1. Seminar in Palliative Care September 26 – October 02, 2010 Salzburg, Austria in Collaboration with

2. The EPEC-O Curriculum is produced by the EPEC TM Project with major funding provided by NCI, with supplemental funding provided by the Lance Armstrong Foundation. Education in Palliative and End-of-life Care - Oncology The Project EPEC-O TM

3. Delirium Frank D. Ferris, MD, FAAHPM Institute for Palliative Medicine at San Diego Hospice University of California San Diego University of Toronto

4. Scott A. Irwin, MD, PhD Director, Psychiatry Programs Rosene D. Pirrello, RPh Director, Pharmacy Jeremy M. Hirst, MD Assistant Director, Psychiatry Gary T. Buckholz, MD Director, Fellowship Program Frank D. ferris, MD, FAAHPM Director, International Programs © 2010 The Butcher, Baker, and Candlestick Maker Return: Interdisciplinary Goal-Based Approaches to Delirium Recognition, Work-Up, and Management

5. Key Topics… Definition Prevalence & consequences Many causes Under recognition Assessment  Common language  History & exam  Tools  Differential diagnoses  Goals of care  Diagnostic workup

6. …Key Topics Management Non–pharmacological Pharmacological  Reversible  Irreversible  Terminal

7. Delirium Is... Change in mental status, impaired  Attention  Orientation  Cognition  Consciousness  Reality  Behavior American Psychiatric Association. (2000) Diagnostic and statistical manual of mental disorders. 943

8. ... Delirium Is Develops quickly May fluctuate Underlying medical etiology NOT dementia American Psychiatric Association. (2000) Diagnostic and statistical manual of mental disorders. 943.

9. Associated changes  Day-night reversal  Emotional states  Non-specific neurological abnormalities  Decline in functional ability

10. Types  Hyperactive  Associated behavioral disturbances  Hallucinations  Delusional beliefs  Hypoactive  Quiet  Mistaken for depression or fatigue  Mixed – waxing and waning

11. Delirium Subtypes. Meagher D, et al. (2008) J Neuropsychiatry Clin Neurosci 20: 185 Fang CK, et al. (2008) Jpn J Clin Oncol 38: 56 Stagno D, et al. (2004) Palliat Support Care 2: 171 O'Keeffe ST. (1999) Dement Geriatr Cogn Disord 10: 380 Lipowski ZJ. (1989) N Engl J Med 320: 578 Spiller JA, Keen JC. (2006) Palliat Med 20: 17

12. Delirium is Highly Prevalent and has Serious Consequences…

13. Reported Prevalence Hospitalized elderly14 – 56 % ICU70 – 87 % Advanced cancer25 – 85 % and / or end-of-life

14. Reported Prevalence Fang CK, et al. (2008) Jpn J Clin Oncol 38: 56 Pompei P, et al. (1994) J Am Geriatr Soc 42: 809 Inouye SK. (1998) Clin Geriatr Med 14: 745 McNicoll L, et al. (2003) J Am Geriatr Soc 51: 591 Ely EW, et al. (2001) Crit Care Med 29: 1370 Hart RP, et al. (1996) Psychosomatics 37: 533 Massie MJ, et al. (1983) Am J Psychiatry 140: 1048 Breitbart W, Strout D. (2000) Clin Geriatr Med 16: 357 Bruera E, et al. (1992) J Pain Symptom Manage 7: 192 Lawlor PG, et al. (2000) Arch Intern Med 160: 786

15. Consequences... 6 month mortalityup to 25 % Increased mortality10 – 78 % Prolonged hospitalizations

16. …Consequences... Fang CK, et al. (2008) Jpn J Clin Oncol 38: 56 Pompei P, et al. (1994) J Am Geriatr Soc 42: 809 Inouye SK. (1998) Clin Geriatr Med 14: 745 Lawlor PG, et al. (2000) Arch Intern Med 160: 786 Trzepacz PT, et al. (1985) Gen Hosp Psychiatry 7: 101 Inouye SK. (1994) American Journal of Medicine 97: 278 American Psychiatric Association. (1999) Am J Psychiatry 156: 1 Maltoni M, Amadori D. (2002) Hematol Oncol Clin North Am 16: 715 Thomas RI, et al. (1988) Arch Gen Psychiatry 45: 937

