Challenging Symptom Management:

Delirium, Agitation and

Sleeplessness

Shellie Williams, M.D.

University of Chicago Medicine

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Disclosure of Conflict of Interest

This presenter has no conflict of interest to disclose.

Objectives

• Identify the common pathophysiology for challenging

symptoms in the palliative care patient.

• Recognize predisposing and precipitating factors for

delirium in the palliative care patient.

• Treat the distressing symptom of agitation associated with

delirium.

• Outline a treatment strategy for sleep disturbance in the

palliative care patient.

Mrs. A

75 yo widow with triple negative stage IV breast cancer (bone, brain mets). Recent xrt brain mets. Daughters note 3 day confusion, lethargy, withdrawn, not

sleeping. HR 110, furrow brow, dry mucosa, abdomen distended,

reaching in air, yelling for her deceased husband with periods of sedation. In ER 0.9 Nacl 125 cc/hr, hydromorphone 1mg iv for pain

and ativan 1mg for agitation. Home Decadron 6 mg bid, Fentanyl patch 50 mcg, Zofran 4 mg q 6 prn. Labs: bun/cr 50/1.4. UA sg 1.030, CXR LLL atelactasis,

KUB diffuse stool pattern. Her daughters tearfully watch her in a confused and

agitated state. “What is happening?” “This is not our mother!”

Challenging Symptoms: Delirium,

Agitation, Sleeplessness

DELIRIUM

AGITATION

INSOMNIA

Pathophysiology of Challenging Symptoms:

Tumor, AIDs,

CHF, ESRD

Somatic Nerves Autonomic Nerves

Tumor byproducts

Metabolites: urea, Nh3,

ketones

Brain Function

Alteration

SYMPTOMS:

Delirium

Sleeplessness

Agitation

Host Immune

Cells

J Pall Med 06:9 (2): 391-408 J Pall Med 06:9(2):391-408

Delirium: Defined, DSM-V Disturbance of consciousness (ie, reduced clarity of

awareness of the environment) with reduced ability to focus,

sustain, or shift attention.

Change in cognition (eg, memory deficit, disorientation,

language disturbance, perceptual disturbance) not better

accounted for by a preexisting or established dementia.

The disturbance develops over a short period (usually hours

to days) and tends to fluctuate during the course of the day.

Evidence from the history, physical examination, or lab

findings is present that indicates the disturbance is caused

by a direct physiologic consequence of a general medical

condition, intoxicating substance, medication or other

cause.

Delirium: Prevalence

22%-44% palliative care unit patients at admission

50% advanced cancer patients

68%-90% palliative care patients 30 days prior to death

Reversible in 50% palliative population

1. Leonard M, etal. J Psychosom Res. 2008 Sep;65(3):289-98 2. Morita T, etal. J Pain Sympt Manage 2007;34:579-589

Delirium: Morbidity/Mortality

Life threatening diagnosis

10-26% Higher Mortality

22-76% Increased rate death months post hospitalization

Excess rates Caregiver Stress

Leading cause for Palliative Sedation requests

J Psycho Som Res 2008 J Pain Sym Man 2011; 26 (2) 97-109

Delirium: Pathophysiology

Neurotransmitter Theory:

Cholinergic deficits: benadryl, scopalmine

Norephinephrine excess: antidepressants

Dopamine excess: anti-parkinson meds, anti-psychotics

Cytokines-IL1, IL2, TNF

Cerebral Hypoxia

Stress related hormonal changes

Delirium: Predisposing Factors

Advanced Cancer/Terminal diagnosis

Opioid Therapy

Multiple co-morbidities

Cognitive Impairment

Surgical need

Renal/Hepatic Impairment

Sensory Impairment

Imminent Dying

Advanced Age

Lawlor, P. JAMA, 2000; 284(19): 2427-29

Delirium: Precipitating Factors

Medications

Infection

Metabolic Disturbances

Dehydration

Immobility

Untreated pain

Environment: ICU, changes

Malnutrition

Delirium: Presentation

Spiller, etal. Palliative Medicine, 2006; 20: 17-23

• Agitation

• Insomnia

• 20-30%

Hyperactive

• Fluctuation

Mixed • Sedate

• Nonverbal

• 70-80%

Hypoactive

Delirium: Presentation Terminal

Delirium

Cardinal sign of imminent death (hours-days)

