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1.  Pre- and Post-Transplantation Risk Factors for Delirium Onset and Severity in Patients Undergoing Hematopoietic Stem-Cell Transplantation 
Journal of Clinical Oncology  2011;29(7):895-901.
To determine pre- and post-transplantation risk factors for delirium onset and severity during the acute phase of myeloablative hematopoietic stem-cell transplantation (HSCT).
Patients and Methods
Ninety adult patients with malignancies admitted to the Fred Hutchinson Cancer Research Center for their first HSCT were assessed prospectively from 1 week before transplantation to 30 days after transplantation. Delirium was assessed three times per week using the Delirium Rating Scale and the Memorial Delirium Assessment Scale. Potential risk factors were assessed by patient self-report, charts, and computerized records. Multivariable analysis of time to onset of a delirium episode was undertaken using Cox proportional hazards regression with time-varying covariates. Analysis for delirium severity was carried out using a linear mixed effects model. Validation and sensitivity analyses were performed on the final models.
Forty-five patients (50%) experienced a delirium episode. Pretransplantation risk factors for onset and higher severity of delirium were higher mean alkaline phosphatase and blood urea nitrogen (BUN) levels. Poorer pretransplantation executive functioning was also associated with higher delirium severity. Higher doses of opioid medications were the only post-transplantation risk factor for delirium onset (hazard ratio, 1.05; 95% CI, 1.02 to 1.08). Higher opioid doses, current and prior pain, and higher BUN levels were post-transplantation risk factors for greater delirium severity (all P < .01).
Pre- and post-transplantation factors can assist in identifying patients who are at risk for delirium during myeloablative HSCT and may enable clinical interventions to prevent delirium onset or decrease delirium symptoms.
PMCID: PMC3068062  PMID: 21263081
2.  Novel risk markers and long-term outcomes of delirium: The Successful Aging after Elective Surgery (SAGES) Study Design and Methods 
Delirium--a costly, life-threatening, and potentially preventable condition--is a common complication for older adults following major surgery. While the basic epidemiology of delirium after surgery has been defined, the contribution of delirium to long-term outcomes remains uncertain, and novel biomarkers from plasma and neuroimaging have yet to be examined. This program project was designed to contribute to our understanding of the complex multifactorial syndrome of delirium.
Long-term prospective cohort study.
3 academic medical centers (2 hospitals and 1 coordinating center).
Patients without recognized dementia (targeted cohort = 550 patients) age 70 and older scheduled to undergo elective major surgery are assessed at baseline prior to surgery, daily during their hospital stay, and for 18-36 months after discharge.
The Successful Aging after Elective Surgery (SAGES) study is an innovative, interdisciplinary study that includes biomarkers, neuroimaging, cognitive reserve markers, and serial neuropsychological testing to examine the contribution of delirium to long-term cognitive and functional decline. The primary goal is to examine the contribution of delirium to long-term cognitive and functional decline. In addition, novel risk markers, for delirium are being examined, including plasma biomarkers (e.g., cytokines, proteomics), advanced neuroimaging markers (e.g., volumetric, white matter hyperintensity, noncontrast blood flow, and diffusion tensor measures) and cognitive reserve markers (e.g., education, occupation, lifetime activities).
Results from this study will contribute to a fuller understanding of the etiology and prognosis of delirium. Ultimately, we hope this project will provide the groundwork for future development of prevention and treatment strategies for delirium, designed to minimize the long-term negative impact of delirium in older adults.
PMCID: PMC3489992  PMID: 22999782
Delirium; Dementia; Surgery; Elderly; Long Term Outcomes; Risk Factors
3.  Risk Factors for Delirium in Patients Undergoing Hematopoietic Stem Cell Transplantation 
Delirium is common following hematopoietic stem-cell transplantation (HSCT) and is associated with increased morbidity and mortality. Early recognition and treatment have been shown to improve long term outcomes. We sought to investigate the relationship between potential risk-factors and the development of delirium following HSCT.
Fifty-four inpatients admitted for HSCT were assessed prospectively for delirium every 2-3 days through their inpatient stay using standardized delirium and neuropsychological measures. Patient’s self-reports of medical history, medical records, and neurocognitive and psychiatric assessments were used to identify risk factors. Both pre- and post-HSCT risk factors were examined.
Delirium incidence was 35% and occurred with highest frequency in the 2 weeks following transplant. The only pre-transplantation risk factors was lower oxygen saturation (p=0.003). Post-transplantation risk factors for delirium included higher creatinine (p<0.0001), higher blood urea nitrogen levels (p=0.005), lower creatinine clearance (p=0.0006), lower oxygen saturation (p=0.001), lower hemoglobin (p=0.04) and lower albumin (p=0.03). There was no observed association with level of cognitive performance, transplant type, disease severity, medical co-morbidity index, age or conditioning regimen.
Routine laboratory values can assist in the identification of high risk patients before delirium onset to improve early detection and treatment of delirium following HSCT.
PMCID: PMC4120828  PMID: 22860240
delirium; risk factors; cancer; hematopoietic stem-cell transplantation
4.  Outcome and quality of life in patients with postoperative delirium during an ICU stay following major surgery 
Critical Care  2013;17(5):R257.
Delirium is an acute disturbance of consciousness and cognition that has been shown to be associated with poor outcomes, including increased mortality. We aimed to evaluate outcome after postoperative delirium in a cohort of surgical intensive care unit (SICU) patients.
This prospective study was conducted over a 10-month period in a SICU. Postoperative delirium was diagnosed in accordance with the Intensive Care Delirium Screening Checklist (ICDSC). The primary outcome was mortality at 6-month follow-up. Hospital mortality and becoming dependent were considered as secondary outcomes, on the basis of the evaluation of the patient’s ability to undertake both personal and instrumental activities of daily living (ADL) before surgery and 6 months after discharge from the SICU. For each dichotomous outcome - hospital mortality, mortality at 6-month follow-up, and becoming dependent - a separate multiple logistic regression analysis was performed, which included delirium as an independent variable. Another outcome analyzed was changes in health-related quality of life, as determined using short-form 36 (SF-36), which was administered before and 6 months after discharge from the SICU. Additionally, for each SF-36 domain, a separate multiple linear regression model was used for each SF-36 domain, with changes in the SF-36 domain as a dependent variable and delirium as an independent variable.
