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Background: Delirium is common during critical illness and is associated with long-term cognitive impairment and disability. Antipsychotics are frequently used to treat delirium, but their effects on long-term outcomes are unknown. We aimed to investigate the effects of antipsychotic treatment of delirious, critically ill patients on long-term cognitive, functional, psychological, and quality-of-life outcomes., Methods: This prespecified, long-term follow-up to the randomised, double-blind, placebo-controlled phase 3 MIND-USA Study was conducted in 16 hospitals throughout the USA. Adults (aged ≥18 years) who had been admitted to an intensive care unit with respiratory failure or septic or cardiogenic shock were eligible for inclusion in the study if they had delirium. Participants were randomly assigned-using a computer-generated, permuted-block randomisation scheme with stratification by trial site and age-in a 1:1:1 ratio to receive intravenous placebo, haloperidol, or ziprasidone for up to 14 days. Investigators and participants were masked to treatment group assignment. 3 months and 12 months after randomisation, we assessed survivors' cognitive, functional, psychological, quality-of-life, and employment outcomes using validated telephone-administered tests and questionnaires. This trial was registered with ClinicalTrials.gov, NCT01211522, and is complete., Findings: Between Dec 7, 2011, and Aug 12, 2017, we screened 20 914 individuals, of whom 566 were eligible and consented or had consent provided to participate. Of these 566 patients, 184 were assigned to the placebo group, 192 to the haloperidol group, and 190 to the ziprasidone group. 1-year survival and follow-up rates were similar between groups. Cognitive impairment was common in all three treatment groups, with a third of survivors impaired at both 3-month and 12-month follow-up in all groups. More than half of the surveyed survivors in each group had cognitive or physical limitations (or both) that precluded employment at both 3-month and 12-month follow-up. At both 3 months and 12 months, neither haloperidol (adjusted odds ratio 1·22 [95% CI 0·73-2.04] at 3 months and 1·12 [0·60-2·11] at 12 months) nor ziprasidone (1·07 [0·59-1·96] at 3 months and 0·94 [0·62-1·44] at 12 months) significantly altered cognitive outcomes, as measured by the Telephone Interview for Cognitive Status T score, compared with placebo. We also found no evidence that functional, psychological, quality-of-life, or employment outcomes improved with haloperidol or ziprasidone compared with placebo., Interpretation: In delirious, critically ill patients, neither haloperidol nor ziprasidone had a significant effect on cognitive, functional, psychological, or quality-of-life outcomes among survivors. Our findings, along with insufficient evidence of short-term benefit and frequent inappropriate continuation of antipsychotics at hospital discharge, indicate that antipsychotics should not be used routinely to treat delirium in critically ill adults., Funding: National Institutes of Health and the US Department of Veterans Affairs., Competing Interests: Declaration of interests The following declarations of interest are reported outside of the submitted work. MFM reports grants from the National Institutes of Health (NIH) and the US Department of Veterans Affairs. LMB reports grants from the NIH and the American Association of Critical Care Nurses. MNG reports grants from the NIH, the Agency for Healthcare Research and Quality, and the US Centers for Disease Control and Prevention; consulting fees for a role as scientific advisor for Endpoint Health; honoraria for grand rounds presentation at Yale University (New Haven, CT, USA); travel support from the American Thoracic Society executive committee; and participation on the data safety monitoring board for a trial on monoclonal antibodies for COVID-19, funded by Regeneron (NCT04452318). AM reports consulting fees from Zoll, Eli Lilly, LivaNova, and Jazz Pharmaceuticals; and a philanthropic contribution from ResMed to the University of California San Diego (La Jolla, CA, USA). BAK reports grants from the NIH, payment for expert testimony for a medicolegal case in the state of Indiana (USA), payment for participation on a data safety monitoring board for the PANDORA trial, and a leadership role as president of the American Delirium Society. SSC reports grants from the NIH and direct payments for participation on the data safety monitoring board of an NIH-funded study unrelated to delirium. CLH reports grants from the NIH. PR reports grants from the NIH and the US Department of Defense, payment and travel support for a continuing medical education event at the Johns Hopkins School of Medicine, and previous leadership of the Association of Academic Anesthesiology Chairs and Society of Academic Associations of Anesthesiology and Perioperative Medicine. BTP reports leadership as co-chair of the Society of Critical Care Medicine ICU Liberation Committee. PPP reports grants from the NIH. NEB reports grants from the NIH and travel support for the Society of Intensive Care Medicine Singapore annual meeting. CGH reports consulting fees for Sedana Medical. MBP reports grants from CSL Behring, the NIH, and the US Department of Defense; royalties for serving as an associate editor with Elsevier on a surgical textbook; travel support for continuing medical education events with the Eastern Association for the Surgery of Trauma, Society of University Surgeons, and American College of Surgeons; a patent for image-derived prognostic models unrelated to this work; participation on a data safety monitoring board for Liberate Medical; and leadership as treasurer for the Eastern Association for the Surgery of Trauma. JLS reports honoria for presentations for the Society of Critical Care Medicine, American College of Chest Physicians, the Chilean Society of Critical Care Medicine, and the Spanish Society of Hospital Pharmacy; travel support for meetings with the Society of Critical Care Medicine, the Saudi Society of Clinical Pharmacy, and the Chilean Society of Critical Care Medicine; and leadership on committees with the Society of Critical Care Medicine. EWE reports grant support from the NIH and the US Department of Veterans Affairs, honoraria for continuing medical education lectures sponsored by Pfizer, and study support (investigational drug provision, no direct payments) from Eli Lilly. TDG reports grants from the NIH, research funding from Ceribell, and personal fees from Haisco Pharmaceutical and Lungpacer Medical. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. 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Background: We sought to identify potentially modifiable in-hospital factors associated with global cognition, post-traumatic stress disorder (PTSD) symptoms, and depression symptoms at 12 months., Methods: This was a multi-center prospective cohort study in adult hospitalized patients with acute COVID-19. The following in-hospital factors were assessed: delirium; frequency of in-person and virtual visits by friends and family; and hydroxychloroquine, corticosteroid, and remdesivir administration. Twelve-month global cognition was characterized by the MOCA-Blind. Twelve-month PTSD and depression were characterized using the PTSD Checklist for the DSM-V and Hospital Anxiety Depression Scale, respectively., Findings: Two hundred three patients completed the 12-month follow-up assessments. Remdesivir use was associated with significantly higher cognition at 12 months based on the MOCA-Blind (adjusted odds ratio [aOR] = 1.98, 95% CI: 1.06, 3.70). Delirium was associated with worsening 12-month PTSD (aOR = 3.44, 95% CI: 1.89, 6.28) and depression (aOR = 2.18, 95% CI: 1.23, 3.84) symptoms. Multiple virtual visits per day during hospitalization was associated with lower 12-month depression symptoms compared to those with less than daily virtual visits (aOR = 0.40, 95% CI: 0.19, 0.85)., Conclusion: Potentially modifiable factors associated with better long-term outcomes included remdesivir use (associated with better cognitive function), avoidance of delirium (associated with less PTSD and depression symptoms), and increased virtual interactions with friends and family (associated with less depression symptoms)., (© 2023 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Objectives: We examined whether preadmission history of depression is associated with less delirium/coma-free (DCF) days, worse 1-year depression severity and cognitive impairment., Design and Measurements: A health proxy reported history of depression. Separate models examined the effect of preadmission history of depression on: (a) intensive care unit (ICU) course, measured as DCF days; (b) depression symptom severity at 3 and 12 months, measured by the Beck Depression Inventory-II (BDI-II); and (c) cognitive performance at 3 and 12 months, measured by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) global score., Setting and Participants: Patients admitted to the medical/surgical ICU services were eligible., Results: Of 821 subjects eligible at enrollment, 261 (33%) had preadmission history of depression. After adjusting for covariates, preadmission history of depression was not associated with less DCF days (OR 0.78, 95% CI, 0.59-1.03 p = 0.077). A prior history of depression was associated with higher BDI-II scores at 3 and 12 months (3 months OR 2.15, 95% CI, 1.42-3.24 p = <0.001; 12 months OR 1.89, 95% CI, 1.24-2.87 p = 0.003). We did not observe an association between preadmission history of depression and cognitive performance at either 3 or 12 months (3 months beta coefficient -0.04, 95% CI, -2.70-2.62 p = 0.97; 12 months 1.5, 95% CI, -1.26-4.26 p = 0.28)., Conclusion: Patients with a depression history prior to ICU stay exhibit a greater severity of depressive symptoms in the year after hospitalization.

