Annals of Delirium July 2012 Editorial
A Delirium Tipping Point Why   does   delirium   continue   to   be   persistently   under   recognised   and   mismanaged   across   the   health   care   spectrum?   What   reasons   do   we   have   to   explain   the   fact   that   despite   sound   ethical,   empirical   and   economical  arguments  this  highly  preventable  condition  continues  to   be   ignored   by   healthcare   planners?   Perhaps   most   perplexing,   how   can   such  a  devastating  disease  remain  invisible  to  the  general  public  for  so   long?   Conspicuous   by   their   absence   are   patient   and   carer   delirium   support  groups.   These   are   the   questions   we,   as   an   emerging   group   of   passionate   clinicians,   researchers   and   educators   within   the   European   Delirium   Association,   wrestle   with   on   a   daily   basis.   The   answers   are   undoubtedly   complex   and   to   use   a   favourite   word   amongst   delirium   cognoscenti,  "multifactorial".  Arguably  a  toxic  mix  of  the  complexity  of   the  illness  together  with  an,  as  yet,  comparatively  less  well  understood   pathophysiology   may   account   for   the   lack   of   ownership   encountered   at  so  many  different  levels.       In  trying  to  piece  together  the  pieces  of  this  jigsaw  puzzle  and  answer   the   big   questions   I   am   reminded   of   the   efforts   of   the   committed   group   of   clinicians   and   researchers   led   by   Blessed   and   Roth   studying   dementia   in   the   late   60s   and   early   70s.   The   challenge   was   great   however   by   a   series   of   small   but   significant   steps,   all   of   which   increased  our  understanding  of  dementia,  a  tipping  point  was  reached.    

    Tackling   the   issue   of   complexity,   in   this   edition   of   Annals,   Dr   Emma   Vardy   offers   a   personal   insight   into   the   problems   associated   with   applying   the   Confusion   Assessment   Method   in   the   acute   setting.   The   challenges   in   unravelling   the   pathophysiology   of   delirium   are   well   known   and   in   a   cutting   edge   article   Dr   Colm   Cunningham   considers   the   value   of   animal   models   in   basic   sciences.   Importantly,   he   is   not   afraid  to  honestly  answer  the  key  questions  as  we  try  to  link  bench  to   clinical  findings.         So  as  we  increase  our  understanding  of  delirium,  how  near  are  we  to   reaching   a   delirium   tipping   point?   The   challenges   remain   in   terms   of   recognition   and   raising   awareness   however   two   recent   events   that   I   have  encountered  provide  hope  that  we  may  not  be  far  away.     Firstly,   whilst   visiting   a   Dignity   award   winning   Trust   in   Birmingham,   I   was   introduced   to   a   simple   yet   effective   initiative   called,   ”Another   cup   of  tea  and  a  slice  of  cake".  This  very  English  innovation  involves  trying   to   reduce   dehydration   and   malnutrition   as   well   as   increase   stimulation   on   wards.   With   military   precision   volunteers,   managed   by   an  activities  coordinator,  facilitate  a  posh  tea  party  within  each  ward   bay  complete  with  china  plates,  fine  tea  and  cake.    When  asked  what   the   driver   for   this   was   staff   were   quite   clear   it   was   about   preventing   delirium   through   good   hydration   and   nutrition.   The   collective   response   made   me   wonder   whether   finally   staff   recognise   the   importance   of   delirium   prevention   and   crucially   link   delirium   to   dignity.    


©  European  Delirium  Association  2012  

The   second   delirium   story   of   hope   occurred   recently   when   assessing   an   OSCE   examination   station   for   medical   students.   The   task   for   the   students  was  to  explain  a  diagnosis  of  delirium  to  a  distressed  relative.     As   expected   they   struggled   with   describing   delirium   indicators   confidently.   However,   since   assessment   drives   learning,   the   fact   that   delirium   was   a   core   part   of   the   exam   process   represents   significant   progress  for  tomorrows  doctors.  Even  more  encouraging  was  a  chance   remark  from  the  seasoned  role  player  playing  the  part  of  the  relative   of   a   delirious   patient.   Reflecting   back   on   the   session   she   specifically   mentioned   how   real   and   important   the   scenario   was.   Finally   it   appears   the   reality   that   delirium   is   more   than   an   epiphenomenon   is   being  recognised.     Of  course  these  are  but  two  stories  of  hope  but  we  should  take  heart   from   them.   If   we   continue   on   our   quest   for   greater   understanding   and   couple   it   with   raising   delirium   on   the   public   agenda   we   can   remain   confident   that   a   larger   number   of   such   positive   encounters   will   emerge.   Different   challenges   will   present   themselves   however   under   recognition  may  no  longer  be  chief  amongst  them.   Dr  Andrew  Teodorczuk  

questions  in  delirium  pathophysiology  that  remain  unanswered. The   lack   of   animal   models   relevant   to   delirium   pathophysiology   has   been   one   of   the   significant   gaps   in   the   delirium   research   field   and   recent   studies   by   our   laboratory   have   tried   to   address   this   problem,   using   new   mouse   models   to   replicate   aspects   of   prior   degenerative   pathology  and  superimposed  systemic  inflammation  (Field  et  al,  2012;   Murray   et   al.,   2012).   Significantly,   we   showed   in   the   first   of   these   studies,   that   mild/moderate   systemic   inflammation   in   a   normal   animal   is   insufficient   to   induce   working   memory   deficits   but   when   the   same  inflammatory  challenge  is  made  in  animals  with  prior  pathology,   these   animals   now   show   acute   and   transient   working   memory   deficits   (Murray  et  al.,  2012).  This  ‘prior  pathology’  consists  of  robust  synaptic   loss  in  the  hippocampus  and  thalamus,  induced  by  the  ME7  model  of   prion  disease,  and  microglia  that  are  primed  by  the  primary  pathology   to  produce  exaggerated  responses  to  subsequent  inflammatory  insult   (Cunningham   et   al.,   2005).   Many   researchers   might   argue   that   this   prion   disease   model   is   not   directly   relevant   to   more   common   predisposing   factors   for   delirium,   such   as   Alzheimer’s   disease   and   age-­‐associated  cognitive  impairment.  While  this  is  an  understandable   view,   what   these   data   show,   unequivocally,   is   that   where   there   is   existing  pathology  or  ‘vulnerability’  in  particular  regions  of  the  brain,   systemic   inflammation   can   selectively   disrupt   function   in   those   regions   more   easily   than   it   can   in   normal   animals.   As   such,   it   provides   a   plausible   recapitulation   of   the   observation   that   systemic   infection   can   produce   profound   CNS   effects   in   some   patients   while   leaving   others   unaffected.   Understanding   this   dichotomy   is   central   to   elucidating  delirium  pathophysiology.  Useful  mechanistic  information   will  emerge  from  this  model.   Making  a  better  model   Nonetheless,  there  are  good  reasons  to  try  to  take  this  observation  out   of   the   prion   disease   setting   and   replicate   it   in   a   neuropathological  

A new animal model with potential to reconcile and dissect cholinergic and neuroinflammatory hypotheses of delirium
Colm Cunningham, Delirium Basic Research Group, Trinity College

It   has   been   recognized   for   some   time   that   existing   memory   impairment   is   one   of   the   biggest   risk   factors   for   the   subsequent   occurrence   of   delirium.   However,   it   is   not   clear   how   this   prior   impairment  interacts  with  the  typical  acute  precipitants  of  delirium,  to   induce  the  deficits  observed  in  patients.  This  is  just  one  among  many    

