Abstract
Objectives
To test the hypothesis that pre-sepsis depressive symptoms are associated with an increased risk of new cognitive impairment in severe sepsis survivors.
Design
Prospective longitudinal cohort study.
Setting
Population-based cohort of older U.S. adults interviewed as part of the Health and Retirement Study (1998–2006).
Participants
447 patients with normal pre-sepsis cognition who survived 540 hospitalizations for severe sepsis and completed at least one follow-up interview.
Measurements
Severe sepsis was identified using a validated algorithm in Medicare claims. Depressive symptoms were assessed prospectively with a modified version of the Center for Epidemiologic Studies Depression Scale. Cognitive function was assessed using versions of the Telephone Interview for Cognitive Status (TICS). We used logistic regression with robust standard errors to examine associations between substantial depressive symptoms at any interview before sepsis and incident cognitive impairment (either mild or moderate-to-severe cognitive impairment) at any interview after sepsis.
Results
The prevalence of substantial depressive symptoms in those with normal cognition before sepsis was 38% (95%Confidence Interval [CI]: 34%, 42%). After severe sepsis, 18% (95%CI: 15%, 20%) of survivors had incident cognitive impairment. In unadjusted analyses, pre-sepsis substantial depressive symptoms were associated with post-sepsis incident cognitive impairment (Odds Ratio [OR] 2.56, 95%CI: 1.53, 4.27). After adjustment for demographics, health-risk behaviors, clinical characteristics of the sepsis episode, and pre-sepsis TICS scores, pre-sepsis substantial depressive symptoms remained the strongest factor associated with post-sepsis incident cognitive impairment (OR 2.58, 95%CI: 1.45, 4.59).
Conclusion
Pre-sepsis substantial depressive symptoms are independently associated with incident post-sepsis cognitive impairment. Depressed older adults may be particularly at risk for developing cognitive impairment after a serious medical illness.
Keywords: depression, sepsis, cognition, outcome assessment (health care)
INTRODUCTION
Cognitive impairment is a serious public health problem in light of the aging of the population. Cognitively impaired older adults are at increased risk of mortality.1 Furthermore, cognitive impairment is associated with increased healthcare costs with disproportionate burdens on Medicare and Medicaid, 2,3 and greater burdens on families and informal caregivers.4
Millions of Americans survive critical illnesses annually,5 and over half are 65 or older.6 Emerging evidence suggests that older patients are at greater risk of developing cognitive impairment following critical illnesses.3,6 In particular, severe sepsis, which has been called the “quintessential disease of the aged,” 7 is the most common non-cardiac cause of critical illness,8 and has been shown to be independently associated with substantial, persistent cognitive impairment in survivors.3,9 Yet, it is unknown which patients with severe sepsis are at greatest risk of developing cognitive impairment.
A growing body of research has identified that late-life depression is associated with increased risk of dementia.10–12 Studies have found an association between depression and cognitive decline in carriers of the APOE-ε4 allele, a genetic marker for Alzheimer’s disease.13,14 Depression may also increase the risk of cognitive impairment due to behavioral factors such as smoking, sedentary lifestyle, and poor adherence with treatment of chronic medical conditions.12 Importantly, depression, cognitive impairment, and sepsis are all associated with increased pro-inflammatory markers,11,12,15 suggesting plausible physiologic and behavioral links between depression and cognitive impairment in the aftermath of severe sepsis.
The present study utilizes an ongoing longitudinal cohort of older Americans to test the hypothesis that pre-sepsis depressive symptoms are associated with an increased risk of incident cognitive impairment in severe sepsis survivors.
METHODS
Study Population
Our study cohort is from the Health and Retirement Study (HRS), a longitudinal investigation of community-dwelling U.S. adults over age 50. Details of the HRS have been described previously.3 The HRS protocol was approved by the University of Michigan Institutional Review Board.
We studied all HRS respondents with at least 1 interview from 1998–2004 who were not cognitively impaired, who had Medicare claims-based data for a subsequent hospitalization for severe sepsis from 1998–2005, and who had at least one depression assessment before sepsis. All patients were followed up through death or the 2006 interview. Our analyses focus on severe sepsis hospitalizations that patients survived long enough to complete at least 1 interview.
