual 5 symptoms (75th percentile) had, on average, 27.8 times the odds (interquartile range, 12.7-60.6) of having delirium compared with patient assessments with zero Diagnostic Statistical Manual 5 criteria (25th percentile) present (p < 0.001). A cut-off of greater than or equal to 4 Bush Francis Catatonia Screening Instrument items was both sensitive (91%; 95% CI, 82.9-95.3) and specific (91%; 95% CI, 87.6-92.9) for Diagnostic Statistical Manual 5 catatonia. CONCLUSIONS: Given that about one in three patients had both catatonia and delirium, these data prompt reconsideration of Diagnostic Statistical Manual 5 criteria for "Catatonic Disorder Due to Another Medical Condition" that preclude diagnosing catatonia in the presence of delirium.

Delirium and Benzodiazepines Associated With Prolonged ICU Stay in Critically Ill Infants and Young Children.

OBJECTIVES: Delirium is prevalent among critically ill children, yet associated outcomes and modifiable risk factors are not well defined. The objective of this study was to determine associations between pediatric delirium and modifiable risk factors such as benzodiazepine exposure and short-term outcomes. DESIGN: Secondary analysis of collected data from the prospective validation study of the Preschool Confusion Assessment Method for the ICU. SETTING: Tertiary-level PICU. PATIENTS: Critically ill patients 6 months to 5 years old. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Daily delirium assessments were completed using the Preschool Confusion Assessment Method for the ICU. Associations between baseline and in-hospital risk factors were analyzed for likelihood of ICU discharge using Cox proportional hazards regression and delirium duration using negative binomial regression. Multinomial logistic regression was used to determine associations between daily risk factors and delirium presence the following day. Our 300-patient cohort had a median (interquartile range) age of 20 months (11-37 mo), and 44% had delirium for at least 1 day (1-2 d). Delirium was significantly associated with a decreased likelihood of ICU discharge in preschool-aged children (age-specific hazard ratios at 60, 36, and 12 mo old were 0.17 [95% CI, 0.05-0.61], 0.50 [0.32-0.80], and 0.98 [0.68-1.41], respectively). Greater benzodiazepine exposure (75-25th percentile) was significantly associated with a lower likelihood of ICU discharge (hazard ratio, 0.65 [0.42-1.00]; p = 0.01), longer delirium duration (incidence rate ratio, 2.47 [1.36-4.49]; p = 0.005), and increased risk for delirium the following day (odds ratio, 2.83 [1.27-6.59]; p = 0.02). CONCLUSIONS: Delirium is associated with a lower likelihood of ICU discharge in preschool-aged children. Benzodiazepine exposure is associated with the development and longer duration of delirium, and lower likelihood of ICU discharge. These findings advocate for future studies targeting modifiable risk factors, such as reduction in benzodiazepine exposure, to mitigate iatrogenic harm in pediatric patients.

Exploring Delirium's Heterogeneity: Association Between Arousal Subtypes at Initial Presentation and 6-Month Mortality in Older Emergency Department Patients.

OBJECTIVES: To determine how delirium subtyped by level of arousal at initial presentation affects 6-month mortality. DESIGN: This was a preplanned secondary analysis of two prospective cohort studies. SETTING: Academic tertiary care emergency department (ED). PARTICIPANTS: 1,084 ED patients who were 65 years old or older. MEASUREMENTS: At the time of enrollment, trained research personnel performed the Confusion Assessment Method for the Intensive Care Unit and the Richmond Agitation Sedation Score to determine delirium and level of arousal, respectively. Patients were categorized as having no delirium, delirium with normal arousal, delirium with decreased arousal, or delirium with increased arousal. Death was ascertained by medical record review and the Social Security Death Index. Cox proportional hazard regression was used to analyze the association between delirium arousal subtypes and 6-month mortality. RESULTS: Delirium with normal arousal was the only subtype that was significantly associated with increased 6-month mortality (hazard ratio [HR]: 3.1, 95% confidence interval [CI]: 1.3-7.4) compared with the no delirium group after adjusting for confounders. The HRs for delirium with decreased and increased arousal were 1.4 (95% CI: 0.9-2.1) and 1.3 (95% CI: 0.3-5.4), respectively. CONCLUSIONS: Delirious ED patients with normal arousal at initial presentation had a threefold increased hazard of death within 6 months compared with patients without delirium. There was a trend towards increased hazard of death in delirious ED patients with decreased arousal, but this relationship did not reach statistical significance. These data suggest that subtyping delirium by arousal may have prognostic value but requires confirmation with a larger study.

