Delirium's pathophysiology is poorly understood. We sought to determine if plasma biomarkers of inflammation, coagulation, endothelial activation, and blood brain barrier (BBB) injury were associated ...with emergency department (ED) delirium duration.
We enrolled hospitalized patients who were 65 years or older from the ED. Plasma biomarkers of inflammation (interleukin-6 IL-6, IL-8, soluble tumor necrosis factor receptor I sTNFRI), coagulation (Protein C), endothelial activation (plasminogen activating inhibitor-1 PAI-1), and BBB injury (S100B) at were measured using blood obtained at enrollment. The dependent variable was ED delirium duration which was determined by the Brief Confusion Assessment Method assessed in the ED and hospitalization. Proportional odds logistic regression analyses were performed adjusted for relevant confounders and allowing for interaction by baseline dementia status.
A total of 156 patients were enrolled. IL-6 (POR = 1.59, 95%CI: 1.09-2.32) and PAI-1 (POR = 2.96, 95%CI: 1.48 to 6.85) were independently associated with more prominent ED delirium duration in subjects without dementia only. No significant associations between IL-8, Protein C, sTNRFI, and S100B and ED delirium duration were observed.
Plasma Biomarkers of systemic inflammation and endothelial activation are associated with ED delirium duration in older ED patients without dementia.
OBJECTIVES:To describe the frequency of co-occurring newly acquired cognitive impairment, disability in activities of daily livings, and depression among survivors of a critical illness and to ...evaluate predictors of being free of post-intensive care syndrome problems.
DESIGN:Prospective cohort study.
SETTING:Medical and surgical ICUs from five U.S. centers.
PATIENTS:Patients with respiratory failure or shock, excluding those with preexisting cognitive impairment or disability in activities of daily livings.
INTERVENTIONS:None.
MEASUREMENTS AND MAIN RESULTS:At 3 and 12 months after hospital discharge, we assessed patients for cognitive impairment, disability, and depression. We categorized patients into eight groups reflecting combinations of cognitive, disability, and mental health problems. Using multivariable logistic regression, we modeled the association between age, education, frailty, durations of mechanical ventilation, delirium, and severe sepsis with the odds of being post-intensive care syndrome free. We analyzed 406 patients with a median age of 61 years and an Acute Physiology and Chronic Health Evaluation II of 23. At 3 and 12 months, one or more post-intensive care syndrome problems were present in 64% and 56%, respectively. Nevertheless, co-occurring post-intensive care syndrome problems (i.e., in two or more domains) were present in 25% at 3 months and 21% at 12 months. Post-intensive care syndrome problems in all three domains were present in only 6% at 3 months and 4% at 12 months. More years of education was associated with greater odds of being post-intensive care syndrome free (p < 0.001 at 3 and 12 mo). More severe frailty was associated with lower odds of being post-intensive care syndrome free (p = 0.005 at 3 mo and p = 0.048 at 12 mo).
CONCLUSIONS:In this multicenter cohort study, one or more post-intensive care syndrome problems were present in the majority of survivors, but co-occurring problems were present in only one out of four. Education was protective from post-intensive care syndrome problems and frailty predictive of the development of post-intensive care syndrome problems. Future studies are needed to understand better the heterogeneous subtypes of post-intensive care syndrome and to identify modifiable risk factors.
As critical illness survivorship increases, patients and health care providers are faced with management of long-term sequelae including cognitive and functional impairment. Longitudinal studies have ...demonstrated impairments persisting at least 1–5 years after hospitalization for critical illness. Cognitive domains impacted include memory, attention, and processing speed. Functional impairments include physical weakness, reduced endurance, and dependence on others for basic tasks of daily living such as bathing or feeding. In characterizing the trajectory of long-term recovery, multiple risk factors have been identified for subsequent impairment, including increased severity of illness and severe sepsis, prolonged mechanical ventilation, and delirium. Preadmission status including frailty, high level of preexisting comorbidities, and baseline cognitive dysfunction are also associated with impairment after critical illness. Development of cognitive and functional impairment is likely multifactorial, and multiple mechanistic theories have been proposed. Neuroinflammation, disruption of the blood–brain barrier, and structural alterations in the brain have all been observed in patients with long-term cognitive dysfunction. Systemic inflammation has also been associated with alterations in muscle integrity and function, which is associated with intensive care unit–acquired weakness and prolonged functional impairment. Efforts to ease the burden of long-term impairments include prevention strategies and rehabilitation interventions after discharge. Delirium is a well-established risk factor for long-term cognitive dysfunction, and using delirium-prevention strategies may be important for cognitive protection. Current evidence favors minimizing overall sedation exposure, careful selection of sedation agents including avoidance of benzodiazepines, and targeted sedation goals to avoid oversedation. Daily awakening and spontaneous breathing trials and early mobilization have shown benefit in both cognitive and functional outcomes. Multifactorial prevention bundles are useful tools in improving care provided to patients in the intensive care unit. Data regarding cognitive rehabilitation are limited, while studies on functional rehabilitation have conflicting results. Continued investigation and implementation of prevention strategies and rehabilitation interventions will hopefully improve the quality of life for the ever-increasing population of critical illness survivors.