Of 775 SICU-admitted adults, 562 were enrolled in the study, of which 89 (16%) experienced postoperative delirium. Delirium was an independent risk factor for mortality at the 6-month follow-up (OR = 2.562, P <0.001) and also for hospital mortality (OR = 2.673, P <0.001). Delirium was also an independent risk factor for becoming dependent for personal ADL (P-ADL) after SICU discharge (OR = 2.188, P <0.046). Moreover, patients who experienced postoperative delirium showed a greater decline in SF-36 domains after discharge, particularly in physical function, vitality, and social function, as compared to patients without postoperative delirium.
Postoperative delirium was an independent risk factor for 6-month follow-up mortality, hospital mortality, and becoming independent in P-ADL after SICU discharge. It was also significantly associated with a worsening in the quality of life after surgery.
PMCID: PMC4057091  PMID: 24168808
5.  “Delirium superimposed on dementia is associated with prolonged length of stay and poor outcomes in hospitalized older adults” 
Current literature does not identify the significance of underlying cognitive impairment and delirium on older adults during and 30 days following acute care hospitalization.
Describe the incidence, risk factors, and outcomes associated with incident delirium superimposed on dementia.
24-month prospective cohort study
community hospital
139 older adults (>65 years) with dementia
This prospective study followed patients daily during hospitalization and one month post-hospital. Main measures included dementia (Modified Blessed Dementia Rating Score, IQ CODE), daily mental status change, dementia stage/severity (Clinical Dementia Rating, Global Deterioration Scale), delirium (Confusion Assessment Method), and delirium severity (Delirium Rating Scale-Revised-98). All statistical analysis was performed using SAS 9.3 and significance with an alpha level of 0.05. Logistic regression, analysis of covariance or linear regression was performed controlling for age, gender and dementia stage.
The overall incidence of new delirium was 32% (44/140). Those with delirium had a 25% short term mortality rate, increased length of stay and poorer function at discharge. At one month follow-up, subjects with delirium had greater functional decline. Males were more likely to develop delirium and for every one unit increase in dementia severity (Global Deterioration Scale), subjects were 1.5 times more likely to develop delirium.
Delirium prolongs hospitalization for persons with dementia. Thus, interventions to increase early detection of delirium have the potential to decrease the severity and duration of delirium and to prevent unnecessary suffering and costs from the complications of delirium and unnecessary readmissions to the hospital.
PMCID: PMC3928030  PMID: 23955965
6.  Probable risk factors for postoperative delirium in patients undergoing spinal surgery 
European Spine Journal  2008;17(11):1531-1537.
Postoperative delirium and its risk factors had been widely reported in several kinds of surgeries; however, there is only one known article relative to postoperative delirium in spinal surgery. We retrospectively examined the incidence of postoperative delirium and the probable risk factors in patients undergoing spinal surgery in our hospital, with the same aged non-delirium patients as controls, over a 6-month period. Studies about postoperative delirium were reviewed and referenced for variable factors collecting in our study. T tests, χ2 test and logistic regression analysis were performed to evaluate the various factors related to postoperative delirium. A total of 18 patients (3.3%), all of them were aged 54 years or older, had postoperative delirium after surgery. Patients without postoperative delirium aged 54 years or older served as the control group. The percentage of patients older than 65 years (P = 0.003), with comorbid diseases such as diabetes mellitus (P = 0.042) or central nervous system disorders (P = 0.013), with a surgical history (P = 0.028) in delirium group was larger than the control group. The absolute number of medications being taken before the operation in the delirium patients was also more than the control group (P = 0.000). The percentage of patients transfused with 800 mL or more blood was also larger (P = 0.024) in delirium group was larger than the control group. Logistic regression analysis showed that central nervous system disorder (OR 6.480), surgical history (OR 3.499), age older than 65 years (OR 3.390), diabetes mellitus (OR 2.981), transfused 800 mL or more blood (OR 2.537), and hemoglobin less than 100 g/L (OR 0.281) were significantly related to the occurrence postoperative delirium. Our findings suggest that postoperative delirium in spinal surgery can also occurred in younger patients and with an acceptable incidence in total. The risk for postoperative delirium is multifactorial. More prospective research is necessary in order to evaluate these and other risk factors in greater detail.
PMCID: PMC2583180  PMID: 18795347
Postoperative delirium; Spinal surgery; Delirium observation screening (DOS) scale; Logistic regression analysis
7.  The attributable mortality of delirium in critically ill patients: prospective cohort study 
Objective To determine the attributable mortality caused by delirium in critically ill patients.
Design Prospective cohort study.
Setting 32 mixed bed intensive care unit in the Netherlands, January 2011 to July 2013.
Participants 1112 consecutive adults admitted to an intensive care unit for a minimum of 24 hours.
Exposures Trained observers evaluated delirium daily using a validated protocol. Logistic regression and competing risks survival analyses were used to adjust for baseline variables and a marginal structural model analysis to adjust for confounding by evolution of disease severity before the onset of delirium.
Main outcome measure Mortality during admission to an intensive care unit.
Results Among 1112 evaluated patients, 558 (50.2%) developed at least one episode of delirium, with a median duration of 3 days (interquartile range 2-7 days). Crude mortality was 94/558 (17%) in patients with delirium compared with 40/554 (7%) in patients without delirium (P<0.001). Delirium was significantly associated with mortality in the multivariable logistic regression analysis (odds ratio 1.77, 95% confidence interval 1.15 to 2.72) and survival analysis (subdistribution hazard ratio 2.08, 95% confidence interval 1.40 to 3.09). However, the association disappeared after adjustment for time varying confounders in the marginal structural model (subdistribution hazard ratio 1.19, 95% confidence interval 0.75 to 1.89). Using this approach, only 7.2% (95% confidence interval −7.5% to 19.5%) of deaths in the intensive care unit were attributable to delirium, with an absolute mortality excess in patients with delirium of 0.9% (95% confidence interval −0.9% to 2.3%) by day 30. In post hoc analyses, however, delirium that persisted for two days or more remained associated with a 2.0% (95% confidence interval 1.2% to 2.8%) absolute mortality increase. Furthermore, competing risk analysis showed that delirium of any duration was associated with a significantly reduced rate of discharge from the intensive care unit (cause specific hazard ratio 0.65, 95% confidence interval 0.55 to 0.76).
