BACKGROUND Survivors of critical illness often have a prolonged and disabling form of cognitive impairment that remains inadequately characterized. METHODS 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. RESULTS 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. CONCLUSIONS 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 ClinicalTrials.gov number, NCT00392795.)

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Objective To test the hypothesis that duration of delirium in the intensive care unit (ICU) is an independent predictor of long-term cognitive impairment after critical illness requiring mechanical ventilation. Design Prospective cohort study. Setting Medical ICU in a large community hospital in the United States. Patients Mechanically ventilated medical ICU patients who were assessed daily for delirium while in the ICU and underwent comprehensive cognitive assessments 3 and 12 months after discharge. Measurements and Main Results Of 126 eligible patients, 99 survived ≥3 months post-critical illness; long-term cognitive outcomes were obtained for 77 (78%) patients. Median age was 61 years, 51% were admitted with sepsis/ARDS, and median duration of delirium was 2 days. At 3-and 12-month follow-up, 79% and 71% of survivors had cognitive impairment, respectively (with 62% and 36% being severely impaired). After adjusting for age, education, preexisting cognitive function, severity of illness, severe sepsis, and exposure to sedative medications in the ICU, increasing duration of delirium was an independent predictor of worse cognitive performance—determined by averaging age- and education-adjusted T-scores from nine tests measuring seven domains of cognition—at 3-month (p = 0.02) and 12-month follow-up (p = 0.03). Duration of mechanical ventilation, alternatively, was not associated with long-term cognitive impairment (p = 0.20 and 0.58). Conclusions In this study of mechanically ventilated medical ICU patients, duration of delirium was independently associated with long-term cognitive outcomes, representing a potentially modifiable predictor of this common public health problem.

Objective To demonstrate the feasibility of a placebo-controlled trial of antipsychotics for delirium in the intensive care unit (ICU) and to test the hypothesis that antipsychotics would improve days alive without delirium or coma. Design Randomized, double-blind, placebo-controlled trial. Setting Six tertiary care medical centers in the United States. Patients 101 mechanically ventilated medical and surgical ICU patients. Intervention Patients were randomly assigned to receive haloperidol or ziprasidone or placebo every 6 hours for up to 14 days. Frequency of administration was adjusted twice daily according to delirium status, level of sedation, and side effects. Measurements and Main Outcomes The primary end point was the number of days patients were alive without delirium or coma. During the 21-day study period, patients in the haloperidol group spent a similar number days alive without delirium or coma (median [IQR], 14.0 [6.0–18.0] days) as did patients in the ziprasidone (15.0 [9.1–18.0] days) and placebo groups (12.5 [1.2–17.2] days) (p = 0.66). No differences were found in secondary clinical outcomes, including ventilator-free days (p = 0.25), hospital length of stay (p = 0.68), and mortality (p = 0.81). Ten (29%) patients in the haloperidol group reported symptoms consistent with akathisia, compared with 6 (20%) patients in the ziprasidone group and 7 (19%) patients in the placebo group (p = 0.60), and a global measure of extrapyramidal symptoms was similar between treatment groups (p = 0.46). Conclusions A randomized, placebo-controlled trial of antipsychotics for delirium in mechanically ventilated ICU patients is feasible. Treatment with antipsychotics in this limited pilot trial did not improve the number of days alive without delirium or coma nor did it increase adverse outcomes. Thus, a large trial is needed to determine whether use of antipsychotics for ICU delirium is appropriate.

In this trial, management of mechanically ventilated medical ICU patients with a wake up and breathe protocol resulted in similar cognitive, psychological, and functional outcomes among patients tested 3 and 12 months post-ICU. The proven benefits of this protocol, including improved 1-year survival, were not offset by adverse long-term outcomes. Clinical trial registered with www.clinicaltrials.gov (NCT 00097630).

Objective 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. Measurements 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. Results 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. Conclusions 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.

APOE4 allele represents the first demonstrated genetic predisposition to longer duration of delirium in humans.

Objective Evidence is emerging that delirium duration is a predictor of long-term cognitive impairment (LTCI) in Intensive Care Unit (ICU) survivors. Relationships between (a) delirium duration and brain white matter integrity, and (b) between white matter integrity and LTCI are poorly understood and could be explored using Magnetic Resonance Imaging (MRI). Design, Setting, Patients A two-center, prospective cohort study incorporating delirium monitoring, neuroimaging and cognitive testing in ICU survivors. Measurements Delirium was evaluated with the Confusion Assessment Method for the ICU (CAM-ICU) and cognitive outcomes were tested at 3 and 12-month follow-up. Following the ICU stay, Fractional Anisotropy (FA), a measure of white matter integrity, was calculated quantitatively using Diffusion Tensor Imaging (DTI) with a 3-Tesla MRI scanner at hospital discharge and three-month follow-up. We examined associations between (a) delirium duration and FA and (b) between FA and cognitive outcomes using linear regression adjusted for age and sepsis. Results A total of 47 patients with median age of 50 years completed the DTI-MRI protocol. Greater duration of delirium (3 vs. 0 days) was associated with lower FA (i.e. reduced FA=white matter disruption) in the genu (−0.02; p = 0.04) and splenium (−0.01; p = 0.02) of the corpus callosum and anterior limb of the internal capsule (−0.02; p = 0.01) at hospital discharge. These associations persisted at 3 months for the genu (−0.02; p= 0.02) and splenium (−0.01; p= 0.004). Lower FA in the anterior limb of internal capsule at discharge (−10.35; p= 0.05) and in genu of corpus callosum at three months (−8.81; p = 0.006) was associated with worse cognitive scores at 3 and 12 months. Conclusions In this pilot investigation, delirium duration in the ICU was associated with white matter disruption at both discharge and 3 months. Similarly, white matter disruption was associated with worse cognitive scores up to 12 months later. This hypothesis-generating investigation may help design future studies to explore these complex relationships in greater depth.