The American Geriatrics Society/National Institute on Aging Bedside‐to‐Bench Conference: Research Agenda on Delirium in Older Adults

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 (Figure 1). Delirium can be thought of as acute brain failure that occurs when stressors exceed the brain's homeostatic reserve (Figure 2). Celsus initially described delirium in the 1st century CE (c. 47 CE, Aulus Cornelius Celsus, De Medicina, 2.7.28), but little in the way of progress was made until the early 1980s, when delirium first appeared in the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM III). The most current definition of delirium was recently published in the 5th edition of the DSM and includes a disturbance in attention and awareness; a change in cognition that is not better accounted for by a preexisting, established, or evolving dementia; that the disturbance develops over a short period and tends to fluctuate during the course of the day, and that there is evidence that a direct physiological consequence of a general medical condition, an intoxicating substance, medication use, or more than one etiology causes the disturbance.1 The DSM definition can be difficult to operationalize or quantify in certain settings. Although a number of approaches exist, the diagnostic approach most commonly used is the Confusion Assessment Method (CAM) four-item diagnostic algorithm, which trained physicians and nurses and other allied health personnel can apply;2 the use of the CAM format for delirium evaluation has expanded widely, and valid and reliable forms are now in use in numerous healthcare settings (e.g., b-CAM for “brief” emergency medicine evaluations,3 p-CAM intensive care unit (ICU) for pediatric use,4 and CAM-ICU for intensive care unit use).5 Different clinical phenotypes have been described, including the psychomotor variants of hyperactive and hypoactive delirium, frank hallucinations or delusions, and abnormal levels of consciousness. The incidence of delirium varies widely depending upon the population studied, ranging from approximately 15% after some types of elective surgery to as high as 80% in ICU populations.6 Delirium is associated with a variety of poor outcomes, including cognitive and functional decline, longer hospital stay, greater healthcare use, and long-term morbidity and mortality. The number of indexed articles in standard bibliographic databases on delirium has increased from fewer than 50 per year in the 1980s to more than 350 per year in 2012, highlighting increased efforts to differentiate delirium from other cognitive disorders and the impetus for developing novel treatment strategies. The relationships between delirium and other geriatric syndromes such as sleep disorders, voiding dysfunction, and frailty are developing areas of research.7 Sleep disorders are extremely common in older adults and may result from a combination of age-related changes in sleep physiology, comorbid conditions, medications, primary sleep disorders, and other factors. Thus, sleep complaints in older adults may be viewed as a geriatric syndrome.8 Sleep disturbances and delirium may be linked through impaired circadian rhythms and lower melatonin secretion observed during delirium.9, 10 Alternatively, sleep deprivation11 and other primary sleep disorders such as obstructive sleep apnea may contribute to delirium in some clinical settings.12 Sleep disturbance and disruption of circadian cycling is a common feature accompanying delirium.1 Additional data suggesting an association between sleep disturbances and delirium come from studies that seek to improve sleep of hospitalized individuals that have also observed reductions in delirium. The multifactorial Hospital Elder Life Program13, 14 intervention strategy and the Johns Hopkins quality improvement intervention15 included nonpharmacological sleep protocols and demonstrated that fewer people developed delirium. Although a variety of interventions have been developed, research is needed to better understand the pathophysiological basis of the relationship between altered sleep and delirium in older adults and to use such information to develop and validate interventions that are optimally suited for individuals at risk for both conditions. Voiding dysfunction and delirium are classic geriatric syndromes that share multifactorial etiologies and often coexist in the same individual.7 Nevertheless, there has been little exploration of the relationship between these two syndromes. A wealth of knowledge has been gained from functional16 and structural17 neuroimaging studies exploring the role of specific brain circuits in the ability of the nervous system to sense, process, and implement actions relevant to continence and voiding based on bladder filling and a variety of other nongenitourinary factors, which indicates an important role of the brain in voiding dysfunction. Nevertheless, the hypothesized association between delirium and bladder function or incontinence is based more on clinical observations than systematic research reports, yet three lines of evidence support an association between these two syndromes. First, voiding dysfunction and urinary incontinence are common in patients with delirium and can be challenging to manage in individuals with clouded sensorium who may have difficulty attending to their voiding needs.18 Second, a condition known as cystocerebral syndrome, in which cognitive decline is observed in the setting of acute or subacute urinary retention, is likely to be much more common than the six case reports in the literature would suggest.19 Third, urinary tract infections, as with all infections, are a common cause of delirium. Finally, although treatments for voiding dysfunction, including urinary catheters and anticholinergic medications, may be associated with delirium,20 