Postoperative delirium is a geriatric syndrome that manifests as changes in cognition, attention, and levels of consciousness after surgery. It occurs in up to 50% of patients after major surgery and ...is associated with adverse outcomes, including increased hospital length of stay, higher cost of care, higher rates of institutionalization after discharge, and higher rates of readmission. Furthermore, it is associated with functional decline and cognitive impairments after surgery. As the age and medical complexity of our surgical population increases, practitioners need the skills to identify and prevent delirium in this high-risk population. Because delirium is a common and consequential postoperative complication, there has been an abundance of recent research focused on delirium, conducted by clinicians from a variety of specialties. There have also been several reviews and recommendation statements; however, these have not been based on robust evidence. The Sixth Perioperative Quality Initiative (POQI-6) consensus conference brought together a team of multidisciplinary experts to formally survey and evaluate the literature on postoperative delirium prevention and provide evidence-based recommendations using an iterative Delphi process and Grading of Recommendations Assessment, Development and Evaluation (GRADE) Criteria for evaluating biomedical literature.
Epidemiology and risk factors for delirium across hospital settings Vasilevskis, Eduard E., MD; Han, Jin H., MD, MSc; Hughes, Christopher G., MD ...
Baillière's best practice and research in clinical anaesthesiology/Bailliere's best practice & research. Clinical anaesthesiology,
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Delirium is one of the most common causes of acute end-organ dysfunction across hospital settings, occurring in as high as 80% of critically ill patients that require intensive care unit (ICU) care. ...The implications of this acute form of brain injury are profound. Across many hospital settings (emergency department, general medical ward, postoperative and ICU), a patient who experiences delirium is more likely to experience increased short- and long-term mortality, decreases in long-term cognitive function, increases in hospital length of stay and increased complications of hospital care. With the development of reliable setting-specific delirium-screening instruments, researchers have been able to highlight the predisposing and potentially modifiable risk factors that place patients at highest risk. Among the large number of risk factors discovered, administration of potent sedative medications, most notably benzodiazepines, is most consistently and strongly associated with an increased burden of delirium. Alternatively, in both the hospital and ICU, delirium can be prevented with the application of protocols that include early mobility/exercise. Future studies must work to understand the epidemiology across settings and focus upon modifiable risk factors that can be integrated into existing delirium prevention and treatment protocols.
In Duchenne muscular dystrophy, a lack of dystrophin leads to extensive muscle weakness and atrophy that is linked to cellular metabolic dysfunction and oxidative stress. This dystrophinopathy ...results in a loss of tethering between microtubules and the sarcolemma. Microtubules are also believed to regulate mitochondrial bioenergetics potentially by binding the outer mitochondrial membrane voltage dependent anion channel (VDAC) and influencing permeability to ADP/ATP cycling. The objective of this investigation was to determine if a lack of dystrophin causes microtubule disorganization concurrent with mitochondrial dysfunction in skeletal muscle, and whether this relationship is linked to altered binding of tubulin to VDAC. In extensor digitorum longus (EDL) muscle from 4-week old D2.mdx mice, microtubule disorganization was observed when probing for alpha-tubulin. This cytoskeletal disorder was associated with a reduced ability of ADP to stimulate respiration and attenuate H.sub.2 O.sub.2 emission relative to wildtype controls. However, this was not associated with altered alpha-tubulin-VDAC2 interactions. These findings reveal that microtubule disorganization in dystrophin-deficient EDL is associated with impaired ADP control of mitochondrial bioenergetics, and suggests that mechanisms alternative to alpha-tubulin's regulation of VDAC2 should be examined to understand how cytoskeletal disruption in the absence of dystrophin may cause metabolic dysfunctions in skeletal muscle.
Critical illness is associated with cognitive impairment, but mental health and functional disabilities in survivors of intensive care are inadequately characterised. We aimed to assess associations ...of age and duration of delirium with mental health and functional disabilities in this group.
In this prospective, multicentre cohort study, we enrolled patients with respiratory failure or shock who were undergoing treatment in medical or surgical ICUs in Nashville, TN, USA. We obtained data for baseline demographics and in-hospital variables, and assessed survivors at 3 months and 12 months with measures of depression (Beck Depression Inventory II), post-traumatic stress disorder (PTSD, Post-Traumatic Stress Disorder Checklist-Event Specific Version), and functional disability (activities of daily living scales, Pfeffer Functional Activities Questionnaire, and Katz Activities of Daily Living Scale). We used linear and proportional odds logistic regression to assess the independent associations between age and duration of delirium with mental health and functional disabilities. This study is registered with ClinicalTrials.gov, number NCT00392795.
