Drugs in Delirium Helpful or Harmful?
Presentations text content in Drugs in Delirium Helpful or Harmful?
Drugs in DeliriumHelpful or Harmful?
Amie Jo Digatono, PharmD, BCPP
October 26, 2017Slide2
Describe the impact and pathophysiology of delirium
Identify patients who are at increased risk for delirium
Review the current evidence for medication use in the prevention and treatment of deliriumSlide3
Neither I nor my spouse have any relevant financial or non-financial relationships to disclose.Slide4
What role do medications play in the treatment of delirium?
play in the prevention of delirium in patients hospitalized for illness or surgery?
What medications should we avoid in vulnerable patients to reduce the risk of delirium?Slide5
Patient Case: Introduction
M.S. 56 year old female
PMH: schizoaffective disorder, depression, history of cocaine use disorder (in remission), history of stroke, personality disorder NOS, obesity, hyperlipidemia, and urinary incontinence (neurogenic bladder)
CC: Evening staff report poor cooperation with cares, at times striking out toward staff, mood lability (tearfulness), and increased hallucinations
Current medications: olanzapine 15 mg bid, divalproex EC 750 mg bid, sertraline 50 mg daily, simvastatin 40 mg
, oxybutynin XL 10 mg daily and diphenhydramine 50 mg q4h PRN anxiety or sleep
M.S. was seen in morning rounds and haloperidol 5 mg bid started for hallucinationsSlide6
What is delirium?1
Disturbance in attention
Reduced attention, focus, and ability to shift focus
Disturbance in cognition
Impaired memory, language, orientation or perception
Acute change from baseline
Develops over a short time and may fluctuate over time
Different than dementia
Caused by illness, substance intoxication or withdrawal, or medication
Hyperactive, hypoactive, and mixed
Mood lability, sleep cycle disruptionSlide7
Where is Delirium found?1
HospitalSevere illnessSepsis, infectionsSurgical unitsCardiovascular surgeryAIDS-relatedCancer-relatedICUAIDS: Acquired immunodeficiency syndromeICU: Intensive care unit
Long-term care facilities
Impact of Delirium1-4
Affects many patients30% older medical patients11-42% patients hospitalized on medical units10-50% older post-surgical patients70% ICU patients42% hospice patients85% terminally ill cancer patientsLonger hospital stays and increased healthcare costsAdd $16,303 to $64,421/delirious patient/year$38-152 billion/year in the U.S.
Results in significant distress for patients and caregivers
Less likely to return to baseline functioning
More long-term care facility placements
Increased rate of decline in patients with dementia
Associated with an increased rate of deathSlide9
Mechanism unknown, likely multiple mechanisms involved
GABA (gamma-aminobutyric acid)
Older age (>65 years)
Underlying brain disease
Previous episode of delirium
Femoral neck fractures
InfectionDehydrationElectrolyte imbalancesHypercalcemiaImmobilityUse of restraintsMalnutritionThiamine deficiencyUse of bladder catheters
Substance intoxication or withdrawal
Patient Case: Review of Risk Factors
M.S. continues to have mood lability and difficulty participating in her cares. Despite escalating doses of haloperidol (up to 30 mg/day), she continues to talk to shadow-people in her room and has been lowering herself to the ground to access the pool.
Evaluated by the evening medical team and diagnosed with delirium
Difficulty following staff directions -> Disturbance in attention
Hallucinations -> Disturbance in cognition (perception)
Acute change, fluctuated over a 24 hour period
Increased irritability and mood lability
What are M.S.’s risk factors for delirium?
History of stroke
Possible previous episode of delirium?
Polypharmacy with psychoactive medications?Slide13
Delirium Treatment Goals7,8
Identify and treat any underlying medical condition or toxicity
Provide supportive cares
Provide orientation when neededFacilitate family visits, orientation to date and timeEnsure adequate hydrationProvide adequate nutritionConsider thiamine supplementation in patientsEncourage activity to maintain mobilityMeals up in chair to decrease risk of aspiration
Minimize nighttime disruptions to facilitate sleep
Use planned toileting to reduce incontinence
Assess and treat constipation
Mild to moderate agitationSlide15
No medication that is FDA-approved for treatment of delirium or agitation associated with delirium
Pharmacologic agents may be considered for severe agitation
When verbal de-escalation has failed
What role is there for the following agents in the treatment of delirium?