bladder antispasmodics alone appear to be a rare cause of delirium.21 From a pathophysiological standpoint, further research is needed to understand the bidirectional relationships between sleep disturbances, incontinence, and delirium, including their underlying central processes in elderly adults, and to use such information to develop and validate interventions optimally suited for individuals with these overlapping conditions. The geriatric conditions of delirium and frailty, although phenotypically distinct, may represent different clinical manifestations of age-related vulnerability,22 yet the potential associations between these conditions are not well understood. From an epidemiological perspective, frailty may serve as a risk factor for delirium and vice versa. For example, in individuals undergoing noncardiac or vascular surgery, preoperative frailty is independently associated with greater odds of developing postoperative delirium.23, 24 Conversely, although no studies have directly linked delirium with the subsequent development of frailty, evidence supports an association between delirium and poor outcomes. For example, delirium after an acute illness or surgery is an independent predictor of cognitive decline,25-27 functional decline or disability,28-30 and mortality,31, 32 suggesting a link between delirium and poor long-term recovery that may indicate the presence of new or worsened frailty. The pathophysiological mechanisms common to delirium and frailty include high baseline levels of inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor-alpha, high oxidative stress, mitochondrial dysfunction, high free radical production, cellular senescence, and dysregulation of the hypothalamic–pituitary–adrenal axis and sympathetic nervous system that may result in aberrant stress responses.33-35 Alone or in combination, these mechanisms are implicated in the dysregulation of neuronal activity (delirium) and the loss of network complexity between physiological systems (frailty). A better understanding of the common mechanisms between delirium and frailty may aid in the development of multicomponent prevention and treatment strategies for both conditions. By definition, most delirium in older adults is associated with concomitant medical or surgical illness, an observation that has suggested a role for one or more stressors. In general, older adults are thought to have less physiological reserve and therefore less capacity to maintain homeostasis in response to stress (homeostenosis) than younger individuals.36 The effects of stressors are probably coordinated rather than independent, and the affected systems are interrelated rather than isolated.37 Psychoneuroimmunology is the study of the complex interactions between psychological, neural, and immunological processes in response to stress. Neuroimmunology systems appear to be related to the pathophysiology of delirium, specifically because delirium may be the human manifestation of an exaggerated or maladaptive form of “sickness syndrome,”38 which is the sum of the coordinated adaptive changes that occur in individuals, primarily in response to infection. Two lines of experimental evidence highlight the role of neuroinflammation in delirium pathophysiology through alteration of the blood–brain barrier (BBB) and de novo synthesis or elaboration of inflammatory mediators in the central nervous system (CNS). The BBB normally protects the CNS, but BBB dysfunction can expose neuronal tissue to systemic inflammatory mediators and may lead to delirium.39, 40 Alteration of BBB endothelial cells has been associated with greater BBB permeability and impaired brain microcirculation, and systemic endothelial dysfunction is associated with delirium during critical illness.41 Neuroinflammatory activity also appears to play a role in neurotransmitter dysregulation. Cholinergic hypofunction has been implicated in delirium42 and demonstrated as a susceptibility factor for acute inflammation-induced cognitive dysfunction in mice.43 High CNS IL-6 levels are associated with degeneration of gamma-aminobutyric acid (GABA)ergic interneurons and the development of delirium.44, 45 IL-1β and cyclooxygenase-1-derived prostaglandins have been shown to be causative of acute cognitive dysfunction in an animal model of delirium superimposed on dementia.46 Studies of GABAergic medications (e.g., benzodiazepines), which have been associated with a high incidence of delirium, provide clinical data in support of GABAergic dysregulation contributing to delirium.47 One of the interesting implications of the construct of psychoneuroimmunology in relationship to delirium is the potential for psychological factors to play a role. Factors influencing resilience (the capacity to manage or adapt to insult) have recently been described as components of the construct of reserve capacity.48 Conceptually, enhanced emotional and physiological reactivity to stress may be due to a deficiency in reserve capacity or limited opportunities to replenish reserve resources.49, 50 Psychosocial therapeutic approaches attempting to improve reserve may present a novel treatment strategy to reduce the severity of pathophysiological insults and thereby improve delirium and long-term cognitive outcomes.51 Understanding the cognitive manifestations of the specific and interrelated mechanisms underlying delirium remains a fundamental challenge. Animal models provide a unique opportunity to determine whether purported associations are actually causal. Pragmatically, an animal model may examine a subset of crucial processes in delirium. A recurring debate throughout the conference was the relevance of animal models to understanding the multifaceted complexity of delirium in humans and their role in promoting translation of mechanistic findings to potential