We enrolled 821 patients with a median age of 61 years (IQR 51-71), assessing 448 patients at 3 months and 382 patients at 12 months after discharge. At 3 months, 149 (37%) of 406 patients with available data reported at least mild depression, as did 116 (33%) of 347 patients at 12 months; this depression was mainly due to somatic rather than cognitive-affective symptoms. Depressive symptoms were common even among individuals without a history of depression (as reported by a proxy), occurring in 76 (30%) of 255 patients with data at 3 months and 62 (29%) of 217 individuals at 12 months. Only 7% of patients (27 of 415 at 3 months and 24 of 361 at 12 months) had symptoms consistent with post-traumatic distress disorder. Disabilities in basic activities of daily living (ADL) were present in 139 (32%) of 428 patients at 3 months and 102 (27%) of 374 at 12 months, as were disabilities in instrumental ADL in 108 (26%) of 422 individuals at 3 months and 87 (23%) of 372 at 12 months. Mental health and functional difficulties were prevalent in patients of all ages. Although old age was frequently associated with mental health problems and functional disabilities, we observed no consistent association between the presence of delirium and these outcomes.
Poor mental health and functional disability is common in patients treated in intensive-care units. Depression is five times more common than is post-traumatic distress disorder after critical illness and is driven by somatic symptoms, suggesting approaches targeting physical rather than cognitive causes could benefit patients leaving critical care.
National Institutes of Health AG027472 and the Geriatric Research, Education and Clinical Center (GRECC), Department of Veterans Affairs Medical Center, Tennessee Valley Healthcare System.
A 77 year-old male is admitted to the hospital after sustaining a hip fracture. He has a past medical history of chronic obstructive pulmonary disease, hypertension, hyperlipidemia, chronic back ...pain, and hearing loss. Prior to surgery he receives midazolam for agitation and morphine for pain control. He undergoes a general anesthetic for his fracture repair, requiring high doses of fentanyl for pain control. Postoperatively, he has poor pulmonary mechanics and is taken to the ICU intubated and mechanically ventilated. On postoperative day one, his sedation is weaned and he is put on a spontaneous breathing trial. While he appears intermittently awake, he will not follow commands and only intermittently makes eye contact. The patient is left intubated due to his altered mental status.
Anthropogenically induced global climate change has profound implications for marine ecosystems and the economic and social systems that depend upon them. The relationship between temperature and ...individual performance is reasonably well understood, and much climate-related research has focused on potential shifts in distribution and abundance driven directly by temperature. However, recent work has revealed that both abiotic changes and biological responses in the ocean will be substantially more complex. For example, changes in ocean chemistry may be more important than changes in temperature for the performance and survival of many organisms. Ocean circulation, which drives larval transport, will also change, with important consequences for population dynamics. Furthermore, climatic impacts on one or a few 'leverage species' may result in sweeping community-level changes. Finally, synergistic effects between climate and other anthropogenic variables, particularly fishing pressure, will likely exacerbate climate-induced changes. Efforts to manage and conserve living marine systems in the face of climate change will require improvements to the existing predictive framework. Key directions for future research include identifying key demographic transitions that influence population dynamics, predicting changes in the community-level impacts of ecologically dominant species, incorporating populations' ability to evolve (adapt), and understanding the scales over which climate will change and living systems will respond.
OBJECTIVES:During critical illness, impaired endothelial vascular reactivity predicts prolonged acute brain dysfunction, but relationships between endothelial activation, blood-brain ...barrier/neurological injury, and acute brain dysfunction, including delirium, remain unexamined. We tested the hypothesis that elevated plasma markers of endothelial activation and blood-brain barrier/neurological injury are associated with delirium duration during critical illness.
DESIGN:Prospective cohort study.
SETTING:Medical and surgical ICUs in an academic medical center.
PATIENTS:Adults in acute respiratory failure and/or shock.
INTERVENTIONS:None.
MEASUREMENTS AND MAIN RESULTS:We enrolled subjects within 72 hours of organ failure diagnosis in the ICU. We measured plasma concentrations of plasminogen activator inhibitor-1, E-selectin, and angiopoietin-2 as markers of endothelial activation and S100B as a marker of blood-brain barrier/neurological injury in blood collected at enrollment. We assessed patients for delirium and coma twice daily after enrollment using the Confusion Assessment Method for the ICU and the Richmond Agitation-Sedation Scale. Among 134 patients with a median (interquartile) age of 57 years (46–66 yr) and Acute Physiology and Chronic Health Evaluation II of 26 (19–31), delirium occurred in 94 patients (70%) with a median duration of 2 days (0–4 d). Higher plasminogen activator inhibitor-1 (p = 0.002), E-selectin (p = 0.02), and S100B (p < 0.001) concentrations were associated with fewer delirium/coma-free days after adjusting for age, Charlson comorbidity index, modified Sequential Organ Failure Assessment score, and severe sepsis. Similarly, higher plasminogen activator inhibitor-1 (p = 0.007) and S100B (p = 0.01) concentrations were associated with longer delirium duration in survivors. Adjusting for S100B did not alter plasminogen activator inhibitor-1 and E-selectin associations with delirium, suggesting that these associations were not mediated by blood-brain barrier/neurological injury.
CONCLUSIONS:Elevated plasma markers of endothelial activation and blood-brain barrier/neurological injury during critical illness are associated with prolonged delirium after biomarker measurement. Future research is needed to determine whether these processes have pathophysiologic roles in delirium and whether therapies targeted at the endothelium or blood-brain barrier can prevent and/or treat delirium during critical illness.
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