Conclusions Overall, delirium prolongs admission in the intensive care unit but does not cause death in critically ill patients. Future studies should focus on episodes of persistent delirium and its long term sequelae rather than on acute mortality.
Trial registration NCT01905033.
PMCID: PMC4243039  PMID: 25422275
8.  Markers of cerebral damage during delirium in elderly patients with hip fracture 
BMC Neurology  2009;9:21.
S100B protein and Neuron Specific Enolase (NSE) can increase due to brain cell damage and/or increased permeability of the blood-brain-barrier. Elevation of these proteins has been shown after various neurological diseases with cognitive dysfunction. Delirium is characterized by temporal cognitive deficits and is an important risk factor for dementia. The aim of this study was to compare the level of S100B and NSE of patients before, during and after delirium with patients without delirium and investigate the possible associations with different subtypes of delirium.
The study population were patients aged 65 years or more acutely admitted after hip fracture. Delirium was diagnosed by the Confusion Assessment Method and the subtype by Delirium Symptom interview. In maximal four serum samples per patient S100B and NSE levels were determined by electrochemiluminescence immunoassay.
Of 120 included patients with mean age 83.9 years, 62 experienced delirium. Delirious patients had more frequently pre-existing cognitive impairment (67% vs. 18%, p < 0.001). Comparing the first samples during delirium to samples of non-delirious patients, a difference was observed in S100B (median 0.16 versus 0.10 μg/L, p = < 0.001), but not in NSE (median 11.7 versus 11.7 ng/L, p = 0.97). Delirious state (before, during, after) (p < 0.001), day of blood withdrawal (p < 0.001), pre- or postoperative status (p = 0.001) and type of fracture (p = 0.036) were all associated with S100B level. The highest S100B levels were found 'during' delirium. S100B levels 'before' and 'after' delirium were still higher than those from 'non-delirious' patients. No significant difference in S100B (p = 0.43) or NSE levels (p = 0.41) was seen between the hyperactive, hypoactive and mixed subtype of delirium.
Delirium was associated with increased level of S100B which could indicate cerebral damage either due to delirium or leading to delirium. The possible association between higher levels of S100B during delirium and the higher risk of developing dementia after delirium is an interesting field for future research. More studies are needed to elucidate the role of S100B proteins in the pathophysiological pathway leading to delirium and to investigate its possibility as biomarker for delirium.
PMCID: PMC2695414  PMID: 19473521
9.  Impaired Executive Function Is Associated with Delirium After Coronary Artery Bypass Graft Surgery 
To determine the extent to which preoperative performance on tests of executive function and memory was associated with delirium after coronary artery bypass graft (CABG) surgery.
Prospective observational cohort study.
Two academic medical centers and one Department of Veterans Affairs medical center in Massachusetts.
Eighty subjects without preoperative delirium undergoing CABG or CABG-valve surgery completed baseline neuropsychological assessments with validated measures of memory and executive function.
Beginning on postoperative Day 2, a battery to diagnose delirium was administered daily. Confirmatory factor analysis (CFA) was used to define two cognitive domain composites (memory and executive function). The loading pattern of neuropsychological measures onto the latent cognitive domains was determined a priori. Poisson regression was used to model the association between neuropsychological performance and cognitive domain composite scores and risk of postoperative delirium. The association was expressed as the difference between impaired (0.5 standard deviations (SDs) below mean) and nonimpaired (0.5 SDs above mean) performers.
Forty subjects (50%) developed delirium. Measures of memory function were not significantly related to delirium. Of the executive function measures, verbal fluency, category fluency, Hopkins Verbal Learning Test learning, and backward recounting of days and months were significantly related to delirium. Preoperative mental status was a strong predictor of postoperative delirium. After controlling for age, sex, education, medical comorbidity, mental status, and the other cognitive domain, CFA cognitive domain composites suggest that risk for delirium is specific for executive functioning impairment (relative risk (RR) = 2.77, 95% confidence interval (CI) = 1.12–6.87) but not for memory impairment (RR = 0.49, 95% CI = 0.19–1.25).
Worse preoperative performance in executive function was independently associated with greater risk of developing delirium after CABG.
PMCID: PMC2398689  PMID: 16776789
aged; delirium; CABG surgery; executive function; cognitive impairment; factor analysis
10.  Serum anticholinergic activity and cerebral cholinergic dysfunction: An EEG study in frail elderly with and without delirium 
BMC Neuroscience  2008;9:86.
Delirium increases morbidity, mortality and healthcare costs especially in the elderly. Serum anticholinergic activity (SAA) is a suggested biomarker for anticholinergic burden and delirium risk, but the association with cerebral cholinergic function remains unclear. To clarify this relationship, we prospectively assessed the correlation of SAA with quantitative electroencephalography (qEEG) power, delirium occurrence, functional and cognitive measures in a cross-sectional sample of acutely hospitalized elderly (> 80 y) with high dementia and delirium prevalence.
61 consecutively admitted patients over 80 years underwent an extensive clinical and neuropsychological evaluation. SAA was determined by using radio receptor assay as developed by Tune, and standard as well as quantitative EEGs were obtained.
15 patients had dementia with additional delirium (DD) according to expert consensus using DSM-IV criteria, 31 suffered from dementia without delirium (D), 15 were cognitively unimpaired (CU). SAA was clearly detectable in all patients but one (mean 10.9 ± 7.1 pmol/ml), but was not associated with expert-panel approved delirium diagnosis or cognitive functions. Delirium-associated EEG abnormalities included occipital slowing, peak power and alpha decrease, delta and theta power increase and slow wave ratio increase during active delirious states. EEG measures correlated significantly with cognitive performance and delirium severity, but not with SAA levels.
