Publications

The American Geriatrics Society, with support from the National Institute on Aging and the John A. Hartford Foundation, held its seventh Bedside-to-Bench research conference, entitled “Delirium in Older Adults: Finding Order in the Disorder” on February 9–11, 2014, to provide participants with opportunities to learn about cutting-edge research developments, draft recommendations for future research involving translational efforts, and opportunities to network with colleagues and leaders in the field. This meeting was the first of three conferences that will address delirium, sleep disorders, and voiding difficulties and urinary incontinence, emphasizing, whenever possible, the relationships and potentially shared clinical and pathophysiological features between these common geriatric syndromes.

OBJECTIVES: To determine the stability of psychomotor subtypes of delirium over time and identify characteristics associated with delirium psychomotor subtypes in individuals undergoing surgical repair of hip fracture.

DESIGN: Prospective cohort study.

SETTING: The Transfusion Trigger Trial for Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair Cognitive Ancillary Study was conducted at 13 participating sites from 2008 to 2009.

PARTICIPANTS: Individuals who had undergone surgical repair of hip fracture (N=139).

MEASUREMENTS: Delirium was assessed up to four times postoperatively using the Confusion Assessment Method (CAM) and the Memorial Delirium Assessment Scale. Psychomotor subtypes of delirium were categorized as hypoactive, hyperactive, mixed, and normal psychomotor activity.

RESULTS: Incidence of postoperative delirium was 41% (n=57). Of 90 CAM-positive (CAM+) observations, 56% were hypoactive, 10% were hyperactive, 21% were mixed, and 14% had normal psychomotor symptoms. Of 26 participants with more than one CAM+ assessment, 50% maintained subtype stability over time. Participants with hypoactive or normal psychomotor symptoms (n=31) were less likely to have chart documentation of delirium than participants with any hyperactive symptoms (n=19) (22% vs 58%, P=.009).

CONCLUSION: Psychomotor subtypes of delirium often fluctuate from assessment to assessment, rather than representing fixed categories of delirium. Hypoactive delirium is the most common presentation of delirium but is the least likely to be documented by healthcare providers.

OBJECTIVES: To examine baseline (preoperative) neuropsychological test performance in a cohort of elderly individuals undergoing elective surgery and the association between specific neuropsychological domains and postoperative delirium.

DESIGN: Ongoing prospective cohort study.

SETTING: Successful Aging after Elective Surgery Study.

PARTICIPANTS: Elderly adults (N=300) scheduled for elective (noncardiac) surgery.

MEASUREMENTS: Neuropsychological testing, including standardized assessments of memory, divided and sustained attention, speed of mental processing, verbal fluency, working memory, language, and an overall measure of premorbid cognitive functioning, was performed 2 to 4 weeks before surgery. The relationship between the individual neuropsychological tests and delirium status was examined using linear regression, adjusting for age, sex, and education.

RESULTS: Study participants were generally highly educated (mean years of education 15.0±2.9), with minimal or no cognitive impairment (mean Modified Mini-Mental State Examination score 93.2 out of 100). After adjustment, participants who developed postoperative delirium had performed significantly lower preoperatively on measures of speed of mental processing and divided attention (Trail-Making Test Part B, mean difference 17.55, P=.02), category fluency (animal naming, mean difference -1.94, P=.01), sustained visual attention (Visual Search and Attention, mean difference -3.19, P<.001), and working memory with new learning and recall (Hopkins Verbal Learning Test-Revised Total mean difference -0.53 to -0.79, P<.01).

CONCLUSION: Individuals who later develop delirium have lower scores on tests evaluating the areas of complex attention, executive functioning, and rapid access to verbal knowledge or semantic networks at baseline. Future studies to better understand how the cognitive profiles identified may predispose individuals to developing delirium may help pave the way to greater understanding of the mechanisms of delirium.

BACKGROUND: Early and late readmissions may have different causal factors, requiring different prevention strategies.

OBJECTIVE: To determine whether predictors of readmission change within 30 days after discharge.

DESIGN: Retrospective cohort study.

SETTING: Academic medical center.

PARTICIPANTS: Patients admitted between 1 January 2009 and 31 December 2010.

MEASUREMENTS: Factors related to the index hospitalization (acute illness burden, inpatient care process factors, and clinical indicators of instability at discharge) and unrelated factors (chronic illness burden and social determinants of health) and how they affect early readmissions (0 to 7 days after discharge) and late readmissions (8 to 30 days after discharge).