FDA: Food & Drug AdministrationSlide16
Uses: Alzheimer disease, Parkinson disease dementia (rivastigmine), Lewy body dementia (off-label)
Mechanism: Increase acetylcholine in the CNS
Examples: rivastigmine, donepezil, galantamine
No role in the treatment of delirium
RCT by van
, et al. (2010) studying rivastigmine as add-on to haloperidol in ICU was stopped early due to increased mortality in the rivastigmine group
CNS: central nervous system
RCT: randomized controlled trialSlide17
Uses: schizophrenia, psychosis, mania, bipolar disorder, depression (adjunct)
Mechanism: block the activity of dopamine at the D2 receptor. Second generation antipsychotics also antagonize serotonin 2A receptors
Examples: haloperidol, risperidone, olanzapine, quetiapine, and aripiprazole
No clear evidence supporting use in literature
Meta-analysis by Neufeld, et al. (2016) found no improvement in outcomes with antipsychotics in either prevention or treatment of delirium.
No difference in 30-day mortality, length of stay, severity or duration of delirium
Outcomes such as patient distress not measuredSlide18
Consensus statements and guidelines (e.g. APA, NICE) do support use of antipsychotic medications in certain instances for short duration (≤7 days)
Indications: patients with significant distress due to delirium, who may be at risk of harm to self or others, or whose symptoms interfere with treatment of underlying cause; when verbal de-escalation and non-pharmacologic interventions have failed
Choice of agent
Haloperidol historically has had the most use
Olanzapine, risperidone, chlorpromazine, ziprasidone, & quetiapine have also been studied
APA: American Psychiatric Association
NICE: National Institute for Health and Care Excellence (U.K.)Slide19
Antipsychotic Agents: Preferred2,6
Formulations: tablet, oral solution, IM/IV solutionInitial dose: 0.5-1 mgDaily max: 5-10 mg/dayAdverse effects: dystonia, akathisia, parkinsonismAdvantages: minimal anticholinergic side effects and hypotensionDisadvantages: QTc prolongation, avoid in Parkinson diseaseIM: intramuscular IV: intravascular
Formulations: tablet, orally disintegrating tablet, IM injection
Initial dose: 2.5-5 mg
Daily max: 10 mg
Adverse effects: hypotension, parkinsonism, sedation
Advantages: less dystonia
Disadvantages: more anticholinergic side effectsSlide20
Formulations: tablet, oral disintegrating tabletInitial dose: 0.5 mgDaily max: 1 mg/dayAdverse effects: parkinsonism, hypotension, sedationAdvantages: less anticholinergic adverse effects Disadvantages: may cause orthostatic hypotension, not available in a short-acting injection
Initial dose: 12.5-25 mg
Daily max: 50 mg/day
Adverse effects: hypotension, sedation, agitation
Advantages: may be considered in Parkinson disease
Disadvantages: may cause orthostatic hypotension, injection not availableSlide21
Uses: anxiety disorders, seizure disorders, sedation, catatonia (off-label), panic disorder (off-label)
Mechanism: increases activity of GABA in CNS to provide anxiolysis and sedation
Examples: lorazepam, diazepam, clonazepam, and midazolam
Limited role in treating delirium
Few studies, less effective or no different from antipsychotic agents in treatment of delirium
May worsen confusion and sedation
Preferred for delirium due to alcohol or benzodiazepine withdrawal
May be considered if antipsychotics are contraindicated, or side effects limit use
Starting dose: lorazepam 0.5-1 mgSlide22
Summary: Medication use in the Treatment of Delirium
Non-pharmacologic interventions are first-line
Consider thiamine supplementation in nearly all patients
Pharmacologic therapy may be considered in severe agitation
Haloperidol is the most studied and most frequently used, but avoid in patients with prolonged QTc
Olanzapine may also be considered as a first line agent
Avoid antipsychotics in patients with Parkinson disease or Lewy Body dementia
Increased sensitivity to movement adverse effects
Use of quetiapine or benzodiazepines may be appropriate
Avoid benzodiazepines in most patients
Preferred for delirium associated with alcohol or benzodiazepine withdrawalSlide23
Patient Case: Treatment
M.S. continued on haloperidol while delirium work-up progressed. She received fluids for slight dehydration. Urinalysis was negative for UTI. Work-up eventually revealed fungal skin infection. Nystatin powder topically to affected areas TID initiated.
