Behandling av delirium - kva er det eigentleg som virker? Leiv Otto Watne Oslo Delirium Research Group Behandling av delirium - kva er det eigentleg som virker? Leiv Otto Watne Oslo Delirium Research Group

Disposisjon Introduksjon Nytt (og litt gamalt) frå forskning Behandling

Photo: Rita Romskaug

-Cork University Hospital, Irland: 407 acute adult inpatients beds -15th of May 2010 were all patients assessed for delirium -19,6 % had delirium Only 43,6% had delirium or one of its synonyms documented in the case notes!! Ryan DJ, BMJ Open Jan 7;3

DSM-5 kriterier for delirium AForstyrret oppmerksomhet (redusert evne til å fokusere, opprettholde og endre oppmerksomhet) og bevissthet (redusert orientering til miljøet omkring seg) BForstyrrelsene utvikler seg i løpet av kort tid (vanligvis timer til noen få dager), representerer en endring fra vanlig oppmerksomhet og bevissthet, og har tendens til å fluktuere i grad av alvorlighet gjennom døgnet CForstyrret kognisjon (f.eks. hukommelse, orientering, språk) eller persepsjonsforstyrrelser DForstyrrelsene i kriteriene A og C blir ikke bedre forklart av en allerede kjent nevrokognitiv lidelse eller oppvåkningsfasen fra et koma EDet er holdepunkter fra sykehistorie, klinisk undersøkelse eller laboratoriesvar for at forstyrrelsen er en direkte fysiologisk konsekvens av en annen medisinsk tilstand, forgiftning av kjemiske substanser (rusmidler eller legemidler), abstinens, annen toksisk påvirkning eller har multiple årsaker Oppmerksomhet Bevissthet Rask utvikling Endring Fluktuasjon Kognisjon Persepsjonsforstyrrelser Eks ikke «bare» demens Infeksjon. Lårhalsbrudd. Hjerteinfarkt. Hjerneslag. Medikamenter + + +

Neerland, Watne, Wyller. Tidsskr Nor Legeforen 2013

Delirium eller demens? DELIRIUM Brå debut Fluktuerende forløp Varer fra timer til måneder Forstyrret døgnrytme Nedsatt oppmerksomhet Redusert hukommelse Desorganisert tenkning DELIRIUM Brå debut Fluktuerende forløp Varer fra timer til måneder Forstyrret døgnrytme Nedsatt oppmerksomhet Redusert hukommelse Desorganisert tenkning DEMENS Stabilt forløp Varer over tid- mer enn 6 mnd Normal el forstyrret døgnrytme Bevart oppmerksomhet Sterkt redusert hukommelse DEMENS Stabilt forløp Varer over tid- mer enn 6 mnd Normal el forstyrret døgnrytme Bevart oppmerksomhet Sterkt redusert hukommelse

«Ultimately, the differentiation might depend on the presence of an acute change in mental status or behaviour from baseline noted by an informed caregiver, or could be established only in retrospect by resolution of symptoms after precipitating factors have been removed or the acute illness has been treated. If uncertain, mental status changes should be treated as delirium, until proven otherwise” Fong, Lancet Neurology, 2015

Davis; Brain An episode of delirium dramatically increased the risk of incident dementia (OR 8.7). -Delirium was also associated with deterioration of preexisting dementia (OR 3.1).

“Molecular Mechanisms in Delirium and Dementia”

Behandling – ikkje-farmakologisk

-852 indremedisinske pasienter over 70 år -Inkludert ved «prospektive matching strategy» til ein «intervention unit» eller to «usual care unit» -Intervensjonen var å innføre standardprotokoller for handtering av 6 risikofaktorer for delirium: kognitiv svikt, søvn, immobilitet, dehydrering og svekkelse av syn og hørsel -Delirium diagnostisert med CAM («rated by the researchers»)

What was the intervention? Cognitive impairment: communication to reorientate to the surroundings Sleep deprivation: noise reduction strategies, relaxition music, warm drink, back massage Immobility: exercises three times daily Visual impairment: visual aids Hearing impairment: amplifying devices, earwax disimpaction Dehydration: encouragement of oral intake of fluids