Demographic and Clinical Characteristics
We obtained data on demographics (i.e., age, race and ethnicity, sex, education, and marital/partnered status) and health-risk behaviors (i.e., alcohol use and smoking) from the HRS interviews.
Baseline comorbidity (Charlson Comorbidity score)16 and severe sepsis-related clinical characteristics were abstracted from the Medicare claims, including an organ dysfunction score (the sum of the number of organ failures of cardiovascular, neurologic, hematologic, hepatic, renal, or respiratory origin),3,8 hospital length of stay (LOS), intensive care unit (ICU) admission, as well as requirements for mechanical ventilation (MV), major surgery, and dialysis.
Definition of Severe Sepsis
We used a validated and widely-used claims-based definition of severe sepsis.7,17,18 The definition requires evidence of a concomitant infection and new-onset organ dysfunction during the same hospitalization, consistent with the international consensus conference definitions of severe sepsis.17
Exposure of Interest
The exposure of interest was the presence of pre-sepsis substantial depressive symptoms. The HRS assessed depression at each wave with an 8-item version of the Center for Epidemiologic Studies Depression Scale (CES-D).19 Prior studies have reported that this modified version loses little of the structure and precision of the original scale.20,21 We used a cutoff score of 4 or higher on the 8-item CES-D to define substantial depressive symptoms at any interview before severe sepsis because this threshold was estimated to be comparable to the cutoff score of 16 or higher on the full CES-D by HRS investigators.22
Outcomes of Interest
Our primary outcome was incident cognitive impairment (either mild or moderate-to-severe) found at any HRS interview following severe sepsis. The HRS assessed cognitive impairment among self-respondents using two modified versions of the Telephone Interview for Cognitive Status (TICS) during biennial interviews.3 Respondents ages 65 or older were administered a 35-point scale that included tests of memory, serial 7 subtractions, naming, and orientation. Self-respondents younger than 65 were administered a more limited 27-point scale that excluded the orientation items. We defined thresholds on the cognitive assessments for “normal” cognitive functioning, mild and moderate-to-severe cognitive impairment based on prior HRS studies.3,23
To identify incident cognitive impairment following a hospitalization for severe sepsis, we excluded all patients that were found to have mild or moderate-to-severe cognitive impairment at any HRS interview before sepsis. Previous examination has identified that those in the mild and moderate-to-severe cognitive impairment categories had a level of cognitive dysfunction consistent with a diagnosis of dementia, and an average of 1.1 and 2.5 limitations in Instrumental Activities of Daily Living respectively.23
In addition to our primary analysis of interest, we also separately examined whether the association differed between pre-sepsis substantial depressive symptoms and either new post-sepsis mild cognitive impairment or new post-sepsis moderate-to-severe cognitive impairment.
Statistical Analysis
Our unit of analysis for all analyses was the hospitalization. We present all descriptive statistics as means and standard deviations (SDs) and/or medians and interquartile ranges (IQR) for continuous variables and as percentages for proportions. We conducted univariate analyses examining the association between patient baseline and severe sepsis episode-related characteristics and pre-sepsis substantial depressive symptom status using one-way analysis of variance for continuous variables and chi-squared or Fisher’s exact tests for categorical variables.
To examine if pre-sepsis substantial depressive symptoms were associated with incident cognitive impairment (either mild or moderate-to-severe) post-sepsis, we used logistic regression models with robust error variances to account for patients who had more than 1 distinct hospitalization for severe sepsis.24 After an initial unadjusted regression, we then added three groups of potential confounding variables chosen a priori that have been found to be important in cognitive impairment and general medical/critical illness-related research:3,7,12 1) demographics (age, sex, race, education, marital status); 2) health risk behaviors (alcohol use and smoking) and chronic medical comorbidity (Charlson score); and 3) severe sepsis episode characteristics (organ dysfunction score, LOS, ICU admission, MV, major surgery, and dialysis). In a fourth logistic regression model, we adjusted for TICS 27-point scores at the last HRS wave before sepsis in order to weigh the respective associations of pre-sepsis cognitive function and depressive symptoms with odds of incident cognitive impairment post-sepsis. As sensitivity analyses, we fitted models adjusting for TICS 35-point scores at the last HRS wave pre-sepsis and the change in TICS 27-point scores from 2 HRS waves to 1 HRS wave pre-sepsis, respectively.