Delirium resolved after a few days and M.S. returned to the behavioral health unit. After a few more days, haloperidol was tapered and discontinued.
Was M.S.’s delirium treated appropriately?
Identified and treated underlying condition
Provided supportive care
Antipsychotic medication for delirium tapered
The End ??Slide24
Prevention of Delirium6,8,11
Focused on modifying risk factors and reducing precipitating events
Non-pharmacologic interventions are preferred
Same interventions as for treatment
Geriatric order set
What role is there for pharmacologic agents in the prevention of delirium?
Systematic review by Tremblay and Gold (2016) summarizes evidence for various pharmacological interventions for the prevention of post-operative delirium
Antipsychotics, cholinesterase inhibitors, statins, steroids, gabapentin, benzodiazepines, and melatonin, tryptophan, and ramelteonSlide25
Drugs to prevent delirium: Antipsychotics11
Most evidence, mix of positive and negative trials
5 mg IV x5 days, IV infusion +/- bolus, 1.5 mg orally x3 days
Two trials in cardiac patients
1 mg orally post-op, 0.5 mg bid
Limited positive outcomes noted
One trial showed reduced incidence, but increased severity of deliriumSlide26
Drugs to prevent delirium8,11,12
GabapentinSmaller, pilot clinical trial900 mg daily x4 daysReduction in post-op delirium & reduction in PCA useBenzodiazepinesOne trial, focused on improvement in sleepDiazepam IM, flunitrazepam IV infusion, and pethidine (meperidine) IV infusionLess delirium, but significant “morning lethargy”
Donepezil: three trials, no difference found
Rivastigmine: two trials, no difference found
Observational studies only
Results mixed, possible difference in relation to presence/absence of sepsis
One trial in cardiac patients
Dexamethasone 8 mg IV pre- & post-op
Reduction seen post-op day 1 onlySlide27
Drugs to prevent Delirium: Melatonin8,11
Hormone produced in pineal gland that plays a role in sleep-wake cycle
Synthesized from tryptophan (via serotonin)
Available over-the-counter as a dietary supplement (not FDA-regulated)
One positive, one negative trial: 3 or 5 mg/day
Minimal adverse effects
Melatonin agonist approved by FDA for insomnia
No difference seen in post-op patients, trials in patients with medical illness have shown better results
1 g orally
x9 days studied with no difference seenSlide28
SUMMARY: Medication use in the PREVENTION of Delirium
Despite continued investigation, there is still insufficient evidence to recommend the routine use of any pharmacologic agent for the prevention of delirium in acute medical illness, peri-operative patients, or the ICU
Non-pharmacologic interventions are still first-line
Consider changes to modify risk factors and reduce precipitating events
Polypharmacy in general patient populationSlide29
Drugs that may cause or prolong delirium1
Antibiotics and antivirals
Over-the-Counter (OTC) preparations
Hypnotics and Sedatives
Non-steroidal anti-inflammatory drugs (NSAIDs)
Drugs that may cause or prolong delirium1,5
Benztropine, scopolamine, tolterodine
Reduced cholinergic activity
Amantadine, levodopa, pramipexole, ropinirole
Increased dopamine activity
Serotonin reuptake inhibitors
Fentanyl, hydromorphone, morphine
Primary mechanism of action is blocking effects of acetylcholine
Examples: atropine, benztropine, trihexyphenidyl, scopolamine, tolterodine
More commonly accepted as potentially inappropriate in vulnerable populations (age >65 years)
Medications with anticholinergic side effects
Primary mechanism of action is something else
Anticholinergic properties are considered adverse effects
Examples: amitriptyline, diphenhydramine, hydroxyzine, olanzapine, paroxetine
Still potentially inappropriate, but more difficult to determine risk
Seven different expert-based rating scales with high variability, probably oversimplified
Higher anticholinergic burden is associated with cognitive and physical impairment in vulnerable populationsSlide32
Anticholinergic Cognitive Burden (ACB) Scale
