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Delirium • Management • Therapy • Care Multiple factors and the role of opioids • Pain due to bone metastases, poor pain control • Fentanyl TTS 300 ug • Slight change in cognition MRI negative • Morphine IV 400 mg/day good pain control • Acute delirium with high fever haloperidol 12 mg/day lorazepam 12 mg/day. Full recovery • Chronic cognitive change persists repeated MRI shows meningeal metastases Gaudreau JD et al Cancer 2007; 109:2365-2373 and J Clin Oncol 2005; 23: 6712-6718 Delirium subjective perception Do you feel confused Not at all Very confused Delirious 21 11 Not delirious 14 5 Bosisio, Borreani, Grassi, Caraceni Rivista Italiana di Cure Palliative vol. 4, n 1/2002 The delirium experience (Breitbart et al Psychosomatics 2002; 43: 183) • 101 consecutive patients who recovered from delirium • MDAS • 53% could recall the episode • Delirium experience questionnaire – Distress level over 4 grades Crammer JL Br J Psychiatry 2002, 18: 71-75 Delirium recall depends on delirium severity 100 100 90 80 70 60 55 50 % of patients recalling 40 30 20 16 10 0 severe Breitbart et al 2002 moderate mild Delirium subjective distress • 80% of patients report from moderate to severe distress • Distress predictors – Pt = perceptual disturances and delusions – Spouse = performance – Nurse = D. severity and and perceptual disturbances 4 Average distress score 3,5 3 2,5 2 1,5 1 0,5 0 Patient Spouse Nurse Delirium and the family • High levels of distress in spouse and caregivers create anxiety also in the long term • How can we help ? Susan B 2003; Breitbart W 2002; Morita 2004; Morita 2007; Buss M 2007 Delirium and the family • Respect for the patient’s subjective perceptions and experiences, • Coordination of care to enhance communication, • Improving communication to explain the reasons for delirium and its course. • A care giver being with the patient was associated with lower family emotional distress Morita et al JPSM 2007 Therapeutic interventions • • • • • Reduce overall risk Treat reversible causes (30-50% in pc) Non pharmacological management Family counselling Drug therapy A geriatric model of risk modification • Orientation protocol • Non pharmacological protocol for night sleep management • Mobilization • Visual and auditory aids Inouye et al 1999 • Hydration Reduction of delirium incidence from 15 to 9 %. in patients ≥ 70 years of age Conscious states = wakefulness and sleep • Cholinergic n. (opioids) Cortex • Noradrenergic n. (Clonidine) Thalamus • Histaminergic n. (prometazine) • Dopaminergic n. (haloperidol) • Serotonergic n. (ssri) • Gabaergic (Benzodiazepine propofol) Evidences for pharmacological treatment are poor • • • • • Lonergan E Cochrane review 2007 Lonergan E Cochrane review 2009 Seitz D J Clin Psychiatry 2007 Lacasse H Ann Pharmacother 2006 Jackson Cochrane review 2004 Drug therapy • • • • • • Haloperidol Phenotiazine neuroleptics Atypical neuroleptics Anthistamine Clonidine Sedation - Benzodiazepines Haloperidol doses Low doses 2.5 mg/24 hs 61% Intermediate 15 mg/24 hs 32% High 30 mg/24 hs 7% Olofson et al Supp Care Cancer Retrospective study 1996 Haloperidol titration Time .1 . 2 thirty minutes .3 .4 .5 .6 .7 .8 .9 . 10 . 11 . 12 Haloperidol 0.5 mg 0.5 mg 0.5 mg 1 mg 1 mg 1 mg 2 mg 2 mg 2 mg 5 mg 5 mg 5 mg Akechi Supp Care Cancer 1996 Prospective study Average dose 1st day = 6 +/- 4 Entire period = 5.4 +/- 3.4 mg Other neuroleptics Drug dose T/2 (hs) Droperidol Chlorpromazine Promazine Methotrimeprazine 1-10 mg 25-50 mg 25 mg 25-50 mg 2-3 16-30 15-30 16-78 Atypical neuroleptics • Antagonism on the dopamine receptors and serotonin receptors D2 D4 etc 5HT2a Drug Daily dose t/2 (hs) Clozapine 25-100 mg 8 Olanzapine (also injectable) 5-10 mg 30 Risperidone 0.5-2 mg 3-20 20-30* Quetiapine 100-300 mg 3-6 Ziprasidone 120-160 os 15-60 im 7 Clinical experience in delirium - Passik 1999 Sipahimalani 1998 Meehan 2002 (IM) Breitbart 2002 Skrobik 2004 Ravona-Springer 1998 Sipahimalani 1997 Schwartz 2000 Torres 2001 Leso 2002 Lonergan et al Antipsychotics for delirium (Review) Cochrane database of systematic reviews 2007, Issue 2. http://www.cochranelibrary.com Olanzapine – 82 cancer patients assessed at 2-3 and 4-7 days – Oral olanzapine – Mean starting dose 3.0 mg (SD 0.14, range 2.510) – Mean final dose 6.3 mg (SD 0.5 range 2.5-20) – 30% reported sedation 20 18 16 14 12 MDAS score 10 8 6 4 2 0 T0 Breitbart W. Et al 2002 Psychosomatics T1 T2 Predictors of response • Logistic regression analysis - worse response OR – Age > 70 – CNS spread – Hypoactive delirium – Hypoxia – History of dementia – Delirium severity Breitbart et al 2002 171.5 74.9 11.3 5.9 0.34 5.03 Olanzapine • Skrobik Y.K. et al Intensive Care Med 2004 – ICU patients Delirium Index (5 day assessment) – 45 haloperidol vs 28 olanzapine orally – Mean daily dose olanzapine 4.54 mg, range (2.5-13) haloperidol 6.5 mg, range 1-28 Benzodiazepine • Lorazepam 2 mg IV or IM repeated after 15-30 minutes (IV) • It is first choice in alcohol withdrawal delirium Effect not sufficient or contraindication to benzodiazepines • Prometazine 50 mg im, children 1-2 mg/kg (can be combined with haloperidol, benzodiazepine, opioid) If sedation is primarily desired • Lorazepam os, im, ev – 0.5-2 mg, children 0.1 mg/kg q 1-2h, to effect • Midazolam – 5-15 mg sq /im/ev, children 0.1-0.15 mg/kg, than infusion iv/sq 0.1- 0.6 mg/kg/h; Effect not sufficient or contraindication to benzodiazepines • clonidine: – orally 1-5 mcg/kg q8h, or 0.1mg q 8-24 h, (titration every 24 h to maximum 0.6 mg/day) – iv infusion 0.1- 2 mcg/kg/h – iv occasional dose 2mcg/kg Pandharipande et al JAMA 2008; 298: 2644-2653 Opioid-induced delirium • Oversedation - hypoactive delirium • Cognitive impairment • Hyperactive delirium Opioid-induced delirium • Dose reduction (Caraceni et al JPSM 1994) • Switch opioid (Maddocks et al JPSM 1996) • Switch route (parenteral spinal ?) • Haloperidol • Psychostimulants, (Modafinil ?) • Donepezil (Slatkin 2001, Bruera JPSM 2003) Gaudreau JD et al Cancer 2007; 109:2365-2373 and J Clin Oncol 2005; 23: 6712-6718 Conclusions • Palliative care should develop more the subjective and family related areas of delirium research • Intervention strategies are still based on very limited scientific evidences • Prevention of delirium in PC • Opioid-related deliria