In elderly with acute disease, EEG parameters reliable indicate delirium, but SAA does not seem to reflect cerebral cholinergic function as measured by EEG and is not related to delirium diagnosis.
PMCID: PMC2564970  PMID: 18793418
11.  Long-Term Cognitive Impairment after Critical Illness 
The New England journal of medicine  2013;369(14):1306-1316.
Survivors of critical illness often have a prolonged and disabling form of cognitive impairment that remains inadequately characterized.
We enrolled adults with respiratory failure or shock in the medical or surgical intensive care unit (ICU), evaluated them for in-hospital delirium, and assessed global cognition and executive function 3 and 12 months after discharge with the use of the Repeatable Battery for the Assessment of Neuropsychological Status (population age-adjusted mean [±SD] score, 100±15, with lower values indicating worse global cognition) and the Trail Making Test, Part B (population age-, sex-, and education-adjusted mean score, 50±10, with lower scores indicating worse executive function). Associations of the duration of delirium and the use of sedative or analgesic agents with the outcomes were assessed with the use of linear regression, with adjustment for potential confounders.
Of the 821 patients enrolled, 6% had cognitive impairment at baseline, and delirium developed in 74% during the hospital stay. At 3 months, 40% of the patients had global cognition scores that were 1.5 SD below the population means (similar to scores for patients with moderate traumatic brain injury), and 26% had scores 2 SD below the population means (similar to scores for patients with mild Alzheimer's disease). Deficits occurred in both older and younger patients and persisted, with 34% and 24% of all patients with assessments at 12 months that were similar to scores for patients with moderate traumatic brain injury and scores for patients with mild Alzheimer's disease, respectively. A longer duration of delirium was independently associated with worse global cognition at 3 and 12 months (P = 0.001 and P = 0.04, respectively) and worse executive function at 3 and 12 months (P = 0.004 and P = 0.007, respectively). Use of sedative or analgesic medications was not consistently associated with cognitive impairment at 3 and 12 months.
Patients in medical and surgical ICUs are at high risk for long-term cognitive impairment. A longer duration of delirium in the hospital was associated with worse global cognition and executive function scores at 3 and 12 months. (Funded by the National Institutes of Health and others; BRAIN-ICU number, NCT00392795.)
PMCID: PMC3922401  PMID: 24088092
12.  Cognitive Trajectories after Postoperative Delirium 
Delirium is common after cardiac surgery and may be associated with long-term changes in cognitive function. We examined postoperative delirium and the cognitive trajectory during the first year after cardiac surgery.
We enrolled 225 patients 60 years of age or older who were planning to undergo coronary-artery bypass grafting or valve replacement. Patients were assessed preoperatively, daily during hospitalization beginning on postoperative day 2, and at 1, 6, and 12 months after surgery. Cognitive function was assessed with the use of the Mini–Mental State Examination (MMSE; score range, 0 to 30, with lower scores indicating poorer performance). Delirium was diagnosed with the use of the Confusion Assessment Method. We examined performance on the MMSE in the first year after surgery, controlling for demographic characteristics, coexisting conditions, hospital, and surgery type.
The 103 participants (46%) in whom delirium developed postoperatively had lower pre-operative mean MMSE scores than those in whom delirium did not develop (25.8 vs. 26.9, P<0.001). In adjusted models, those with delirium had a larger drop in cognitive function (as measured by the MMSE score) 2 days after surgery than did those without delirium (7.7 points vs. 2.1, P<0.001) and had significantly lower postoperative cognitive function than those without delirium, both at 1 month (mean MMSE score, 24.1 vs. 27.4; P<0.001) and at 1 year (25.2 vs. 27.2, P<0.001) after surgery. With adjustment for baseline differences, the between-group difference in mean MMSE scores was significant 30 days after surgery (P<0.001) but not at 6 or 12 months (P = 0.056 for both). A higher percentage of patients with delirium than those without delirium had not returned to their preoperative baseline level at 6 months (40% vs. 24%, P = 0.01), but the difference was not significant at 12 months (31% vs. 20%, P = 0.055).
Delirium is associated with a significant decline in cognitive ability during the first year after cardiac surgery, with a trajectory characterized by an initial decline and prolonged impairment. (Funded by the Harvard Older Americans Independence Center and others.)
PMCID: PMC3433229  PMID: 22762316
13.  Proton magnetic resonance spectroscopy in adult cancer patients with delirium 
Psychiatry research  2011;191(2):128-132.
Delirium is associated with a host of negative outcomes, including increased risk of mortality, longer hospital stay, and poor long-term cognitive function. The pathophysiology of delirium is not well understood. Cancer patients undergoing a bone marrow transplant (BMT) are at high risk for developing delirium and Proton Magnetic Resonance Spectroscopy (1H-MRS) could lead to better understanding of the delirium process.
Fourteen BMT patients and 10 controls completed 1H-MRS, positioned above the corpus callosum, shortly after delirium onset or at study end if no delirium occurred.
In the BMT-delirium group, statistically significantly elevated tCho/tCr was found in contrast to the BMT-no delirium group (p<0.05). The BMT–delirium group also showed statistically significantly lesser NAA/tCho compared to both controls (p=0.01) and the BMT–no delirium group (p=0.04).
Elevated choline and reduced NAA indicate inflammatory processes and white matter damage as well as neuronal metabolic impairment. Further research is needed to separate the choline peaks, as well as more detailed collection of medication regimens to determine whether a higher choline concentration is a function of the delirium process or cancer treatment effects.
