Functional brain imaging in survivors of critical illness: A prospective feasibility study and exploration of the association between delirium and brain activation patterns.

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

The association between brain volumes, delirium duration, and cognitive outcomes in intensive care unit survivors: the VISIONS cohort magnetic resonance imaging study*.

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

The relationship between delirium duration, white matter integrity, and cognitive impairment in intensive care unit survivors as determined by diffusion tensor imaging: the VISIONS prospective cohort magnetic resonance imaging study*.

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

Neuroimaging in delirious intensive care unit patients: a preliminary case series report.

Objective. There exists uncertainty regarding the role of magnetic resonance imaging in the evaluation of intensive care unit delirious patients. This case series describes preliminary magnetic resonance imaging findings obtained because of delirium, subsequent in-hospital clinical decisions, and post-discharge neurocognitive outcomes in intensive care unit survivors.Design. Case series.Setting. Intensive care unit.Participants. Eight patients who underwent magnetic resonance imaging for delirium in the absence of focal neurological findings as part of their intensive care unit clinical care.Measurements. Magnetic resonance imaging findings, clinical decisions following magnetic resonance imaging, and three-month neuropsychological outcomes were obtained.Results. Of the eight patients, six (75%) demonstrated white matter hyperintensities, one (12%) had mild atrophy, and no patient had ischemic/hemorrhagic lesions. Magnetic resonance imaging did not lead to new diagnoses or immediate changes in therapy. All six patients who underwent neuropsychological testing had severe impairments in memory, executive function, and attention at three months, despite the absence of baseline cognitive impairment.Conclusion. Magnetic resonance imaging findings in these delirious intensive care unit patients did not alter the immediate treatment course and these patients had neuropsychological impairments at three months. Future research is warranted to define the role of current and newer magnetic resonance imaging techniques in assessing and managing delirious intensive care unit patients, and to examine relationships between in-hospital magnetic resonance imaging findings (i.e. white matter hyperintensities) and short- and long-term neurological outcomes.

Brain autopsy findings in intensive care unit patients previously suffering from delirium: a pilot study.

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

Pathophysiology of delirium in the intensive care unit.

Delirium, or acute brain dysfunction, is a life-threatening global disturbance in cognitive functioning that frequently manifests in critically ill patients. This review examines the current status of knowledge regarding the pathophysiology of delirium in the ICU, in particular, evaluating the role of iatrogenic factors such as sedatives and analgesic administration in brain dysfunction. This hypothesis is considered along with several other plausible mechanisms of ICU delirium, including sepsis, postoperative cognitive dysfunction, and changes in biomarkers and neurotransmitters. The review concludes by highlighting potential future directions in molecular genetics for the elucidation of delirium and its long-term consequences.

The cognitive consequences of critical illness: practical recommendations for screening and assessment.

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

Loss of IQ in the ICU brain injury without the insult.

Critically ill patients are at high risk of developing serious neurological dysfunctions including delirium and long-term neurocognitive impairment. Here a novel mechanism is proposed for this highly deleterious condition. A growing body of evidence has shown that critical illness and its treatment can lead to de novo cerebral atrophy including white and grey matter abnormalities, delirium, and neurocognitive decline. In healthy individuals, normal and consistent connectivity between the posterior parietal cortex (PPC), medial temporal lobe (MTL) and prefrontal cortex (PFC) maintains consciousness and normal cognitive functioning. The circuit is innervated, activated and maintained by the ascending reticular activating system (ARAS) arising from the brainstem. As elderly individuals begin to show signs of grey matter atrophy in the PPC, MTL and PFC, functional connectivity between these regions remains intact; however, the strength of the connections is no longer robust as it once was in the healthy CNS. This circuit continues to be activated and maintained via the ARAS. Individuals treated in the ICU are subject to a number of medical and pharmacological challenges which may disrupt normal CNS connectivity. Serious illnesses such as sepsis, acute respiratory distress syndrome (ARDS), and acute lung injury (ALI), as well as sedative and analgesic medications commonly prescribed in the ICU have the potential to disrupt the functional link in the circuit described above. Minor fluctuations in the ARAS (i.e. hyper or hypo activation) may be sufficient in elderly individuals to cause a disruption which surpasses the critical threshold of functional connectivity necessary to maintain normal (i.e. non-delirious) consciousness. In combination with exposure to other ICU related threats to neurocognitive function, prolonged decoupling of this circuit may lead to deleterious neurodegenerative consequences such as excitotoxicity. Over time this has the potential to result in apoptosis and long-term cognitive impairment. Delirium appears to be a good candidate for the causal mechanism of ICU related cognitive decline and may be a critical point of intervention.