17. …Consequences... Stress, discomfort, reduced quality of life Patients, nurses, family members Even if hypoactive Namba M, et al. (2007) Palliat Med 21: 587 Morita T, et al. (2007) J Pain Symptom Manage 34: 579 Cohen, MZ, et al. (2009) J Palliat Care 25:164 Bruera, E, et al. (2009) Cancer 15:2004

18. 101 cancer patients who recovered from delirium, 54 % recalled experience  Hypoactive delirium 43 %  Hyperactive delirium 66 % Distress ( many reported severe )  Patients3.2 out of 4  Spouses / caregivers 3.75  Nurses3.09 …Consequences Breitbart W, et al. (2002) Psychosomatics 43: 183

19. Video – Hypoactive Delirium

20. Key points 1.Pathophysiology 2.Assessment 3.Management

21. Delirium has Many, Many Causes… Many are Discoverable and Reversible…

22. Medical Causes of Delirium Levenson JL, (2005) The American Psychiatric Publishing textbook of psychosomatic medicine See Appendix in Handout

23. Medications Causing Delirium Levenson JL, (2005) The American Psychiatric Publishing textbook of psychosomatic medicine See Appendix in Handout

24. Most Common Causes… Fluid imbalance Infections Hepatic / renal failure Hypoxia Hematological disturbance Medications  Anticholinergics  Benzodiazepines  Opioids  Steroids

25. …Most Common Causes… Lawlor PG, et al. (2000) Arch Intern Med 160: 786 Morita T, et al. (2001) J Pain Symptom Manage 22: 997 Gaudreau JD, et al. (2005) J Clin Oncol 23: 6712 Han L, et al. (2001) Arch Intern Med 161: 1099 Breitbart W, et al. (1996) Am J Psychiatry 153: 231 Gaudreau JD, et al. (2007) Cancer 109: 2365 Ancelin ML, et al. (2006) BMJ 332: 455

26. …Most Common Causes Hazard ratio of developing delirium ( 43 inpatients with cancer ) Benzodiazepines 2.04 if > 2 mg / day ( 1.05 – 3.97 ) Corticosteroids 2.67 if > 15 mg / day ( 1.18 – 6.03 ) Morphine equivalents 2.12 if > 90 mg / day ( 1.09 – 4.13 ) Gaudreau JD, et al. (2005) J Clin Oncol 23: 6712

27. Many Causes are Treatable... 237 hospice inpatients with cancer  213 ( 90 % ) had 245 episodes of delirium  Causes found in 93 of the 153 who had a workup Multi-factorial in > 50 %  Complete remission in 20 % Morita T, et al. (2001) J Pain Symptom Manage 22: 997

28. …Many Causes are Treatable 104 inpatients with advanced cancer receiving palliative care  71 had 94 episodes of delirium  Reversible in 50 % Lawlor PG, et al. (2000) Arch Intern Med 160: 786

29. Delirium is Under–Recognized…

30. Often Under–Recognized... 2716 hospice patients Delirium recognized in only 17.8 % of home care patients 28.3 % of inpatients Irwin SA, et al. (2008) Palliative and Supportive Care 6: 159

31. …Often Under–Recognized 107 end-stage cancer inpatients Delirium recognition rate : 44.9 % 20.5 % of hypoactive cases Fang CK, et al. (2008) Jpn J Clin Oncol 38: 56

32. Complex presentation Inconsistent language Hypoactive sub-type Thought to be normal part of end-of-life Why Under–Recognized ?