©  European  Delirium  Association  2012  

setting  not  involving  prions  and  in  a  neuroanatomical/neurochemical   setting   that   is   relevant   to   delirium   as   it   is   observed   in   the   geriatric   population.   Prominent   hypotheses   of   delirium   pathophysiology   include  both  hypocholinergic  and  neuroinflammatory  hypotheses  and   whether  these  are  parallel  and/or  interacting  is  largely  unknown.     Last  month  in  The  Journal  of  Neuroscience  we  published  new  findings   (Field   et   al.,   2012)   showing   that   systemic   inflammation   induced   by   gram-­‐negative   bacterial   endotoxin   (LPS)   induces   working   memory   deficits,  but  only  in  animals  with  prior  pathology  in  the  basal  forebrain   cholinergic   nuclei   (BFCN).   The   BFCN,   which   comprises   the   medial   septum,   the   diagonal   bands   and   the   nucleus   basalis   (see   Figure   1),   is   the   source   of   most   acetylcholine   in   the   forebrain   and   this   area   degenerates   markedly   during   Alzheimer’s   disease.   To   specifically   lesion   this   region   we   used   the   ribosomal   toxin   saporin,   covalently   linked  to  an  antibody  directed  against  the  p75  neurotrophin  receptor   that   is   highly   expressed   on   basal   forebrain   cholinergic   neurons.   We   showed   that   intracerebroventricular   injection   of   this   toxin   (p75NTR-­‐ saporin)  at  low  doses  could  induce  approximately  20%  destruction  of   the   cholinergic   cells   of   the   medial   septum   without   obvious   effect   on   working  memory  function.  However,  if  these  animals  were  allowed  to   recover   for   40   days   post-­‐surgery,   and   then   challenged   with   systemic   LPS,   only   those   animals   with   prior   lesions   showed   acute   working   memory   deficits.   Many   of   our   previous   predictions   about   the   interaction  of  prior  pathology  and  systemic  inflammation  were  based   on   the   original   demonstration   of   microglial   priming   and   subsequent   exaggerated  inflammatory  responses  to  systemic  inflammatory  insult   (Cunningham   et   al.,   2005).   However,   40   days   after   p75NTR-­‐saporin   lesions,   microglia   did   not   show   exaggerated   inflammatory   cytokine   induction   after   systemic   inflammation.   Thus   the   acute   working   memory  deficits  appear  to  occur  in  the  absence  of  microglial  priming.   This  independence  of  microglial  priming  does  not  imply  a  lack  of  CNS   inflammatory   response   to   systemic   LPS,   it   simply   means   that    

microglia   appear   to   respond   equally   to   systemic   inflammation   in   the   lesioned   and   normal   animals.   This   implies   that   the   ‘vulnerability’   in   these   animals   represents   a   neuronal   susceptibility   to   disruption   of   function.   We   showed,   using   the   acetylcholine   muscarinic   receptor   antagonist   scopolamine,   that   the   T-­‐maze   working   memory   task   used   in   these   studies   was   indeed   dependent   on   cholinergic   function   and   further  showed  that  treatment  with  the  acetylcholinesterase  inhibitor   donepezil,   1   hour   after   LPS,   protected   against   the   working   memory   deficit  observed.  Collectively  these  data  show  that  the  loss  of  20%  of   cholinergic  neurons  of  the  basal  forebrain  cholinergic  system  does  not   robustly  affect  cognitive  function  under  normal  conditions,  but  leaves   these   animals   vulnerable   to   significant   cognitive   disruption   upon   an   acute   systemic   inflammatory   insult.   The   data   also   show   that   preserving   acetylcholine   levels   using   an   acetylcholinesterase   inhibitor   is   protective   in   this   setting,   which   may   have   relevance   for   the   recent   trial  of  rivastigmine  for  ICU  delirium  (discussed  below).    

  Figure  1      

©  European  Delirium  Association  2012  

Figure  1   Prior   pathology   and  superimposed   systemic   inflammation   interact   to   produce   acute   and   transient   working   memory   deficits:   towards   reconciling   cholinergic   and   inflammatory   hypotheses   of   delirium.   This   scheme   shows   the   basal   forebrain   cholinergic   nuclei   (BFCN),   illustrating   the   septohippocampal   pathway,   the   ventral   diagonal   band  projections  to  the  amygdala  and  piriform  and  insular  cortices   and   the   nucleus   basalis   projection   to   the   frontal,   parietal   and   temporal   cortices   (after   Wolff   1991).   Intracerebroventricular   injection   (left   panel)   of   the   ribosomal   toxin   saporin,   linked   to   an   antibody  against  the  p75  neurotrophin  receptor,  which  is  enriched   on   BFCN   cells,   induces   selective   neuronal   death   in   these   regions.   This  approach  facilitates  targeted,  selective  and  limitable  lesioning   of  this  area  and  consequently  decreased  cholinergic  tone  (shown  in   grey,  right  panel)  in  these  projection  fields.  In  lesioned  animals,  LPS   induces   acute   and   transient   working   memory   deficits,   resembling   delirium.   Neither   lesion   nor   LPS   alone   were   sufficient   to   induce   such   deficits.   LPS-­‐induced   CNS   inflammatory   responses   were   equivalent   in   lesioned   and   non-­‐lesioned   animals   and   the   acetylcholinesterase   inhibitor   donepezil   could   block   these   deficits   (Field   et   al.,   2012).   Thus   systemic   inflammation   in   ‘vulnerable’   animals   may   be   used   to   interrogate   aspects   of   delirium   pathophysiology  

impairment/dementia   and   that   this   limited   cholinergic   lesion   model   will  be  an  extremely  useful  tool  in  delineating  molecular  pathways  to   dysfunction   that   are   relevant   to   delirium.   However,   it   is   clear   that   many   delirium   researchers   are   hesitant   about   the   application,   to   clinical   delirium,   of   data   arising   from   these   animal   models   and   a   number  of  pertinent  questions  do  arise.   Q Can we really say that these mice are delirious? Q Is this a hippocampal phenomenon? Q What, therefore, is the role of the prefrontal cortex? The   occurrence   of   working   memory   deficits   using   a   task   that   has   been   shown   to   be   hippocampal-­‐dependent   has   made   it   easy   to   ignore   or   dismiss   these   data   as   not   relevant   to   delirium.   We   do   not   imply   that   delirium   is   a   hippocampal   phenomenon.   Firstly,   we   cannot   yet   say   what   other   regions   of   the   brain   are   also   recruited   by   this   task.   Secondly,  the  induction  of  these  cognitive  deficits  by  recapitulation  of   key   etiological   factors   for   delirium   must   be   emphasized:   there   are   simply   no   other   studies   that   have   even   attempted   to   address   the   multi-­‐factorial  nature  of  dysfunction  during  delirium  and  as  such,  the   data   from   our   studies   on   the   interaction   of   systemic   inflammation   and   prior  CNS  pathology  have  a  utility  for  delirium  research  irrespective  of   whether   the   cognitive   impairments   observed   constitute   delirium   per   se.   Thirdly,   it   is   important   to   stress   that   mice   and   men   are   different   and   while   we   cannot   say   that   these   mice   are   definitely   delirious   nor   can  we  assert  that  they  are  not.  However,  we  can  say  that  they  have  an   acute   onset   and   transient   attentional/working   memory   deficit,   induced   by   a   systemic   inflammatory   challenge,   which   occurs   only   in   mice   with   prior   cholinergic   pathology.   Asking   the   most   relevant   questions   of   mice   during   acute   episodes   of   sickness,   in   which   appetitive   and   exploratory   drives   are   profoundly   suppressed   is   challenging.   The   water-­‐motivated,   working   memory,   T-­‐maze  

  We   believe   that   these   findings   have   significant   implications   for   delirium,   particularly   in   the   setting   of   existing   cognitive    