86% Imminently Dying

Hypoactive >80%

Refractory to correction in some cases (50%)

Spiller, etal. Palliative Medicine, 2006; 20: 17-23

Delirium: Agitation Presentation

Hyper-alert

Pacing

Picking Skin

Refusals of care

Vivid hallucinations

Delusions

Homicidal

Suicidal

Spiller, JA. Pall Med 2006; 20: 17-23

Delirium: Family Experience

• Impedes Communication • Limits patient/family precious time

• Creates anxiety & fear

• Overwhelm with care of patient • Feel premature separation • Shift in burden of decision-making

Delirium: Guiding Steps for Family

and Clinician

• Normal in advanced disease • Treatable in most • Patient’s and family’s goals of care direct

evaluation, treatment • Weigh burden of evaluation • Evaluate likelihood a reversible etiology will be

found (50%) • Feasibility of treatment

Delirium: Diagnosis (CAM)

Confusion Assessment Method

Inouye SK, etal. Ann Intern Med;113:941-948

Acute Onset & Fluctuating Course

AND Inattention

+ either

Disorganized

Thinking Altered LOC

Delirium: Evaluation

• Caregiver interview: “Is Mrs. X more confused lately?”

• Confusion Assessment Method (CAM)

• Head to toe exam

• Medication, substance use Review (Tox screen)

• Infection (LP, Cultures, CXR)

• Metabolic (CMP, CBC, ABG, TSH, Folate, B12, RPR, HIV)

• Underlying Palliative Dx (MRI, CT, EEG, EKG, ECHO)

Delirium: Differential Diagnosis

Delirium: 1st Line Prevention

Management

• Frequent Reorientation

• Familiar setting, caregivers

• Oral Rehydration

• Attention to Lighting

• Sensory Aides

• Avoid Restraints/immobilization

• Daily Routine: Limit under/over stimulation

• Sleep Routine

Delirium: 1st Line Management

Treatment of underlying cause…

Multi-factorial, GOC directed

Medications Review

High risk: Steroids, Opioids, Anti-cholinergic, Antibiotics

Rotate opioids

Wean benzodiazepines and anticholinergics

Treat withdrawal, intoxication

Delirium: 1st Line Management

Supportive care:

Nutrition: assistance, supplements, PPN

Pain: schedule analgesics

Skin: oral and body hygiene, change position

Bowels: schedule softner, laxative

Delirium: 1st Line Management

Family/Caregiver Education

Reversible 50-80% cases, 1 week

Longer course severe illness

Representation of active dying

Non-pharmacolgic interventions

Role of medications to treat Agitation:

Neuroleptics, Sedatives

Drug category Indication Examples Benefit/SE

Antipsychotics Dopamine 2 receptor

1st line agitation

Haloperidol 0.5-2 mg po, IV q 30. T½ 4h. Max 5 mg/24 hr Chloropromazine 12.5-25 mg q 30 min, max 100mg/24. T½ 16h. Olanzapine 2.5-5 mg po qd, max 20 mg. T½ 20 h. Quetiapine 12.5-25 bid, max 400/d T½ 6h.

