An animal model of delirium during dementia

By Keith Jenkins,2014-04-29 21:52
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An animal model of delirium during dementia

    Personal experiences of delirium for the EDA website: request

     for help

     Annals of Delirium Personal experiences of delirium are an extremely effective way of July 2010 gaining the attention of healthcare workers either in the lecture

     theatre or on the wards. These stories are also an important way of Editorial enhancing clinical expertise in delirium practitioners. Welcome to this second edition of Annals of Delirium, an eclectic

    publication designed to educate, inform and provoke. The field of Because of this we would like to start a new initiative of collecting delirium study is moving at an increasing pace; it is difficult to keep these experiences and stories for the EDA website, with some also up with all the information now available in the medical literature published in the EDA newsletter. The extent of delirium throughout and hold down a full-time job (as most of us do). Hopefully this will the community means that clinicians often have their own stories; help keep you up to date until we can all submerge ourselves on for instance one of my surgical colleagues clearly remembers the feast of information that will be available at the European during a bout of childhood pneumonia getting particularly upset at Delirium Association annual Congress in November. the large pile of coal that was sharing his bed. Clinicians will

     frequently also have had contact with patients or colleagues who In this edition our President Jouko Laurila reflects on a delirium have had delirium and who are willing to share their experiences conference he attended in the States and looks forward to the EDA with others.

    Congress in Amsterdam. Dr Barbara Kamholz outlines the

    progress being made in the USA regarding delirium. Dr Colm We would like to invite you to share delirium experiences and Cunningham from Trinity College Dublin has provided a summary of stories with the wider community so they can be used to inform and his published paper recently published in Neurobiology of Aging on persuade people to take greater care of delirium. Any length or animal models in delirium. It is a fundamental step to start pinning format (ie. including pictures) is acceptable. All languages are very down the pathophysiology of delirium. Andrew Teodorczuk left welcome; if an English translation could be provided this would be those of us who attended the education workshop in the Leeds helpful but this is not required. All experiences and stories will be meeting last October with food for thought. He has now written a fully anonymised. Please email or write to me the Editor (all paper for the Annals, which I am sure you will find interesting. communications will be strictly confidential and handled by the Again we have the editor‟s choice – recent publications you might Editor only until anonymised).

    have missed and our news section including the results of our

    website poll. met vriendelijke groet!

     Valerie Page

    If there‟s any delirium related matter you would like to share with Editor,

    your colleagues at home and abroad then send it in to the Annals Department of Anaesthesia, Watford General Hospital, Vicarage and we will publish it! (Editor‟s approval permitting). Road, Watford. WD18 0HB. UK

    ; European Delirium Association 2010 International Congress 11 - 12 November , Amsterdam

Dear Readers,

    As most of you have already noticed, the scientific programme of While everything went wrong in the imaginary play happening in the the 5th Scientific Congress on Delirium is now published online middle of the night, the audience had to through the reasons why ( and suggest alternative ways for Nurse Betty to handle her difficult And what a programme! Sophia de Rooij and colleagues have done night shift.

    brilliantly. Attached to this conference was also a follow-up meeting of the The congress covers many topics familiar to delirium audiences but ongoing establishment of the American Delirium Society. also features some thrilling new openings, such as Delirium in I had a chance to present the whole audience with the history and Palliative Care and Delirium Tremens both of which are aims of EDA, as well as EDA‟s influence as a source of information, highlighted also by workshops. research network, and as an important arena for general Once again the keynote speakers are among the brightest stars in multidisciplinary discussion. I also mentioned our Annals of Delirium the delirium sky. There‟s no doubt also that the younger scientists and, naturally, advertised our forthcoming Amsterdam congress. I will send their abstracts to Amsterdam, the most important delirium was very pleased to notice that many of the participants already event in the world in 2010. Please subscribe as soon as possible, new about the congress and were even planning to attend (must be send your abstracts and spread the word about this congress to all Barbara Kamholz‟s influence).

    your colleagues wherever you go!

    A month ago, on June 8-9, I was privileged to take part to an Let‟s all meet in Amsterdam!