©  European  Delirium  Association  2012  

represents   a   task   that   is   tailored   to   assess   correct   and   incorrect   responses  in  a  task  reliant  on  both  attention  and  working  memory,  in   a   manner   that   is   not   confounded   by   sickness-­‐induced   performance   deficits   such   as   suppressed   activity,   slower   response   time,   suppressed   appetite   etc.   In   order   to   successfully   solve   the   T-­‐maze   task,   animals   must   attend   to   the   maze   exit   on   first   entry,   be   attentive   to   the   body-­‐ turn   they   made   to   escape   the   maze   and   recall   this   choice   just   30   seconds   later,   in   order   to   make   the   opposite   turn   to   find   the   new   location  of  the  exit  on  re-­‐exposure  to  the  maze.  Whether  the  deficit  is   attentional   or   purely   working   memory   is   difficult   to   dissect,   but   it   is   undeniably  distinct  from  longer  term,  or  reference,  memory.  We  have   clearly  shown  that  mice  are  not  impaired  on  that  type  of  hippocampal-­‐ memory   after   LPS   treatment   (Cunningham   et   al.,   2009).   This   is   consistent  with  data  showing  that  patients  with  delirium  were  able  to   access   previously   learned   information   but   showed   impairments   on   tasks   involving   online   processing   of   novel,   trial   specific,   information   (Brown   et   al.,   2011).   Thus   there   are   important   parallels   between   the   type   of   cogntive   impairments   seen   in   delirium   and   those   in   animals   with   cholinergic   “vulnerability”:   we   are   not   simply   describing   a   generalised  hippocampal  deficit.   As   for   the   relative   contribution   of   the   basal   forebrain,   the   hippocampus   and   the   prefrontal   cortex,   it   appears   that   the   dose   and   route   of   p75NTR-­‐saporin   used   in   the   current   study   appeared   to   target   the   septal   neurons   that   project   to   the   hippocampus   more   than   they   affected   the   nucleus   basalis   neurons   that   project   to   the   prefrontal   cortex.   This   latter   path   and   the   prefrontal   cortex   in   general,   are   less   developed   in   mice   than   in   humans   and   this   is   a   limitation   of   mouse   research  for  many  fields  of  neuroscience,  including  delirium.  This  does   not   invalidate   the   use   of   mice   to   investigate   the   mechanisms   by   which   systemic   inflammation   and   prior   CNS   pathology   interact.   It   is   worth   noting   that   most   neuropsychological   and   even   neurodegenerative   conditions,   including   depression,   schizophrenia,   Alzheimer’s   disease   and   Parkinson’s   disease,   are   studied   using   models   that   do   not    

recapitulate  several  key  features  of  these  conditions.  This  is  the  reality   in   developing   and   using   animal   models   and   the   important   thing   is   to   focus  on  the  questions  that  these  models  can  answer.   Q Despite the long-standing cholinergic hypothesis of delirium, there are now data showing that acetylcholinesterase inhibition is not helpful in ICU delirium. Can these findings be reconciled with the current data? The   clinical   study   of   van   Eijk   and   colleagues   (2010)   found   no   protective  effect  of  rivastigmine  against  delirium  in  the  ICU.  However,   our   data   are   most   relevant   to   patients   where   there   is   existing   cholinergic   vulnerability,   as   is   frequently   the   case   in   Alzheimer’s   disease   and   in   some   other   age-­‐related   CNS   pathologies.   If   the   individual   has   neurodegeneration   in   the   cholinergic   system   and   then   suffers   a   moderate   systemic   inflammatory   insult   such   as   infection   or   surgery,   it   is   plausible   that   boosting   cholinergic   function   would   protect  against  the  deleterious  effects  of  this  inflammation,  as  we  have   shown   to   be   the   case   in   our   mouse   study.   However,   in   ICU   patients   who  have  suffered  severe  trauma  or  severe  sepsis,  we  believe  that  it  is   highly   unlikely   that   bolstering   a   single   neurotransmitter   system   will   be   able   to   correct   the   marked   divergence   from   homeostasis   in   multiple   systems,   including   severe   inflammation,   impaired   tissue   perfusion   and   hypoxia,   blood   brain   barrier   breakdown   and   multi   organ   dysfunction.   Obviously   the   multiple,   often   quite   divergent,   routes   to   delirium   will   influence   correct   treatment   strategies.   We   do   not   propose   that   cholinergic   dysfunction   is   the   ‘final   common   pathway’   in   delirium   pathhophysiology   but   we   believe   that   our   data   demonstrate  that  systemic  inflammation  and  cholinergic  vulnerability   interact   to   induce   acute   attentional   and/or   working   memory   deficits   and   in   that   scenario,   bolstering   cholinergic   function   was   found   to   be   beneficial.   This   clearly   has   relevance   for   delirium,   at   least   in   the   geriatric   population.   The   fact   that   donepezil   offered   only   partial   protection   even   in   animals   that   had   a   known   cholinergic   deficit  

©  European  Delirium  Association  2012  

already   actually   predicts   that   cholinergic   enhancement   would   be   unlikely   to   be   beneficial   in   settings   such   as   ICU   delirium.   Therefore   this   study   and   the   results   of   the   rivastigmine   trial   are   by   no   means   incompatible  and  this  animal  model  allows  us  to  ask  simple  questions   in  this  domain  and  to  provide  empirical  evidence  that  can  contribute   to   supporting   or   rejecting   clinical   hypotheses.   We   now   know   that   moderate   systemic   inflammation   can   produce   dysfunction   in   an   already   compromised   cholinergic   system   but   cannot   do   so   in   intact   animals.  Severe  trauma  and  sepsis  is  likely  to  lead  to  CNS  dysfunction   by   multiple   routes,   against   which   cholinesterase   inhibition   is   apparently   powerless.   Just   as   it   is   too   simplistic   to   assume   that   hypocholinergic   function   is   the   final   common   pathway   to   delirium   simply   because   robust   cholinergic   inhibition   can   produce   a   delirious   state,   so   is   it   unwise   to   reject   the   importance   of   cholinergic   function   just   because   cholinesterase   inhibition   did   not   protect   against   delirium   in  one  profoundly  sick  population.     Q Since the deficits observed here are independent of microglial priming, does this rule out a role for this phenomenon in delirium? What   these   data   show   is   that   loss   of   cholinergic   input   is,   of   itself,   sufficient   to   make   neurons   proximal   to   the   terminal   fields   of   cholinergic   neurons   susceptible   to   dysfunction   upon   exposure   to   inflammatory   mediators.   This   means   that   priming   is   not   essential   for   the   acute   dysfunction.   However,   priming   leads   to   higher   levels   of   inflammatory   mediators   being   produced   in   the   areas   of   prior   pathology   and   thus   their   presence   would   be   predicted   to   further   exacerbate   the   effects.   Therefore,   there   are   both   inflammatory   and   neuronal   vulnerabilities   to   consider.   There   are   two   main   factors   that   might   have   influenced   microglial   priming   in   this   model:   the   time   post-­‐ surgical   injection   of   p75NTR-­‐saporin   and   the   degree   of   loss   of   cholinergic  input.  

1)   Time   post-­‐surgery:   CNS   pathology   primes   microglia   and   we   have   previously   shown   that   this   can   last   up   to   28   days   post   axonal   degeneration   (Palin   et   al,   2008).   It   is   clearly   no   longer   present   at   40   days  post-­‐insult  in  the  current  study  and  we  must  investigate  whether   priming  actually  occurs  and  how  long  it  lasts  in  the  current  model.  2)   Loss   of   cholinergic   tone:   acetylcholine   can   directly   suppress   macrophage/microglial  activation  (Tracey  et  al.  2007).  We  show  that  a   limited   cholinergic   lesion   (<20%)   does   not   prime   the   microglia.   However,   one   might   predict   that   larger   lesions   will   be   required   to   remove   sufficient   acetylcholine   to   lift   this   suppression   of   microglia   activity.   This   is   also   under   investigation.   The   prediction   is   that   if   cholinergic  dysfunction  is  sufficient  for  acute  deficits,  in  the  absence  of   microglial   priming,   then   the   additional   factor   of   microglial   priming   will  only  add  to  the  severity  and  duration  of  these  deficits.  