5 % delirium 56 % delirium

Behandling – farmakologisk

Dopamine  Serotonine  Melatonine  Acetylcholine  Noradrenaline  GABA *) some evidence for profylactic or therapeutic use in RCTs Steiner, Eur J Anaesthesiol 2011 Maldonado, Am J Geriatr Psychiatry 2013 Typical antipsychotics Atypichal antipsychotics Melatonine/ -agonists Cholinesterase- inhibitors Alpha2-receptor- agonists GABA receptors Haloperidol* Quietapin* Risperidone* Olanzapin* Melatonin* Ramelteon* Donepizil Rivastigmin Dexmedetomidin* Benzo- diazepines Chlome- tiazole

Dopamine  Serotonine  Melatonine  Acetylcholine  Noradrenaline  GABA Typical antipsychotics Atypichal antipsychotics Melatonine/ -agonists Cholinesterase- inhibitors Alpha2-receptor- agonists GABA receptors Haloperidol* Quietapin* Risperidone* Olanzapin* Melatonin* Ramelteon* Donepizil Rivastigmin Dexmedetomidin* Benzo- diazepines Chlome- tiazole

Dopamine  Serotonine  Typical antipsychotics Atypichal antipsychotics Haloperidol* Quietapin* Risperidone* Olanzapin* ProfylaxisTreatment Antipsychotics

ProfylaxisTreatment Antipsychotics StudyDrugNPopulation Kaneko (1999)haloperidol vs placebo 80Orthopedic surgery Kalisvaart (2005)haloperidol vs placebo 430Hip fracture patients Prakanrattana (2007) risperidone vs placebo 126Cardiac surgery Larsen (2010)olanzapine vs placebo400Elective arthroplasty Wang (2012)haloperidol vs placebo 457Non-cardiac surgery Hakim (2012)risperidone vs placebo 101Cardiac surgery

Zhang; Crit Care, 2013

Hirota; J Clin Psychiatri 2013

Dopamine  Serotonine  Typical antipsychotics Atypichal antipsychotics Haloperidol* Quietapin* Risperidone* Olanzapin* ProfylaxisTreatment Antipsychotics

StudyDrugNPopulation Breitbart (1996)haloperidol vs chlorpromazine vs lorazepam 30AIDS Skrobik (2003)haloperidol vs olanzapine73ICU Han (2004)haloperidol vs risperidone28Mixed Lee (2005)amilsulpride vs quetiapine40Mixed Hu (2006)olanzapine vs haloperidole vs control175«senile delirium» Kim (2010)risperidone vs olanzapine32Mixed Tahir (2010)quetiapine vs placebo42Mixed Devlin (2010)quetiapine vs placebo36ICU Girard (2010)haloperidol vs ziprasidone101ICU Grover (2011)haloperidol vs risperidone vs olanzapine 64Mixed Maneeton (2013)quetiapine vs haloperidol52Mixed Page (2013)haloperidole vs placebo141ICU ProfylaxisTreatment Antipsychotics

ProfylaxisTreatment Antipsychotics

StudyDrugNPopulation Breitbart (1996)haloperidol vs chlorpromazine vs lorazepam 30AIDS Skrobik (2003)haloperidol vs olanzapine73ICU Han (2004)haloperidol vs risperidone28Mixed Lee (2005)amilsulpride vs quetiapine40Mixed Hu (2006)olanzapine vs haloperidole vs control175«senile delirium» Kim (2010)risperidone vs olanzapine32Mixed Tahir (2010)quetiapine vs placebo42Mixed Devlin (2010)quetiapine vs placebo36ICU Girard (2010)haloperidol vs ziprasidone101ICU Grover (2011)haloperidol vs risperidone vs olanzapine 64Mixed Maneeton (2013)quetiapine vs haloperidol52Mixed Page (2013)haloperidole vs placebo141ICU ProfylaxisTreatment Antipsychotics

141 mechanically ventilated patients Haloperidol 2·5 mg x 3 i.v. vs placebo

«present evidence do not support the use of antipsychotics for prevention or treatment of delirium» «…early intervention with low-dose treatment for short periods 1-2 weeks is prudent for many patients.»