PMCID: PMC3030637  PMID: 21227658
delirium; spectroscopy; choline; cancer; magnetic resonance imaging; cognition
14.  Screening, detection and management of delirium in the emergency department – a pilot study on the feasibility of a new algorithm for use in older emergency department patients: the modified Confusion Assessment Method for the Emergency Department (mCAM-ED) 
Delirium in emergency department (ED) patients occurs frequently and often remains unrecognized. Most instruments for delirium detection are complex and therefore unfeasible for the ED. The aims of this pilot study were first, to confirm our hypothesis that there is an unmet need for formal delirium assessment by comparing informal delirium ratings of ED staff with formal delirium assessments performed by trained research assistants. Second, to test the feasibility of an algorithm for delirium screening, detection and management, which includes the newly developed modified Confusion Assessment Method for the Emergency Department (mCAM-ED) at the ED bedside. Third, to test interrater reliability of the mCAM-ED.
This was a pilot study with a pre-post-test design with two data collection periods before and after the implementation of the algorithm. Consecutive ED patients aged 65 years and older were screened and assessed in the ED of a tertiary care center by trained research assistants. The delirium detection rate of informal ratings by nurses and physicians was compared with the standardized mCAM-ED assessment performed by the research assistants. To show the feasibility at the ED bedside, defined as adherence of ED staff to the algorithm, only post-test data were used. Additionally, the ED nurses’ assessments were analyzed qualitatively. To investigate the agreement between research assistants and the reference standard, the two data sets were combined.
In total, 207 patients were included in this study. We found that informal delirium assessment was inappropriate, even after a teaching intervention: Sensitivity of nurses to detect delirium without formal assessment was 0.27 pretest and 0.40 post-test, whilst sensitivity of physicians’ informal rating was 0.45 pre-test and 0.6 post-test. ED staff demonstrated high adherence to the algorithm (76.5%). Research assistants assessing delirium with the mCAM-ED demonstrated a high agreement compared to the reference standard (kappa = 0.729).
Informal assessment of delirium is inadequate. The mCAM-ED proved to be useful at the ED bedside. Performance criteria need to be tested in further studies. The mCAM-ED may contribute to early identification of delirious ED patients.
PMCID: PMC3975151  PMID: 24625212
Emergency medicine; Emergency nursing; Emergency department; Delirium; Geriatrics; Feasibility; Confusion assessment method
15.  Outcomes of Early Delirium Diagnosis After General Anesthesia in the Elderly 
Anesthesia and analgesia  2013;117(2):471-478.
Postoperative delirium in the elderly, measured days after surgery, is associated with significant negative clinical outcomes. In this study, we evaluated the prevalence and in-hospital outcomes of delirium diagnosed immediately after general anesthesia and surgery in elderly patients.
Consecutive English-speaking surgical candidates, aged 70 years or older, were prospectively enrolled during July to August 2010. After surgery, each participant was evaluated for a Diagnostic and Statistical Manual of Mental Disorders IV diagnosis of delirium in the postanesthesia care unit (PACU) and repeatedly thereafter while hospitalized. Delirium in the PACU was evaluated for an independent association with change in cognitive function from preoperative baseline testing and discharge disposition.
Ninety-one (58% female) patients, 78% of whom were living independently before surgery, were found to have a prevalence of delirium in the PACU of 45% (41/91); 74% (14/19) of all delirium episodes detected during subsequent hospitalization started in the PACU. Early delirium was independently associated with impaired cognition (i.e., decreased category word fluency) relative to presurgery baseline testing (adjusted difference [95% confidence interval] for change in T-score: −6.02 [−10.58 to −1.45]; P = 0.01). Patients whose delirium had resolved by postoperative day 1 showed negative outcomes that were intermediate in severity between those who were never delirious during hospitalization and those whose delirium in the PACU persisted after transfer to hospital wards (adjusted probability [95% confidence interval] of discharge to institution: 3% [0%–10%], 26% [1%–51%], 39% [0%–81%] for the 3 groups, respectively).
Delirium in the PACU is common, but not universal. It is associated with subsequent delirium on the ward, and potentially with a decline in cognitive function and increased institutionalization at hospital discharge.
PMCID: PMC4017627  PMID: 23757476
16.  Strategies for prevention of postoperative delirium: a systematic review and meta-analysis of randomized trials 
Critical Care  2013;17(2):R47.
The ideal measures to prevent postoperative delirium remain unestablished. We conducted this systematic review and meta-analysis to clarify the significance of potential interventions.
The PRISMA statement guidelines were followed. Two researchers searched MEDLINE, EMBASE, CINAHL and the Cochrane Library for articles published in English before August 2012. Additional sources included reference lists from reviews and related articles from 'Google Scholar'. Randomized clinical trials (RCTs) on interventions seeking to prevent postoperative delirium in adult patients were included. Data extraction and methodological quality assessment were performed using predefined data fields and scoring system. Meta-analysis was accomplished for studies that used similar strategies. The primary outcome measure was the incidence of postoperative delirium. We further tested whether interventions effective in preventing postoperative delirium shortened the length of hospital stay.
We identified 38 RCTs with interventions ranging from perioperative managements to pharmacological, psychological or multicomponent interventions. Meta-analysis showed dexmedetomidine sedation was associated with less delirium compared to sedation produced by other drugs (two RCTs with 415 patients, pooled risk ratio (RR) = 0.39; 95% confidence interval (CI) = 0.16 to 0.95). Both typical (three RCTs with 965 patients, RR = 0.71; 95% CI = 0.54 to 0.93) and atypical antipsychotics (three RCTs with 627 patients, RR = 0.36; 95% CI = 0.26 to 0.50) decreased delirium occurrence when compared to placebos. Multicomponent interventions (two RCTs with 325 patients, RR = 0.71; 95% CI = 0.58 to 0.86) were effective in preventing delirium. No difference in the incidences of delirium was found between: neuraxial and general anesthesia (four RCTs with 511 patients, RR = 0.99; 95% CI = 0.65 to 1.50); epidural and intravenous analgesia (three RCTs with 167 patients, RR = 0.93; 95% CI = 0.61 to 1.43) or acetylcholinesterase inhibitors and placebo (four RCTs with 242 patients, RR = 0.95; 95% CI = 0.63 to 1.44). Effective prevention of postoperative delirium did not shorten the length of hospital stay (10 RCTs with 1,636 patients, pooled SMD (standard mean difference) = -0.06; 95% CI = -0.16 to 0.04).