33. …Frank to Gary & Jeremy…

34. Careful Assessment & Communication of Findings is Key to Successful Management of Delirium…

35. Common Language is Essential…

36. Assessment  Clinical history, physical examination, observations over time  Mental status exam  Review of medication use  Thorough medical and laboratory work-up to elucidate underlying cause

37. History Context of the patient Symptoms  Quality  Severity  Temporal profile  Effect of treatments

38. Assessment Tools… “ Gold Standard ”  Experienced clinician  DSM-IV criteria Three types of standardized tools 1. Screening 2. Diagnosis 3. Symptom severity

39. Sensitivity 94 – 100 % Specificity 90 – 95 % Laurila JV, et al. (2002) Int J Geriatr Psychiatry 17: 1112 Inouye SK, et al. (1990) Ann Intern Med 113: 941

40. Differential Diagnoses to Consider… American Psychiatric Association. (2000) Diagnostic and statistical manual of mental disorders. 943

41. Differentiate Delirium From Dementia Depression Anxiety Akathisia Psychotic disorders Personality disorders Developmental disorders

42. Dementia Slow decline in brain function > expected with normal aging May have  Problems with memory, attention, language, emotions, & problem solving  Confusion, hallucinations, delusions

43. Delirium vs. Dementia DeliriumDementia Change in alertness YesNo OnsetHours to daysGradual FluctuationOftenNo

44. Depression Symptom, episode, recurrent disorder Major depression  Several symptoms  > 2 weeks duration  Impaired function

45. Delirium vs. Depression DeliriumDepression Change in alertness YesNo OnsetHours to daysGradual FluctuationOftenNo

46. Potential Reversibility of Delirium Guides Work-up & Management…

47. Potential Reversibility of Delirium Potentially Reversible Irreversible  Patient is dying ( terminal delirium )  Goals of care  Work–up / reversal unsuccessful

48. Goals of Care Initial patient & family goals  Goals can change Goals after diagnosis  Diagnostic work-up vs. palliate Goals after work-up  Reverse vs. palliate vs. irreversible

49. Diagnostic Work-up May Include Chemistry Hematology Endocrine Vitamin levels Cardiac Infection Toxicology Imaging

50. Delirium Management…

51. Management Strategies… Ensure safety Address environment Manage based on potential reversibility & goals of care Adapted from APA Practice Guidelines 2004 American Psychiatric Association. (1999) Am J Psychiatry 156: 1 Cook IA. (2004) Available online at: http://wwwpsychorg/psych_pract/treatg/pg/prac_guidecfm

52. …Management Strategies… Reverse  Treat underlying causes Relieve  Non-pharmacological  Pharmacological Consult psychiatry

53. …Management Strategies TreatmentBenefitsRisksBurdens Time-limited therapeutic trials

54. Always Use Non-pharmacological Treatments…

55. Non-Pharmacological Treatments Can Address Disordered thinking Disorientation Sleep disturbance Immobility Risk of falls / injury Sensory deprivation Dehydration Environmental factors

56. Prevention of Delirium... TargetTreatment Orientation Introduce care team / daily schedule each shift, oriented 1 – 3x / day ActivityCognitive stimulation 3x / day MobilityAmbulate / range of motion 3x / day SleepNon-pharmacological sleep protocol Sensory aidsGlasses, hearing aids DehydrationRehydrate as needed 852 patients age > 70 admitted to medicine service

57. …Prevention of Delirium In the treatment group  Fewer episodes of delirium 62 vs. 90 ( 9.9 % vs. 15 %, p = 0.03 )  Shorter duration 105 vs. 161 days ( p = 0.02 ) Followup showed up to an 89 % reduction of risk of delirium Inouye SK, et al. (1999) N Engl J Med 340: 669 Inouye SK, et al. (2003) Arch Intern Med 163: 958