Incidence and Risk Factors for Intensive Care Unit-related Post-traumatic Stress Disorder in Veterans and Civilians.

RATIONALE: The incidence and risk factors of post-traumatic stress disorder (PTSD) related to the intensive care unit (ICU) experience have not been reported in a mixed veteran and civilian cohort. OBJECTIVES: To describe the incidence and risk factors for ICU-related PTSD in veterans and civilians. METHODS: This is a prospective, observational, multicenter cohort enrolling adult survivors of critical illness after respiratory failure and/or shock from three Veterans Affairs and one civilian hospital. After classifying those with/without preexisting PTSD (i.e., PTSD before hospitalization), we then assessed all subjects for ICU-related PTSD at 3 and 12 months post hospitalization. MEASUREMENTS AND MAIN RESULTS: Of 255 survivors, 181 and 160 subjects were assessed for ICU-related PTSD at 3- and 12-month follow-up, respectively. A high probability of ICU-related PTSD was found in up to 10% of patients at either follow-up time point, whether assessed by PTSD Checklist Event-Specific Version (score ≥ 50) or item mapping using the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV). In the multivariable regression, preexisting PTSD was independently associated with ICU-related PTSD at both 3 and 12 months (P < 0.001), as was preexisting depression (P < 0.03), but veteran status was not a consistent independent risk factor for ICU-related PTSD (3-month P = 0.01, 12-month P = 0.48). CONCLUSIONS: This study found around 1 in 10 ICU survivors experienced ICU-related PTSD (i.e., PTSD anchored to their critical illness) in the year after hospitalization. Preexisting PTSD and depression were strongly associated with ICU-related PTSD.

Endothelial Activation and Blood-Brain Barrier Injury as Risk Factors for Delirium in Critically Ill Patients.

OBJECTIVES: During critical illness, impaired endothelial vascular reactivity predicts prolonged acute brain dysfunction, but relationships between endothelial activation, blood-brain barrier/neurological injury, and acute brain dysfunction, including delirium, remain unexamined. We tested the hypothesis that elevated plasma markers of endothelial activation and blood-brain barrier/neurological injury are associated with delirium duration during critical illness. DESIGN: Prospective cohort study. SETTING: Medical and surgical ICUs in an academic medical center. PATIENTS: Adults in acute respiratory failure and/or shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We enrolled subjects within 72 hours of organ failure diagnosis in the ICU. We measured plasma concentrations of plasminogen activator inhibitor-1, E-selectin, and angiopoietin-2 as markers of endothelial activation and S100B as a marker of blood-brain barrier/neurological injury in blood collected at enrollment. We assessed patients for delirium and coma twice daily after enrollment using the Confusion Assessment Method for the ICU and the Richmond Agitation-Sedation Scale. Among 134 patients with a median (interquartile) age of 57 years (46-66 yr) and Acute Physiology and Chronic Health Evaluation II of 26 (19-31), delirium occurred in 94 patients (70%) with a median duration of 2 days (0-4 d). Higher plasminogen activator inhibitor-1 (p = 0.002), E-selectin (p = 0.02), and S100B (p < 0.001) concentrations were associated with fewer delirium/coma-free days after adjusting for age, Charlson comorbidity index, modified Sequential Organ Failure Assessment score, and severe sepsis. Similarly, higher plasminogen activator inhibitor-1 (p = 0.007) and S100B (p = 0.01) concentrations were associated with longer delirium duration in survivors. Adjusting for S100B did not alter plasminogen activator inhibitor-1 and E-selectin associations with delirium, suggesting that these associations were not mediated by blood-brain barrier/neurological injury. CONCLUSIONS: Elevated plasma markers of endothelial activation and blood-brain barrier/neurological injury during critical illness are associated with prolonged delirium after biomarker measurement. Future research is needed to determine whether these processes have pathophysiologic roles in delirium and whether therapies targeted at the endothelium or blood-brain barrier can prevent and/or treat delirium during critical illness.