Concluding remarks In  considering  the  value  of  this  and  other  animal  models,  purportedly   relevant   to   delirium,   clinical   researchers   must   be   measured   in   their   expectations.   It   may   be   difficult   to   recapitulate   delirium   in   a   mouse   and  even  if  one  can  achieve  this  it  will  be  extremely  difficult  to  verify   that   mice   are   indeed   delirious.   What   we   must   focus   on   is   recreating   key   etiologies   that   lead   to   delirium   in   the   clinic,   demonstrating   that   these   factors   interact   in   ways   that   are   consistent   with   clinical   observations   and   then   using   these   models   to   delineate   mechanisms   and  to  make  predictions  for  ongoing  clinical  studies.     In   other   words,   we   must   focus   on   what   these   models   do   provide   rather   than   on   what   they   do   not   provide.   Our   recent   studies   show   unequivocally   that   systemic   inflammation   induces   acute   and   transient   attentional/working  memory   deficits,  which  are  relevant  to  delirium,   in   animals   with   prior   pathology   in   the   basal   forebrain   cholinergic  


©  European  Delirium  Association  2012  

system.  Whether  or  not  these  animals  fit  all  the  criteria  for  delirium,  in   as  much  as  anyone  can  definitively  say  what  these  criteria  should  be  in   a   mouse,   they   offer   a   unique   tool   to   investigate   the   interaction   between  cholinergic  and  neuroinflammatory  routes  to  acute          neuropsychological   dysfunction   and   this   already   represents   a   significant  advance  on  previous  knowledge  in  this  field.  In  particular,   this   model   allows   us   to   interrogate   whether   it   is   microglial   priming,   hypocholinergia   or   some   other   aspect   of   neuronal   susceptibility,   or   indeed   all   three   that   create   the   susceptibility   to   systemic   infection-­‐ induced   dysfunction   in   vulnerable   individuals.   The   data   arising   from   such  models  should  obviously  form  part  of  the  discussion  on  delirium   pathophysiology.   Full reference for citation Prior   Pathology   in   the   Basal   Forebrain   Cholinergic   System   Predisposes   to   Inflammation-­‐Induced   Working   Memory   Deficits:   Reconciling   Inflammatory   and   Cholinergic   Hypotheses   of   Delirium.   The  Journal  of  Neuroscience,  May  2,  2012  •  32(18):6288  –  6294   Robert  H.  Field,  Anna  Gossen,  and  Colm  Cunningham  
This article is freely available (open access) through The Journal of Neuroscience

cholinergic  hypotheses  of  delirium.  Journal  of  Neuroscience,  32  6288-­‐ 6294.   Cunningham,  C.,  Wilcockson,  D.C.,  Campion,  S.,  Lunnon,  K.  &  Perry,  V.H.   (2005)  Central  and  systemic  endotoxin  challenges  exacerbate  the  local   inflammatory  response  and  increase  neuronal  death  during  chronic   neurodegeneration.  J  Neurosci,  25,  9275-­‐9284.   Cunningham,  C.,  Campion,  S.,  Lunnon,  K.,  Murray,  C.L.,  Woods,  J.F.,   Deacon,  R.M.,  Rawlins,  J.N.  &  Perry,  V.H.  (2009)  Systemic  inflammation   induces  acute  behavioral  and  cognitive  changes  and  accelerates   neurodegenerative  disease.  Biol  Psychiatry,  65,  304-­‐312.   Brown,  L.J.,  Ferner,  H.S.,  Robertson,  J.,  Mills,  N.L.,  Pessotto,  R.,  Deary,  I.J.   &  MacLullich,  A.M.  (2011)  Differential  effects  of  delirium  on  fluid  and   crystallized  cognitive  abilities.  Arch  Gerontol  Geriatr,  52,  153-­‐158.   van  Eijk,  M.M.,  Roes,  K.C.,  Honing,  M.L.,  Kuiper,  M.A.,  Karakus,  A.,  van   der  Jagt,  M.,  Spronk,  P.E.,  van  Gool,  W.A.,  van  der  Mast,  R.C.,  Kesecioglu,   J.  &  Slooter,  A.J.  (2010)  Effect  of  rivastigmine  as  an  adjunct  to  usual   care  with  haloperidol  on  duration  of  delirium  and  mortality  in   critically  ill  patients:  a  multicentre,  double-­‐blind,  placebo-­‐controlled   randomised  trial.  Lancet,  376,  1829-­‐1837.   Palin,  K.,  Cunningham,  C.,  Forse,  P.,  Perry,  V.H.  &  Platt,  N.  (2008)   Systemic  inflammation  switches  the  inflammatory  cytokine  profile  in   CNS  Wallerian  degeneration.  Neurobiol  Dis,  30,  19-­‐29.   Tracey,  K.J.  (2007)  Physiology  and  immunology  of  the  cholinergic   antiinflammatory  pathway.  J  Clin  Invest,  117,  289-­‐296  

References Fiel  Murray,  C.,  Sanderson,  D.J.,  Barkus,  C.,  Deacon,  R.M.,  Rawlins,  J.N.,   Bannerman,   D.M.   &   Cunningham,   C.   (2012)   Systemic   inflammation   induces  acute  working  memory  deficits  in  the  primed  brain:  relevance   for  delirium.  Neurobiol  Aging,  33,  603-­‐616  e  603.   Field,  R.H.,  Gossen,  A.  &  Cunningham,  C.  (2012)  Prior  pathology  in  the   basal  forebrain  cholinergic  system  predisposes  to  inflammation   induced  working  memory  deficits:  reconciling  inflammatory  and    

©  European  Delirium  Association  2012  

Personal experience of the complexity of diagnosing delirium
 Dr  Emma  Vardy   I   am   a   Consultant   Geriatrician   and   Associate   Clinical   lecturer.     My   clinical   role   involves   elderly   medical   inpatient   work   as   well   as   providing  an  older  peoples  liaison  service  on  the  general  medical  and   medical   assessment   wards.     Until   recently   my   research   interest   has   focussed   on   dementia,   mainly   Alzheimer’s   disease.     More   recently   I   have   become   more   interested   in   delirium   at   both   a   clinical   and   a   research  level.    This  opinion  piece  describes  my  journey  into  delirium:   The   continuing   development   of   any   healthcare   professional   involves   being   open   to   the   fact   that   there   is   always   something   to   learn,   even   on   subjects   about   which   you   thought   you   knew   a   lot!     I   shall   describe   here  my  recent  re-­‐evaluation  of  my  skills  in  the  diagnosis  of  delirium.   Through  preparing  a  protocol  for  a  piece  of  clinical  research  I  started   to   explore   the   ‘gold   standard’   method   for   diagnosis   of   delirium.     Perhaps   to   be   expected   was   the   fact   that   there   were   of   course   tests   that   I   had   not   any   experience   of,   such   as   the   Delirium   Rating   Scale   (DRS).    I  rapidly  became  aware  that  with  research  into  delirium  comes   a   variety   of   methods   for   delirium   assessment.     First   there   are   a   number   of   different   tests   and   combinations   of   tests.     They   differ   in   terms   of   goal,     that   is   some   are   diagnostic,   others   measure   severity.     Secondly   methodologies   differ   in   both   the   frequency   and   timing   of   application   of   these   tests.     Added   to   this   is   the   fact   that   currently   available   methods   come   in   different   formats   ,   for   example   the   confusion  assessment  method  (CAM)  and  the  CAM-­‐ICU,  in  recognition   of   the   fact   that   most   definitely   one   size   does   not   fit   all.       As   my   knowledge  of  methods  of  diagnosis  of  delirium  broadened  I  started  to   question   what   I   had   previously   seen   as   the   ‘basics’   in   diagnosing   delirium,  not  something  I  had  originally  expected.    