To test if our results were biased by follow-up timing, we conducted two sets of sensitivity analyses. First, we tested the association of pre-sepsis substantial depressive symptoms with incident cognitive impairment at the first HRS interview after sepsis. Second, we tested whether the association between pre-sepsis substantial depressive symptoms with post-sepsis incident cognitive impairment was present even when considering patients who died during the follow-up period as cognitively impaired. We also examined whether our results were affected by using different cutoff scores to define substantial depressive symptoms on the 8-item CES-D.
We used similar models to test if pre-sepsis substantial depressive symptoms were differently associated with incident mild versus moderate-to-severe cognitive impairment separately.
We used two-sided significance tests for all analyses with statistical significance set at a P value of 0.05. Analyses were performed with the IBM SPSS Statistics 18 (SPSS Inc., Chicago, IL) and STATA 11 (Stata Corporation, College Station, TX) statistical software programs.
RESULTS
From 1998–2005, 447 HRS respondents with normal cognitive functioning survived 540 hospitalizations for severe sepsis. Patients were followed up for up to 4 surveys before severe sepsis (mean: 6.9 years) and up to 4 surveys (mean: 7.0 years) afterward. Table 1 describes the 517 hospitalizations for severe sepsis (96%) that completed at least one depression assessment before their severe sepsis hospitalization.
Table 1.
Patient and clinical characteristics of severe sepsis hospitalizations by pre-sepsis depression status
| Variables | Total (n = 517)a | Substantial Depressive Symptoms at Any Interview Pre-sepsis (n = 195) | Without Substantial Depressive Symptoms (n = 322) | Test Statistics Comparing Patients With and Without Substantial Depressive Symptomsb |
|---|---|---|---|---|
| Panel A: Baseline Characteristics (at last HRS interview before sepsis) | ||||
|
| ||||
| Age (years) | 76.1 (8.5) | 75.1 (8.5) | 76.8 (8.4) | F = 4.63* |
| Female | 282 (54.5%) | 121 (62.1%) | 161 (50.0%) | χ2 = 7.11† |
| Race | ||||
| White | 416 (80.5%) | 148 (75.9%) | 268 (83.2%) | χ2 = 4.63 |
| Black | 95 (18.4%) | 45 (23.1%) | 50 (15.5%) | |
| Other | 6 (1.2%) | 2 (1.0%) | 4 (1.2%) | |
| Education | ||||
| High school or less | 199 (38.5%) | 94 (48.2%) | 105 (32.6%) | χ2 = 27.92‡ |
| Some college | 180 (34.8%) | 74 (37.9%) | 106 (32.9%) | |
| College graduate | 138 (26.7%) | 27 (13.8%) | 111 (34.5%) | |
| Living Arrangement | ||||
| Married/partnered | 281 (54.5%) | 97 (50.0%) | 184 (57.1%) | χ2 = 5.24 |
| Unmarried but living with others | 85 (16.5%) | 41 (21.1%) | 44(13.7%) | |
| Unmarried and living alone | 150 (29.1%) | 56 (28.9%) | 94 (29.2%) | |
| Alcohol use (days/week) | 1.6 (1.1) | 1.3 (0.8) | 1.7 (1.2) | F = 18.70‡ |
| Smoking Status | ||||
| Never smoked | 170 (32.9%) | 63 (32.3%) | 107 (33.2%) | χ2 = 0.07 |
| Former smoker | 277 (53.6%) | 106 (54.4%) | 171 (53.1%) | |
| Current smoker | 70 (13.5%) | 26 (13.3%) | 44 (13.7%) | |
| Charlson Comorbidity Score | 1.9 (1.5) | 2.1 (1.6) | 1.7 (1.4) | F = 9.15† |
|
| ||||
| Panel B: Characteristics of the Severe Sepsis Hospitalization | ||||
|
| ||||
| Organ Dysfunction Score | 1.2 (0.4) | 1.2 (0.4) | 1.2 (0.4) | F = 0.05 |
| Acute organ dysfunction | ||||
| Cardiovascular | 140 (27.1%) | 51 (26.2%) | 89 (27.6%) | χ2 = 0.14 |
| Neurologic | 41 (7.9%) | 16 (8.2%) | 25 (7.8%) | χ2 = 0.03 |
| Hematologic | 102 (19.7%) | 39 (20.0%) | 63 (19.6%) | χ2 = 0.01 |
| Hepatic | 3 (0.6%) | 1 (0.5%) | 2 (0.6%) | p = 1.0 |
| Renal | 203 (39.3%) | 79 (40.5%) | 124 (38.5%) | χ2 = 0.20 |
| Respiratory | 105 (20.3%) | 39 (20.0%) | 66 (20.5%) | χ2 = 0.02 |
| Admitted to an intensive care unit | 226 (43.7%) | 76 (39.0%) | 150 (46.6%) | χ2 = 2.86 |
| Required mechanical ventilation | 105 (20.3%) | 39 (20.0%) | 66 (20.5%) | χ2 = 0.02 |
| Required major surgery | 113 (21.9%) | 35 (17.9%) | 78 (24.2%) | χ2 = 2.80 |
| Required dialysis | 21 (4.1%) | 11 (5.6%) | 10 (3.1%) | χ2 = 2.00 |
| Hospital length of stay (days) | 10.9 (10.3) | 10.5 (7.9) | 11.2 (11.6) | F = 0.61 |
All values are mean (± SD) or n (%) unless otherwise indicated.
