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Drugs in Delirium Helpful or Harmful?

Amie Jo Digatono, PharmD, BCPP. October 26, 2017. Objectives. 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 delirium.

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Drugs in Delirium Helpful or Harmful?

Presentation on theme: " Drugs in Delirium Helpful or Harmful?"— Presentation transcript:


Drugs in DeliriumHelpful or Harmful?

Amie Jo Digatono, PharmD, BCPP

October 26, 2017



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 delirium


Disclosure Statement

Neither I nor my spouse have any relevant financial or non-financial relationships to disclose.


Key Questions

What role do medications play in the treatment of delirium?

What role

do medications

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?


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 hallucinations


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

Other features

Hyperactive, hypoactive, and mixed

Mood lability, sleep cycle disruption


Where is Delirium found?1

HospitalSevere illnessSepsis, infectionsSurgical unitsCardiovascular surgeryAIDS-relatedCancer-relatedICUAIDS: Acquired immunodeficiency syndromeICU: Intensive care unit

Long-term care facilities

Emergency department

Palliative care


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

Poorer outcomes

Associated with an increased rate of death



Mechanism unknown, likely multiple mechanisms involved

Neurotransmitter imbalances

Decreased acetylcholine

Excessive dopamine




GABA (gamma-aminobutyric acid)

Proinflammatory cytokines


Risk Factors1,6

Older age (>65 years)

Cognitive impairment

Underlying brain disease


Parkinson disease


Sensory impairment

Previous episode of delirium

Femoral neck fractures

Severe illness


Precipitating Factors1,7

InfectionDehydrationElectrolyte imbalancesHypercalcemiaImmobilityUse of restraintsMalnutritionThiamine deficiencyUse of bladder catheters


Renal failure

Hepatic failure

Respiratory failure



Substance intoxication or withdrawal


Psychoactive drugs


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?


Delirium Treatment Goals7,8

Identify and treat any underlying medical condition or toxicity

Provide supportive cares

Manage agitation


Non-Pharmacologic Interventions6,8

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

Treat pain

Minimize nighttime disruptions to facilitate sleep

Use planned toileting to reduce incontinence

Assess and treat constipation

Verbal De-escalation

Mild to moderate agitation


Pharmacologic Agents6,8

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?



Cholinesterase inhibitors

FDA: Food & Drug Administration


Cholinesterase inhibitors5,8,9

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 trial


Antipsychotic Agents2,8,10

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 measured


Antipsychotic Agents2,6-8,10

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.)


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 effects


Antipsychotic Agents2


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


Formulations: tablet

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 available



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 mg


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 withdrawal


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 ??


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 ramelteon


Drugs to prevent delirium: Antipsychotics11


Most evidence, mix of positive and negative trials

Non-cardiac surgeries

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 delirium


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”

Cholinesterase inhibitors

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 only


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 seen


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 population


Drugs that may cause or prolong delirium1


Antibiotics and antivirals


Herbal Medications

Over-the-Counter (OTC) preparations

Hypnotics and Sedatives

Muscle relaxants


Antiepileptic agents


Antihypertensive agents

Dopamine agonists


Hypoglycemic agents

Non-steroidal anti-inflammatory drugs (NSAIDs)

Psychotropic agents


Drugs that may cause or prolong delirium1,5





Benztropine, scopolamine, tolterodine

Reduced cholinergic activity

Dopamine agonists

Amantadine, levodopa, pramipexole, ropinirole

Increased dopamine activity


Cefepime, quinolones

GABA antagonism


Serotonergic dysfunction


Serotonin reuptake inhibitors

Serotonergic dysfunction



Anticholinergic activity

Fentanyl, hydromorphone, morphine

GABA antagonism


Dexamethasone, methylprednisolone

Anticholinergic activity


Anticholinergic Medications1,5,13

Anticholinergic medications

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

Anticholinergic Burden

Seven different expert-based rating scales with high variability, probably oversimplified

Higher anticholinergic burden is associated with cognitive and physical impairment in vulnerable populations


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, trazodoneWarfarin


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

Additional findings

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 oxybutynin



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 codeine


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 agents


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%


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 burden






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