delirium: pharmacological impact on incidence and treatment uyen dinh, pharm.d. october 22, 2015

DELIRIUM: PHARMACOLOGICAL IMPACT ON INCIDENCE AND TREATMENT

Uyen Dinh, Pharm.D. October 22, 2015

Background

Hippocrates 500 BC: phrenitis (mental abnormalities caused by fever, poisoning, or head trauma)

Celsus 1st century: delirium (syndrome of mental disorders during fever or head trauma)

Derived from Latin delirare (deviate from a straight line, crazy, deranged, out of one’s wit, to rave, to be silly)

Appreciate the history and increased importance of delirium in hospitalized patients

Have an increased knowledge of the pathophysiology and clinical features of delirium

Understand the differences between hyperactive, hypoactive and mixed delirium and their treatment strategies

Be able to identify risk factors for the development of delirium

Recognize the common medications that can exacerbate or cause delirium

Have an increased awareness of non-pharmacologic and pharmacologic treatment strategies

Be a champion in the prevention of delirium

Objectives

Disturbance in attention (i.e., reduced ability to direct, focus, sustain, and shift attention) and awareness.

Change in cognition (i.e., memory deficit, disorientation, language disturbance, perceptual disturbance) that is not better accounted for by a preexisting, established, or evolving dementia.

Develops over a short period and fluctuates during the course of the day.

There is evidence from the history, physical examination, or laboratory findings that the disturbance is caused by a direct physiologic consequence of a general medical condition, an intoxicating substance, medication use, or more than one cause.

DSM-5 Diagnosis Criteria

Most “essential” topic in the care of elderly pts and the least understood clinical issue with the greatest knowledge gap and optimal management

Acute confusional stage, encephalopathy, acute brain failure, ICU psychosis

Medical condition/diagnosis Syndrome of multiple symptoms Acute onset of fluctuating mental status changes

that are short-term (days to hours) and associated with physical or mental illnesses

Distinct clinical features from dementia

Delirium

Features Delirium Dementia

Onset/Duration Acute, sudden/hours to days

Insidious/months to years

Arousal Hyper/hypo alert, fluctuates

Usually alert

Attention Impaired Intact/frequent impairment

Memory Impaired (registration) Impaired (temporal)

Mental Status Acute Attentional impairment

Motor Signs Brief/involuntary twitching

Occasional/parkinsonism

Orientation Impaired Impaired

Psychotic features Visual/tactile hallucinations

Occasional visual hallucinations; paranoid delusions common

Sleep Usually disturbed Usually normal

Thought process Disorganized Impoverish

Delirium vs. Dementia

ICU: 16-89 % 20-50% non-intubated pts 60-89% intubated pts Mean duration 3 days (1-44 days)

56% of hospitalized pts 10% of ED pts 20-79% older pts

Frequency

Neurotransmitter imbalance Inflammatory Acute Stress Response Anatomic/Neuronal Injury

Pathophysiology

Pathophysiology

Flacker JM, Lipsitz LA. Neural mechanisms of delirium: current hypothesis and evolving concepts. J Gerontol Biol Sci Med Sci 1999:54A:B243.

Acetylcholine Dopamine/Norepinephrine Serotonin GABA (-amionobutyric acid) Glutamate Phenylalanine

Amino acid precursor for dopamine, adrenaline Competes with tryptophan at transport channels into brain High level : increased delirium

Tryptophan Amino acid precursor for serotonin, melatonin Low level: hyperactive delirium High level: hypoactive delirium

Neurotransmitters

Low level Antagonism at the receptor level Anticholinergics Positive correlation between delirium and cumulative anticholinergic effect measured by serum anticholinergic activity

Acetylcholine

Overactivation of the dopaminergic system Increased serotonergic active Relative serotonin deficiency Supported by serotonin syndrome and drugs that increase dopamine, norepinephrine, serotonin levels

Dopamine/Serotonin

Inhibitory neurotransmitter GABA agonist inhibits dopamine release GABA antagonist or sudden w/d of GABA agonist increases hyperdopaminergic effect

GABA

GABA and N-metyl-D-aspartate (NMDA) receptor

Etoh augments GABA activity, inhibits NMDAsedation

Etoh downregulates GABA and upregulates NMDA receptors w/ chronic use

Cessation of etohincr excitatory activitydelirium

Benzos, dexmedetomidine effective

Etoh Withdrawal Delirium

Yo B@#*&, that’s crazy talk!