Dopamine  Serotonine  Melatonine  Acetylcholine  Noradrenaline  GABA *) some evidence for profylactic or therapeutic use in RCTs Steiner, Eur J Anaesthesiol 2011 Maldonado, Am J Geriatr Psychiatry 2013 Typical antipsychotics Atypichal antipsychotics Melatonine/ -agonists Cholinesterase- inhibitors Alpha2-receptor- agonists GABA receptors Haloperidol* Quietapin* Risperidone* Olanzapin* Melatonin* Ramelteon* Donepizil Rivastigmin Dexmedetomidin* Benzo- diazepines Chlome- tiazole

Dopamine  Serotonine  Melatonine  Acetylcholine  Noradrenaline  GABA Typical antipsychotics Atypichal antipsychotics Melatonine/ -agonists Cholinesterase- inhibitors Alpha2-receptor- agonists GABA receptors Haloperidol* Quietapin* Risperidone* Olanzapin* Melatonin* Ramelteon* Donepizil Rivastigmin Dexmedetomidin* Benzo- diazepines Chlome- tiazole

Melatonine  Melatonine/ -agonists Melatonin* Ramelteon* ProfylaxisTreatment Antipsychotics

ProfylaxisTreatment Melatonin/-agonists StudyDrugNPopulation Sultan (2010)melatonin vs midazolam vs clonidine vs placebo 203Hip arthroplasty Al-Aama (2010)melatonin vs placebo 145General medicine De Jonhge (2014)melatonin vs placebo 452Hip fracture patients Hatta (2014)ramelteon vs placebo 67Medical patients (including in ICU)

Dopamine  Serotonine  Melatonine  Acetylcholine  Noradrenaline  GABA *) some evidence for profylactic or therapeutic use in RCTs Steiner, Eur J Anaesthesiol 2011 Maldonado, Am J Geriatr Psychiatry 2013 Typical antipsychotics Atypichal antipsychotics Melatonine/ -agonists Cholinesterase- inhibitors Alpha2-receptor- agonists GABA receptors Haloperidol* Quietapin* Risperidone* Olanzapin* Melatonin* Ramelteon* Donepizil Rivastigmin Dexmedetomidin* Benzo- diazepines Chlome- tiazole

Dopamine  Serotonine  Melatonine  Acetylcholine  Noradrenaline  GABA Typical antipsychotics Atypichal antipsychotics Melatonine/ -agonists Cholinesterase- inhibitors Alpha2-receptor- agonists GABA receptors Haloperidol* Quietapin* Risperidone* Olanzapin* Melatonin* Ramelteon* Donepizil Rivastigmin Dexmedetomidin* Benzo- diazepines Chlome- tiazole

Acetylcholine  Cholinesterase- inhibitors Donepizil Rivastigmin ProfylaxisTreatment Cholinesterase inhibitors

ProfylaxisTreatment Cholinesterase inhibitors StudyDrugNPopulation Moretti (2004)rivastigmine vs aspirine 246Homedwelling persons with vascular dementia Liptzin (2005)donepezil vs placebo 80elective joint replacment surgery Sampson (2006)donepezil vs placebo 33elective total hip replacement Gamberini (2009)rivastigmine vs placebo 120elective cardiac surgery Zaslavsky (2012)rivastigmine vs placebo 28elective surgery under general anesthesia

Acetylcholine  Cholinesterase- inhibitors Donepizil Rivastigmin ProfylaxisTreatment Cholinesterase inhibitors

ProfylaxisTreatment Cholinesterease inhibitors StudyDrugNPopulation Overshott (2010)rivastigmin vs placebo 15General medicine Van Eijk (2010)rivastigmin vs placebo 104Medical/surgical ICU

Van Eijk. Lancet 2010

Dopamine  Serotonine  Melatonine  Acetylcholine  Noradrenaline  GABA *) some evidence for profylactic or therapeutic use in RCTs Steiner, Eur J Anaesthesiol 2011 Maldonado, Am J Geriatr Psychiatry 2013 Typical antipsychotics Atypichal antipsychotics Melatonine/ -agonists Cholinesterase- inhibitors Alpha2-receptor- agonists GABA receptors Haloperidol* Quietapin* Risperidone* Olanzapin* Melatonin* Ramelteon* Donepizil Rivastigmin Dexmedetomidin* Benzo- diazepines Chlome- tiazole