24 hospitalizations (4%) were missing pre-sepsis depressive symptom data.
F-statistic with 516 degrees of freedom, Pearson χ2 with 2 degrees of freedom, or Fisher’s Exact p-value.
P < 0.05
P < 0.01
P < 0.001
Prevalence of Pre-Sepsis Depressive Symptoms and Post-Sepsis Cognitive Impairment
The prevalence of substantial depressive symptoms in patients with normal cognitive function at any HRS interview pre-sepsis was 38% (95%Confidence Interval [CI]: 34%, 42%). At the most recent interview before sepsis (a median of 1.2 years pre-sepsis), the prevalence of substantial depressive symptoms in HRS respondents with normal cognition was 32% (95%CI: 23%, 41%).
Figure 1 presents the incidence of cognitive impairment after severe sepsis among survivors who were previously cognitively intact. Among patients with normal cognitive function pre-sepsis, 17% (95%CI: 14%, 20%) were cognitively impaired at a median of 0.9 years after severe sepsis, of which 40% (95%CI: 30%, 50%) had mild cognitive impairment and 60% (95%CI: 50%, 70%) had moderate-to-severe cognitive impairment.
Figure 1. Point prevalence of cognitive impairment among severe sepsis survivors with normal cognition before sepsis.
(Grouped by timing of HRS Interview Wave)
Abbreviations (in alphabetical order): CI = confidence interval; IQR = interquartile range.
Interpretive Example: The point prevalence of cognitive impairment was 17% (95%CI: 14%, 20%) at the first HRS interview after severe sepsis.
Factors Associated with Post-Sepsis Incident Cognitive Impairment
In unadjusted analyses, pre-sepsis substantial depressive symptoms were associated with 2.56-times the odds (95%CI: 1.53, 4.27) of post-sepsis incident cognitive impairment. This association remained significant after sequentially adjusting for baseline characteristics, severe sepsis-related clinical characteristics, and TICS 27-point scores at the last HRS wave before sepsis (Odds Ratio [OR] 2.58, 95%CI: 1.45–4.59) (Table 2). The association between pre-sepsis substantial depressive symptoms and incident cognitive impairment post-sepsis remained significant in all of our sensitivity analyses, including models that adjusted for the TICS 35-point scores at the last HRS wave pre-sepsis (OR 2.48, 95%CI: 1.38, 4.45) as well as the change in TICS 27-point scores from 2 HRS waves to 1 HRS wave pre-sepsis (OR 3.49, 95%CI: 1.86, 6.54) (additional data available from authors upon request).
Table 2.