RESULTS: 13 334 admissions, representing 8078 patients, were included in the analysis. Early readmissions were associated with markers of acute illness burden, including length of hospital stay (odds ratio [OR], 1.02 [95% CI, 1.00 to 1.03]) and whether a rapid response team was called for assessment (OR, 1.48 [CI, 1.15 to 1.89]); markers of chronic illness burden, including receiving a medication indicating organ failure (OR, 1.19 [CI, 1.02 to 1.40]); and social determinants of health, including barriers to learning (OR, 1.18 [CI, 1.01 to 1.38]). Early readmissions were less likely if a patient was discharged between 8:00 a.m. and 12:59 p.m. (OR, 0.76 [CI, 0.58 to 0.99]). Late readmissions were associated with markers of chronic illness burden, including receiving a medication indicating organ failure (OR, 1.24 [CI, 1.08 to 1.41]) or hemodialysis (OR, 1.61 [CI, 1.12 to 2.17]), and social determinants of health, including barriers to learning (OR, 1.24 [CI, 1.09 to 1.42]) and having unsupplemented Medicare or Medicaid (OR, 1.16 [CI, 1.01 to 1.33]).

LIMITATION: Readmissions were ascertained at 1 institution.

CONCLUSION: The time frame of 30 days after hospital discharge may not be homogeneous. Causal factors and readmission prevention strategies may differ for the early versus late periods.

PRIMARY FUNDING SOURCE: Health Resources and Services Administration, National Institute on Aging, National Institutes of Health, Harvard Catalyst, and Harvard University.

OBJECTIVE: To determine whether apolipoprotein E (ApoE) is associated with postoperative delirium incidence, severity, and duration in older patients free of dementia at baseline.

METHODS: The authors examined 557 nondemented patients aged 70 years or older undergoing major noncardiac surgery enrolled in the Successful Aging after Elective Surgery Study. Three ApoE measures were considered: ε2, ε4 carriers versus noncarriers, and a three-category ApoE measure. Delirium was determined using the Confusion Assessment Method (CAM) and chart review. We used generalized linear models to estimate the association between ApoE and delirium incidence, severity (peak CAM Severity [CAM-S] score), and days.

RESULTS: ApoE ε2 and ε4 was present in 15% and 19%, respectively, and postoperative delirium occurred in 24%. Among patients with delirium, the mean peak CAM-S score was 8.0 (standard deviation: 4), with most patients experiencing 1 or 2 delirium days (51% or 28%, respectively). After adjusting for age, sex, surgical procedure, and preoperative cognitive function, ApoE ε4 and ε2 carrier status were not associated with postoperative delirium: RR for ε4=1.0, 95% CI: 0.7-1.5 and RR for ε2=0.9, 95% CI: 0.6-1.4. No association between ApoE and delirium severity or number of delirium days was observed.

CONCLUSION: In older surgery patients free of dementia, our findings do not support the hypothesis that the ApoE genotype does not confer either risk or protection in postoperative delirium incidence, severity, or duration. Thus, an important genetic risk factor for Alzheimer disease does not affect risk of delirium.

BACKGROUND: A proinflammatory state has been associated with several age-associated conditions; however, the inflammatory mechanisms of delirium remain poorly characterized.

METHODS: Using the Successful Aging after Elective Surgery Study of adults age ≥70 undergoing major noncardiac surgery, 12 cytokines were measured at four timepoints: preoperative, postanesthesia care unit, postoperative day 2 (POD2) and 30 days later (POD1M). We conducted a nested, longitudinal matched (on age, sex, surgery type, baseline cognition, vascular comorbidity, and Apolipoprotein E genotype) case-control study: delirium cases and no-delirium controls were selected from the overall cohort (N = 566; 24% delirium). Analyses were independently conducted in discovery, replication, and pooled cohorts (39, 36, 75 matched pairs, respectively). Nonparametric signed-rank tests evaluating differences in cytokine levels between matched pairs were used to identify delirium-associated cytokines.

RESULTS: In the discovery and replication cohorts, matching variables were similar in cases and controls. Compared to controls, cases had (*p < .05, **p < .01) significantly higher interleukin-6 on POD2 in the discovery, replication, and pooled cohorts (median difference [pg/mL] 50.44**, 20.17*, 39.35**, respectively). In the pooled cohort, cases were higher than controls for interleukin-2 (0.99*, 0.77*, 1.07**, 0.73* at preoperative, postanesthesia care unit, POD2, POD1M, respectively), vascular endothelial growth factor (4.10* at POD2), and tumor necrosis factor-alpha (3.10* at POD1M), while cases had lower interleukin-12 at POD1M (-4.24*).

CONCLUSIONS: In this large, well-characterized cohort assessed at multiple timepoints, we observed an inflammatory signature of delirium involving elevated interleukin-6 at POD2, which may be an important disease marker for delirium. We also observed preliminary evidence for involvement of other cytokines.