Background: The temporal association of delirium during critical illness with mortality is unclear, along with the associations of hypoactive and hyperactive motoric subtypes of delirium with mortality. We aimed to evaluate the relationship of delirium during critical illness, including hypoactive and hyperactive motoric subtypes, with mortality in the hospital and after discharge up to 1 year., Methods: We analyzed a prospective cohort study of adults with respiratory failure and/or shock admitted to university, community, and Veterans Affairs hospitals. We assessed patients using the Richmond Agitation-Sedation Scale and the Confusion Assessment Method for the intensive care unit (ICU) and defined the motoric subtype according to the corresponding Richmond Agitation-Sedation Scale if delirium was present. We used Cox proportional hazard models, adjusted for baseline characteristics, coma, and daily hospital events, to determine whether delirium on a given day predicted mortality the following day in patients in the hospital and also to determine whether delirium presence and duration predicted mortality after discharge up to 1 year in patients who survived to hospital discharge. We performed similar analyses for hypoactive and hyperactive subtypes of delirium., Results: Among 1040 critically ill patients, 214 (21%) died in the hospital and 204 (20%) died out-of-hospital by 1 year. Delirium was common, occurring in 740 (71%) patients for a median (interquartile range [IQR]) of 4 (2-7) days. Hypoactive delirium occurred in 733 (70%) patients, and hyperactive occurred in 185 (18%) patients, with a median (IQR) of 3 (2-7) days and 1 (1-2) days, respectively. Delirium on a given day (hazard ratio [HR], 2.87; 95% confidence interval [CI], 1.32-6.21; P = .008), in particular the hypoactive subtype (HR, 3.35; 95% CI, 1.51-7.46; P = .003), was independently associated with an increased risk of death the following day in the hospital. Hyperactive delirium was not associated with an increased risk of death in the hospital (HR, 4.00; 95% CI, 0.49-32.51; P = .19). Among hospital survivors, neither delirium presence (HR, 1.01; 95% CI, 0.82-1.24; P = .95) nor duration (HR, 0.99; 95% CI, 0.97-1.01; P = .56), regardless of motoric subtype, was associated with mortality after hospital discharge up to 1 year., Conclusions: Delirium during critical illness is associated with nearly a 3-fold increased risk of death the following day for patients in the hospital but is not associated with mortality after hospital discharge. This finding appears primarily driven by the hypoactive motoric subtype. The independent relationship between delirium and mortality occurs early during critical illness but does not persist after hospital discharge., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2021 International Anesthesia Research Society.)

The advent of modern critical care medicine has revolutionized care of the critically ill patient in the last 50 years. The Society of Critical Care Medicine (was formed in recognition of the challenges and need for specialized treatment for these fragile patients. As the specialty has grown, it has achieved impressive scientific advances that have reduced mortality and saved lives. With those advances, however, came growing recognition that the burden of critical illness did not end at the doorstep of the hospital. Delirium, once thought to be a mere by-product of critical illness, was found to be an independent predictor of mortality, prolonged mechanical ventilation, and long-lasting cognitive impairment. Similarly, deep sedation and immobility, so often used to keep patients "comfortable" and to facilitate mechanical ventilation and recovery, worsen mortality and lead to the development of ICU-acquired weakness. The realization that these outcomes are inextricably linked to one another and how we manage our patients has helped us recognize the need for culture change. We, as a specialty, now understand that although celebrating the successes of survival, we now also have a duty to focus on those who survive their diseases. Led by initiatives such as the ICU Liberation Campaign of the Society of Critical Care Medicine, the natural progression of the field is now focused on getting patients back to their homes and lives unencumbered by disability and impairment. Much work remains to be done, but the futures of our most critically ill patients will continue to benefit if we leverage and build on the history of our first 50 years., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objectives: Adult ICU survivors that experience delirium are at high risk for developing new functional disabilities and mental health disorders. We sought to determine if individual motoric subtypes of delirium are associated with worse disability, depression, and/or post-traumatic stress disorder in ICU survivors., Design: Secondary analysis of a prospective multicenter cohort study., Setting: Academic, community, and Veteran Affairs hospitals., Patients: Adult ICU survivors of respiratory failure and/or shock., Interventions: We assessed delirium and level of consciousness using the Confusion Assessment Method-ICU and Richmond Agitation and Sedation Scale daily during hospitalization. We classified delirium as hypoactive (Richmond Agitation and Sedation Scale ≤ 0) or hyperactive (Richmond Agitation and Sedation Scale > 0). At 3- and 12-month postdischarge, we assessed for dependence in activities of daily living and instrumental activities of daily living, symptoms of depression, and symptoms of post-traumatic stress disorder. Adjusting for baseline and inhospital covariates, multivariable regression examined the association of exposure to delirium motoric subtype and long-term outcomes., Measurements and Main Results: In our cohort of 556 adults with a median age of 62 years, hypoactive delirium was more common than hyperactive (68.9% vs 16.8%). Dependence on the activities of daily living was present in 37% at 3 months and 31% at 12 months, whereas dependence on instrumental activities of daily living was present in 63% at 3 months and 56% at 12 months. At both time points, depression and post-traumatic stress disorder rates were constant at 36% and 5%, respectively. Each additional day of hypoactive delirium was associated with higher instrumental activities of daily living dependence at 3 months only (0.24 points [95% CI, 0.07-0.41; p = 0.006]). There were no associations between the motoric delirium subtype and activities of daily living dependence, depression, or post-traumatic stress disorder., Conclusions: Longer duration of hypoactive delirium, but not hyperactive, was associated with a minimal increase in early instrumental activities of daily living dependence scores in adult survivors of critical illness. Motoric delirium subtype was neither associated with early or late activities of daily living functional dependence or mental health outcomes, nor late instrumental activities of daily living functional dependence., Competing Interests: Dr. Boncyk received support from the National Institute of Health (NIH; 5T32GM108554); Dr. Patel received support from the NIH (AG058639, HL111111, and GM120484) and the Vanderbilt Faculty Research Scholars Program; Dr. Brummel received support from the NIH TR00046 and AG040549 and by the Vanderbilt Clinical and Translational Scholars Program; Dr. Ely received support from the NIH (AG058639, AG027472, AG035117, HL111111, and GM120484), the VA Clinical Science Research and Development Service, and the Veterans Affairs Tennessee Valley Geriatric Research, Education and Clinical Center; Dr. Pandharipande received support from the NIH (AG027472, HL111111, and GM120484); Dr. Hughes received support from American Geriatrics Society Jahnigen Career Development Award and the NIH (HL111111, AG045085, and GM120484). We used Research Electronic Data Capture, a secure online database, supported in part by the NIH TR 000445. Dr. Rengel’s institution received funding from the NIH and the Department of Veterans Affairs. Drs. Jackson, Boncyk, Patel, Brummel, and Ely received support for article research from the NIH. Dr. Patel’s institution received funding from NIH R01 GM120484, NIH R01 AG058639, and VA Merit, RRD, and ORD, and he received funding from the NIH Center for Scientific Review, OLOL Trauma Symposium, Haemonetics, and from the Eastern Association for the Surgery of Trauma, Board of Directors. Dr. Brummel’s institution received funding from NIH, and he received funding from Merck. Dr. Ely received funding from Pfizer, Masimo, Kohler, and NIH/VA. Dr. Pandharipande received a research grant from Pfizer (previously from Hospira) in collaboration with NIH. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

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.

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., (© 2020 S. Karger AG, Basel.)

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 .).

