delirium: pharmacological impact on incidence and treatment uyen dinh, pharm.d. october 22, 2015
TRANSCRIPT
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
References available upon request
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