Many   of   us   will   be   using   tools   such   as   the   confusion   assessment   method   (CAM),   and   this   comes   recommended   both   in   the   NICE   guidelines   (   and   those   of   the   British   Geriatrics   Society   (     This   is   certainly   the   test   with   which   I   am   most   familiar.     The   CAM   consists   of   4   simple   questions,   but   are   they   really   so   simple?     The   CAM   is   easily   accessible,   not   always   so   readily   available  are  details  of  how  to  assess  each  of  the  criterion.      Inattention   and   disorganised   thinking   are   signs   that   take   careful   and   detailed   assessment,   this   question   requires   a   yes   or   no   in   terms   of   diagnosis,   but   actually   eliciting   this   feature   is   more   complex.     The   waters   have   become   a   little   clearer   for   me   on   my   recent   discovery   of   the   CAM   training  manual  (     My   own   personal   professional   development   in   the   diagnosis   of   delirium   has   led   me   to   evaluate   my   own   practice   but   also   my   expectations   of   the   junior   doctors   I   work   with.     I   often   ask   them   to   apply   the   CAM   in   the   medical   inpatient   setting.     But   through   re-­‐ evaluating   my   own   skills   I   have   started   to   consider   just   how   much   I   have   perhaps   presumed   of   some   of   my   juniors   in   the   past.     I   have   considered   whether   the   junior   doctors   that   I   work   with   have   ever   had   any   comprehensive   training   on   applying   the   CAM?     Have   I   ever   even   asked?     In   retrospect   I   have   probably   presumed   skills   that   the   junior   members,    and  dare  I  say  some  more  senior  members  of  the  team,  just   don’t   have.     What   about   the   time   element?   Eliciting   these   signs   properly   takes   time   but   is   not   something   that   can   often   be   pondered   over   by   our   junior   doctors,   for   example,     whilst   on   call.     In   fact   in   recognition   of   this   the   NIHR   Health   technology   assessment   programme   has   just   put   out   a   call   for   triage   tools   for   delirium     (     This   recognition  of  a  need  for  a  simple  and  easy  to  apply  diagnostic  tool  is   particularly  timely,  as  the  detection  of  delirium  becomes  increasingly   important,   with   progress   in   terms   of   the   dementia   strategy   in   acute   hospitals.  

©  European  Delirium  Association  2012  

The   rewards   of   a   good   diagnosis   of   delirium   abound,   leading   to   identification   and   treatment   of   underlying   cause,   reduced   morbidity   and  mortality  and  increased  understanding  and  support  for  carers  and   relatives.    But  it  is  important  that  the  assessment  for  delirium  is  done   well   and   that   delirium   is   correctly   diagnosed.     There   are   various   examples  in  the  literature  of  poor  detection  of  delirium.    Perhaps  less   evident  are  the  consequences  of  incorrectly  diagnosing  delirium.    Over   the   course   of   my   career   two   examples   come   to   mind.     One   was   a   patient   who   had   more   than   one   admission   with   ‘delirium’.     Brain   imaging   after   the   second   or   third   repeat   admission   revealed   underlying   brain   metastases.     The   second   case   relates   to   a   lady   with   an  ‘acute  confusion  state’.    Brain  imaging  was  performed,  after  a  delay,   revealing   an   extradural   haematoma   which   was   operated   upon.     The   safe-­‐guard   to   ensuring   such   cases   are   not   missed   are   present   in   the   NICE  guidelines,  which  state  at  the  end  of  the  treatment  algorithm  that   there   should   be   re-­‐evaluation   for   underlying   causes.     However   these   examples   are   a   sobering   reminder   of   the   importance   of   ensuring   accuracy   of   diagnosis   and   following   a   procedure   of   re-­‐evaluation   of   diagnosis.   In  summary  my  research  into  methods  of  diagnosis  of  delirium  led  me   to   re-­‐evaluate   my   own   clinical   practice   but   also   reflect   on   my   own   presumptions  of  others  knowledge.    There  may  be  new  and  improved   methods  for  diagnosing  delirium  on  the  horizon,  perhaps  more  readily   deliverable.   But   in   the   interim   perhaps   those   of   us   at   the   coal   face   need   to   reflect   on   what   our   colleagues,   particularly   junior   doctors,   may  find  hard  about  making  a  diagnosis  of  delirium  and  seek  to  raise   clinical  standards  overall.   Dr  Emma  Vardy   Newcastle   upon   Tyne   hospitals   NHS   foundation   trust   and   Newcastle   University  

Report on 2nd Annual Indianapolis, Indiana





The   second   annual   American   Delirium   Society   meeting   was   well   attended;   we   were   very   pleased   that   this   year   we   had   123   participants;  a  33%  increase  over  last  year’s  meeting.      Delegates  came   from   China,   Canada,   US   (20   states),   Norway,   Portugal,   Ireland,   England,   Australia   and   Denmark.     Speakers   from   several   continents   were  included  and  the  program  was  full  enough  that  parallel  sessions   were   held.       A   very   broad   range   of   speakers   and   topics   were   presented,   demonstrating   delirium’s   ascendance   as   a   highly   valued   and   increasingly   well   studied   aspect   of   geriatric   care.     ADS’   new   president   Malaz   Boustani,   MD,MPH   provided   an   address   during   opening   night   reception   which   explored   ways   that   drugs   targeted   to   symptomatic   relief   or   disease   modification   of   delirium   could   be   assessed  and  regulated  on  a  global  scale.        The  president  elect,  Karin   Neufeld,   MD,MPH   and   new   treasurer,   Ann   Gruber-­‐Baldini,   PhD,   were   introduced,   as   were   new   ADS   Board   members.       A   number   of   new   collaborations   were   developed   in   the   course   of   this   meeting,   an   achievement  that  all  of  us  in  ADS  heartily  applaud  and  endorse!    On   June   4th,   a   session   on   pathophysiology   and   biomarkers   was   initiated  by  Edward  Marcantonio,  MD,  who  reviewed  technical  aspects   of  biomarker  research.      Other  speakers  included  Alasdair  MacLullich,   MB/ChB,  PhD,Stacie  Denier,  MD,  James  Root,  PhD,  and  Malaz  Boustani,   MD,   MPH,   and   included   studies   relating   to   CSF,   MRI/structural     ICU,   and  surgical  aspects  of  delirium.    The  parallel  session  was  devoted  to   delirium   measurement,   and   was   introduced   by   Paula   Trzepacz,   MD,   who   presented   updates   on   her   collaborative   work   on   the   phenomenology   of   delirium.     This   has   provided   a   replicable   pattern   of   symptomatology  that  may  inform  studies  of  delirium  pathophysiology.     Other   work   on   screening,   measurement,   and   operationalization   of   delirium   measurement   was   presented   by   Laura   Hoofring,   MSN,   ARNP-­‐ PMH,   Jean-­‐David   Gaudreau,   MD,   Edward   Marcantonio,   MD,   and   Ann  