Background: Delirium is frequently missed in most clinical settings. Brief delirium assessments are needed., Objective: To determine the diagnostic accuracy of reciting the months of year backwards (MOTYB) from December to July (MOTYB-6) and December to January (MOTYB-12) for delirium as diagnosed by a psychiatrist and to explore the diagnostic accuracies of the following other brief attention tasks: (1) spell the word "LUNCH" backwards, (2) recite the days of the week backwards, (3) 10-letter vigilance "A" task, and (4) 5 picture recognition task., Design: Preplanned secondary analysis of a prospective observational study., Setting: Emergency department located within an academic, tertiary care hospital., Participants: 234 acutely ill patients who were =65 years old., Measurements: The inattention tasks were administered by a physician. The reference standard for delirium was a comprehensive psychiatrist assessment using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria. Sensitivities and specificities were calculated., Results: Making any error on the MOTYB-6 task had a sensitivity of 80.0% (95% confidence interval [CI], 60.9%-91.1%) and specificity of 57.1% (95% CI, 50.4%- 63.7%). Making any error on the MOTYB-12 task had a sensitivity of 84.0% (95% CI, 65.4%-93.6%) and specificity of 51.9% (95% CI, 45.2%-58.5%). The best combination of sensitivity and specificity was reciting the days of the week backwards task; if the patient made any error, this was 84.0% (95% CI, 65.4%-93.6%) sensitive and 81.9% (95% CI, 76.1%-86.5%) specific., Conclusions: MOTYB-6 and MOTYB-12 had very good sensitivities but had modest specificities for delirium, limiting their use as a standalone assessment. Reciting the days of the week backwards appeared to have the best combination of sensitivity and specificity for delirium., (© 2018 Society of Hospital Medicine.)

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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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 ( P = .007). This association was greatest in patients with less delirium ( P 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., (©2017 American Association of Critical-Care Nurses.)

Background: Delirium is common in mechanically ventilated patients and is associated with cognitive impairment lasting at least 1 year after hospital discharge. Preclinical and observational studies suggest that the use of statins might reduce delirium in intensive care. We assessed whether the pleiotropic effects of statins can reduce delirium in intensive care and decrease subsequent cognitive impairment in a randomised controlled trial., Methods: We did this ancillary study within the SAILS trial, a randomised controlled trial assessing mortality and ventilator-free days for rosuvastatin versus placebo for patients with sepsis-associated acute respiratory distress syndrome. This study was done at 35 hospitals in the USA. Patients were randomly assigned in permuted blocks of eight and stratified by hospital to receive either rosuvastatin (40 mg loading dose and then 20 mg daily until the earliest of 3 days after discharge from intensive care, study day 28, or death) or placebo. Patients and investigators were masked to treatment assignment. Delirium was assessed with the validated Confusion Assessment Method for intensive care. Cognitive function was assessed with tests for executive function, language, verbal reasoning and concept formation, and working, immediate, and delayed memory. We defined cognitive impairment as having one of these domains at least two SDs below population norms or at least two domains at least 1·5 SDs below norms. The primary endpoint was daily delirium status in intensive care up to 28 days in the intention-to-treat population and secondary endpoints were cognitive function at 6 months and 12 months. This trial is registered with ClinicalTrials.gov (NCT00979121 and NCT00719446)., Findings: 272 patients were assessed for delirium daily in intensive care. The mean proportion of days with delirium was 34% (SD 30%) in the rosuvastatin group versus 31% (29%) in the placebo group; hazard ratio 1·14, 95% CI 0·92-1·41, p=0·22. At 6 months, 19 (36%) of 53 patients in the rosuvastatin group versus 29 (38%) of 77 in the placebo group had cognitive impairment, with no significant difference between groups (treatment effect 0·93, 95% CI 0·39-2·22; p=0·87). At 12 months, 20 (30%) of 67 patients versus 23 (28%) of 81 patients had cognitive impairment, with no significant difference between groups (treatment effect 1·1, 95% CI 0·5-2·6; p=0·82)., Interpretation: Most patients had delirium, with around a third of survivors having cognitive impairment over 1 year of follow-up. Despite encouraging preclinical and observational studies, this trial shows no benefit of rosuvastatin in reducing delirium in intensive care or cognitive impairment during 12 months of follow-up although the study was not powered for superiority. Thus, there is continued need to evaluate interventions aimed at attenuating intensive care and post-intensive-care cognitive impairments commonly observed in this population., Funding: National Heart, Lung and Blood Institute; Johns Hopkins Institute for Clinical and Translational Research; the SAILS trial was also supported by AstraZeneca., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: We undertook this pilot prospective cohort investigation to examine the feasibility of functional magnetic resonance imaging (fMRI) assessments in survivors of critical illness and to analyze potential associations between delirium and brain activation patterns observed during a working memory task (N-back) at hospital discharge and 3-month follow-up., Materials and Methods: At hospital discharge and 3 months later, fMRI assessed subjects' functional activity during an N-back task. Multiple linear regression was used to examine associations between duration of delirium and brain activity, and elastic net regression was used to assess the relationship between brain activation patterns at 3 months and cognitive outcomes at 12 months., Results: Of 47 patients who underwent fMRI at discharge, 38 (80%) completed the protocol; of 37 who underwent fMRI at 3 months, 34 (91%) completed the protocol. At discharge, the mean (SD) percentage of correct responses on the most challenging version (the N2 version) of the N-back task was 70.4 (23.2; range of 20-100) compared with 76 (23.4; range of 33-100) at 3 months. No association was observed between delirium duration in the hospital and brain region activity in any brain region at discharge or 3 months after adjusting for relevant covariates (P values across all 11 brain regions of interest were >.25)., Conclusions: Our data support the feasibility of using fMRI in survivors of critical illness at 3-month follow-up but not at discharge. In this small study, delirium was not associated with distinct or abnormal brain activation patterns, although overall performance on a cognitive task of working memory was poorer than observed in other cohorts of individuals with medically related executive dysfunction, mild cognitive impairment, and mild traumatic brain injury., (Copyright © 2015. Published by Elsevier Inc.)

Background: The incidence of delirium in ventilated patients is estimated at up to 82%, and it is associated with longer intensive care and hospital stays, and long-term cognitive impairment and mortality. The pathophysiology of delirium has been linked with inflammation and neuronal apoptosis. Simvastatin has pleiotropic properties; it penetrates the brain and, as well as reducing cholesterol, reduces inflammation when used at clinically relevant doses over the short term. This is a single centre randomised, controlled trial which aims to test the hypothesis that treatment with simvastatin will modify delirium incidence and outcomes., Methods/design: The ongoing study will include 142 adults admitted to the Watford General Hospital Intensive Care Unit who require mechanical ventilation in the first 72 hours of admission. The primary outcome is the number of delirium- and coma-free days in the first 14 days. Secondary outcomes include incidence of delirium, delirium- and coma-free days in the first 28 days, days in delirium and in coma at 14 and 28 days, number of ventilator-free days at 28 days, length of critical care and hospital stay, mortality, cognitive decline and healthcare resource use. Informed consent will be taken from patient's consultee before randomisation to receive either simvastatin (80 mg) or placebo once daily. Daily data will be recorded until day 28 after randomisation or until discharge from the ICU if sooner. Surviving patients will be followed up on at six months from discharge. Plasma and urine samples will be taken to investigate the biological effect of simvastatin on systemic markers of inflammation, as related to the number of delirium- and coma-free days, and the potential of cholinesterase activity and beta-amyloid as predictors of the risk of delirium and long-term cognitive impairment., Discussion: This trial will test the efficacy of simvastatin on reducing delirium in the critically ill. If patients receiving the statin show a reduced number of days in delirium compared with the placebo group, the inflammatory theory implicated in the pathogenesis of delirium will be strengthened., Trial Registration: The trial was registered with the International Standard Randomised Controlled Trial Registry ( ISRCTN89079989 ) on 26 March 2013.