The included studies showed great inconsistencies in definition, incidence, severity and duration of postoperative delirium. Meta-analysis supported dexmedetomidine sedation, multicomponent interventions and antipsychotics were useful in preventing postoperative delirium.
PMCID: PMC3672487  PMID: 23506796
17.  A pilot study of rivastigmine in the treatment of delirium after stroke: A safe alternative 
BMC Neurology  2008;8:34.
Delirium is a common disorder in the early phase of stroke. Given the presumed cholinergic deficiency in delirium, we tested treatment with the acetylcholinesterase inhibitor rivastigmine.
This pilot study was performed within an epidemiological study. In 527 consecutive stroke patients presence of delirium was assessed during the first week with the confusion assessment method. Severity was scored with the delirium rating scale (DRS). Sixty-two patients developed a delirium in the acute phase of stroke. Only patients with a severe and persistent delirium (defined as a DRS of 12 or more for more than 24 hours) were enrolled in the present study. In total 26 fulfilled these criteria of whom 17 were treated with orally administered rivastigmine with a total dose between 3 and 12 mg a day. Eight patients could not be treated because of dysphagia and one because of early discharge.
No major side effects were recorded. In 16 patients there was a considerable decrease in severity of delirium. The mean DRS declined from 14.8 on day one to 8.5 after therapy and 5.6 after tapering. The mean duration of delirium was 6.7 days (range; 2–17).
Rivastigmine is safe in stroke patients with delirium even after rapid titration. In the majority of patients the delirium improved after treatment. A randomized controlled trial is needed to establish the usefulness of rivastigmine in delirium after stroke.
Trial registration
Nederlands Trial Register NTR1395
PMCID: PMC2556687  PMID: 18803862
18.  Delirium is a strong risk factor for dementia in the oldest-old: a population-based cohort study 
Brain  2012;135(9):2809-2816.
Recent studies suggest that delirium is associated with risk of dementia and also acceleration of decline in existing dementia. However, previous studies may have been confounded by incomplete ascertainment of cognitive status at baseline. Herein, we used a true population sample to determine if delirium is a risk factor for incident dementia and cognitive decline. We also examined the effect of delirium at the pathological level by determining associations between dementia and neuropathological markers of dementia in patients with and without a history of delirium. The Vantaa 85+ study examined 553 individuals (92% of those eligible) aged ≥85 years at baseline, 3, 5, 8 and 10 years. Brain autopsy was performed in 52%. Fixed and random-effects regression models were used to assess associations between (i) delirium and incident dementia and (ii) decline in Mini-Mental State Examination scores in the whole group. The relationship between dementia and common neuropathological markers (Alzheimer-type, infarcts and Lewy-body) was modelled, stratified by history of delirium. Delirium increased the risk of incident dementia (odds ratio 8.7, 95% confidence interval 2.1–35). Delirium was also associated with worsening dementia severity (odds ratio 3.1, 95% confidence interval 1.5–6.3) as well as deterioration in global function score (odds ratio 2.8, 95% confidence interval 1.4–5.5). In the whole study population, delirium was associated with loss of 1.0 more Mini-Mental State Examination points per year (95% confidence interval 0.11–1.89) than those with no history of delirium. In individuals with dementia and no history of delirium (n = 232), all pathologies were significantly associated with dementia. However, in individuals with delirium and dementia (n = 58), no relationship between dementia and these markers was found. For example, higher Braak stage was associated with dementia when no history of delirium (odds ratio 2.0, 95% confidence interval 1.1–3.5, P = 0.02), but in those with a history of delirium, there was no significant relationship (odds ratio 1.2, 95% confidence interval 0.2–6.7, P = 0.85). This trend for odds ratios to be closer to unity in the delirium and dementia group was observed for neuritic amyloid, apolipoprotein ε status, presence of infarcts, α-synucleinopathy and neuronal loss in substantia nigra. These findings are the first to demonstrate in a true population study that delirium is a strong risk factor for incident dementia and cognitive decline in the oldest-old. However, in this study, the relationship did not appear to be mediated by classical neuropathologies associated with dementia.
PMCID: PMC3437024  PMID: 22879644
delirium; dementia; neuropathology; population-based; epidemiology
19.  Cerebral perfusion in sepsis-associated delirium 
Critical Care  2008;12(3):R63.
The pathophysiology of sepsis-associated delirium is not completely understood and the data on cerebral perfusion in sepsis are conflicting. We tested the hypothesis that cerebral perfusion and selected serum markers of inflammation and delirium differ in septic patients with and without sepsis-associated delirium.
We investigated 23 adult patients with sepsis, severe sepsis, or septic shock with an extracranial focus of infection and no history of intracranial pathology. Patients were investigated after stabilisation within 48 hours after admission to the intensive care unit. Sepsis-associated delirium was diagnosed using the confusion assessment method for the intensive care unit. Mean arterial pressure (MAP), blood flow velocity (FV) in the middle cerebral artery using transcranial Doppler, and cerebral tissue oxygenation using near-infrared spectroscopy were monitored for 1 hour. An index of cerebrovascular autoregulation was calculated from MAP and FV data. C-reactive protein (CRP), interleukin-6 (IL-6), S-100β, and cortisol were measured during each data acquisition.
Data from 16 patients, of whom 12 had sepsis-associated delirium, were analysed. There were no significant correlations or associations between MAP, cerebral blood FV, or tissue oxygenation and sepsis-associated delirium. However, we found a significant association between sepsis-associated delirium and disturbed autoregulation (P = 0.015). IL-6 did not differ between patients with and without sepsis-associated delirium, but we found a significant association between elevated CRP (P = 0.008), S-100β (P = 0.029), and cortisol (P = 0.011) and sepsis-associated delirium. Elevated CRP was significantly correlated with disturbed autoregulation (Spearman rho = 0.62, P = 0.010).
In this small group of patients, cerebral perfusion assessed with transcranial Doppler and near-infrared spectroscopy did not differ between patients with and without sepsis-associated delirium. However, the state of autoregulation differed between the two groups. This may be due to inflammation impeding cerebrovascular endothelial function. Further investigations defining the role of S-100β and cortisol in the diagnosis of sepsis-associated delirium are warranted.