Also helpful nausea, hiccups (SE) sedation, falls, dry mouth, EPS, hypotension

Risk death RR 1.7 cerebrovascular, cardiac events elderly Less EPS risk atypicals; quetiapine most sedating

Benzodiazepines GABA-A receptor

2nd Line Added agent for Agitation 1st Line if Etoh or BZD withdrawal etiology

Lorazepam po, IV 0.5-5 mg bolus q 4 hour. T ½ Midazolam iv, sc 0.5-5 mg bolus, 0.5-10 mg/hr infuse

Treat seizures and myoclonus (SE) sedation, confusion, paradox agitation, falls Midazolam short T1/2

Sedatives GABA-A receptor

Refractory Agitation Propofol IV 2.5-5 mcg/kg/min (titrate q 10 min) Phenobarbital IV, sc 200 mg load, then 0.5 mg/kg/hr infuse

Rapid onset Muscle relax, bronchodilation Treat seizures (SE)CV depressant

AGITATION TREATMENTS

Delirium: Agitation Pharmacology

Anti-psychotics and Benzodiazepines can be doubled every 30 minutes until effective

Once stable add total amount needed for agitation control and give qd-tid (based T1/2)

Drug wean over 5-7 day period, after delirium stable

Death RR 1.7, AR 3.2 during use

Monitoring GOC based:

Anti-psychotic (QTc <450 at start, <25% increase), EPS symptoms, glucose, BMI

Psychosomatics. 1986; 27 (1 suppl): 33-38.

Delirium: Agitation Management

3rd line therapy: Propofol, Midazolam, Phenobarbital

Titration of the drug/(s) of choice to control Agitation

Goal of therapy NOT to hastening death.

Double Effect:

intent to relieve suffering (good), not hasten death (bad intent)

Delirium Overview

Drug Tx:

1st, 2nd, 3rd

Non-Drug

Tx

Treat Causes

Recognize

SLEEPLESSNESS

Sleeplessness: Insomnia Defined

Difficulty initiating sleep, maintaining sleep, or awakening

earlier than desired.

Lack of sleep occurs despite adequate opportunity and

sleep circumstances.

Lack of sleep causes deficits in daytime function.

International Classification of Sleep Disorders, 3rd Edition, American Academy of Sleep Medicine, 2014

Variants of Insomnia

• Short Term

Less than 3 months

Associated with Stressor

Common (Acute pain, hospitalization, grief)

Resolves with resolution of stressor or adaptation to stressor

Chronic

Sleeplessness >/=3 x weekly

Duration > 3 months

International Classification of Sleep Disorders, 3rd Edition, American Academy of Sleep Medicine, 2014

Sleeplessness:

Normal Sleep Cycle

Circadian Rhythm Fact Sheet. http://www.nigms.nih.gov/Education/Pages/Factsheet_CircadianRhythms.aspx

Sleeplessness:

Normal Sleep Cycle

S

Sleeplessness: Presentation

• Sleep Latency >30 minutes to sleep

• Early awakening >30 minutes prior to desired

• Variability of sleep thru the week

• Diminished tolerance to pain

• Increased fatigue

• Diminished Quality of Life

International Classification of Sleep Disorders, 3rd Edition, American Academy of Sleep Medicine, 2014

Sleeplessness:

Presentation

Sleeplessness: Epidemiology

30-75% Cancer patients experience insomnia

59% Surgery for malignancy

Survey primary care adults:

69% self reported insomnia

50% occasional

19% chronic

Savard, etal. 2011 Shochat, etal. Sleep 1999; 22 Suppl 2; S359.

Sleeplessness:

Etiology in Palliative Care

CO-MORBIDITY

SYMPTOMS

Untreated

Symptoms

Psychogenic

Spiritual Medication

Comorbidities

TERMINAL ILLNESS

Sleeplessness: Natural History

• 388 adults with insomnia

• 74%, Symptoms > 1 year

• 46%, Symptoms > 3 years

• Resolution insomnia in 54%

• 27% relapse within 5 years

Morin, etal. Arch Int Med 2009; 169: 447.