therapies. Animal research has focused on specific mechanisms by which psychoneuroimmunological systems may lead to delirium. We are only beginning to understand the ways in which mechanisms such as predisposing factors (neurodegenerative disease,52 hypocholinergia,43 or primed microglia53) may interact with precipitating factors such as inflammation to cause delirium. The term “biomarker,” a portmanteau of “biological marker,” refers to a broad subcategory of medical signs—that is, “objective indications of medical state observed from outside the patient—which can be measured accurately and reproducibly.”54 Biomarkers could potentially be used to or phenotypes of delirium, and to Biomarkers for delirium be developed broad (e.g., or cellular tissue or physiological such as or from such as and the the the CNS but can be difficult to on a Although is much more the and of for delirium of the in delirium has from on inflammation and studies that the of such as and may the presence of which may in to postoperative delirium. in the are in individuals with and a study of individuals who or demonstrated that individuals with the of preoperative incidence and greater severity of postoperative evidence to the role of risk factors, such as in the presence of one or more has been to be an independent predictor of delirium in critical illness, after for and the risk of delirium in older adults undergoing although other studies no association between and the brain systematic changes general are on and can be used to the state of elderly adults general This approach a way of and may also reduce the incidence of delirium and postoperative cognitive dysfunction in elderly adults after surgery and a that other not in that and direct of activity in the can be used to quantify the and of delirium in a as a diagnostic has been thought to be only to the CAM in and as a delirium neuroimaging studies have the association between delirium and and functional changes in the evidence supports an association between delirium severity and neuroimaging including and on changes of on loss of by on measured and alteration in functional measured by functional although that greater severity of delirium is associated with subsequent loss of and in changes in the and altered functional in these areas provide for clinical of delirium. of these studies include poor and and functional of the etiologies of delirium and neuroimaging broad of studied, and limited for linked to delirium, and age-related brain clinical use for models of delirium. CNS measured and as described have been in models of inflammation and neurotransmitter a critical in understanding the complex interrelated associated with and delirium and in developing treatment strategies. Delirium can develop in individuals the of cognitive although a of evidence supports baseline cognitive or as one of the predisposing risk factors for Delirium was thought to be a syndrome, but the long-term effects of delirium on cognitive function are now First, with baseline cognitive and who develop delirium a decline in cognitive function than who develop Delirium also appears to the of cognitive decline in with Second, in individuals undergoing surgery, delirium was associated with an acute decline in cognitive and cognitive dysfunction that not after Finally, in individuals, of not have evidence of cognitive their illness, the of delirium was independently associated with cognitive decline or new cognitive independent of or other comorbid medical Thus, delirium appears to cognitive in with cognitive and and may result in de novo cognitive in with The mechanisms the clinical associations between acute brain dysfunction and cognitive are and are an of studies in individuals with delirium a variety of studies in individuals with cognitive decline in the setting of delirium a different from (e.g., or vascular when findings the combination of delirium and such findings cognitive than would be with to or manage an of delirium can be and nonpharmacological strategies. such as and are the most commonly used in clinical and have been for delirium prevention and Nevertheless, literature that these may have limited for have been more multicomponent interventions that on of delirium risk factors and approaches to reduce these risk treatment interventions include delirium case and treatment of predisposing and precipitating factors, prevention and of common and of cognitive and that the of these interventions may be specific to the clinical appears to be to an of delirium than is to delirium delirium prevention strategies have focused on delirium risk factor and physiological stressors. of delirium may be to the homeostatic reserve to the ability to for physiological stress such as This may be when the is such as elective or surgery (e.g., is a approach that (e.g., and psychological strategies to and is potential and or support are associated with although not yet may be to delirium no widely delirium intervention is novel strategies are The delirium intervention be and and to individuals, and hospital and have delirium is a complex syndrome, is likely that a approach will be needed to the of Although protocols are certain components of delirium intervention may be For example, have been for the treatment of delirium, and these have been to and understanding of the relationship between delirium, and may in interventions based on and response to these are important when novel delirium interventions in clinical The and be Understanding the population is because may depending on the of individuals with frailty, or critical delirium can be in a number of outcomes, or a combination of are measured and directly Delirium is a common in delirium intervention and is often used as a for delirium but can be because of and interventions that reduce delirium have not been