Trial registration NCT00410111.
PMCID: PMC2481444  PMID: 18457586
20.  Delirium accelerates cognitive decline in Alzheimer disease 
Neurology  2009;72(18):1570-1575.
To examine the impact of delirium on the trajectory of cognitive function in a cohort of patients with Alzheimer disease (AD).
A secondary analysis of data collected from a large prospective cohort, the Massachusetts Alzheimer’s Disease Research Center’s patient registry, examined cognitive performance over time in patients who developed (n = 72) or did not develop (n = 336) delirium during the course of their illnesses. Cognitive performance was measured by change in score on the Information-Memory-Concentration (IMC) subtest of the Blessed Dementia Rating Scale. Delirium was identified using a previously validated chart review method. Using linear mixed regression models, rates of cognitive change were calculated, controlling for age, sex, education, comorbid medical diagnoses, family history of dementia, dementia severity score, and duration of symptoms before diagnosis.
A significant acceleration in the slope of cognitive decline occurs following an episode of delirium. Among patients who developed delirium, the average decline at baseline for performance on the IMC was 2.5 points per year, but after an episode of delirium there was further decline to an average of 4.9 points per year (p = 0.001). Across groups, the rate of change in IMC score occurred about three times faster in those who had delirium compared to those who did not.
Delirium can accelerate the trajectory of cognitive decline in patients with Alzheimer disease (AD). The information from this study provides the foundation for future randomized intervention studies to determine whether prevention of delirium might ameliorate or delay cognitive decline in patients with AD.
= Alzheimer disease;
= Clinical Dementia Rating;
= Information-Memory-Concentration subtest of the Blessed Dementia Rating Scale;
= Massachusetts Alzheimer’s Disease Research Center;
= Massachusetts General Hospital.
PMCID: PMC2677515  PMID: 19414723
21.  Executive Function and Depression as Independent Risk Factors for Postoperative Delirium 
Anesthesiology  2009;110(4):781-787.
Postoperative delirium has been associated with greater complications, medical cost, and increased mortality during hospitalization. Recent evidence suggests that preoperative executive dysfunction and depression may predict postoperative delirium; however, the combined effect of these risk factors remains unknown. We therefore examined the association between preoperative executive function, depressive symptoms, and established clinical predictors of postoperative delirium among 998 consecutive patients undergoing major non-cardiac surgery.
Nine hundred ninety eight patients were screened for postoperative delirium (n = 998) using the Confusion Assessment Method as well as through retrospective chart review. Patients underwent cognitive, psychosocial, and medical assessments preoperatively. Executive function was assessed using the Concept Shifting Task, Letter-Digit Coding, and a modified Stroop Color Word Interference Test. Depression was assessed by the Beck Depression Inventory.
Preoperative executive dysfunction (P = .007) and greater levels of depressive symptoms (P = .049) were associated with a greater incidence of postoperative delirium, independent of other risk factors. Secondary analyses of cognitive performance demonstrated that the Stroop Color Word Interference Test, the executive task with the greatest complexity in this battery, was more strongly associated with postoperative delirium than simpler tests of executive function. Furthermore, patients exhibiting both executive dysfunction and clinically significant levels of depression were at greatest risk for developing delirium postoperatively.
Preoperative executive dysfunction and depressive symptoms were predictive of postoperative delirium among non-cardiac surgical patients. Executive tasks with greater complexity are more strongly associated with postoperative delirium relative to tests of basic sequencing.
PMCID: PMC2757787  PMID: 19326492
22.  The Association between Brain Volumes, Delirium Duration and Cognitive Outcomes in Intensive Care Unit Survivors: A Prospective Exploratory Cohort Magnetic Resonance Imaging Study 
Critical care medicine  2012;40(7):2022-2032.
Delirium duration is predictive of long-term cognitive impairment (LTCI) in Intensive Care Unit (ICU) survivors. Hypothesizing that a neuroanatomical basis may exist for the relationship between delirium and LTCI, we conducted this exploratory investigation of the associations between delirium duration, brain volumes and LTCI.
Design, Setting, and Patients
A prospective cohort of medical and surgical ICU survivors with respiratory failure or shock.
Quantitative high resolution 3-Tesla brain magnetic resonance imaging was used to calculate brain volumes at discharge and three-month follow-up. Delirium was evaluated using the Confusion Assessment Method for the ICU; cognitive outcomes were tested at three- and twelve-month follow-up. Linear regression was used to examine associations between delirium duration and brain volumes, and between brain volumes and cognitive outcomes.
A total of 47 patients completed the MRI protocol. Patients with longer duration of delirium displayed greater brain atrophy as measured by a larger ventricle-to-brain ratio (VBR) at hospital discharge [0.76, 95% confidence intervals (CI) (0.10, 1.41); p=0.03] and at 3-month follow-up [0.62 (0.02, 1.21), p=0.05]. Longer duration of delirium was associated with smaller superior frontal lobe [−2.11 cm3 (−3.89, −0.32); p=0.03] and hippocampal volumes at discharge [−0.58 cm3 (−0.85, −0.31), p<0.001] – regions responsible for executive functioning and memory, respectively. Greater brain atrophy (higher VBR) at three months was associated with worse cognitive performances at twelve months [lower RBANS battery score −11.17 (−21.12, −1.22), p=0.04]. Smaller superior frontal lobes, thalamus, and cerebellar volumes at three months were associated with worse executive functioning and visual attention at twelve months.
These preliminary data show that longer duration of delirium is associated with smaller brain volumes up to three months after discharge, and that smaller brain volumes are associated with LTCI up to 12 months. We cannot, however, rule out that smaller preexisting brain volumes explain these findings.
PMCID: PMC3697780  PMID: 22710202
MRI; delirium; cognitive impairment; ICU; sepsis; neuroimaging; brain; frontal lobe; critical care; intensive care; mechanical ventilation; aging; geriatrics; encephalopathy
23.  Haloperidol prophylaxis in critically ill patients with a high risk for delirium 
Critical Care  2013;17(1):R9.