Sleeplessness: Evaluation

(Sleep History)

• Sleep chronology: Onset, pattern, duration of sleep

• Sleep Hygiene: Change of routine

• Sleep environment: Noise, temperature, odor disrupting

• Physical Symptoms: Cough, sob, pain, hot flashes

• Co-morbidities: CHF, OSA, Restless leg

• Meds: Steroids, Diuretics, ETOH, Caffeine, Stimulants

• Spiritual Concerns: Fears of dying

CAPC Fast Fact # 101: Insomnia Assessment

Sleeplessness: Management

(Sleep Hygiene) 1st Line

• Sleep to restful level

• Routine sleep schedule

• Avoid caffeine after lunch

• Avoid Etoh near bedtime

• Adjust bedroom environment

• Avoid light screens prior to bed

• Don't force sleep

Sleeplessness: Management

1st Line Type of Therapy Description

Stimulus Control (SC) Bed=sleep and sex 20 min sleep trial No daytime napping No TV, eat, worry

Sleep Restriction (SR) Enhance sleep efficiency (SE)= Time sleep/Time bed Decrease time in bed 15-30 min

Cognitive Behavioral Therapy (CBT)

Multi component: SR +SC + cognitive therapy focused on replacing unwanted thoughts

Spielman etal. Insomnia Dx & Treatment, London 2010. p.277 Jungquist, etal. Sleep Med. 2010 Feb 2.

Sleeplessness: Management

Benzodiazepine

Morin AK, etal. Pharmacotherapy. 2007;27:89-110 Passarella S, etal. Am J Health Syst Pharm. 2008; 65:927-934.

Sleeplessness: Management

Benzodiazepine Side Effects:

Amnesia

Paradoxical agitation

Falls

Tolerance

Dependence with

prolonged use

Sleep Architecture:

Increase Sleep time

Decline Sleep latency

Increase Stage 2

Increase delay REM

Sleeplessness: Management

Benzodiazepine Receptor

Morin AK, etal. Pharmacotherapy. 2007;27:89-110

Sleeplessness: Management

Morin AK, etal. Pharmacotherapy. 2007;27:89-110

Sleeplessness: Management

Antidepressants

Trazodone (Deseryl) 25-100 mg

Doxepin (Sinequan) 10-50 mg

Mirtazapine (Remeron) 7.5-15 mg

__________

Limited evidence in absence of depression

Doxepin only FDA approved for insomnia without

depression

T1/2 Doxepin 15 h, 31 h *

Sleeplessness: Management

Other Agents

Drug Dose Onset T1/2 SE

Diphenhydramine

(Benadryl)

25-100 30 m 5-10 Dry

mouth,

confusion

Ramelteon

(Rozerem)

8 mg 1 h 1-2.6 h

*5 h

h/a

Sore

throat

Suvorexant

(Belsomra)

10-20 mg 1 h 12 h Prolong in

obese

Valerian

(Herbal)

400-900 Liver and

heart

toxic

(*) Metabolite

Sleeplessness: Management

Problem Directed

Sleep Issue Therapy

Hormones Venlafaxine

Gabapentin

Pruritis Diphenhydramine

Cholestyramine, Paroxetine

Sleep Latency Zolpidem, Zaleplon

Sleep Maintenance Zolpidem CR, Temazepam

Depression, Anxiety Mirtazapine, Trazadone

Spiritual Counseling

Safer Elderly Eszopiclon, Trazodone

Restless Leg Syndrome Gabapentin, Mirapex

Delirium Haloperidol, Quetiapine

Abrahm, JL. A Physician’s Guide to Pain & Symptom Management in Cancer Patients. JP University Press 2014

Challenging Symptoms:

Treatable

• Establish Disease and Prognosis

• Establish Goals of Care (GOC)

• Assess for symptoms regularly

• Weigh risk: benefit of evaluation and treatment

of symptom

Challenging Symptoms:

Treatable

• Identify symptom cause

• Treat symptom with intent-> Alleviate suffering

• Reassess frequently for symptom control

• Educate family on management and future

needs

J Pall Med 06:9 (2): 391-408 J Pall Med 06:9(2):391-408

…and our life is rounded with a sleep… -William Shakespeare The Tempest, Act IV, Scene 1