Objectives: To determine whether delirium during the hospital stay predicted health-related quality of life (HRQOL) at 1 year after injury in trauma intensive care unit (ICU) survivors without intracranial hemorrhage, and to examine the association between depressive and posttraumatic stress disorder (PTSD) symptoms and each of the HRQOL domains at 1-year follow-up., Design: Prognostic cohort with a 1-year follow-up., Setting: Level 1 trauma ICU., Participants: Adult patients without intracranial hemorrhage (N=173) admitted to a level 1 trauma ICU., Interventions: Not applicable., Main Outcome Measures: HRQOL was measured with the Medical Outcomes Study 36-Item Short-Form Health Survey at 1 year after traumatic injury., Results: Average delirium duration ± SD was .51±1.1 days. Hierarchical multivariable linear regression analyses did not find a statistical relationship between delirium and HRQOL at 1-year follow-up. However, increased levels of depressive symptoms at 1 year were statistically associated with poorer functioning in all physical and mental health HRQOL domains, whereas PTSD at 1 year was statistically associated with all HRQOL domains except role-physical (P<.05)., Conclusions: There was no statistical association between delirium during the hospital stay and HRQOL at 1 year, which may be due to the short time spent in delirium by our study population. Depressive symptoms demonstrated a stronger relationship with mental and physical HRQOL domains at 1 year than PTSD, indicating their own unique pathway after trauma. Findings lend support for the separate assessment and management of depression and PTSD. Additional research on the duration and subtypes of delirium is needed within the trauma ICU population, as the effects are not widely known., (Copyright © 2014 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

The intensive care unit (ICU) is not only a place where lives are saved; it is also a site of harm and iatrogenic injury for millions of people treated in this setting globally every year. Increasingly, hospitals admit only the sickest patients, and although the overall number of hospital beds remains stable in the United States, the percentage of that total devoted to ICU beds is rising. These 2 realities engender a demographic imperative to address patient safety in the critical care setting. This article addresses the medical community's resistance to adopting a culture of safety in critical care with regard to issues surrounding sedation, delirium, and early mobility. Although there is currently much research and quality improvement in this area, most of what we know from these data and published guidelines has not become reality in the day-to-day management of ICU patients. This article is not intended to provide a comprehensive review of the literature but rather a framework to rethink our currently outdated culture of critical care by employing Maslow's hierarchy of needs, along with a few novel analogies. Application of Maslow's hierarchy will help propel health care professionals toward comprehensive care of the whole person not merely for survival but toward restoration of pre-illness function of mind, body, and spirit., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Critical illness is associated with cognitive impairment, but mental health and functional disabilities in survivors of intensive care are inadequately characterised. We aimed to assess associations of age and duration of delirium with mental health and functional disabilities in this group., Methods: In this prospective, multicentre cohort study, we enrolled patients with respiratory failure or shock who were undergoing treatment in medical or surgical ICUs in Nashville, TN, USA. We obtained data for baseline demographics and in-hospital variables, and assessed survivors at 3 months and 12 months with measures of depression (Beck Depression Inventory II), post-traumatic stress disorder (PTSD, Post-Traumatic Stress Disorder Checklist-Event Specific Version), and functional disability (activities of daily living scales, Pfeffer Functional Activities Questionnaire, and Katz Activities of Daily Living Scale). We used linear and proportional odds logistic regression to assess the independent associations between age and duration of delirium with mental health and functional disabilities. This study is registered with ClinicalTrials.gov, number NCT00392795., Findings: We enrolled 821 patients with a median age of 61 years (IQR 51-71), assessing 448 patients at 3 months and 382 patients at 12 months after discharge. At 3 months, 149 (37%) of 406 patients with available data reported at least mild depression, as did 116 (33%) of 347 patients at 12 months; this depression was mainly due to somatic rather than cognitive-affective symptoms. Depressive symptoms were common even among individuals without a history of depression (as reported by a proxy), occurring in 76 (30%) of 255 patients with data at 3 months and 62 (29%) of 217 individuals at 12 months. Only 7% of patients (27 of 415 at 3 months and 24 of 361 at 12 months) had symptoms consistent with post-traumatic distress disorder. Disabilities in basic activities of daily living (ADL) were present in 139 (32%) of 428 patients at 3 months and 102 (27%) of 374 at 12 months, as were disabilities in instrumental ADL in 108 (26%) of 422 individuals at 3 months and 87 (23%) of 372 at 12 months. Mental health and functional difficulties were prevalent in patients of all ages. Although old age was frequently associated with mental health problems and functional disabilities, we observed no consistent association between the presence of delirium and these outcomes., Interpretation: Poor mental health and functional disability is common in patients treated in intensive-care units. Depression is five times more common than is post-traumatic distress disorder after critical illness and is driven by somatic symptoms, suggesting approaches targeting physical rather than cognitive causes could benefit patients leaving critical care., Funding: National Institutes of Health AG027472 and the Geriatric Research, Education and Clinical Center (GRECC), Department of Veterans Affairs Medical Center, Tennessee Valley Healthcare System., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: Survivors of critical illness are frequently left with long-lasting disability. The association between delirium and disability in critically ill patients has not been described. We hypothesized that the duration of delirium in the ICU would be associated with subsequent disability and worse physical health status following a critical illness., Design: Prospective cohort study nested within a randomized controlled trial of a paired sedation and ventilator weaning strategy., Setting: A single-center tertiary-care hospital., Patients: One hundred twenty-six survivors of a critical illness., Measurements and Main Results: Confusion Assessment Method for the ICU, Katz activities of daily living, Functional Activities Questionnaire (measuring instrumental activities of daily living), Medical Outcomes Study 36-item Short Form General Health Survey Physical Components Score, and Awareness Questionnaire were used. Associations between delirium duration and outcomes were determined via proportional odds logistic regression with generalized estimating equations (for Katz activities of daily living and Functional Activities Questionnaire scores) or via generalized least squares regression (for Medical Outcomes Study 36-item Short Form General Health Survey Physical Components Score and Awareness Questionnaire scores). Excluding patients who died prior to follow-up but including those who withdrew or were lost to follow-up, we assessed 80 of 99 patients (81%) at 3 months and 63 of 87 patients (72%) at 12 months. After adjusting for covariates, delirium duration was associated with worse activities of daily living scores (p = 0.002) over the course of the 12-month study period but was not associated with worse instrumental activities of daily living scores (p = 0.15) or worse Medical Outcomes Study 36-item Short Form General Health Survey Physical Components Score (p = 0.58). Duration of delirium was also associated with lower Awareness Questionnaire Motor/Sensory Factors scores (p 0.02)., Conclusion: In the setting of critical illness, longer delirium duration is independently associated with increased odds of disability in activities of daily living and worse motor-sensory function in the following year. These data point to a need for further study into the determinants of functional outcomes in ICU survivors.

Purpose: To assess the associations between a priori-selected markers of inflammation and coagulation and delirium during critical illness., Methods: In this prospective cohort study, we collected blood from mechanically ventilated medical intensive care unit (ICU) patients and measured nine plasma markers of inflammation and coagulation. We assessed patients daily for delirium using the Confusion Assessment Method for the ICU and used multivariable regression to analyze the associations between plasma markers and subsequent delirium, after adjusting for age, severity of illness, and sepsis., Results: Among the 138 patients studied, with median age of 66 years and median Acute Physiology and Chronic Health Evaluation (APACHE) II of 27, 107 (78 %) were delirious at some point during the study. Two markers of inflammation and one of coagulation were significantly associated with delirium. After adjusting for covariates, lower plasma concentrations of matrix metalloproteinase-9 (MMP-9) and protein C were associated with increased probability of delirium (p = 0.04 and 0.01, respectively), and higher concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1) were associated with increased probability of delirium (p < 0.01). Concentrations of C-reactive protein (p = 0.82), myeloperoxidase (p = 0.11), neutrophil gelatinase-associated lipocalin (p = 0.70), D-dimer (p = 0.83), plasminogen activator inhibitor type 1 (p = 0.98), and Von Willebrand factor antigen (p = 0.65) were not associated with delirium., Conclusions: In this study, MMP-9, protein C, and sTNFR1 were independently associated with subsequent ICU delirium. These results suggest that specific aspects of inflammation and coagulation may play a role in the evolution of delirium during critical illness and that these markers should be examined in larger studies of ICU patients.