Associations of pre-sepsis substantial depressive symptoms with incident cognitive impairment in survivors of severe sepsis
| Unadjusted (n = 513) | Adjusted for demographics (n = 512) | Adjusted for health-risk behaviors and comorbidity (n = 512) | Adjusted for sepsis episode clinical characteristics (n = 512) | Adjusted for final pre-sepsis TICS score (n = 480) | |
|---|---|---|---|---|---|
|
| |||||
| Odds Ratio (95% Confidence Interval) | |||||
| Pre-sepsis patient characteristics | |||||
| Substantial symptoms of depression at any HRS interview pre-sepsis | 2.56 (1.53–4.27)‡ | 2.86 (1.68–4.88)‡ | 2.81 (1.64–4.79)‡ | 2.86 (1.66–4.95)‡ | 2.58 (1.45–4.59)† |
| Age | 1.09 (1.05–1.13)‡ | 1.09 (1.05–1.13)‡ | 1.08 (1.04–1.12)‡ | 1.05 (1.01–1.09)* | |
| Female | 2.61 (1.48–4.60)‡ | 2.24 (1.24–4.05)† | 2.19 (1.20–4.00)† | 2.44 (1.30–4.60)† | |
| White | 1.66 (0.82–3.35) | 1.74 (0.84–3.57) | 1.81 (0.89–3.71) | 1.47 (0.71–3.03) | |
| Education | |||||
| - Some college | 0.62 (0.32–1.19) | 0.62 (0.32–1.19) | 0.63 (0.33–1.22) | 0.87 (0.43–1.77) | |
| - College graduate | 0.71 (0.35–1.44) | 0.72 (0.36–1.47) | 0.80 (0.39–1.65) | 1.30 (0.60–2.79) | |
| Single and living alone | 0.89 (0.48–1.66) | 0.97 (0.51–1.84) | 0.87 (0.45–1.66) | 0.91 (0.46–1.78) | |
| Alcohol use (days/week) | 0.85 (0.63–1.15) | 0.86 (0.63–1.18) | 0.95 (0.69–1.31) | ||
| Current smoker | 0.56 (0.20–1.57) | 0.56 (0.20–1.58) | 0.60 (0.21–1.73) | ||
| Charlson Comorbidity Score | 0.90 (0.75–1.09) | 0.94 (0.78–1.15) | 0.88 (0.72–1.07) | ||
| Severe sepsis-related hospitalization characteristics | |||||
| Organ dysfunction score | 0.69 (0.34–1.43) | 0.70 (0.32–1.52) | |||
| Admitted to an ICU | 0.83 (0.47–1.44) | 0.81 (0.44–1.52) | |||
| Required mechanical ventilation | 1.20 (0.58–2.47) | 1.29 (0.58–2.89) | |||
| Required major surgery | 0.45 (0.22–0.95)* | 0.55 (0.26–1.19) | |||
| Required dialysis | 0.15 (0.01–1.60) | 0.19 (0.03–1.24) | |||
| Hospital length of stay | 0.99 (0.96–1.03) | 1.00 (0.97–1.03) | |||
| TICS 27-point score at last HRS wave before sepsis | 0.85 (0.79–0.91)‡ | ||||
Abbreviations: HRS = Health and Retirement Study; ICU = intensive care unit; TICS = Telephone Interview for Cognitive Status.
P < 0.05
P < 0.01
P < 0.001
In our secondary analyses, pre-sepsis substantial depressive symptoms were associated with 3.66-times the odds (95%CI: 1.51, 8.87) of post-sepsis incident mild cognitive impairment and 2.08-times the odds (95%CI: 1.12, 3.85) of post-sepsis incident moderate-to-severe cognitive impairment in our final models.
DISCUSSION
In this nationwide longitudinal investigation, we identified that depression predating severe sepsis was independently associated with over two-and-a-half times the odds of incident cognitive impairment in survivors. Since most severe sepsis survivors with incident cognitive impairment in this cohort had moderate-to-severe impairment, depression in older adults prior to severe sepsis could increase the risk of adverse outcomes with profound impact in terms of increased caregiver burden, nursing home admissions, healthcare costs and mortality.1,2,4
The present study supports an important relationship between depression in older adults and the onset of cognitive impairment.10,12 While observational studies like this one cannot prove causation, the existence of credible biological pathways reduces the concern that these associations are merely artifacts. One plausible causal pathway linking depression, severe sepsis, and subsequent cognitive decline in older adults is through inflammation. Depression has been associated with increased release of pro-inflammatory cytokines which has been hypothesized to lead to neurodegenerative changes in late-life.12 Thus, depression could potentiate the deleterious inflammatory effect of sepsis on the brain.25 Another plausible causal pathway is through delirium. Delirium is common in older patients with sepsis,26 and delirium in critically ill patients has been associated with subsequent long-term cognitive impairment.27 Furthermore, prior studies have found depression to be an independent risk factor for delirium during a hospitalization for medical illness in older adults.28, 29 In addition, not only has depression been associated with increased cognitive decline in carriers of the APOE-ε4 allele,13,14 but the presence of the APOE-ε4 polymorphism has been associated with longer durations of delirium in critically ill patients.30 That is, if, as has been hypothesized, delirium is not merely a sign of an injured brain, but is actually a brain-injuring process, then the deliriogenic effects of depression could potentiate long-term cognitive dysfunction. Further studies are needed to confirm this causal pathway, particularly since in-hospital delirium can be potentially preventable and treatable.26,31
The possibility of a causal association raises important implications for treatment. Treatment of late-life depression may improve cognitive functioning in older adults.30 Further research is needed to test the hypothesis generated here—that successful interventions for the treatment of late-life depression could reduce adverse outcomes such as cognitive impairment in older adults surviving serious medical illnesses such as severe sepsis.