Mediators (interleukin, C-reactive protein, procalcitonin)Endothelial damage, microvascular compromise, pro-thrombotic statereduced brain blood flow

Acetylcholine down-regulates inflammation

Inflammatory

Cortisol regulated in the hypothalamic-pituitary-adrenal axis (HPA)

The release of corticosteroids causes impairment in cognition, attention and psychosis

High level of cortisol associated with post-op delirium

Acute Stress Response

Increased mortality Associated with longer stay and longer

duration of mechanical ventilation 15-day increase in LOS Longer mean duration by ~2 days

Development of post-ICU cognitive impairment

Clinical Impact

Independent predictor of worse scores on neuro-psychological testing and global cognition at 3 and 12 months

Duration of delirium a positive correlation with cognitive impairment and low scoring on daily activities

Increased mortality at 6 mos (41.2 % vs. 15.4%) Number of days of delirium a significant association

with time to death w/n a year after admit to ICU Progression to dementia

Long-term Impact

Economic Impact

$16,000 to $64, 000 additional costs per pt

$4 to 16 Billion annually

2013: “Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the Intensive Care Unit”

2002: “Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult”

2014: “Clinical Practice Guideline for Postoperative Delirium in Older Adults”

Guidelines

Hyperactive: agitation, restlessness Less common (0-2%) More recognizable

Hypoactive: confusion, sedation, decreased responsiveness More common (45-64%) Misdiagnosed/under diagnosed

Mixed: fluctuation between the hyperactive/hypoactive Common (6-55%)

Subsyndromal: having one or more symptoms but not meeting criteria for DSM diagnosis

Delirium Classification

Risk Factors: ICU

Preexisting Dementia, CVA, Epilepsy,

Depression HTN, CHF, Renal/Hepatic Etoh (>2 drinks/day),

Tobacco High disease severity Visual/Hearing impairment Malnutrition

Precipitating Metabolic derangement Uncontrolled pain, anxiety Hypoxia Sepsis Physical restraints Sleep deprivation Coma (medical,

sedatives) Foley, Catheters, Lines,

Tubes Medications

Risk factors: non-ICU

Preexisting

Age Dementia Cognitive impairment Daily living activity

impairment Vision impairment High disease severity Poor nutrition/low BMI Hepatic/ Renal impairment

Precipitating

Metabolic derangement Uncontrolled pain, anxiety Hypoxia Sepsis HOTN Anemia Physical restraints Sleep deprivation Foley, Catheters, Lines, Tubes Immobility Medications >3 new medications added ≥psychoactive meds

Agent MechanismAnticholinergics Anticholinergic effect

Antidepressants Serotonergic dysfunction

Antihistamines Anticholinergic effect

Antipsychotics Anticholinergic effect

Cardiac meds (amiodarone, alpha-blockers, digoxin)

Anticholinergic effect

Benzodiazepines GABA antagonism

Dopaminergics Dopaminergic effect

Narcotics GABA antagonism

NSAIDs Anticholinergic effect

Propofol GABA antagonism

Steroids Anticholinergic effect

Medications

Agent Mechanism

Acyclovir Unknown

Ampho B Unknown

Cephalosporins GABA antagonism

Linezolid Serotonergic dysfunction

Macrolides Unknown

Quinolones GABA antagonism, NMDA agonists, weak dopaminergic

Voriconazole Unknown

Antibiotics

Anticholinergics (i.e., azelastine, brompheniramine, chlorpheniramine, diphenhydramine, meclizine, dimenhydrinate, loratadine) “cold” medications

Antihistamines Vasoconstrictors i.e., phenylephrine, pseudoephedrine Dextromethorphan Alcohol

Pain medications (i.e., aspirin, NSAIDs)

OTCs

Henbane Jimson Weed Mandrake Others?

Dietary Supplements

W/o screening tools, 75% of cases were missed Improved delirium detection using a valid and

reliable tool. Strong recommendation for ICU pts with

moderate to high risk: routine assessment at least once per shift

Intensive Care Delirium Screening Checklist (ICDSC)

Confusion Assessment Method (CAM-ICU)

Screening tools

“Very Good” scoring for psychometric properties (i.e., validity and reliability)

Translated into 20 languages Higher inter-rater reliability High sensitivity (97%, 99%) and specificity

(99%, 64%) when tested against the APA’s criteria

Predictive validation and association with clinical outcomes (i.e., ICU, hospital LOS)

CAM-ICU/ICDSC

No FDA-approved medications ICU use 2001-2007: 66% to 85% for haloperidol; 4% to 50% for atypicals MEDLINE search 1960-2010 of prospective and randomized studies of critically ill pts 3 studies

Treatment

Haloperidol PO vs. Ziprasidone PO vs. Placebo for up to 14 days

Hypothesis: antipsychotics reduce duration of delirium

No significant difference in no. of days (14 days vs. 15 days vs. 12.5 days)