Objectives: To identify valid tools to diagnose delirium superimposed on dementia., Design: Systematic review of studies of delirium tools that explicitly included individuals with dementia., Setting: Hospital., Participants: Studies were included if delirium assessment tools were validated against standard criteria, and the presence of dementia was assessed according to standard criteria that used validated instruments., Measurements: PubMed, Embase, and Web of Science databases were searched for articles in English published between January 1960 and January 2012., Results: Nine studies fulfilled the selection criteria. Of 1,569 participants, 401 had dementia, and 50 had delirium superimposed on dementia. Six delirium tools were evaluated. One study using the Confusion Assessment Method (CAM) with 85% of participants with dementia had high specificity (96-100%) and moderate sensitivity (77%). Two intensive care unit studies that used the CAM for the Intensive Care Unit (CAM-ICU) reported 100% sensitivity and specificity for delirium in 23 individuals with dementia. One study using electroencephalography reported sensitivity of 67% and specificity of 91% in a population with a 100% prevalence of dementia. No studies examined potential effects of dementia severity or subtype on diagnostic accuracy., Conclusions: The evidence base on tools for detection of delirium superimposed on dementia is limited, although some existing tools show promise. Further studies of existing or refined tools with larger samples and more-detailed characterization of dementia are required to address the identification of delirium superimposed on dementia., (© 2012, Copyright the Authors Journal compilation © 2012, The American Geriatrics Society.)

Delirium, an acute brain dysfunction, frequently affects intensive care unit (ICU) patients during the course of a critical illness. Besides the acute morbidities, ICU survivors often experience long-term sequelae in the form of cognitive impairment (LTCI-CI). Though delirium and LTCI-CI are associated with adverse outcomes, little is known on the terminology used to define these acute and chronic co-morbidities. The use of a correct terminology is a key factor to spread the knowledge on clinical conditions. Therefore, we first review the epidemiology, definition of delirium and its related terminology. Second, we report on the epidemiology of LTCI-CI and compare its definition to other forms of cognitive impairments. In particular, we define mild cognitive impairment, dementia and finally postoperative cognitive dysfunction. Future research is needed to interpret the trajectories of LTCI-CI, to differentiate it from neurodegenerative diseases and to provide a formal disease classification., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: Evidence is emerging that delirium duration is a predictor of long-term cognitive impairment in intensive care unit survivors. Relationships between 1) delirium duration and brain white matter integrity, and 2) white matter integrity and long-term cognitive impairment are poorly understood and could be explored using magnetic resonance imaging., Design, Setting, Patients: A two-center, prospective cohort study incorporating delirium monitoring, neuroimaging, and cognitive testing in intensive care unit survivors., Measurements: Delirium was evaluated with the Confusion Assessment Method for the Intensive Care Unit and cognitive outcomes were tested at 3 and 12-month follow-up. Following the intensive care unit stay, fractional anisotropy, a measure of white matter integrity, was calculated quantitatively using diffusion tensor imaging with a 3-T magnetic resonance imaging scanner at hospital discharge and 3-month follow-up. We examined associations between 1) delirium duration and fractional anisotropy and 2) fractional anisotropy and cognitive outcomes using linear regression adjusted for age and sepsis., Results: A total of 47 patients with a median age of 50 yrs completed the diffusion tensor imaging-magnetic resonance imaging protocol. Greater duration of delirium (3 vs. 0 days) was associated with lower fractional anisotropy (i.e., reduced fractional anisotropy = white matter disruption) in the genu (-0.02; p = .04) and splenium (-0.01; p = .02) of the corpus callosum and anterior limb of the internal capsule (-0.02; p =.01) at hospital discharge. These associations persisted at 3 months for the genu (-0.02; p =.02) and splenium (-0.01; p = .004). Lower fractional anisotropy in the anterior limb of internal capsule at discharge and in genu of corpus callosum at three months was associated with worse cognitive scores at 3 and 12 months., Conclusions: In this pilot investigation, delirium duration in the intensive care unit was associated with white matter disruption at both discharge and 3 months. Similarly, white matter disruption was associated with worse cognitive scores up to 12 months later. This hypothesis-generating investigation may help design future studies to explore these complex relationships in greater depth.

Objective: Delirium duration is predictive of long-term cognitive impairment in intensive care unit survivors. Hypothesizing that a neuroanatomical basis may exist for the relationship between delirium and long-term cognitive impairment, we conducted this exploratory investigation of the associations between delirium duration, brain volumes, and long-term cognitive impairment., Design, Setting, and Patients: A prospective cohort of medical and surgical intensive care unit survivors with respiratory failure or shock., Measurements: Quantitative high resolution 3-Tesla brain magnetic resonance imaging was used to calculate brain volumes at discharge and 3-month follow-up. Delirium was evaluated using the confusion assessment method for the intensive care unit; cognitive outcomes were tested at 3- and 12-month follow-up. Linear regression was used to examine associations between delirium duration and brain volumes, and between brain volumes and cognitive outcomes., Results: A total of 47 patients completed the magnetic resonance imaging protocol. Patients with longer duration of delirium displayed greater brain atrophy as measured by a larger ventricle-to-brain ratio at hospital discharge (0.76, 95% confidence intervals [0.10, 1.41]; p = .03) and at 3-month follow-up (0.62 [0.02, 1.21], p = .05). Longer duration of delirium was associated with smaller superior frontal lobe (-2.11 cm(3) [-3.89, -0.32]; p = .03) and hippocampal volumes at discharge (-0.58 cm(3) [-0.85, -0.31], p < .001)--regions responsible for executive functioning and memory, respectively. Greater brain atrophy (higher ventricle-to-brain ratio) at 3 months was associated with worse cognitive performances at 12 months (lower Repeatable Battery for the Assessment of Neuropsychological Status score -11.17 [-21.12, -1.22], p = .04). Smaller superior frontal lobes, thalamus, and cerebellar volumes at 3 months were associated with worse executive functioning and visual attention at 12 months., Conclusions: These preliminary data show that longer duration of delirium is associated with smaller brain volumes up to 3 months after discharge, and that smaller brain volumes are associated with long-term cognitive impairment up to 12 months. We cannot, however, rule out that smaller preexisting brain volumes explain these findings.

Delirium occurs commonly in both general medical and intensive care unit (ICU) patients, with prevalence rates of up to 80% reported. A common expression of acute brain dysfunction, it is related to wide-ranging untoward outcomes such as prolonged hospitalization, increased costs, higher mortality, and, potentially long-term cognitive impairment. Different risk factors are associated with delirium, including sedation, which has implications for patient management. Multicomponent interventions to prevent delirium, developed in the non-ICU setting, can be adapted to critically ill patients with the purpose of reducing its incidence. Future studies should evaluate target interventions to prevent delirium in the ICU., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objectives: To describe the reliability and sustainability of delirium and sedation measurements of bedside intensive care unit (ICU) nurses., Design: Prospective cohort study., Setting: A tertiary care academic medical center., Participants: Five hundred ten ICU patients from 2007 to 2010; 627 bedside nurses., Measurements: Bedside nurses and well-trained reference-rater research nurses independently measured delirium and sedation levels in routine care. Bedside nurses were instructed to use the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) every 12 hours to measure delirium and the Richmond Agitation-Sedation Scale (RASS) every 4 hours to measure sedation. CAM-ICU and RASS assessment agreement were computed using weighted kappa statistics across the entire population and subgroups (e.g., ICU type). Sensitivity and specificity of bedside nurse identification of delirium were calculated to understand sources of discordance., Results: Six thousand one hundred ninety-eight CAM-ICU and 6,880 RASS measurement pairs obtained on 3,846 patient-days. For CAM-ICU measurements, agreement between bedside and research nurses was substantial (weighted kappa = 0.67, 95% confidence interval (CI) = 0.66-0.70) and stable over 3 years of data collection. RASS measures also demonstrated substantial agreement (weighted kappa = 0.66, 95% CI = 0.64-0.68), which was stable across all years of data collection. The sensitivity of delirium nurse assessments was 0.81 (95% CI = 0.78-0.83), and the specificity was 0.81 (95% CI = 0.78-0.85)., Conclusion: Bedside nurse measurements of delirium and sedation are sustainable and reliable sources of information. These measures can be used for clinical decision-making, quality improvement, and quality measurement activities., (© 2011, Copyright the Authors Journal compilation © 2011, The American Geriatrics Society.)