An alternative interpretation for our findings could be that pre-sepsis depression could have signified a prodrome of a dementing illness, and therefore serves as a marker of impending cognitive decline, rather than as a risk factor (in the physiological sense). Prior studies have reported that late-life depression, but not lifetime history of depression, is associated with increased risk of dementia,11,33 suggesting that depression in older adults could signify the onset of dementia. In this context, our findings could be interpreted to suggest that in older adults, a hospitalization for a serious medical illness such as severe sepsis could serve as the insult that progresses late-life depression into frank cognitive decline. If true, then clinicians should monitor the cognition of older adults with a history of depression who survive severe sepsis closely in order to inform treatment decisions and to equip families with the information they need to maximize their loved one’s quality of life.
Our study has several limitations. Our results primarily demonstrate long-term cognitive effects; short-term cognitive deficits (e.g., less than 6–12 months) following a hospitalization could be greater, and some patients may have improvements in transient cognitive deficits prior to their next biennial HRS interview. The neuropsychological battery that we used assessed global cognitive function and could not allow measurement of individual cognitive domains, nor could it establish a clinical diagnosis of dementia. However we used cognitive categories and cutoff scores that have shown good correlation with clinical dementia as assessed by detailed neuropsychiatric interview,34 and, unlike detailed neuropsychiatric assessment, are available on a population-wide basis with substantial pre-hospitalization prospective measurement. Since we assessed depressive symptoms with a questionnaire and not a diagnostic interview, a diagnosis of major depression could not be made. The 8-item CES-D has not been specifically validated for use before and after severe sepsis, and it lacks optimal specificity for the diagnosis of major depressive disorder. Further, although unlikely, we cannot completely exclude the possibility that patients with greater pre-sepsis depressive symptoms could have developed symptoms of mild cognitive impairment before sepsis. In addition, our outcome measurement could not rule out confounding by the presence of persistent post-sepsis depressive symptoms, which would be optimally differentiated by a face-to-face clinical encounter. Finally, the possibility of residual confounding remains as in any observational study.
In conclusion, we found that substantial depressive symptoms prior to a hospitalization for severe sepsis are independently associated with increased odds of new cognitive impairments. Our findings suggest that depressed older adults are at particular risk of developing cognitive impairment after a serious medical illness. Future research aimed at identifying the mechanisms that link depression, sepsis, and cognitive impairment—along with interventions that prevent and/or slow cognitive decline in severe sepsis survivors—is imperative in light of the aging of the population and the enormous toll that depression and severe sepsis exact on older patients, their families and caregivers, and the healthcare system.9
Acknowledgments
We appreciate the expert programming of Laetitia Shapiro and Mohammed Kabeto, both at the University of Michigan.
This work was supported by grants KL2 RR025015-05, K08 HL091249, R01 AG030155, and U01 AG09740 from the National Institutes of Health. The Health and Retirement Study is performed at the Institute for Social Research, University of Michigan.
Sponsor’s Role: The sponsor had no role in the design, methods, subject recruitment, data collection, analysis, or preparation of the manuscript.
Footnotes
Potential Conflicts of Interest: The authors have no relevant potential conflicts of interest to disclose.
Author Contributions: All of the listed authors have participated in the study concept and design, analysis and interpretation of the data, and the drafting and revising of the manuscript. Dr. Davydow has had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Disclaimer: The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs, the National Institutes of Health or the US government.