Employment Outcomes After Critical Illness: An Analysis of the Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunction in ICU Survivors Cohort.

OBJECTIVES: To characterize survivors' employment status after critical illness and to determine if duration of delirium during hospitalization and residual cognitive function are each independently associated with decreased employment. DESIGN: Prospective cohort investigation with baseline and in-hospital clinical data and follow-up at 3 and 12 months. SETTING: Medical and surgical ICUs at two tertiary-care hospitals. PATIENTS: Previously employed patients from the Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunction in ICU Survivors study who survived a critical illness due to respiratory failure or shock were evaluated for global cognition and employment status at 3- and 12-month follow-up. MEASUREMENTS AND MAIN RESULTS: We used multivariable logistic regression to evaluate independent associations between employment at both 3 and 12 months and global cognitive function at the same time point, and delirium during the hospital stay. At 3-month follow-up, 113 of the total survival cohort of 448 (25%) were identified as being employed at study enrollment. Of these, 94 survived to 12-month follow-up. At 3- and 12-month follow-up, 62% and 49% had a decrease in employment, 57% and 49% of whom, respectively, were newly unemployed. After adjustment for physical health status, depressive symptoms, marital status, level of education, and severity of illness, we did not find significant predictors of employment status at 3 months, but better cognition at 12 months was marginally associated with lower odds of employment reduction at 12 months (odds ratio, 0.49; p = 0.07). CONCLUSIONS: Reduction in employment after critical illness was present in the majority of our ICU survivors, approximately half of which was new unemployment. Cognitive function at 12 months was a predictor of subsequent employment status. Further research is needed into the potential relationship between the impact of critical illness on cognitive function and employment status.

The Preschool Confusion Assessment Method for the ICU: Valid and Reliable Delirium Monitoring for Critically Ill Infants and Children.

OBJECTIVES: Delirium assessments in critically ill infants and young children pose unique challenges due to evolution of cognitive and language skills. The objectives of this study were to determine the validity and reliability of a fundamentally objective and developmentally appropriate delirium assessment tool for critically ill infants and preschool-aged children and to determine delirium prevalence. DESIGN AND SETTING: Prospective, observational cohort validation study of the PreSchool Confusion Assessment Method for the ICU in a tertiary medical center PICU. PATIENTS: Participants aged 6 months to 5 years and admitted to the PICU regardless of admission diagnosis were enrolled. MEASUREMENTS AND MAIN RESULTS: An interdisciplinary team created the PreSchool Confusion Assessment Method for the ICU for pediatric delirium monitoring. To assess validity, patients were independently assessed for delirium daily by the research team using the PreSchool Confusion Assessment Method for the ICU and by a child psychiatrist using the Diagnostic and Statistical Manual of Mental Disorders criteria. Reliability was assessed using blinded, concurrent PreSchool Confusion Assessment Method for the ICU evaluations by research staff. A total of 530-paired delirium assessments were completed among 300 patients, with a median age of 20 months (interquartile range, 11-37) and 43% requiring mechanical ventilation. The PreSchool Confusion Assessment Method for the ICU demonstrated a specificity of 91% (95% CI, 90-93), sensitivity of 75% (95% CI, 72-78), negative predictive value of 86% (95% CI, 84-88), positive predictive value of 84% (95% CI, 81-87), and a reliability κ-statistic of 0.79 (0.76-0.83). Delirium prevalence was 44% using the PreSchool Confusion Assessment Method for the ICU and 47% by the reference rater. The rates of delirium were 53% versus 56% in patients younger than 2 years old and 33% versus 35% in patients 2-5 years old using the PreSchool Confusion Assessment Method for the ICU and reference rater, respectively. The short-form PreSchool Confusion Assessment Method for the ICU maintained a high specificity (87%) and sensitivity (78%) in post hoc analysis. CONCLUSIONS: The PreSchool Confusion Assessment Method for the ICU is a highly valid and reliable delirium instrument for critically ill infants and preschool-aged children, in whom delirium is extremely prevalent.