    American delirium conference, Advanced Delirium Science in Jouko Laurila

    Baltimore, Maryland. The conference was organised by the

    Department of Veteran Affairs Employee Education System and

    Office of Geriatrics and Extended Care. It was an educational event

    with some new data presented, as well. There were over 100

    participants. Speakers included Joseph Francis, James Rudolph

    and Barbara Kamholz. In addition to them, I especially enjoyed the

    delirium demonstration in which Joseph Flaherty (geriatrician) acted

    as a delirious World War II veteran and Sharon Gordon (psychiatrist)

    her “Nurse Betty”.

    ; European Delirium Association 2010 International Congress 11 - 12 November , Amsterdam

    An animal model of delirium during dementia. periphery. We had already proposed the existence of these primed Last month saw the publication, on-line, of studies describing the microglia and hypothesized that these exaggerated CNS responses first animal model purposefully designed to mimic delirium during could be a key risk factor for delirium in the aged and demented dementia. The paper, entitled population in a Nature Reviews Neuroscience article in 2003 but its “Systemic inflammation induces acute working memory demonstration required rather involved experiments. deficits in the primed brain: relevance for delirium” has been

    published in the journal Neurobiology of Aging and comes from the In the current study we started with an animal model of progressive laboratory of Dr. Colm Cunningham in Trinity College Dublin amyloidosis, synaptic loss, neurodegeneration and microglial (Murray et al., 2010). The findings reported represent the strongest activation (the ME7 model of prion disease), which also produces empirical evidence yet that systemic inflammation and ongoing progressive impairments in reference and working memory. In the chronic neurodegeneration interact to produce acute and transient early, asymptomatic, stages of disease we then superimposed a impairments in cognitive function in the brain region in which prior systemic challenge with bacterial endotoxin (lipopolysaccharide, pathology has occurred, and suggest that this model has the LPS 100µg/kg) to mimic a mild to moderate gram-negative bacterial potential to reveal insights into inflammatory routes to delirium. infection, since such infections frequently trigger episodes of

     delirium in the aged and demented population. We hypothesized This research has its genesis in the original description of microglial that hippocampal synaptic loss and accompanying microglial priming. In those original experiments (Cunningham et al., 2005) we activation during chronic neurodegeneration in the ME7 model showed that the major brain macrophage population, the microglia, would predispose these animals to acute dysfunction in the was partially activated, or “primed”, in response to their sensing of hippocampus upon systemic inflammatory activation. LPS induced degenerative changes in the diseased brain. These cells then acute and transient working memory deficits in ME7 animals on a respond more robustly to subsequent inflammatory challenges, novel T-maze working memory task, but did not do so in normal whether these challenges are made directly to the CNS or in the animals. LPS-treated ME7 animals showed heightened and ; European Delirium Association 2010 International Congress 11 - 12 November , Amsterdam

    prolonged transcription of inflammatory mediators in the CNS, such as a mouse. However, we have chosen to focus on a number compared to LPS-treated normal animals, despite having equivalent of key features that are potentially analogous to some core levels of circulating cytokines. These data provide a rationale for the cognitive and temporal features of delirium.

    finding that, while elevated systemic cytokines such as IL-6 and IL-8 1) Episodes are of acute onset and transient and can be are associated with delirium in hip fracture patients, pre-existing distinguished from chronic cognitive impairments. cognitive impairment remains the stronger predictor of delirium.

    Similarly the finding that even higher doses of LPS did not induce 2) The interaction of systemic inflammation and existing or incipient acute deficits in normal animals suggests that even the dementia is one very common multi-factorial etiological route to exaggerated inflammatory mediator production facilitated by primed clinical delirium and is mimicked in a biologically relevant way in the microglia may not be sufficient, alone, to induce the acute current study.

    dysfunction. The vulnerability of hippocampal function may be 3) There are similarities in the nature of the cognitive deficits caused by a loss of „cognitive reserve‟. That is to say that there observed in the T-maze and allocentric Y-maze and some of those may be a threshold below which hippocampal synaptic activity must in human delirium: WHO ICD-10 diagnostic criteria include drop before dysfunction is observed on this working memory task. “impairment of recent memory.….disorientation for time as well as, The current data are consistent with the hypothesis that disease in more severe cases, for place”: Our previous studies showed that lowers synaptic activity towards this hypothetical threshold and that ME7+LPS animals made significantly more errors in learning the LPS precipitates a drop below this threshold and the occurrence of location of a fixed exit in a reference memory task, but could working memory deficits. remember this location if the environment was completely familiar