References
- 1.Guehne U, Riedel-Heller S, Angermeyer MC. Mortality in dementia. Neuroepidemiology. 2005;25:153–162. doi: 10.1159/000086680. [DOI] [PubMed] [Google Scholar]
- 2.Kinosian BP, Stallard E, Lee JH, et al. Predicting 10-year care requirements for older people with suspected Alzheimer’s disease. J Am Geriatr Soc. 2000;48:631–638. doi: 10.1111/j.1532-5415.2000.tb04720.x. [DOI] [PubMed] [Google Scholar]
- 3.Iwashyna TJ, Ely EW, Smith DM, et al. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA. 2010;304:1787–1794. doi: 10.1001/jama.2010.1553. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Langa KM, Chernew ME, Kabeto MU, et al. National estimates of the quantity and cost of informal caregiving for the elderly with dementia. J Gen Intern Med. 2001;16:770–778. doi: 10.1111/j.1525-1497.2001.10123.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Iwashyna TJ. Survivorship will be the defining challenge of critical care in the 21st century. Ann Intern Med. 2010;153:204–205. doi: 10.7326/0003-4819-153-3-201008030-00013. [DOI] [PubMed] [Google Scholar]
- 6.Ehlenbach WJ, Hough CL, Crane PK, et al. Association between acute care and critical illness hospitalization and cognitive function in older adults. JAMA. 2010;303:763–770. doi: 10.1001/jama.2010.167. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Milbrandt EB, Eldadah B, Nayfield S, et al. Toward an integrated research agenda for critical illness in aging. Am J Respir Crit Care Med. 2010;182:995–1003. doi: 10.1164/rccm.200904-0630CP. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29:1303–1310. doi: 10.1097/00003246-200107000-00002. [DOI] [PubMed] [Google Scholar]
- 9.Iwashyna TJ, Cooke CR, Wunsch H, et al. The population burden of long-term survivorship after severe sepsis among older Americans. J Am Geriatr Soc. 2012;60:1070–1077. doi: 10.1111/j.1532-5415.2012.03989.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Ownby RL, Crocco E, Acevedo A, et al. Depression and risk for Alzheimer’s disease: Systematic review, meta-analysis, and metaregression analysis. Arch Gen Psychiatry. 2006;63:530–538. doi: 10.1001/archpsyc.63.5.530. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Li G, Wang LY, Shofer JB, et al. Temporal relationship between depression and dementia: findings from a large community-based 15-year follow-up study. Arch Gen Psychiatry. 2011;68:970–977. doi: 10.1001/archgenpsychiatry.2011.86. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Katon WJ, Lin EHB, Williams LH, et al. Comorbid depression is associated with an increased risk of dementia diagnosis in patients with diabetes: A prospective cohort study. J Gen Intern Med. 2010;25:423–429. doi: 10.1007/s11606-009-1248-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Irie F, Masaki KH, Petrovitch H, et al. Apolipoprotein ε4 allele genotype and the effect of depressive symptoms on the risk of dementia in men: The Honolulu-Asia aging study. Arch Gen Psychiatry. 2008;65:906–912. doi: 10.1001/archpsyc.65.8.906. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Corsentino EA, Sawyer K, Sachs-Ericsson N, et al. Depressive symptoms moderate the influence of the apolipoproteine epsilon4 allele on cognitive decline in a sample of community dwelling older adults. Am J Geriatr Psychiatry. 2009;17:155–165. doi: 10.1097/JGP.0b013e31818f3a6b. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Opal SM, Girard TD, Ely EW. The immunopathogenesis of sepsis in elderly patients. Clin Infect Dis. 2005;41:S504–S512. doi: 10.1086/432007. [DOI] [PubMed] [Google Scholar]
- 16.Charlson ME, Pompei P, Ales KL. A new method for classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chron Dis. 1987;40:373–383. doi: 10.1016/0021-9681(87)90171-8. [DOI] [PubMed] [Google Scholar]
- 17.Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med. 2003;31:1250–1256. doi: 10.1097/01.CCM.0000050454.01978.3B. [DOI] [PubMed] [Google Scholar]