Electronic medical records (EMRs) offer the opportunity to streamline the search for patients with possible delirium. The purpose of the current study was to identify words and phrases commonly noted in charts of patients with delirium. The current study included 67 patients (nested within a cohort study of 300 patients) ages 70 and older undergoing major elective surgery with evidence of confusion in their medical charts. Eight keywords or phrases had positive predictive values of 60% to 100% for delirium. Keywords were charted more often in nursing notes than physician notes. A brief list of keywords may serve as a building block for a methodology to screen for possible delirium from charts, with particular attention to nursing notes, for research and real-time clinical decision making.

IMPORTANCE: Major postoperative complications and delirium contribute independently to adverse outcomes and high resource use in patients who undergo major surgery; however, their interrelationship is not well examined.

OBJECTIVE: To evaluate the association of major postoperative complications and delirium, alone and combined, with adverse outcomes after surgery.

DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study in 2 large academic medical centers of 566 patients who were 70 years or older without recognized dementia or a history of delirium and underwent elective major orthopedic, vascular, or abdominal surgical procedures with a minimum 3-day hospitalization between June 18, 2010, and August 8, 2013. Data analysis took place from December 13, 2013, through May 1, 2015.

MAIN OUTCOMES AND MEASURES: Major postoperative complications, defined as life-altering or life-threatening events (Accordion Severity grade 2 or higher), were identified by expert-panel adjudication. Delirium was measured daily with the Confusion Assessment Method and a validated medical record review method. The following 4 subgroups were analyzed: (1) no complications or delirium; (2) complications only; (3) delirium only; and (4) complications and delirium. Adverse outcomes included a length of stay (LOS) of more than 5 days, institutional discharge, and rehospitalization within 30 days of discharge.

RESULTS: In the 566 participants, the mean (SD) age was 76.7 (5.2) years, 236 (41.7%) were male, and 523 (92.4%) were white. Forty-seven patients (8.3%) developed major complications and 135 (23.9%) developed delirium. Compared with no complications or delirium as the reference group, major complications only contributed to prolonged LOS only (relative risk [RR], 2.8; 95% CI, 1.9-4.0); by contrast, delirium only significantly increased all adverse outcomes, including prolonged LOS (RR, 1.9; 95% CI, 1.4-2.7), institutional discharge (RR, 1.5; 95% CI, 1.3-1.7), and 30-day readmission (RR, 2.3; 95% CI, 1.4-3.7). The subgroup with complications and delirium had the highest rates of all adverse outcomes, including prolonged LOS (RR, 3.4; 95% CI, 2.3-4.8), institutional discharge (RR, 1.8; 95% CI, 1.4-2.5), and 30-day readmission (RR, 3.0; 95% CI, 1.3-6.8). Delirium exerted the highest attributable risk at the population level (5.8%; 95% CI, 4.7-6.8) compared with all other adverse events (prolonged LOS, institutional discharge, or readmission).

CONCLUSIONS AND RELEVANCE: Major postoperative complications and delirium are separately associated with adverse events and demonstrate a combined effect. Delirium occurs more frequently and has a greater effect at the population level than other major complications.

There is a need to develop animal models to study postoperative delirium. Inattention is one of the symptoms of delirium. Increases in the levels of α-synuclein and S100β have been reported to be associated with delirium. Therefore, we set out to determine the effects of surgery plus general anesthesia on the behavioral changes (including loss of attention) in mice and on the levels of α-synuclein and S100β in the brain tissues of these mice. C57BL/6J mice (2- to 8-months-old) had a simple laparotomy plus isoflurane anesthesia. The behavioral changes, including attention level and the speed of movements, were determined 12, 24, and 48 h after the surgery plus anesthesia in the mice. The levels of α-synuclein and S100β in the cortex of these mice following the surgery plus anesthesia were determined by Western blot analysis. We found that there was a loss of attention at 24, but not 12 or 48 h following the surgery plus anesthesia (49% ± 5 vs. 33% ± 2.9, P = 0.011, N = 12) in the mice without significantly affecting the speed of their movements. There were increases in the levels of total α-synuclein (139% ± 33.5 vs. 100% ± 13.7, P = 0.037, N = 6) and S100β (142% ± 7.7 vs. 100% ± 6, P = 0.002, N = 6) in the cortex of the mice 12 h following the surgery plus anesthesia. These findings suggested that the surgery plus isoflurane anesthesia might induce behavioral and biochemical/cellular changes associated with delirium. We could use the surgery plus anesthesia in mice to develop an animal model to study postoperative delirium.