58. Use Pharmacological Treatments when Appropriate… & Appropriately…

59. Pharmacological Management No medication is FDA approved for the treatment of delirium No published double-blind, randomized, placebo controlled trials No consensus among oncologists, geriatricians, psychiatrists, or palliative medicine specialists Agar M, et al. (2008) Palliat Med 22: 633

60. HyperactiveHypoactive Successful Hyperactive Medical Rx Hypoactive Unsuccessful Delirium Management Decision Tree Medical Rx Potentially Reversible Irreversible Context & Reasonable Goals of Care

61. Hyperactive Potentially Reversible Potentially Reversible, Hyperactive Antipsychotics Reverse Cause Context & Reasonable Goals of Care

62. IndicationDrug Anti - agitation SedationAmnesia Muscle relaxation Anti - convulsant Haloperidol  Chlorpromazine  Risperidone  Olanzapine  Quetiapine  Antipsychotic Indications

63. 1 st Line Pharmacological Treatment Double-blind RCT of 30 AIDS patients Haloperidol0.4 ‒ 3.6 mg daily, n = 11 vs Chlorpromazine 10 ‒ 80 mg daily, n = 13 vs Lorazepam 0.5 -10 mg daily, n = 6 Haloperidol = chlorpromazine >> lorazepam Haloperidol & chlorpromazine minimal side effects Lorazepam stopped early due to adverse events Breitbart W, et al. (1996) Am J Psychiatry 153: 231

64. PEARL Use 1 st generation antipsychotics Do Not Use Benzodiazepines  Not first-line treatment  Increase confusion, disinhibition, falls  Necessary for alcohol or sedative withdrawal APA Practice Guidelines 2004 American Psychiatric Association. (1999) Am J Psychiatry 156: 1. Cook IA. (2004) Available online at: http://wwwpsychorg/psych_pract/treatg/pg/prac_guidecfm

65. Application of Pharmacological Principles Improves Management…

66. Plasma Concentration 0 Half-life ( t 1/2 ) Time PO / PR  60 min SC / IM  30 min C max t 1/2  24 hrs Anti-psychotic Pharmacokinetic Guidelines C max

67. Sample Orders… For Agitation Haloperidol – 1 mg SC q 30 min PRN If 3 doses not effective, call MD Do not exceed 100 mg in 24 hr Schedule today’s PRNs tomorrow 1 or 2 x / day + same PRN schedule Chlorpromazine – 50 mg SC q 30 min PRN If 3 doses not effective, call MD Do not exceed 2000 mg in 24 hr Schedule today’s PRNs tomorrow 1 or 2 x / day + same PRN schedule

68. …Pharmacological Management Haloperidol = Olanzapine & Risperidone 1. Haloperidol 1 - 28 mg daily, n = 45vs Olanzapine 2.5 - 13.5 mg daily, n = 28 2. Haloperidol 1.5 - 10 mg daily, n = 11vs Olanzapine 5 - 15 mg daily, n = 11 3. Haloperidol1 - 3 mg daily, n = 12vs Risperidone 0.5 - 2 mg daily, n = 12

69. Pharmacological Management Skrobik YK, et al. (2004) Intensive Care Med 30: 444 Sipahimalani A, Masand PS. (1998) Psychosomatics 39: 422 Han CS, Kim YK. (2004) Psychosomatics 45: 297

70. PEARL Treat agitation like a breakthrough symptom, e.g., pain Provide breakthrough ( PRN ) doses on the Time to maximum concentration ( T Cmax ) If 3 doses not effective, call MD ( time-limited trials ) Provide routine doses once every Half-life ( t ½ )

71. Management of Severe Agitation…

72. When is Agitation an Emergency ? Rarely Sometimes Usually Always Allen et al. Treatment of Behavioral Emergencies Expert Consensus, 2001

73. Hierarchy of Treatments Always Usually Sometimes Rarely

74. Severe Agitation... If imminent risk of harm to self or others Haloperidol 2 - 5 mg + Diphenhydramine* 50 - 100 mg x 1 ( protects against EPS & adds sedation ) ± Lorazepam 1 - 2 mg ( or Midazolam ) In same syringe, mix very slowly in order Lorazepam  Haloperidol  Diphenhydramine