     before experiencing LPS-induced sickness (Cunningham et al., Can we really model delirium in mice? 2009). Adding the temporal components required for performance Delirium is obviously a complex syndrome comprising impairments in the working memory T-maze reveals acute and transient in attention, orientation, memory, level of arousal, perception and dysfunction even in a familiar environment. Thus LPS-induced affect, and psychotic disturbances. It is not reasonable to expect impairments become apparent when the processing and retention that we can replicate all of these features in a non-verbal animal of novel, trial-specific information, for just 30 seconds is required to ; European Delirium Association 2010 International Congress 11 - 12 November , Amsterdam

    Full reference: accurately perform the task. Using Hart‟s cognitive test for delirium,

    Carol Murray, David Sanderson, Chris Barkus, R.M.J. Deacon, patients with delirium perform particularly badly relative to patients

    J.N.P. Rawlins, David Bannerman and Colm Cunningham. (2010) with dementia on tasks requiring retention and processing of novel, Systemic inflammation induces acute working memory deficits in

    the primed brain; relevance for delirium during dementia. trial-specific information over similar periods of time.

    Neurobiology of Aging (In press, doi:10.1016/j.neurobiolaging.2010.04.002)

     Thus, we propose that systemic inflammation can target particular

    This paper is OPEN ACCESS. brain regions on the basis of existing pathology in those regions

    and that the current model allows us to study these interactions. Work leading up to these findings: More global pathology, as observed in Alzheimer‟s disease for Cunningham, C., Campion, S., Lunnon, K., Deacon, R.M.J, Rawlins,

    J.N.P. and Perry, V.H. (2009) Systemic inflammation superimposed example, would predict more global cognitive dysfunction upon

    on chronic neurodegeneration induces acute behavioural and systemic inflammatory insult. Therefore the current hippocampal-cognitive changes and accelerates neurological decline. Biological

    Psychiatry 65(4):304-12. centred model, with good reason, predicts only a subset of delirium

     symptoms. It is also worth mentioning that the working memory Cunningham, C., Wilcockson D.C., Campion, S., Lunnon K. and

    Perry, V.H. (2005) Central and systemic endotoxin challenges alternation task used here is also acetylcholine-dependent and

    exacerbate the local inflammatory response and increase neuronal therefore the current data are not inconsistent with a death during chronic neurodegeneration. Journal of Neuroscience

    25(40) 9275-9284. hypocholinergic explanation of delirium. Our current studies in the

     laboratory are directly assessing the role of acetylcholine in these Perry V.H., Newman, T.A. Cunningham, C. (2003). The impact of

    systemic infection on acute impairments.

    the progression of neurodegenerative disease. Nature Reviews Neuroscience. 4, 103-112.

    The pathophysiology of delirium is poorly understood and the lack

    Dr. Colm Cunningham of biologically relevant animal models has severely limited basic

    School of Biochemistry & Immunology research. It is now our priority, equipped with this new model Trinity College Institute of Neuroscience

    TCD system to examine which inflammatory pathways must be activated

    Dublin 2 in order to produce the acute and transient working memory deficits

    reported here. Email: ; European Delirium Association 2010 International Congress 11 - 12 November , Amsterdam

    Figure 2 Figure 1

    A hypothetical scheme to explain the effects of systemic LPS on cognitive In the working memory T-maze alternation task, in which the mouse must function in the „primed‟ brain. In this scheme „priming‟ refers to both the remember, for just 30 seconds, which arm they first visited in order to increase in microglial priming, thereby exaggerating local inflammatory inform the direction they must turn to escape the maze on being replaced mediator production, but also to synaptic loss, making specific there, normal animals (NBH) perform well and are not affected by LPS. neuroanatomical regions more vulnerable to disruption of function. LPS ME7 animals can also maintain good performance in this maze but show may activate local tissue macrophages but also may act directly at the acute and reversible working memory deficits upon systemic challenge cerebral vasculature. PGE2 can diffuse across the blood brain barrier with LPS to mimic bacterial infection. whereas the other molecules depicted are more likely to signal across the blood brain barrier by interacting with specific receptors on the endothelial

    layer. Abbreviations: IL-1b: interluekin 1 beta, TNF-a: tumour necrosis

    factor alpha, IL-6: interleukin 6, IFNa/b: interferon alpha/beta, PGE2:

    prostaglandin E2, IL-1RI: IL-1 receptor I, EP1-4: prostaglandin E receptors

    1-4, LPS: lipopolysaccharide

    ; European Delirium Association 2010 International Congress 11 - 12 November , Amsterdam