- 18.Iwashyna TJ, Odden A, Rohde J, et al. Identifying patients with severe sepsis using administrative claims: patient-level validation of the Angus implementation of the International Consensus Conference Definition of Severe Sepsis. Med Care. 2012 doi: 10.1097/MLR.0b013e318268ac86. In Press. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Radloff LS. The CES-D Scale: A self-report depression scale for research in the general population. Appl Psychol Measurement. 1977;1:385–401. [Google Scholar]
- 20.Soldo BJ, Hurd MD, Rodgers WL, et al. Asset and health dynamics of the oldest old: An overview of the AHEAD study. J Gerontol B Psychol Soc Sci. 1997;52:1–20. doi: 10.1093/geronb/52b.special_issue.1. [DOI] [PubMed] [Google Scholar]
- 21.Kohout FJ, Berkman LF, Evans DA, et al. Two shorter forms of the CES-D (Center for Epidemiological Studies Depression) depression symptoms index. J Aging Health. 1993;5:179–183. doi: 10.1177/089826439300500202. [DOI] [PubMed] [Google Scholar]
- 22.Steffick D. Documentation of affective functioning measures in the Health and Retirement Study. Ann Arbor, Michigan: Survey Research Center; 2000. [Google Scholar]
- 23.Langa KM, Larson EB, Karlawish JH, et al. Trends in the prevalence and mortality of cognitive impairment in the United States: Is there evidence of a compression of cognitive morbidity? Alzheimers Dement. 2008;4:134–144. doi: 10.1016/j.jalz.2008.01.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Huber PJ. Robust statistics. New York: Wiley; 1981. [Google Scholar]
- 25.Jacob A, Brorson JR, Alexander JJ. Septic encephalopathy: Inflammation in man and mouse. Neurochem Int. 2011;58:472–476. doi: 10.1016/j.neuint.2011.01.004. [DOI] [PubMed] [Google Scholar]
- 26.Sprung CL, Peduzzi PN, Shatney CH, et al. The Veterans Administration Systemic Sepsis Cooperative Study Group. Impact of encephalopathy on mortality in the sepsis syndrome. Crit Care Med. 1990;18:801–806. doi: 10.1097/00003246-199008000-00001. [DOI] [PubMed] [Google Scholar]
- 27.Girard TD, Jackson JC, Pandharipande PP, et al. Delirium as a predictor of long-term cognitive impairment in survivors of critical illness. Crit Care Med. 2010;38:1513–1520. doi: 10.1097/CCM.0b013e3181e47be1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Pompei P, Foreman M, Rudberg M, et al. Delirium in hospitalized older persons: Outcomes and predictors. J Am Geriatr Soc. 1994;42:809–815. doi: 10.1111/j.1532-5415.1994.tb06551.x. [DOI] [PubMed] [Google Scholar]
- 29.McAvay GJ, Van Ness PH, Bogardus ST, et al. Depressive symptoms and the risk of incident delirium in older hospitalized adults. J Am Geriatr Soc. 2007;55:684–691. doi: 10.1111/j.1532-5415.2007.01150.x. [DOI] [PubMed] [Google Scholar]
- 30.Ely EW, Girard TD, Shintani AK, et al. Apolipoprotein E4 polymorphism as a genetic predisposition to delirium in critically ill patients. Crit Care Med. 2007;35:112–117. doi: 10.1097/01.CCM.0000251925.18961.CA. [DOI] [PubMed] [Google Scholar]
- 31.Ely EW, Shintani A, Truman B, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004;291:1753–1762. doi: 10.1001/jama.291.14.1753. [DOI] [PubMed] [Google Scholar]
- 32.Butters MA, Becker JT, Nebes RD, et al. Changes in cognitive functioning following treatment of late-life depression. Am J Psychiatry. 2000;157:1949–1954. doi: 10.1176/appi.ajp.157.12.1949. [DOI] [PubMed] [Google Scholar]
- 33.Fuhrer R, Dufouil C, Dartiques JF, et al. Exploring sex differences in the relationship between depressive symptoms and dementia incidence: Prospective results from the PAQUID Study. J Am Geriatr Soc. 2003;51:1055–1063. doi: 10.1046/j.1532-5415.2003.51352.x. [DOI] [PubMed] [Google Scholar]
- 34.Plassman BL, Langa KM, Fisher GG, et al. Prevalence of dementia in the United States: the Aging, Demographics, and Memory Study. Neuroepidemiology. 2007;29:125–132. doi: 10.1159/000109998. [DOI] [PMC free article] [PubMed] [Google Scholar]