©  European  Delirium  Association  2012  

Gruber-­‐Baldini,   PhD.     The   final   session   of   the   day   explored   postoperative  delirium;  this  was  initiated  by  Gregory  Crosby,  MD,  who   discussed  aspects  of  vulnerability  in  the  aging  CNS,  and  was  followed   by   work   on   baseline   cognitive   function   and   its   impact   on   post-­‐ operative   outcomes,   the   assessment   of   delirium/emergent   delirium   in   the   PACU,   brain   dysfunction   in   critical   care,   the   impact   of   analgesic   agents   in   the   postoperative   setting,   and   the   method   of   “ABCDE   bundle”  in  addressing  and  maximizing  postoperative  care  complicated   by   delirium.     Speakers   included   Thomas   Robinson,   MD,   Karin   Neufeld,   MD,   MPH,     Yoanna   Skrobik,   MD,   and   Michele   Balas   PhD,RN,   CRNP,   CCRN.     The   second   and   final   day   included   morning   sessions   on   long   term   outcomes   of   delirium   and   clinically   specific   aspects   of   the   care   of   delirium.      The  outcomes  session  included  a  study  by  Daniel  Davis,  MD,   which   involved   a   large   retrospective   chart   review   with   implications   that   the   pathophysiology   of   Alzheimer’s   Dementia   may   be   distinct   from  that  of  delirium.    Other  speakers  included  Dimitry  Davydow,  MD,   Alasdair   MacLullich,   MD,   ChB,   PhD.     Talks   on   the   psychological   sequelae   of   delirium   as   well   as   the   impact   of   pre-­‐operative   cognitive   dysfunction  on  delirium  outcomes  were  presented  by  O.  Bienvenu  MD,   PhD    and  Frederick  Sieber  MD.    A  comprehensive  literature  review  of   pharmacological  prevention  strategies  in  delirium  by  Jose  Maldonado,   MD   completed   the   session.     The   symposium   on   clinically   specific   aspects  of  delirium  care  included  a  session  by  James  Rudolph,  MD,MS   on   a   comprehensive   approach   to   delirium   identification   and   management   in   acute   settings   (the   “Delirium   Toolbox”),   a   highly   practical   and   effective   session   on   ways   to   de-­‐escalate   agitated   and   irrational   patients   (the   T-­‐A-­‐DA   method,   representing   “tolerate-­‐ anticipate-­‐don’t   agitate”)   which   involved   acting   the   parts   of   patient   and   nurse   by   the   speakers,   Joseph   Flaherty,   MD   and   Sharon   Gordon,   PhD,   and   sessions   on   medications   presenting   risk   to   patients   with   delirium   by   Noll   Campbell,   PharmD,     the   role   of   sleep   in   the   presentation   and   management   of   delirium   in   the   ICU   by   Wes   Ely,    

MD,MPH,   and   techniques   of   early   mobilization   for   patients   with   critical   illness,   by   Amy   Pawlik,   PT,DPT,   CCS   and   Cheryl   Estbrook   OT.       The  final  session  presented  clinical  trial  updates  provided  by  Wes  Ely   (“MIND-­‐USA”),   a   new   delirium   assessment   tool   for   emergency   room   use  (Jin  Han,  MD),  and  other  work  by  Simon  Mears,  MD,  Laura  Sands,   PhD,   MA,   Babar   Khan,   MD,   MS,   Don-­‐Zin   Wang   MD,   PhD,     Jeff   Silverstein,   MD,   and   Gideon   Caplan,   MB,   MS,   and   included   studies   of   new   agents   and   pharmacological   approaches   to   minimizing   delirium   in  different  settings;  Dr  Caplan’s  study  reported  new  findings  on  CN  S   blood  flow  abnormalities  in  patients  with  delirium.     Keynote   speakers   included   Sharon   Inouye,   MD,   MPH,   who   spoke   on   the  future  of  research  in  delirium,  including  an  emphasis  on  the  need   to  codify  and  simplify  diagnostic  categories  of  delirium  in  the  ICD.    The   Delirium   Champion   Award   2012   was   presented   to   Dr   Inouye   in   recognition   of   her   outstanding   contribution   to   the   field.     Ann   Kolanowski,  PhD,  RN  spoke  about  the  vital  role  nurses  play  in  delirium   assessment   and   intervention,   and   provided   updates   on   the   methodology  of  dissemination  of  delirium  teaching  for  nurses.      There   were  16  posters  accepted  for  presentation.   Next  year’s  conference  will  be  in  Indianapolis,  Indiana,  in  June    -­‐  actual   date   to   be   confirmed     shortly.     Preparations   are   being   made   for   a   conference  in  Baltimore,  MD  area  for  the  following  year  (2014).        We   sincerely  hope  that  this  year’s  meeting  was  helpful  and  gratifying  for   attendees,  and  that  next  year’s  will  be  even  better!   Barbara  Kamholz,  MD   Board  Member,  EDA  and  ADS  

©  European  Delirium  Association  2012  

Raising delirium consciousness using the media
Dr   Valerie   Page,   Consultant   Anaesthesia   and   Critical   Care,   Watford   General  Hospital,   Dr   Daniel   Davis,   Research   Fellow,   Institute   of   Public   Health,   University  of  Cambridge   Tony  Jameson-­‐Allen,  Accredited  Knowledge  Management  Consultant   and   Director,   Evolution   Networking   Ltd,   UK.   www.evolution-­‐   Introduction   “The  greatest  trick  the  devil  ever  played  was  convincing  the  world  that   he  did  not  exist.”  Charles  Baudelaire   Delirium   occurs   in   one   in   five   general   hospital   patients.   It   remains   underappreciated   and   under   researched.   The   European   Delirium   Association   remit   includes   campaigning   at   local,   national   and   international  levels  in  order  to  influence  policy.  The  area  of  advocacy   has  remained  under  addressed.   There   needs   to   be   an   increased   awareness   of   delirium   clinically,   politically   and   publicly.   This   project   assessed   the   effectiveness   of   using   traditional   advertising,   websites   and   social   media   to   achieve   this.  The  aim  was  to  discover  how  best  to  use  traditional  and  modern   forms  of  media  to  lobby  on  behalf  of  patients  with  delirium.   Methods   Stage  1:   Selected   websites   and   social   media   resources   relating   to   delirium   were   identified   (see   table   1).     The   effectiveness   was   judged   by   the   number  of  times  a  webpage  was  viewed.    

Stage  2:   A   banner   advert   was   purchased   for   the   UK   national   newspaper   Guardian   website   directing   readers   to   the   UK   ICU   delirium   website;   the  number  of  clicks  resulting  from  this  advert  was  collected.  (Figure   1).   Resource   Date  started   Outcome/’Hits’   527  317  last  12  months   43   500   views   since   launch   Average   1000   visits   per   month   3468  views  since  launch   73  556  page  views   49  members   21   clicks   from   18   000   appearances  

Wikipedia  Delirium  Page   Dec  2002   Youtube   ICU   delirium   Aug  2008   clip   ICU  delirium  website   Delirium  videocasts*   EDA**  website   EDA**  facebook  group   Aug  2008   April  2009   July  2009   June  2011  

Guardian   web   banner   July  2011   advert   Results  

The   web   pages   had   large   variations   in   number   of   times   they   were   viewed.  The  most  successful  was  the  Wikipedia  delirium  page  with  an   average   of   nearly   44,000   per   month.   Encouragingly   the   UK   Youtube   clip   was   activated   43   400   times   in   less   than   4   years.     (Figure   2)     Conversely   the   Guardian   banner   advert   generated   an   astoundingly   low  total  of  12  responses  from  over  25,000  appearances    