Background: Delirium occurs frequently in the intensive care unit (ICU), but its pathophysiology is still unclear. Low levels of insulin-like growth factor 1 (IGF-1), a hormone with neuroprotective properties, have been associated with delirium in some non-ICU studies, but this relationship has not been examined in the ICU. We sought to test the hypothesis that low IGF-1 concentrations are associated with delirium during critical illness., Methods: Mechanically ventilated medical ICU patients were prospectively enrolled, and blood was collected after enrollment for measurement of IGF-1 using radioimmunometric assay. Delirium and coma were identified daily using the Confusion Assessment Method for the ICU and the Richmond Agitation-Sedation Scale, respectively. The association between IGF-1 and delirium was evaluated with logistic regression. In addition, the association between IGF-1 and duration of normal mental state, measured as days alive without delirium or coma, was assessed using multiple linear regression., Results: Among 110 patients, the median age was 65 years (IQR, 52-75) and APACHE II was 27 (IQR, 22 -32). IGF-1 levels were not a risk factor for delirium on the day after IGF-1 measurement (p = 0.97), at which time 65% of the assessable patients were delirious. No significant association was found between IGF-1 levels and duration of normal mental state (p = 0.23)., Conclusions: This pilot study, the first to investigate IGF-1 and delirium in critically ill patients, found no association between IGF-1 and delirium. Future studies including serial measurements of IGF-1 and IGF-1 binding proteins are needed to determine whether this hormone has a role in delirium during critical illness.

Background: Within the traumatic brain injury population, outcomes are affected by hypoxic events in the early injury period. Previous work shows a high prevalence of cognitive deficits in patients with multiple injuries who do not have intracranial hemorrhage identified on admission head computed tomography scan. We hypothesize that intensive care unit (ICU) delirium and long-term cognitive impairment (LTCI) are more likely in patients who have a hypoxic event within the first 48 hours of ICU admission., Methods: A total of 173 patients with multiple injuries (Injury Severity Score [ISS] >15) who presented to a Level I trauma center from July 2006 to July 2007 were enrolled in a study on long-term cognitive deficit. Ninety-seven patients required ICU management and all had continuous oxygen saturation data collected. The Confusion Assessment Method for the ICU was collected twice a day on all patients in ICU. Of the total enrolled population, 108 (62%) were evaluated 12 months after discharge by neuropsychological tests. Cognitive impairment was defined as having 2 neuropsychological test scores, 1.5 standard deviations below the mean or 1 neuropsychological test score, and 2 standard deviations below the mean. Demographic data, ISS, initial 24-hour blood requirements, presence of hypoxia (SpO(2) <90% and <85%) or hypotension (systolic blood pressure <90 mm Hg), emergency department (ED) pulse, Glasgow Coma Scale score, ventilator and ICU days were recorded. Significant univariate identification of clinical variables was used for multivariate analysis., Results: Fifty-five of 97 ICU patients (57%) were Confusion Assessment Method-ICU positive for delirium and 59 of 108 (55%) demonstrated cognitive impairment at 12-month follow-up. There was no significant association between hypoxia and ICU delirium (74.5% vs. 74%; p = 0.9) or LTCI (89% vs. 83%; p = 0.5). Ventilator days (8.7 ± 8.9 vs. 2.9 ± 4.6; p < 0.0001), ED pulse (109 ± 28.5 vs. 94 ± 22.8; p = 0.01), and blood transfusions (10 U ± 10.8 U vs. 5 U ± 5.3 U; p = 0.015) were significant independent predictors of delirium. Ventilator days (odds ratio, 1.16; 95% confidence interval, 1.05-1.29; p = 0.004) and ED pulse (odds ratio, 1.02; 95% confidence interval, 1.00-1.04; p = 0.03) remained significant predictors of ICU delirium after adjusting for ISS, hypoxic state, blood transfusions, and ED blood pressure. Among ED Glasgow Coma Scale score (10.5 ± 5.1 vs. 11.4 ±5.5; p = 0.7), ISS (33.3 ± 10.1 vs. 32.2 ± 9.0; p = 0.5), ventilator days (6.5 ± 7.5 vs. 6.2 ± 8.8; p = 0.4), blood transfusions (8.1 ± 6.8 vs. 9.4 ± 8.1; p = 0.4), and delirium (62% vs. 62.5%; p = 0.9), there were no significant univariate associations with LTCI., Conclusions: Hypoxic events in the ICU do not have a direct correlation with ICU delirium or LTCI in the patients with multiple injuries without evidence of intracranial hemorrhage.

Purpose: Delirium affects 50% to 80% of intensive care unit (ICU) patients and is associated with increased risk of mortality. Given the paucity of data reporting the neuropathologic findings in ICU patients experiencing delirium, the purpose of this pilot, hypothesis-generating study was to evaluate brain autopsies in ICU patients who suffered from delirium to explore possible neuroanatomical correlates., Materials and Methods: Using delirium databases at Vanderbilt University, we identified patients who had delirium in the ICU and subsequently died and received a brain autopsy during the same hospitalization. Brain autopsy reports were collected retrospectively on all 7 patients who met these criteria., Results: Patients' mean age was 55 (SD ± 8.4) years, and median number of days spent with delirium was 7 (± 5 interquartile range). In 6 (86%) of 7 patients, pathologic lesions normally attributed to hypoxia or ischemia were noted in the hippocampus, pons, and striatum. Hippocampal lesions represented the most common neuropathologic site of injury, present in 5 (71%) of 7 patients., Conclusions: Hypoxic ischemic injury in multiple locations of the brain was a common finding. The biological plausibility of hippocampal lesions as a contributor to long-term cognitive impairment warrants postmortem investigation on a larger scale with comparison to patients not experiencing ICU delirium., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Objective: To test the hypothesis that duration of delirium in the intensive care unit is an independent predictor of long-term cognitive impairment after critical illness requiring mechanical ventilation., Design: Prospective cohort study., Setting: Medical intensive care unit in a large community hospital in the United States., Patients: Mechanically ventilated medical intensive care unit patients who were assessed daily for delirium while in the intensive care unit and who underwent comprehensive cognitive assessments 3 and 12 mos after discharge., Measurements and Main Results: Of 126 eligible patients, 99 survived>or=3 months after critical illness; long-term cognitive outcomes were obtained for 77 (78%) patients. Median age was 61 yrs, 51% were admitted with sepsis/acute respiratory distress syndrome, and median duration of delirium was 2 days. At 3-mo and 12-mo follow-up, 79% and 71% of survivors had cognitive impairment, respectively (with 62% and 36% being severely impaired). After adjusting for age, education, preexisting cognitive function, severity of illness, severe sepsis, and exposure to sedative medications in the intensive care unit, increasing duration of delirium was an independent predictor of worse cognitive performance-determined by averaging age-adjusted and education-adjusted T-scores from nine tests measuring seven domains of cognition-at 3-mo (p=.02) and 12-mo follow-up (p=.03). Duration of mechanical ventilation, alternatively, was not associated with long-term cognitive impairment (p=.20 and .58)., Conclusions: In this study of mechanically ventilated medical intensive care unit patients, duration of delirium (which is potentially modifiable) was independently associated with long-term cognitive impairment, a common public health problem among intensive care unit survivors.

Delirium is a common manifestation of acute brain dysfunction in critically ill patients with prevalence as high as 75%. In the last years there has been a progressive increase of publications regarding intensive care (ICU) delirium, acknowledging its importance. The occurrence of delirium in ICU is related to more adverse outcomes including self-extubation and removal of catheters, prolonged hospitalization, increased costs, higher mortality, and potentially, long-term cognitive impairment. The pathophysiology explaining the processes subtending the development of delirium is still elusive, though several theories have been discussed. It is known that different risk factors are associated with delirium in the ICU. Patients in ICU frequently receive medications to treat pain and to ensure sedation, but an association between these drugs and delirium has been shown. Therefore, this pharmacological exposure should be modified to reduce the risk factors. Giving the multifactorial genesis of delirium, multicomponent interventions to prevent delirium developed in non-ICU settings can be adapted to critically ill patients with the purpose of reducing the incidence. When delirium is diagnosed the use of typical and atypical antipsychotics may be effective for its treatment. Future studies should evaluate target interventions to prevent delirium in the ICU.