Dopamine  Serotonine  Melatonine  Acetylcholine  Noradrenaline  GABA Typical antipsychotics Atypichal antipsychotics Melatonine/ -agonists Cholinesterase- inhibitors Alpha2-receptor- agonists GABA receptors Haloperidol* Quietapin* Risperidone* Olanzapin* Melatonin* Ramelteon* Donepizil Rivastigmin Dexmedetomidin* Benzo- diazepines Chlome- tiazole

Noradrenaline  Alpha2-receptor- agonists Dexmedetomidin* ProfylaxisTreatment Alfa2 receptor agonists

ProfylaxisTreatment Alfa2 receptor agonists StudyDrugNPopulation Pandharipande (2007) dexmedetomidine vs lorazepam 106Surgical/Medical ICU. Mechanically ventilated Riker (2009)dexmedetomidine vs midazolam 375Surgical/Medical ICU. Expected mechincal ventilation >24 h Maldonado (2009)dexmedetomidine vs propofol vs midazolam 90Surgical ICU Shebabi (2009)dexmedetomidine vs morphine 299Surgical ICU

Maldonado, 2009

Noradrenaline  Alpha2-receptor- agonists Dexmedetomidin* ProfylaxisTreatment Alfa2 receptor agonists

ProfylaxisTreatment Alfa2 receptor agonists StudyDrugNSetting Raede (2009)dexmedetomi din vs placeboe 20patients undergoing mechanical ventilation

THE OSLO STUDY OF CLONIDINE IN ELDERLY PATIENTS WITH DELIRIUM – LUCID Bjørn Erik Neerland, MD 1 ; Karen Roksund Hov, MD 1,2 ; Vegard Bruun Wyller, MD, PhD 3,4 ; Eirik Qvigstad, MD, PhD 5 ; Eva Skovlund, MSc, PhD 6 ; Alasdair MJ MacLullich, MRCP, PhD 7 ; Torgeir Bruun Wyller 1,2 1 Oslo Delirium Research Group, Department of Geriatric Medicine, University of Oslo 2 Department of Geriatric Medicine, Oslo University Hospital, Oslo, Norway 3 Department of Pediatrics, Akershus University Hospital, Lørenskog, Norway 4 Institute of Clinical Medicine, University of Oslo, Oslo, Norway 5 Department of Cardiology, Oslo University Hospital, Oslo, Norway 6 School of Pharmacy, University of Oslo, Oslo, Norway 7 Edinburgh Delirium Research Group, Geriatric Medicine, University of Edinburgh

Dopamine  Serotonine  Melatonine  Acetylcholine  Noradrenaline  GABA *) some evidence for profylactic or therapeutic use in RCTs Steiner, Eur J Anaesthesiol 2011 Maldonado, Am J Geriatr Psychiatry 2013 Typical antipsychotics Atypichal antipsychotics Melatonine/ -agonists Cholinesterase- inhibitors Alpha2-receptor- agonists GABA receptors Haloperidol* Quietapin* Risperidone* Olanzapin* Melatonin* Ramelteon* Donepizil Rivastigmin Dexmedetomidin* Benzo- diazepines Chlome- tiazole

Dopamine  Serotonine  Melatonine  Acetylcholine  Noradrenaline  GABA Typical antipsychotics Atypichal antipsychotics Melatonine/ -agonists Cholinesterase- inhibitors Alpha2-receptor- agonists GABA receptors Haloperidol* Quietapin* Risperidone* Olanzapin* Melatonin* Ramelteon* Donepizil Rivastigmin Dexmedetomidin* Benzo- diazepines Chlome- tiazole

GABA GABA receptors Benzo- diazepines Chlome- tiazole «No adequately trials to support the use of benzodiapines. (…) cannot be recommended.»

Inouye Lancet ”….pharmacological approaches to prevention and treatment are not recommended at this time.” EASY TO SAY, BUT NOT SO EASY TO DO!!

What happens in real life?

Summary – pharmacological treatment of delirium Haloperidol To selected patients, low dose, short duration Atypical antipsychotics Olanzapin, risperidon, quietiapin can be an alternative Cholinesterase inhibitors Probably not effective. Harmful? Benzodiazepins/chlometiazol No good studies. Probably unfavourable for most patients. Melatonin/-agonists Promising. Probably safe. Alfa2-adrenergic agonist (dexmedetomidin/clonidin) Promising. Not tested against placeboe.

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