©  European  Delirium  Association  2012  

Discussion   Heightened  media  attention  to  an  issue  has  been  shown  to  pressurise   policy   makers   to   generate   immediate,   short-­‐term   solutions   to   the   problem   which   then   shift   to   long-­‐term   solutions.   Delirium   needs   a   simple  but  powerful  device  as  a  means  of  disseminating  knowledge  on   the  impact  on  patient  outcomes  –  death  and  dementia.   After  the  massacre  of  schoolchildren  in  Dunblane,  Scotland,  Parliament   was   introducing   a   law   to   ban   certain   firearms,   but   not   .22   handguns.   The   team,   with   no   money   and   no   time,   decide   to   act.   They   discovered   that  Robert  Kennedy  had  been  assassinated  with  a  .22  gun.  Using  a  stock   photograph   of   Kennedy,   they   had   a   poster   printed   to   go   on   a   lorry   parked   outside   Parliament   on   the   day   of   the   debate.   "If   a   .22   handgun   is   less   deadly,"   it   asked,   "why   isn't   he   less   dead?"   An   amendment   was   added  to  include  the  banning  of  .22  guns.   Regarding   promotional   campaigns   Ed   Jones   of   Saatchi   &   Saatchi   said   "Your   message   has   to   be   really   powerful   and   life-­‐transforming,   otherwise   you   are   wasting   your   money."   There   is   no   doubt   that   the   facts  of  delirium  are  as  powerful  as  cancer  or  HIV  yet  still  the  subject   does   not   feature   in   the   public   or   to   a   lesser   extent   the   clinical   consciousness.   On   the   BBC   health   website   cancer   is   covered   in   great   depth  with  a  number  of  helpful  links;  delirium  does  not  even  feature.     There   is   growing   interest   in   use   of   Facebook   for   disseminating   information   and   establishing   informal   networks.   It   has   been   demonstrated   that   spending   money   on   a   single   advert   was   nowhere   near  as  effective  as  entries  on  high  profile  social  media  based  websites   such   as   Wikipedia   and   Youtube.   Currently   the   Internet   can   be   freely   utilized   to   educate   and   influence   politically,   clinically   and   publicly.   There   is   growing   interest   in   use   of   Facebook   for   disseminating   information  and  establishing  informal  networks.  

  This   project   was   a   means   in   discovering   how   best   to   use   different   forms   of   media   to   lobby   on   behalf   of   patients   with   delirium.   The   findings   suggest   that   currently   the   use   of   responsive,   informal,   and   contemporary   means   will   gain   greater   exposure   to   delirium   than   a   traditional   advertising   campaign.   It   would   be   reasonable   to   assume   that   will   generate   a   higher   awareness   amongst   clinicians   and   the   public.   Further   work   is   needed   to   discover   how   to   promote   delirium   publicly,  build  on  the  momentum  that  has  been  established,  to  manage   the   response   and   to   capitalize   on   any   media   opportunities   as   they   arise.  

Figure  1  Banner  advertisement  for  ICU  delirium  website    



©  European  Delirium  Association  2012  

Figure  2  CAM-­‐ICU  demonstration  on  Youtube  

*“Haloperidol prophylaxis decreases delirium incidence in elderly patients after noncardiac surgery: A randomized controlled trial”
W  Wang,  HL  Li,  DX  Wang  ,  et  al,  Crit  Care  Med  2012:  40  (3);  731-­‐739   Earlier   this   year,   a   Chinese   group   published   the   results   of   a   study   examining  the  potential  role  of  haloperidol  for  prophylaxis  in  surgical   patients  admitted  to  critical  care*.    The  study  was  carefully  designed,   using   a   prospective,   randomised,   double   blind   placebo   controlled   method  conducted  across  two  sites.    Subjects  were  older  patients  (>65   years   old),   post   non-­‐cardiac   surgery   and   admitted   to   ICU   post   operatively.     Exclusion   criteria   were   rigorous,   the   entire   study   was   safety  conscious  and  this  meant  that  the  doses  of  haloperidol  used  in   the  active  arm  were  very  conservative.    A  0.5mg  bolus  of  haloperidol   was  followed  by  a  12  hour  infusion  running  at  0.1mg  of  haloperidol  an   hour.    The  total  prophylactic  dose  of  haloperidol  given  was  thus  1.7mg   versus   the   control   arm,   where   patients   received   a   matching   volume   of     saline.    Usual  sedation  (propofol  or  midazolam)  was  used  and  titrated   to   RASS   -­‐2   to   +1,   with   daily   sedation   breaks   for   intubated   patients.     Postoperative   pain   was   managed   with   patient   controlled   analgesia   administered   intravenously   or   epidurally,   with   supplemental   analgesia   being   given   as   fentanyl   boluses   +/-­‐   a   fentanyl   infusion.     Multicomponent   interventions   to   reduce   modifiable   delirium   risk   factors  were  used  in  all  patients.    Delirium  assessments  were  carried   out  once  a  day  in  the  early  evening  using  CAM-­‐ICU.    The  primary  end   point  was  delirium  incidence  in  the  first  7  days  post-­‐operatively,  with   multiple  secondary  endpoints.   The  final  analysis  was  made  on  229  patients  in  the  haloperidol  group   compared  with  228  patients  in  the  placebo  group.    Overall  the  groups   were   well   matched   on   baseline   characteristics.     There   were   some   statistically   significant   differences   noted   in   perioperative   variables,   the  duration  of  anaesthesia  was  longer  in  the  haloperidol  group  (5.51  


©  European  Delirium  Association  2012  

vs   4.81   hours,   p=0.003),   the   duration   of   surgery   was   longer   in   the   haloperidol   group   (4.51   vs   3.79   hours,   p=0.001)   and   the   total   intraoperative   infusion   volume   was   greater   in   the   haloperidol   group   (2700ml   vs   2550ml,   p=0.048).     All   other   variables   were   not   statistically  different,  including  the  total  doses  of  opioid  analgesics  and   sedatives  administered.     The  primary  outcome  results  showed  an  incidence  of  delirium  in  the  7   days   post   surgery   of   15.3%   in   the   haloperidol   group   compared   with   23.2%   in   the   placebo   group   which   translates   into   an   NNT   of   13   to   prevent   one   case   of   delirium.     Much   of   the   benefit   appears   to   be   confined   to   patients   who   received   intra-­‐abdominal   surgery,   representing   about   three   quarters   of   the   cohort.     The   difference   in   delirium   incidence   in   the   rest   of   the   cohort   (intra-­‐thoracic   surgery,   spinal   and   extremital   surgery   and   superficial   surgery)   was   not   apparently   numerically   large,   nor   statistically   significant.     This   gives   rise   to   the   obvious   question   (‘why?’),   however   the   authors   do   not   speculate.   Overall,   the   reported   ICU   length   of   stay   was   short,   with   a   median   of   21.3   hours   in   the   haloperidol   group   and   23.0   hours   in   the   placebo   group   (p=0.024).     When   looking   at   just   patients   who   developed   delirium,   the   intervention   resulted   in   a   reduced   ICU   length   of   stay   (19.6  hours  haloperidol  group,  41.4  hours  placebo  group,  p=0.006).   The  reported  time  to  onset  of  delirium  was  quite  long,  on  average  6.2   days   in   the   haloperidol   group   and   5.7   days   in   the   placebo   group   (p=0.021),  however,  this  analysis  included  all  the  patients  who  did  not   suffer   delirium,   which   when   expressed   as   a   mean,   would   make   the   onset  of  delirium  time  very  long.    As  a  bonus,  because  of  the  reduced   incidence   of   delirium   in   one   group,   it   also   makes   the   difference   statistically   significant.     When   more   realistically   analysing   only    