Context: Lorazepam is currently recommended for sustained sedation of mechanically ventilated intensive care unit (ICU) patients, but this and other benzodiazepine drugs may contribute to acute brain dysfunction, ie, delirium and coma, associated with prolonged hospital stays, costs, and increased mortality. Dexmedetomidine induces sedation via different central nervous system receptors than the benzodiazepine drugs and may lower the risk of acute brain dysfunction., Objective: To determine whether dexmedetomidine reduces the duration of delirium and coma in mechanically ventilated ICU patients while providing adequate sedation as compared with lorazepam., Design, Setting, Patients, and Intervention: Double-blind, randomized controlled trial of 106 adult mechanically ventilated medical and surgical ICU patients at 2 tertiary care centers between August 2004 and April 2006. Patients were sedated with dexmedetomidine or lorazepam for as many as 120 hours. Study drugs were titrated to achieve the desired level of sedation, measured using the Richmond Agitation-Sedation Scale (RASS). Patients were monitored twice daily for delirium using the Confusion Assessment Method for the ICU (CAM-ICU)., Main Outcome Measures: Days alive without delirium or coma and percentage of days spent within 1 RASS point of the sedation goal., Results: Sedation with dexmedetomidine resulted in more days alive without delirium or coma (median days, 7.0 vs 3.0; P = .01) and a lower prevalence of coma (63% vs 92%; P < .001) than sedation with lorazepam. Patients sedated with dexmedetomidine spent more time within 1 RASS point of their sedation goal compared with patients sedated with lorazepam (median percentage of days, 80% vs 67%; P = .04). The 28-day mortality in the dexmedetomidine group was 17% vs 27% in the lorazepam group (P = .18) and cost of care was similar between groups. More patients in the dexmedetomidine group (42% vs 31%; P = .61) were able to complete post-ICU neuropsychological testing, with similar scores in the tests evaluating global cognitive, motor speed, and attention functions. The 12-month time to death was 363 days in the dexmedetomidine group vs 188 days in the lorazepam group (P = .48)., Conclusion: In mechanically ventilated ICU patients managed with individualized targeted sedation, use of a dexmedetomidine infusion resulted in more days alive without delirium or coma and more time at the targeted level of sedation than with a lorazepam infusion., Trial Registration: clinicaltrials.gov Identifier: NCT00095251.

Critically ill patients are at risk for several secondary complications, including delirium and long-term cognitive impairment. The exact mechanisms of delirium and ICU-related cognitive decline are not fully understood; however, the authors review several recent investigations that have proposed plausible explanations. This article also includes several practical guidelines for the identification and management of delirium to aid in the development and implementation of clinical procedures that will lower the risk for ICU delirium and cognitive decline.

Objective: To test for an association between apolipoprotein E (APOE) genotypes and duration of intensive care unit delirium., Design: Prospective, observational cohort study., Setting: A 541-bed, community-based teaching hospital., Patients: Fifty-three mechanically ventilated intensive care unit patients., Interventions: None., Measurements and Main Results: All patients were managed with standardized sedation and ventilator weaning protocols as part of an ongoing clinical trial and were evaluated prospectively for delirium with the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). DNA was extracted from whole blood samples obtained on enrollment, and APOE genotype was determined using polymerase chain reaction followed by restriction enzyme digestion by investigators blinded to the clinical information. Delirium occurred in 47 (89%) patients at some point during the intensive care unit stay. Of the 53 patients, 12 (23%) had an APOE4 allele (APOE4+) and 41 (77%) had only APOE2 or APOE3 alleles (APOE4-). APOE4+ patients were younger (53.2 +/- 21.9 vs. 65.4 +/- 13.4, p = .08) and less often admitted for pneumonia (0% vs. 29.3%, p = .05) compared with APOE4- patients, yet they had a duration of delirium that was twice as long: median (interquartile range), 4 (3, 4.5) vs. 2 (1, 4) days (p = .05). No other clinical outcomes were significantly different between the APOE4+ and APOE4- patients. Using multivariable regression analysis to adjust for age, admission diagnosis of sepsis or acute respiratory distress syndrome or pneumonia, severity of illness, and duration of coma, the presence of APOE4 allele was the strongest predictor of delirium duration (odds ratio, 7.32; 95% confidence interval, 1.82-29.51, p = .005)., Conclusions: APOE4 allele represents the first demonstrated genetic predisposition to longer duration of delirium in humans.

Purpose of Review: Critically ill patients have a high risk of developing neurologic dysfunction including delirium and long-term cognitive impairment. In this paper we examine possible relationships between delirium and long-term cognitive impairments and explore this in the context of critical illness., Recent Findings: Critical illness and its treatment can lead to neurologic morbidity including neuropathological abnormalities, delirium, and cognitive impairments. The association between delirium and long-term cognitive impairments has been shown in a number of populations. Among intensive care unit cohorts, delirium appears to be one of many possible causes of cognitive impairments and may be a leading modifiable cause. The mechanisms of both delirium and intensive care unit related cognitive impairment remain unclear, although a variety of common mechanisms have been proposed., Summary: Potential neurologic consequences of critical illness include delirium and long-term cognitive impairments. Defining the extent of their association in intensive care unit cohorts is an important research priority due to the high prevalence of delirium and persistent cognitive impairments in critically ill patients. Future research should focus on strategies for the early identification of delirium and cognitive impairments, elucidating mechanisms of brain injury, and the development and implementation of therapeutic modalities designed to prevent or decrease delirium and cognitive morbidity.

Objectives: To describe the motoric subtypes of delirium in critically ill patients and compare patients aged 65 and older with a younger cohort., Design: Prospective cohort study., Setting: The medical intensive care unit (MICU) of a tertiary care academic medical center., Participants: Six hundred fourteen MICU patients admitted during a process improvement initiative to monitor levels of sedation and delirium., Measurements: MICU nursing staff assessed delirium and level of consciousness in all MICU patients at least once per 12-hour shift using the Confusion Assessment Method for the Intensive Care Unit and the Richmond Agitation-Sedation Scale. Delirium episodes were categorized as hypoactive, hyperactive, and mixed type., Results: Delirium was detected in 112 of 156 (71.8%) subjects aged 65 and older and 263 of 458 (57.4%) subjects younger than 65. Mixed type was most common (54.9%), followed by hypoactive delirium (43.5%) and purely hyperactive delirium (1.6%). Patients aged 65 and older experienced hypoactive delirium at a greater rate than younger patients (41.0% vs 21.6%, P<.001) and never experienced hyperactive delirium. Older age was strongly and independently associated with hypoactive delirium (adjusted odds ratio=3.0, 95% confidence interval=1.7-5.3), compared with no delirium in a model that adjusted for other important determinants of delirium including severity of illness, sedative medication use, and ventilation status., Conclusion: Older age is a strong predictor of hypoactive delirium in MICU patients, and this motoric subtype of delirium may be missed in the absence of active monitoring.

Background: Delirium is a common psychiatric disorder in general hospital elderly patients. Several delirium screening tests exist. Few nurse based delirium severity measures are available. The aim of this study was to evaluate the Delirium-O-Meter, a new nurses' behavioural rating scale that is an efficient and sensitive measure of delirium severity., Methods: Analysis of cross sectional and repeated assessments data. Participants were 92 elderly general hospital patients; 56 with delirium, 24 with dementia or other cognitive disturbances (no delirium) and 12 with other psychiatric disorders or no mental disorder. Measures were the Delirium-O-Meter (DOM), Delirium Rating Scale-Revised version (DRS-R-98), Delirium Observation Scale (DOS), Behavioural observation scale for geriatric inpatients (GIP) and Mini Mental State Examination (MMSE)., Results: The majority of DOM items show a (near-) normal score distribution. Reliability of the DOM was high; Cronbach's alpha values ranged from 0.87-0.92; Intra Class Correlation (ICC) range was 0.84-0.91 for total scores and 0.40-0.97 for item scores. Factor analysis produced a 'Cognitive/Motivational' factor explaining almost half of variance and a smaller 'Psychotic/Behavioural' factor. The two-factor model results support the conceptual distinction between hyperactive and hypoactive delirium. DOM observations differentiated delirium from non delirium patients. DOM total scores were highly related to the DRS-R-98, DOS, MMSE and GIP apathy and cognitive sub scales, but less so to the GIP affective disturbances subscale, indicating convergent and divergent validity. Temporal difference scores calculated for DRS-R-98 and DOM assessments on subsequent days were also highly related (rho = 0.80-0.95)., Conclusions: The newly constructed DOM is a brief and valid nurses' behavioural rating scale that can be useful for measuring different aspects of delirium and for efficiently monitoring delirium severity in elderly patients., (Copyright (c) 2005 John Wiley & Sons, Ltd.)