Delirium is associated with increased morbidity and mortality. We implemented a delirium prevention policy in intensive care unit (ICU) patients with a high risk of developing delirium, and evaluated if our policy resulted in quality improvement of relevant delirium outcome measures.
This study was a before/after evaluation of a delirium prevention project using prophylactic treatment with haloperidol. Patients with a predicted risk for delirium of ≥ 50%, or with a history of alcohol abuse or dementia, were identified. According to the prevention protocol these patients received haloperidol 1 mg/8 h. Evaluation was primarily focused on delirium incidence, delirium free days without coma and 28-day mortality. Results of prophylactic treatment were compared with a historical control group and a contemporary group that did not receive haloperidol prophylaxis mainly due to non-compliance to the protocol mostly during the implementation phase.
In 12 months, 177 patients received haloperidol prophylaxis. Except for sepsis, patient characteristics were comparable between the prevention and the historical (n = 299) groups. Predicted chance to develop delirium was 75 ± 19% and 73 ± 22%, respectively. Haloperidol prophylaxis resulted in a lower delirium incidence (65% vs. 75%, P = 0.01), and more delirium-free-days (median 20 days (IQR 8 to 27) vs. median 13 days (3 to 27), P = 0.003) in the intervention group compared to the control group. Cox-regression analysis adjusted for sepsis showed a hazard rate of 0.80 (95% confidence interval 0.66 to 0.98) for 28-day mortality. Beneficial effects of haloperidol appeared most pronounced in the patients with the highest risk for delirium. Furthermore, haloperidol prophylaxis resulted in less ICU re-admissions (11% vs. 18%, P = 0.03) and unplanned removal of tubes/lines (12% vs. 19%, P = 0.02). Haloperidol was stopped in 12 patients because of QTc-time prolongation (n = 9), renal failure (n = 1) or suspected neurological side-effects (n = 2). No other side-effects were reported. Patients who were not treated during the intervention period (n = 59) showed similar results compared to the untreated historical control group.
Our evaluation study suggests that prophylactic treatment with low dose haloperidol in critically ill patients with a high risk for delirium probably has beneficial effects. These results warrant confirmation in a randomized controlled trial.
Trial registration Identifier: NCT01187667.
PMCID: PMC4056261  PMID: 23327295
24.  The Long-Term Effect of Delirium on the Cognitive Trajectory of Persons with Dementia 
Archives of internal medicine  2012;172(17):1324-1331.
Delirium is characterized by acute cognitive impairment. We examined the effect of delirium on long-term cognitive trajectory in older adults with Alzheimer's disease (AD).
Prospectively collected longitudinal data from a nested cohort of hospitalized patients with AD (n=263) in the Massachusetts Alzheimer's Disease Research Center Patient Registry during 1991–2006 (median follow-up: 3.2 years). Cognitive function was measured using the Information-Memory-Concentration (IMC) section of the Blessed Dementia Rating Scale. Delirium was identified using a validated chart review method. The pace of cognitive deterioration was contrasted using random effect regression models.
Over half of the sample of patients with AD developed delirium during hospitalization (56%). The pace of cognitive deterioration prior to hospitalization did not differ between patients who developed delirium (1.4 IMC points/year, 95% confidence interval, CI,0.7,2.1) and those who did not (0.8 IMC points/year, 95% CI: 0.3,1.3) (P=0.24). In the year following hospitalization, patients who had developed delirium experienced greater cognitive deterioration (3.1 IMC points/year, 95% CI: 2.1,4.1) relative to patients who did not develop delirium (1.4 IMC points/year, 95% CI: 0.2,2.6) after adjusting for confounders. The ratio of these changes suggests that following delirium, cognitive deterioration proceeds at 2.2 times the rate in patients without delirium in the year after hospitalization. The delirium group maintained a more rapid pace of cognitive deterioration throughout the 5-year period following hospitalization. Sensitivity analyses excluding rehospitalized patients and matching on baseline cognitive function and baseline pace of cognitive deterioration produced essentially identical results. The acceleration due to delirium was independent of dementia severity, comorbidity, and demographic characteristics.
Delirium is highly prevalent among persons with AD who are hospitalized and associated with an increased pace of cognitive deterioration which is maintained for up to 5 years. Strategies to prevent delirium may offer a promising avenue to explore for ameliorating cognitive deterioration in AD.
PMCID: PMC3740440  PMID: 23403619
25.  Measures of Executive Function and Depression Identify Patients at Risk for Postoperative Delirium 
Anesthesiology  2009;110(4):788-795.
Postoperative delirium is associated with increased morbidity and mortality. Pre-existing cognitive impairment and depression have been frequently cited as important risk factors for this complication. This prospective cohort study was designed to determine if individuals who perform poorly on preoperative cognitive tests and/or exhibited depressive symptoms would be at high risk for the development of postoperative delirium.
One hundred nondemented patients, 50 years and older, scheduled for major, elective noncardiac surgery completed a preoperative test battery that included measures of global cognition, executive function and symptoms of depression. Known preoperative risk factors for delirium were collected and examined with the results of the preoperative test battery to determine the independent predictors of delirium.
The overall incidence of delirium was 16% and was associated with increased hospital length of stay (p<0.05) and an increased incidence of postoperative complications (p<0.01). Delirious subjects did not differ from their non-delirious cohorts with regard to their preoperative global cognitive function, preexisting medical comorbidities, age, anesthetic management or history of alcohol use. Preoperative executive scores (p<0.001) and depression (p<0.001), as measured by the Trail Making B test and Geriatric Depression Scale Short Form, respectively, were found to be independent predictors of postoperative delirium.
Low preoperative executive scores and depressive symptoms independently predict postoperative delirium in older individuals. A rapid, simple test combination including tests of executive function and depression could improve physicians’ ability to recognize patients who might benefit from a perioperative intervention strategy to prevent postoperative delirium.
PMCID: PMC2953946  PMID: 19326494

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