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Pathophysiology and Management of Delirium. Alasdair MacLullich Edinburgh Delirium Research Group Geriatric Medicine University of Edinburgh. Background. 75-90 patients per 500-bedded hospital 1 in 5 dead in a month  New institutionalisation Distressing Cost = £€$ Billions

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Pathophysiology and Management of Delirium


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    1. Pathophysiology and Management of Delirium Alasdair MacLullich Edinburgh Delirium Research Group Geriatric Medicine University of Edinburgh

    2. Background

    3. 75-90 patients per 500-bedded hospital 1 in 5 dead in a month  New institutionalisation Distressing Cost = £€$ Billions Yet … grossly underdiagnosed and undertreated

    4. Mortality in delirium ~ 20% dead in 30 days ~ 40% dead in 1 year

    5. Persistent delirium Cole et al., Age and Ageing 2009

    6. Pathophysiology

    7. Predisposing factors • Young and old age • Cognitive impairment • Cardiovascular comorbidity • Depressive illness • Male sex

    8. Neuroimaging markers of delirium risk Caudate volume p=0.031 MacLullich et al., in preparation

    9. Acute causes of delirium: the whole of medicine?

    10. Acute causes of delirium • Hypoxia • Hypercapnia • Hypercalcaemia • Hypoglycaemia • Drugs, esp. some classes • Stroke • Traumatic brain injury • Infection • Myocardial infarction • Acute renal failure • Psychological stress • etc.

    11. "So why does this UTI make my nan go loopy, doc?"

    12. Direct brain insults • Hypoxia • Hypercapnia • Hypercalcaemia • Hypoglycaemia • Drugs, esp. some classes • Stroke • Traumatic brain injury • etc.

    13. Aberrant stress responses • Infection • Myocardial infarction • Psychological stress • etc.

    14. Direct brain insults Aberrant stress responses Delirium

    15. Stress systems and delirium

    16. stressor Inflammation Glucocorticoids CRH ACTH SNS catecholamines

    17. Complexity of stress responses McEwen, 2008

    18. Stress responses result from: threat change uncertainty novelty loss of control injury illness (including infection) pain

    19. Acute versus chronic stress A healthy, adaptive stress response is short-term The stress response is catabolic Systems need to restore energy supplies, etc., after an episode of stress Prolonged stress is harmful

    20. Glucocorticoids and cognition Moderate cortisol required for adequate arousal  cortisol enhances focused attention  cortisol impairs divided attention  cortisol impairs complex cognition

    21. Prefrontal regulation during alert, non-stress conditions Arnsten 2009

    22. Amygdala control during stress conditions Arnsten 2009

    23. Prefrontal vs amygdala modes of cognition? stressful stimulus amygdala DA, NA PFC function GCs HPA Adapted from Arnsten, Nat Rev Neurosci, 2009

    24. Sickness behaviour syndrome (Hart, 1988) • Acute illness associated with: • weakness • lethargy • inability to concentrate • depression • reduced social interaction • reduced appetite • reduced activity

    25. Sickness behaviour is adaptive (like fever) • coordinated response of physiology and behaviour • conserves energy • resources focused on threat • helps reduce spread of infection (withdrawal)

    26. Inflammation: communication with CNS • Several routes: • vagus afferents (thoracic/abdominal inflammation) • cytokines activate cells in CNS where BBB is absent • cytokines and other mediators communicate via BBB • cytokines enter brain (eg. TNFα via specific receptors)

    27. Acute Stress HPA, SNS, inflammation Effects on brain No cognitive effects Mild cognitive effects

    28. Adaptive brain states • Normal state • No psychosocial stress • No acute illness • Planning, complex thought • Prefrontal cortex processing dominates • (2) Psychosocial stress • Threat, novelty, uncertainty, fear • Outward focus/high vigilance • Prepared for action • Amygdala processing dominates • (3) Illness, injury • No immediate threat/call to action • Sickness behaviour syndrome •  CNS activation: drowsiness pathways • Brain substrates unclear

    29. ‘Direct’ insults may result in a stress response • Hypoxia • Hypercapnia • Hypoglycaemia • Stroke • Traumatic brain injury

    30. HPA axis and delirium

    31. High glucocorticoids can cause Cognitive deficits, including inattention Depression Psychosis Delirium

    32. Psychological stress: dendritic atrophy &  neurogenesis

    33. Higher GC concentrations exacerbate • hypoxia • excitotoxicity • hypoglycaemia • β-amyloid toxicity

    34. LHPA feedback regulation limbic cortex (eg. anterior cingulate) — hypothalamus + negative feedback loops pituitary + adrenal + Cortisol

    35. Adaptive stress response: fast shut-off stressor GR occupied • cortisol (nmol/l) time (hrs)

    36. Impaired shut-off: prolonged occupation of GR operation ?GR occupied 1200 1000 800 • cortisol 600 400 200 0 1 2 3 4 5 6 7 8 9 10 days

    37. Cerebrospinal fluid analyses in delirium Delirium (> 20%) Delirium (40-60%) outcome hip # surgery CSF via spinal anaesthesia

    38. CSF cortisol higher in hip fracture patients with delirium p=0.045 Pearson 2010

    39. Inflammation and delirium

    40. Inflammation and delirium Multiple studies linking peripheral IL-6, etc., with delirium CSF IL-8 higher in delirium Animal models (Cunningham) peripheral LPS induces CNS IL-1b, etc

    41. Peripheral inflammation induces CNS IL-6 Expression of CNS IL-6 Peripheral bacterial endotoxin injection Peripheral saline injection Cunningham et al, J Neurosci, 2005

    42. Peripheral inflammation induces CNS IL-1β Peripheral saline injection Peripheral bacterial endotoxin injection Cunningham et al, J Neurosci, 2005

    43. Delirium is associated with  CSF IL-8 MacLullich et al, submitted

    44. Delirium is associated with  CSF IL-1β 3 2 IL-1β concentration (pg/ml) 1 Yes No Delirium Cape et al, submitted

    45. Interactions among stress systems

    46. LHPA feedback regulation limbic cortex (eg. anterior cingulate) — hypothalamus + CYTOKINES negative feedback loops pituitary + adrenal + Cortisol

    47. HPA-immune system interactions IL-6 stimulates HPA axis TNFalpha, IL-1β downregulate multidrug resistance protein:  CNS glucocorticoids TNFalpha and IL-1β upregulate 11β-HSD1:  CNS glucocorticoids Pre-treatment with glucocorticoids: CNS inflammatory response to peripheral LPS Etc.

    48. Cortisol interactions with neurotransmitters • Reduce cholinergic transmission • Enhance dopaminergic transmission • cortisol: ‘amphetamine-like effect’ • Enhance noradrenergic transmission • Inhibit GABA

    49. Acute Stress HPA, SNS, inflammation Effects on brain Vulnerable brain No cognitive effects Delirium Mild cognitive effects

    50. Delirium: acute and chronic stress Delirium often triggered by acute event However, stimulus often chronic (days, weeks) Fracture Infection Delirium itself may be a stressor Fear, uncertainty, loss of control Stress response duration is abnormally sustained