patients   who   suffered   delirium,   the   mean   time   to   onset   of   delirium   was   found   to   be   1.7   days   (haloperidol   group)   vs   1.5   days   (placebo   group)   and   was   not   statistically   significant.     The   mean   number   of   delirium  free  days  was  5.7  (haloperidol  group)  vs  5.6  (placebo  group)   and  was  also  not  statistically  significant.    So  the  intervention  reduces   the   numbers   of   patients   experiencing   delirium,   but   not   the   time   to   the   onset  of  delirium  for  those  who  suffer  from  it.   There   was   no   difference   in   hospital   length   of   stay   overall   (11.0   days   for   both   groups,   p=0.255),   or   between   the   groups   in   patients   who   went   on   to   develop   delirium   (14   days   haloperidol   group   vs   12   days   placebo  group,  p=0.512).   In   terms   of   overall   safety,   there   were   no   differences   between   the   groups   with   respect   to   arrhythmia’s,   extended   QTc   interval,   extrapyramidal   symptoms,   RASS   or   mortality.     The   intervention   is   clearly  safe.   Overall,   this   study   shows   that   a   small   prophylactic   dose   of   haloperidol   reduces  the  incidence  of  delirium  in  the  first  7  days  for  older  patients   admitted   to   ICU   after   non-­‐cardiac   surgery   (NNT=13)   and   that   the   effect  is  largely  confined  to  patients  receiving  abdominal  surgery.    The   intervention  reduces  median  ICU  length  of  stay  in  delirious  patients  by   21.8   hours   which   is   both   clinically   meaningful   and   statistically   significant.     There   was   no   effect   on   the   time   to   onset   of   delirium   in   delirious  patients  or  any  effect  on  hospital  length  of  stay,  either  overall   or   for   the   delirious   subgroup.     The   haloperidol   dose   used   resulted   in   no   adverse   effects   and   is   therefore   safe.     The   authors   conclude   that   further  investigation  is  warranted.      

©  European  Delirium  Association  2012  

Editor’s Choice
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*     Morandi   A,   Rogers   BP,   Gunther   MLet   al   for   the   VISIONS   Investigation   (VISualizing   Icu   SurvivOrs   Neuroradiological   Sequelae).     Crit   Care   Med.   2012   Jul;40(7):2182-­‐2189.       The   association   between   brain   volumes,   delirium   duration,   and   cognitive   outcomes   in   intensive   care   unit   survivors:   The   VISIONS   cohort   magnetic   resonance   imaging   study*     Gunther   ML,   Morandi   A,   Krauskopf  E  et  al  for  VISIONS  Investigation  (VISualizing  Icu  SurvivOrs   Neuroradiological   Sequelae).     Crit   Care   Med.   2012   Jul;40(7):2022-­‐ 2032.   Neuroimaging   offers   a   means   to   help   unravel   the   pathogenesis   of   delirium.      The  Vanderbilt  group  in  Nashville  published  2  papers  in  the   July   edition   of   Critical   Care   Medicine   which   describe   MRI   findings   on   47   patients   who   survived   critical   illness.       These   papers   are   worth   looking   up   firstly   because   they   add   to   the   ever   increasing   body   of   evidence   that   suggest   delirium   results   in   actual   brain   damage;   secondly   they   have   excellent   descriptions   how   MRI   scanning   can   be   used  to  determine  pathological  changes  in  the  brain.       The   first   study   demonstrated   an   association   between   delirium   duration  and  white  matter  disruption  using  MRI  with  diffusion  tensor   imaging   (DTI).     White   matter   consists   mostly   of   myelinated   axons,   white   matter   integrity   is   required   to   control   consciousness   and   attention.     The   use   of   MRI   with   DTI   provides   investigators   with   quantitative   assessment   of   the   integrity   of   white   matter   and   white   matter   tracts   –   fractional   anisotropy.       This   study   provided  

preliminary   data   to   inform   the   hypothesis   connecting   white   matter   integrity  with  delirium  duration  and  long-­‐term  cognitive  impairment.     The   second   paper   showed   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.     They   did   point   out   that   they   could   not   rule   out   that   patients   had   smaller   brain   volumes   before   admission.       The   ventricle-­‐to-­‐brain   ratio   as   determined   by   MRI   is   an   excellent   indicator   of   generalised   brain   atrophy.       The   authors   illustrate   their   findings   by   comparing   scans   of   2   previously   fit,   cognitively   intact   women   in   their   mid-­‐forties   only   one   of   which   suffered  ICU  delirium  (figure  2).   Acute   confusional   States   in   the   elderly-­‐diagnosis   and   treatment.     Lorenzl   S,   Füsgen   I,   Noachtar   S.     Dtsch   Arztebl   Int.   2012   May;109(21):391-­‐400.  Epub  2012  May  25.       This   is   a   useful   overview   of   delirium   in   the   elderly   from   Deutsches   Ärzteblatt   International   (even   if   it   does   not   have   delirium   in   the   title!)     It  is  free  to  download. med   Mental   Illness   –   Comprehensive   Evaluation   or   Checklist?   P   McHugh   and   P   Slavney   The   New   England   Journal   of   Medicine   2012;   366:   1853-­‐ 55   This   excellent   opinion   piece   discusses   some   of   the   issues   relating   to   the  Diagnostic  and  Statistical  Manual  of  Mental  Disorders  -­‐  DSM.    The   following  quote  hits  the  nail  on  the  head  regarding  delirium.  


©  European  Delirium  Association  2012  

“Identifying   a   disorder   by   its   symptoms   does   not   translate   into   understanding   it.     Clinicians   need   some   heuristic   concept   of   its   nature,   grasped  in  terms  of  cause  or  mechanism,  to  render  it  intelligible  and  to   justify  their  actions  in  practice  and  research”.   Free  to  read     Valerie  Page    

EDA  membership  benefits   •                            Access  to  the  member’s  only  section  of  the  EDA  website   •                            Reduction  in  the  annual  EDA  conference  registration  fee     •                            Eligibility  to  become  EDA  Board  Member   •                            Opportunities  to  contact  and  exchange  ideas  with  delirium                                          experts.   The   annual   fee   is   30   Euros.     This   fee   will   be   used   to   support   development   of   the   website,   the   costs   of   online   Board   meetings   (around   200   Euros,   twice   per   year),   to   underwrite   our   annual   meeting,  and  for  other  costs.  All  accounts  will  be  published  annually     Payment   may   be   by   a   standing   order   or   by   a   cheque   sent   to   John   Young,  Treasurer   The  bank  account  details:   Royal  Bank  of  Scotland,  East  Parade,  Leeds,  LS1  5PS,  UK.   Account  no:  10147495     Sort  Code:    16-­‐23-­‐17   IBAN&  SWFT  No:    BG64RBOS16231710147495     John  Young,  Treasurer  EDA,     Professor  of  Elderly  Care  Medicine   Academic  Unit  of  Elderly  Care  and  Rehabilitation   Bradford  Institute  for  Health  Research   Temple  Bank  House   Bradford  Royal  Infirmary   Duckworth  Lane   Bradford,  UK,  BD9  6RJ    

October  Delirium  Congress   The   European   Delirium   Association   annual   congress   is   in   Bielefeld,   Germany  from  October  18th  to  19th.     It  is  always  a  quality  meeting  so   if  you  only  go  to  one  meeting  a  year  -­‐  make  it  this  one!   Further  details:   European  Survey  –  you  can  help   The   EDA   has   decided   to   conduct   a   survey   to   help   understand   the   range   of   opinions   among   mailing   list   members   on   various   aspect   of   delirium   care.   We   greatly   appreciate   your   expertise   and   we   believe   that   this   survey   will   provide   a   significant   advancement   in   our   understanding   of   current   practice.   The   findings   will   be   presented   at   EDA  Bielefeld  2012,  and  submitted  for  publication  in  a  peer-­‐reviewed   journal.   You  can  find  the  survey  here:        

©  European  Delirium  Association  2012  

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