Available at www.agingbraincare.orgMedications are given a score of 1, 2, or 3Score of 1: In vitro evidenceScore of 2: Evidence of anticholinergic effects from literature, package insert, or expert opinionScore of 3: Evidence of possible delirium from literature, package insert, or expert opinionPotentially unexpected inclusions (Score of 1)Atenolol, digoxin, nifedipine, triamtereneCimetidine, ranitidineBupropion, haloperidol, trazodoneWarfarinSlide33
Drugs to Avoid14
Systematic review by Clegg and Young (2011) identified three classes of medications to avoid in people at risk of delirium
Opioids: moderate quality evidence indicating 2-fold increased risk
Benzodiazepines: moderate quality evidence of increased risk, worse with longer acting agents
Dihydropyridines: low quality evidence, specifically for nifedipine
Digoxin: low quality evidence suggesting no association
Haloperidol: high quality evidence suggesting no association, evidence not as clear for other neuroleptics
Antihistamines: moderate quality evidence showed trend, but not significant, to increased risk
Low quality evidence, uncertain risk: H2-receptor blockers, tricyclic antidepressants, steroids, drugs for Parkinson disease, NSAIDs, and oxybutyninSlide34
Analgesia and Delirium
Pain can precipitate delirium
Acetaminophen is often not sufficient
NSAIDs carry risk for elderly patients including renal failure and cardiovascular effects
Opioids may have serotonergic, anticholinergic, and GABA antagonistic properties
Comparative Risk of Delirium with Opioids
, et al. (2017) conducted a systematic review evaluating use in older patients
Compared to no opioid, meperidine and tramadol were associated with increased risk of delirium
Compared to other opioids, only meperidine was associated with increased risk
Morphine, fentanyl, oxycodone, and codeineSlide35
Summary: Medication use in vulnerable populations
Assess risk versus benefit in each case
Use a resource, such as the Anticholinergic Cognitive Burden Scale, to screen medications for anticholinergic activity
Reduce or eliminate (if possible) medications with anticholinergic properties
Risk appears to be more established with benzodiazepines and opioids
Reduce or eliminate (if possible) benzodiazepine and opioids; use tapers
If benzodiazepines or opioids are used, use cautiously and avoid long-acting agents, those with active metabolites, or with serotonergic properties (meperidine, tramadol)
Avoid nifedipine, but not necessarily other calcium channel blockers
More evidence needed to identify other precipitant or protective agentsSlide36
Reducing Inappropriate Benzodiazepine use in older patients (EMPOWER Trial)16
Tannenbaum, et al (2014) conducted a cluster randomized trial to test the effects of a direct-to-consumer intervention versus usual care on rates of benzodiazepine use in older adults
65-95 years old, minimum of 5 active prescriptions, benzodiazepine dispensed monthly x3 months
Mean duration of use 9.6 years (intervention group) vs. 11.2 years (control)
Excluded patients with mental illness or dementia, or living in long term care facility
Just less than half of patients had previously attempted tapering
In the intervention group, 62% talked to their physician or pharmacist about stopping benzodiazepine therapy
At 6 months, 27% patients in the intervention group had discontinued use vs. 5% in control group. Dose reduction happened in another 11%Slide37
Patient Case wrap-up
After her second episode(!) of delirium resolved, M.S.’s medications were reviewed. Although reluctant to stop oxybutynin, she agreed to a trial off after a discussion regarding increased risk of delirium. Diphenhydramine was also discontinued and melatonin 3 mg nightly was started.
Nursing staff increased frequency of skin monitoring and the next discovery of infection was not accompanied by delirium.
What strategies for delirium prevention were employed?
Engaged patient in decision making
Increased monitoring for infection (avoid precipitating factor)
Decreased anticholinergic burdenSlide38
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