Delirium education: paradoxes and contradictions

     Dr Andrew Teodorczuk, Teaching Research Fellow, Northumbria

     Healthcare Trust, North Tyneside General Hospital, United



     However, a further controversy is that many interventions are Within the field of delirium education an important paradox exists. deficient in educational theory. Despite the old adage that, “nothing Despite growing research evidence for the effectiveness of training is more practical than a good theory”, little attention has been paid interventions, rather puzzlingly, educators working in the hospital to its role in delirium education (Teodorczuk et al., 2009). struggle to change staff behaviour through teaching. This paper aims to introduce readers to relevant educational Historically, education has been a mainstay in delirium theories which can improve teaching and be applied in a local management. Rockwood and colleagues originally demonstrated setting. The first part will examine traditional theories and the that raising awareness of delirium plays a key role towards second will consider a more contemporary theory. improving recognition (Rockwood et al., 1994). More recent studies show educational interventions not only prevent incident delirium, Traditional educational theories include behaviourism, cognitivism, but also reduce medication use, length of stay and severity (Inouye humanism (including adult learning theory), social constructivism et al., 1999, Milisen et al., 2001, Lundstrom et al., 2005, Pierre, and social learning (Merriam et al., 2007). Though all hold different 2005). stances in terms of the mechanisms which lead to learning, they are similar in that they consider learning which occurs at an individual level (Table 1). General guidance for educators is to adopt a blended approach in order to shape the teaching to meet the needs Yet, delirium educators report problems with translating these of the learner and goals of the educational encounter. Hence, if the strong research findings to the local setting. A pragmatic multi-site purpose of education is to improve assessment of cognitive state, a study showed, even with additional teaching, hospital staff have teacher may adopt a behaviourist approach combined with an considerable difficulty adopting theoretically sound guidelines to element of modelling to shape learning towards optimal practice of influence care outcomes in a positive manner (Young and George, the skill. 2003). In part, the paradox can be attributed to the fact that education is a social process; what works in one setting may not be suitable for another with different teacher, learner and environmental factors.

    ; European Delirium Association 2010 International Congress 11 - 12 November , Amsterdam

Theory View of learning Focus of teaching Example of applying theory into practice


    Behaviourist A change in an individual‟s Adapting the environment Rewarding good delirium practice through praise

    behaviour to shape the learner‟s


    Cognitivist An information building Trying to structure the Activating prior knowledge of delirium and addressing any

    process and prior knowledge content of a teaching misunderstandings

    play a central role in encounter to enable a

    organising learning learner to “assimilate” the


    Social A social process in which Creation of a “reflective Encouraging the learner to reflect on own practice of delirium management constructivism the context and conditions of dialogue” to enable and think critically about how it could be improved

    learning are crucial critical thinking to occur

    Humanism Self-growth is the key Creating the conditions to Encouraging the learner to take responsibility for learning and identifying

    component of learning help the learners achieve own cases to learn around

    their own development

    Vicarious Learning occurs as a result Teacher models best Shadowing a liaison nurse who is an expert in delirium management

    learning of observing and modelling practice

    ; European Delirium Association 2010 International Congress 11 - 12 November , Amsterdam

    Table 1 Traditional learning theories theory and practice result of a developmental dialogue between agencies, a learning

     agreement was set out which resulted in improved coordination and Despite an understanding of these educational theories being communication with clearer loci of responsibility, reduced necessary for delirium education, traditional theories alone may be duplication of visits and greater sharing of knowledge amongst insufficient to bring about an improvement in delirium care in the providers. Ultimately, Engestrom argues, this higher level learning, complex ward environment. Arguably, such “individual level” though potentially more dangerous because it involves challenging learning theories may be less applicable in the workplace because systems, brought about greater change than a traditional the key difficulty that staff encounter resides with implementation, educational approach.