Treatment

Quetiapine vs. Placebo added to Haloperidol IV prn for up to 10 days (36 pts)

Shorter time to first resolution of delirium with quetiapine vs. placebo (1 day vs. 4.5 days)

Reduced duration of delirium with quetiapine (1.5 days vs. 5 days)

No difference in mortality, length of stay More likely to be dc’ed to home or rehab center

(89% vs. 56%)

Treatment

Olanzapine PO vs. Haloperidol PO No difference in delirium severity after 5

days Higher occurrence of EPSEs with haloperidol

Treatment

Drug Sedation

Anti-cholinergic

EPSE HOTN Wt. gain

DM

Aripiprazole - - +/- - +/- -

Chlorpromazine +++ ++ ++ +++ ++ ++

Clozapine +++ +++ - +++ +++ +++

Haloperidol + + +++ + + +/-

Olanzapine ++ + +/- + +++ +++

Quetiapine ++ + - ++ ++ ++

Risperidone + + + ++ ++ +

Antipsychotic Comparison

Ref #1: 7

Limited evidence to support the use of antipsychotics in ICU pts

Positive outcome (earlier resolution, decreased severity and duration of delirium) in non-ICU pts

Remains drug of choice with increased use No clear advantage between antipsychotics ? Better outcome with quetiapine

Conclusion

Now What?!

Identify/treat non-pharmacologic causes

Minimize/eliminate risk factors

Utilize screening tools to evaluate and monitor

Minimize/eliminate medications

Minimize sedation/change agents

Haloperidol vs. Atypicals?

Deep: no response to voice, movement or eye opening with physical stimulation or unarousable

Light: not fully alert; has sustained awakening to voice with possibility of restlessness or agitation

No clear census Meds for sedation if required Titration to allow for responsiveness/awareness (purposeful

response to commands) Light sedation or daily awakening trial w/ deep sedation both

effective in reducing deep sedation and associated adverse effects.

“High dose sedation dosing strategy will negatively affect cognitive function” Higher incidence of PTSD/depression or anxiety with deep sedation

vs. light sedation (43% vs. 61%) Higher incidence of delirium (22% vs. 17%)

Prevention: Deep vs. Light Sedation

Benzodiazepines Propofol Dexmedetomidine Ketamine Barbiturates i.e., Pentobarbital coma Narcotics

Sedatives: what and how much

Fentanyl Hydromorphone Morphine

Consideration: age, renal function, allergies, tolerance, knowledge/comfort, BMI

Narcotics

Meta-analysis January 1950 to April 2012 of surgical elderly pts

Risperidone 1mg PO post-op vs. placebo Olanzapine 5mg PO pre and post-op vs. placebo Haloperidol 0.5mg PO tid through POD #3 Haloperidol 5mg IV POD #1-5 vs. placebo Haloperidol 0.5mg IV bolus then 0.1mg/h x12 hrs post-op vs. placebo

Prevention: Prophylactic Antipsychotics

Prophylactic Prevention

Rivastigmine given evening prior to surgery vs. placebo

Donepezil started 2 wks before and after surgery vs. placebo

Donepezil for 30 days post op vs. placebo Donepezil for 3 days post op vs. placebo Newly prescribed cholinesterase inhibitors

not recommended for prevention or treatment of delirium post-op

Prevention: Cholinergics

Highest grading by the Critical Care Guideline

Mean reduction in incidence: 9.7%-31.8% Reduction in duration and severity Reduction in mechanical days, time to tx out

of ICU, LOS Multi-modal and multidisciplinary

Prevention: Nonpharmacologics

Interventions

Early mobilization (passive range-of-motion, PT/OT)

Reorientation Cognitive stimulation Bladder/bowel function Music therapy Nutrition/hydration Sleep protocol Noise reduction Family involvement

Glasses/hearing aids Adaptive equipment Clock/calendar/daily

schedule Minimize/Remove risk

factors Education of staff and

pts/family Pain control Eliminate/minimize meds

ABCDE Bundle

“Implications of prescribing atypical antipsychotics in the ICU: continuation at transfer and discharge prescriptions”

Eight-month retrospective cohort study 84% of patients continued at transfer out of ICU 28.6% received discharge prescriptions

More likely to have TBI DC’ed to a facility other than home

More than two-thirds with documentation of delirium resolution at discharge

Post-ICU Continuation

28/59 patients (47%) continued atypical antipsychotics after transfer from MICU

34% continued at discharge Estimated additional cost $45, 000 for

outpatient prescriptions/yr

Post-ICU Continuation

www.icudelirium.org www.healthinaging.org www.hospitalelderlifeprogram

uyen.x.dinh@healthpartners.com

References available upon request

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