75. …Severe Agitation… Allen et al. Treatment of Behavioral Emergencies Expert Consensus, 2001 Wise MG, Rundell JR. (2005) Clinical manual of psychosomatic medicine Bottomley DM, Hanks GW. (1990) J Pain Symptom Manage 5: 259

76. …Severe Agitation – Alternatives… Chlorpromazine 50 - 100 mg SC  Increase dose by 50 mg once every Time to Maximum Concentration ( t Cmax ) until controlled  Up to 2 gm / day  If SC administration painful, e.g., burning, consider IV infusion with dexamethasone  Likely don’t need diphenhydramine  ± Lorazepam

77. …Severe Agitation - Alternatives Olanzapine 5 - 10 mg IM  May repeat x 1 in 2 hr  May repeat x 1 again 4 hr later  Up to 30 mg / day ( Expensive ) Ziprasidone 10 - 20 mg IM  May repeat 10 mg every 2 hr  May repeat 20 mg every 4 hr  Up to 40 mg / day ( Expensive )

78. Warning Drug Increased Mortality in Dementia- related Psychosis Suicidal Ideation in Children, Adolescents, Young adults Post - injection Delirium Sedation Syndrome Haloperidol  Chlorpromazine  Risperidone  Olanzapine  Quetiapine  Antipsychotics – Black Box Warnings

79. Agent(s) Dose in CPZ equiv 1 st Generation Incidence-Rate Ratio 2 nd Generation Incidence-Rate Ratio Low < 100 mg 1.311.59 Moderate 100–299 mg 2.012.13 High > 300 mg 2.422.86 Antipsychotics – Sudden Cardiac Death P values significant for dose-response relationship P value not significant for 1 st vs. 2 nd generation risk NEJM 2009; 360 : 225 - 35

80. Hypoactive Potentially Reversible Potentially Reversible, Hypoactive ? Reverse Cause Context & Reasonable Goals of Care

81. HyperactiveHypoactive Successful Hyperactive Medical Rx Hypoactive Unsuccessful Delirium Management Decision Tree Medical Rx Potentially Reversible Irreversible Context & Reasonable Goals of Care

82. Terminal Delirium Delirium during dying process Prospective, irreversible Altered level of consciousness Tachycardia Abnormal breathing patterns Loss of swallow / gag Oral / tracheal secretions Loss of sphincter control Oliguria / anuria Cyanosis Peripheral cooling Venous pooling / mottling

83. Two Roads to Death Restless Confused Tremulous Hallucinations Mumbling Delirium Myoclonic Jerks Sleepy Lethargic Obtunded Semicomatose Comatose Seizures USUAL ROAD ( Hypoactive ) DIFFICULT ROAD ( Hyperactive ) NormalNormal DeadDead

84. Two Roads to Death As reprinted in: Advance planning. In: Ferris FD, Flannery JS, McNeal HB, Morissette MR, Cameron R, Bally GA, eds. Module 4: Palliative care. In: A Comprehensive Guide for the Care of Persons with HIV Disease. Toronto, Ontario: Mount Sinai Hospital and Casey House Hospice Inc; 1995:118-120, see http://www.ipcrc.net/clinical-resources- disease-management-AIDS-guide.php Originally published in: Freemon FR. Delirium and organic psychosis. In: Organic Mental Disease. Jamaica, NY: SP Medical and Scientific Books; 1981:81-94

85. Hyperactive Irreversible Irreversible Terminal, Hyperactive Benzodiazepines, Barbiturates, Propofol Support Signs of Active Dying

86. Indication Drug Anti - agitation SedationAmnesia Muscle relaxation Anti - convulsant Lorazepam Midazolam Benzodiazepine Indications Antipsychotics /   Opioids 