shown to reduce in the is no delirium severity the hyperactive of delirium and may or hypoactive delirium, although the recently four-item CAM severity is an to address delirium severity or (e.g., would not only potentially provide a for intervention but would also of future The effects of delirium on healthcare use and long-term are Thus, delirium are including relevant such as healthcare hospital of stay, and through such studies involving older the of use of to cognition is often difficult to in with delirium than elective although could be more in the of a of which and are delirium intervention have to for is that specific of individuals (e.g., delirium superimposed on or hypoactive may in their response to different intervention strategies. delirium is fundamental to Delirium is a clinical and therefore of study personnel and quality to reliable throughout the of is also important to the and quality efforts in the in delirium may also to of delirium can be difficult in certain such as individuals with and with hypoactive is more but and such as can different studies by for of clinical although there is no for delirium intervention approaches may in such as individuals undergoing surgery and The acute stress and inflammation associated with surgery older adults at risk of delirium. The risk of postoperative delirium is to be related to the of the surgical and is affected by a number of other factors including comorbid conditions, of in to surgical and factors associated with recovery from the such as medications, and The and of can the stress response and may serve as one way to the risk of postoperative For example, although only the response to surgery, with the stress or may result in of the stress Thus, is hypothesized that the of or could the incidence of postoperative delirium. Although the literature has not shown a is an of The of or and other are the of in delirium prevention and treatment in the setting as a primary or The of these studies are participants and older who are undergoing or other surgical of these are treatment of delirium and are a variety of including and strategies are in novel and and and and strategies (e.g., are the of Finally, studies are nonpharmacological interventions including the Hospital Elder Life treatment of sleep and a delirium intervention is in clinical remains a challenge. the translational from to has been an of and more than with limited and is opportunity to and its through clinical for of information and A number of and research from the and at the are to broad Studies examine the and between delirium and other geriatric including sleep disorders and voiding dysfunction, and for intervention opportunities that be for individuals at risk or more than one of these syndromes. of the of frailty to delirium in a variety of clinical settings be as the role of delirium in the subsequent development of frailty in medical and surgical settings. studies and of both understanding of and ability to manifestations of delirium (e.g., superimposed on will be to the relationship between delirium, and other conditions. better understanding of and of delirium, whether delirium a or whether would be to delirium to be One such could be delirium in individuals with or delirium in individuals with of psychoneuroimmunological systems is to the understanding of delirium pathophysiology and may provide potential (e.g., of endothelial BBB cognitive for developing novel approaches to delirium prevention and of the between neurotransmitter systems and psychoneuroimmunological could provide opportunities to resilience to stress and delirium and treatment strategies be used as physiological to better understand the role of aberrant in the CNS (e.g., stress (e.g., and cognitive and systemic health factors (e.g., sleep in delirium of relevant for different potential of delirium, including and brain and protocols for and the BBB will understanding and clinical of delirium. between of delirium and severity remains to be of neuroimaging and after delirium be used to examine brain such as and neurotransmitter and with neuroimaging to provide a of neuroimaging of delirium. of neuroimaging of delirium neuroimaging data such as the could provide an approach to the is a to develop for delirium and quality for in all research is a to develop for definition of delirium in animal be also developed for data of and to be to delirium be to including cognitive as a primary or of clinical interventions for delirium of or functional and related to delirium (e.g., acute hospital of also be as outcomes. the homeostatic reserve to physiological stress is an in delirium and may be to homeostatic is an to the role of in the acute stress response and other potentially risk factors for delirium in the The of a delirium research for data to the study of delirium would be extremely We would to who conference, in Older Adults: Finding Order in the a The National Institute on Aging conference through This conference was also by the John A. Hartford Foundation, We are to and the participants who their and with the The in are of the and not represent the of the American Geriatrics or other of for in has a with Hospital based on for brain development by for on brain and of these have been to from for and has for for and has for from and is by the as its is an of the from and for an is a of The of the has a research from in with an support in the form of a from and from and for an of delirium. to in the of through on the and the and as The an was with of of of and and of of of of and Institute of of of of and Institute of of of National Institute on of and of of of American Geriatrics Society, of of of Life and of of and of of A. of of of for the of Bedside-to-Bench of on of and of of Johns Hopkins of of of of of of of Johns Hopkins of of The and of Johns Hopkins and