    not assimilation, of knowledge. For example, a doctor may “know”

    that prescribing a drug in a particular clinical encounter is potentially Social Activity Theory is suited to complex care scenarios with dangerous, but this may not stop such behaviour if the ward multiple agency involvement. As such, it is particularly applicable to expectation is to prescribe. delirium care. Moreover, from our preliminary exploration of staff‟s

     learning needs, it is evident that the greatest barriers to learning are A contemporary theory with a high degree of applicability to delirium at an organisational and system level. Social Activity Theory has education is Engestrom‟s Social Activity Theory (Engestrom, 2009). the potential to address these barriers and generate innovative Activity theory, originated from Vygotsky‟s work, and seeks to tackle transformational methods of change. Clearly the contradictions the problem of changing behaviour across boundaries and agencies. which have to be resolved will vary between hospitals and no blue In contrast to more traditional theories, it views knowledge as print will exist; however adoption of a broader view of education and residing outside of individuals and within organisations. Accordingly identification of the contradictions which compromise care will knowledge is shared across socio-cultural boundaries, rather than facilitate organisational learning.

    being vertically transmitted in a traditional fashion.

     In summary, this brief paper has given an account of the A central tenet of the theory is that organisational challenges are controversies within delirium education and limitations of traditional not resolvable by the sum total of separate individuals. Furthermore, approaches. Furthermore, the need for conceptualisating education learning should occur by an “expansive" process. This cycle of beyond an individual level and integrating more contemporary expansion involves questioning; contradiction analysis; modelling; educational theory are outlined. Returning to the paradox of why examining the model; implementing the model; examining and delirium educators struggle to change behaviour through teaching, finally consolidating new practice. arguably the answer rests with the difficulty that staff encounter

     implementing new knowledge within the organisations where they In practice, social activity theory has been used in the Helsinki work. To bring about real change, system learning should proceed Boundary Crossing Lab project to improve previously dysfunctional in tandem with traditional education approaches. care in paediatric hospitals. A major contradiction or “knot” was

    identified between the person centred care pathway in the

    community and the disease centred protocols in hospital. As a

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     YOUNG, L. J. & GEORGE, J. (2003) Do guidelines improve the

    process and outcomes of care in delirium? Age Ageing, 32, ENGESTROM, Y. (2009) Expansive learning: toward an activity-

    theoretical reconceptualization. IN ILLERIS, K. (Ed.) 525-8.

    Contemporary Theories of Learning.



    Acknowledgements. COONEY, L. M., JR. (1999) A multicomponent intervention

    to prevent delirium in hospitalized older patients. N Engl J This paper is based on a workshop facilitated at the European

    Med, 340, 669-76. Delirium Association Scientific Meeting, Leeds 2009. I would like to

    LUNDSTROM, M., EDLUND, A., KARLSSON, S., BRANNSTROM, thank Dr Sally Corbett, workshop co-facilitator for her help.

    B., BUCHT, G. & GUSTAFSON, Y. (2005) A multifactorial

    intervention program reduces the duration of delirium, length

    of hospitalization, and mortality in delirious patients. J Am

    Geriatr Soc, 53, 622-8.

    MERRIAM, S. B., S., C. R. & BAUMGARTNER, L. M. (2007)

    Learning in adulthood, San Francisco, Jossey-Bass.



    DELOOZ, H. H., SPIESSENS, B. & BROOS, P. L. (2001) A

    nurse-led interdisciplinary intervention program for delirium

    in elderly hip-fracture patients. J Am Geriatr Soc, 49, 523-32.

    PIERRE, J. S. (2005) Delirium: a process improvement approach to

    changing prescribing practices in a community teaching

    hospital. J Nurs Care Qual, 20, 244-50; quiz 251-2.


    D., JARRETT, P. & O'BRIEN, B. (1994) Increasing the

    recognition of delirium in elderly patients. J Am Geriatr Soc,

    42, 252-6.


    LADINSKA, E. (2009) Developing effective educational

    approaches for Liaison Old Age Psychiatry teams: a

    literature review of hospital staff‟s learning needs in relation

    to managing the confused older patient. International

    Psychogeriatrics. In press

    ; European Delirium Association 2010 International Congress 11 - 12 November , Amsterdam

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