Introduction: Delirium occurs in most ventilated patients and is independently associated with more deaths, longer stay, and higher cost. Guidelines recommend monitoring of delirium in all intensive care unit (ICU) patients, though few data exist in non-ventilated patients. The study objective was to determine the relationship between delirium and outcomes among non-ventilated ICU patients., Method: A prospective cohort investigation of 261 consecutively admitted medical ICU patients not requiring invasive mechanical ventilation during hospitalization at a tertiary-care, university-based hospital between February 2002 and January 2003. ICU nursing staff assessed delirium and level of consciousness at least twice per day using the Confusion Assessment Method for the ICU (CAM-ICU) and Richmond Agitation-Sedation Scale (RASS). Cox regression with time-varying covariates was used to determine the independent relationship between delirium and clinical outcomes., Results: Of 261 patients, 125 (48%) experienced at least one episode of delirium. Patients who experienced delirium were older (mean +/- SD: 56 +/- 18 versus 49 +/- 17 years; p = 0.002) and more severely ill as measured by Acute Physiology and Chronic Health Evaluation II (APACHE II) scores (median 15, interquartile range (IQR) 10-21 versus 11, IQR 6-16; p < 0.001) compared to their non-delirious counterparts. Patients who experienced delirium had a 29% greater risk of remaining in the ICU on any given day (compared to patients who never developed delirium) even after adjusting for age, gender, race, Charlson co-morbidity score, APACHE II score, and coma (hazard ratio (HR) 1.29; 95% confidence interval (CI) 0.98-1.69, p = 0.07). Similarly, patients who experienced delirium had a 41% greater risk of remaining in the hospital after adjusting for the same covariates (HR 1.41; 95% CI 1.05-1.89, p = 0.023). Hospital mortality was higher among patients who developed delirium (24/125, 19%) versus patients who never developed delirium (8/135, 6%), p = 0.002; however, time to in-hospital death was not significant the adjusted (HR 1.27; 95% CI 0.55-2.98, p = 0.58)., Conclusion: Delirium occurred in nearly half of the non-ventilated ICU patients in this cohort. Even after adjustment for relevant covariates, delirium was found to be an independent predictor of longer hospital stay.

Objective: To implement sedation and delirium monitoring via a process-improvement project in accordance with Society of Critical Care Medicine guidelines and to evaluate the challenges of modifying intensive care unit (ICU) organizational practice styles., Design: Prospective observational cohort study., Setting: The medical ICUs at two institutions: the Vanderbilt University Medical Center (VUMC) and a community Veterans Affairs hospital (York-VA)., Subjects: Seven hundred eleven patients admitted to the medical ICUs for >24 hrs and followed over 4,163 days during a 21-month study period., Interventions: Unit-wide nursing documentation was changed to accommodate a sedation scale (Richmond Agitation-Sedation Scale) and delirium instrument (Confusion Assessment Method for the ICU). A 20-min introductory in-service was performed for all ICU nurses, followed by graded, staged educational interventions at regular intervals. Data were collected daily for compliance, and randomly 40% of nurses each day were chosen for accuracy spot-checks by reference raters. An implementation survey questionnaire was distributed at 6 months., Measurements and Main Results: The implementation project involved 64 nurses (40 at VUMC and 24 at York-VA). Sedation and delirium monitoring data were recorded for 711 patients (614 at VUMC and 97 at York-VA). Compliance with the Richmond Agitation-Sedation Scale was 94.4% (21,931 of 23,220) at VUMC and 99.7% (5,387 of 5,403) at York-VA. Compliance with the Confusion Assessment Method for the ICU was 90% (7,323 of 8,166) at VUMC and 84% (1,571 of 1,871) at York-VA. The Confusion Assessment Method for the ICU was performed more often than requested on 63% of shifts (5,146 of 8,166) at VUMC and on 8% (151 of 1871) of shifts at York-VA. Overall weighted-kappa between bedside nurses and references raters for the Richmond Agitation-Sedation Scale were 0.89 (95% confidence interval, 0.88 to 0.92) at VUMC and 0.77 (95% confidence interval, 0.72 to 0.83) at York-VA. Overall agreement (kappa) between bedside nurses and reference raters using the Confusion Assessment Method for the ICU was 0.92 (95% confidence interval, 0.90-0.94) at VUMC and 0.75 (95% confidence interval, 0.68-0.81) at York-VA. The two most-often-cited barriers to implementation were physician buy-in and time., Conclusions: With minimal training, the compliance of bedside nurses using sedation and delirium instruments was excellent. Agreement of data from bedside nurses and a reference-standard rater was very high for both the sedation scale and the delirium assessment over the duration of this process-improvement project.

Delirium is a common neurobehavioral syndrome that occurs across health care settings which is associated with adverse outcomes, including death. There are limited data on long-term cognitive outcomes following delirium. This report reviews the literature regarding relationships between delirium and cognitive impairment. Psych Info and Medline searches and investigation of secondary references for all English language articles on delirium and subsequent cognitive impairment were carried out. Nine papers met inclusion criteria and documented cognitive impairment in patients following delirium. Four papers reported greater cognitive impairment among patients with delirium than matched controls. Four papers reported higher incidence of dementia in patients with a history of delirium. One study found 1 of 3 survivors of critical illness with delirium developed cognitive impairment. The evidence suggests a relationship between delirium and cognitive impairment, although significant questions remain regarding the nature of this association. Additional research on delirium-related effects on long-term cognitive outcome is needed.

Objective: Recently published clinical practice guidelines of the Society of Critical Care Medicine recommend monitoring for the presence of delirium in all mechanically ventilated patients because of the potential for adverse outcomes associated with this comorbidity, yet little is known about healthcare professionals' opinions regarding intensive care unit delirium or how they manage this organ dysfunction. The aim of this survey was to assess the medical community's beliefs and practices regarding delirium in the intensive care unit., Design: Survey administration was conducted both without a delirium definition (phase 1) and then with a definition of delirium (phase 2)., Setting: Critical care meetings and continuing medical education/board review courses from October 2001 to July 2002., Participants: A convenience sample of physicians (n = 753), nurses (n = 113), pharmacists (n = 13), physician assistants (n = 12), respiratory care practitioners (n = 8), and others (n = 13)., Interventions: Survey., Measurements and Main Results: Participants completed 912 of the surveys. The majority (68%) of respondents thought that >25% of adult mechanically ventilated patients experience delirium. Delirium was considered a significant or very serious problem in the intensive care unit by 92% of healthcare professionals, yet underdiagnosis was acknowledged by 78%. Only 40% reported routinely screening for delirium, and only 16% indicated using a specific tool for delirium assessment. Delirium was considered important in the outcome of elderly and young patients by 89% and 60% of the respondents, respectively (p <.0001). The most serious complications these professionals associated with delirium were prolonged mechanical ventilation, self-injury, and respiratory difficulties. Delirium was treated with haloperidol by 66% of the respondents, with lorazepam by 12%, and with atypical antipsychotics by <5%. More than 55% administered haloperidol and lorazepam at daily doses of < or =10 mg, but some used >50 mg/day of either medication., Conclusions: Most healthcare professionals consider delirium in the intensive care unit a common and serious problem, although few actually monitor for this condition and most admit that it is underdiagnosed. Data from this survey point to a disconnect between the perceived significance of delirium in the intensive care unit and current practices of monitoring and treatment.