87. Benzodiazepines Breitbart W, Strout D. (2000) Clin Geriatr Med 16: 357 Bottomley DM, Hanks GW. (1990) J Pain Symptom Manage 5: 259 Rousseau P. (2004) J Support Oncol 2: 181 Ferris FD. (2004) Clin Geriatr Med 20: 641 Morita T, et al. (2003) J Palliat Med 6: 557 Stiefel F, et al. (1992) J Pain Symptom Manage 7: 94 Levenson JL, Publishing AP. (2005) The American Psychiatric Publishing textbook of psychosomatic medicine. xxi

88. Sample Orders to Control Agitation… Lorazepam PO / Buccal Mucosa  Starting dose = 1 mg PO / Buccal q 1 h PRN  If 3 doses not effective, call MD  Up to 40 mg in 24 hr  Schedule today’s PRNs tomorrow q 8 h + PRN doses q 1 h

89. …Sample Orders to Control Agitation… Midazolam SC  Loading dose = 0.2 mg / kg then 0.1 mg / kg q 30 min x 2 PRN  Maintenance dose / hr = 25 % total dose to sedate  Consider alternative if need > 10 mg / hr

90. …Sample Orders to Control Agitation… Propofol IV  Starting dose = 1 mg / kg / hr  Increase by 0.5 mg / kg / hr increments every 15 – 30 min PRN  Maximum for EOL = 6 mg / kg / hr

91. …Sample Orders to Control Agitation… Lundström S, Zachrisson U, Furst CJ. When Nothing Helps: Propofol as Sedative and Antiemetic in Palliative Cancer Care. J Pain Sympt Manage 2005; 30 (6): 570-577 McWilliams K, Keeley PW, Waterhouse ET. Propofol for Terminal Sedation in Palliative Care: A Systematic Review. J Palliat Med 2010; 13 (11): 73-76

92. …Sample Orders to Control Agitation Phenobarbital IV or SC  Loading dose = 10 mg / kg  May repeat x 2 within 2 – 3 hrs  Continuous infusion 10 – 20 mg / hr  Titrate PRN  Maintenance = 600 – 2400 mg / 24 hr

93. PEARL Treat agitation like a breakthrough symptom, e.g., pain Provide breakthrough ( PRN ) doses on the Time to maximum concentration ( T Cmax ) If 3 doses not effective, call MD ( time-limited trials ) Provide routine doses once every Half-life ( t ½ )

94. Benzodiazepines Lethal Doses  Lorazepam LD 50 = 5,000 mg  Midazolam LD 50 = 10,000 mg Don’t worry about  Amnesia, confusion, restlessness  Hypotension  Respiratory depression

95. Hyperactive Irreversible Irreversible, Hyperactive Antipsychotics, Benzodiazepines, Barbiturates, Propofol Support Goals of Care or Work-up / Treatment Unsuccessful

96. Hypoactive Irreversible Irreversible, Hypoactive Support Goals of Care or Work-up / Treatment Unsuccessful ?

97. Mental Health Experts Can Help Diagnoses often complex Clinicians unfamiliar with non-pharmacological treatments Clinicians often uncomfortable with pharmacological treatments, especially off-label use Develop new treatments

98. Key Topics… Definition Prevalence & consequences Many causes Under recognition Assessment  Common language  History & exam  Tools  Differential diagnoses  Goals of care  Diagnostic workup

99. …Key Topics Management Non–pharmacological Pharmacological  Reversible  Irreversible  Terminal

100. Summary Cases can be complex Clinicians often unfamiliar with all possible treatments Complex cases stressful

101. Agar M, Lawlor P. Cur Op Onc 2008; 20 ( 4 ): 360 - 66 Ganzini, L. Ann Long-Term Care 2007; 15 ( 3 ): 35 - 40 Breitbart W, Alici Y. Agitation and Delirium at the End of Life: "We Couldn't Manage Him". JAMA 2008; 300: 2898 - 2910 Additional Reviews