High-Alert Medications and Suspected Delirium

Background information and research related to these tables:

·  A wide range of medications and medication issues may contribute to delirium

o  Inappropriate dosing

§  Too high- for example: digoxin toxicity

§  Too low- for example: uncontrolled pain may lead to delirium

o  Drug-drug interactions

o  Drug-disease interactions[i]

§  Studies demonstrate increase risk in cancer patients on opioids

§  Studies demonstrate delirium risk is decreased in post-surgical patients when pain is control

o  Inappropriate drug selection

§  Increased drug sensitivities in the elderly

·  Potential pathophysiology of delirium based on specific neurotransmitters[ii]:

§  Excess of dopamine

§  Depletion of acetylcholine

§  GABA, serotonin, endorphins and glutamate also play a role

·  Many medications maybe suspect, but few are consistently associated with the development of delirium.[iii]

o  According to one critical review, psychoactive medications appear to be involved in delirium cases in 15-75% of cases

o  Drugs were considered a definite cause of delirium in only 2-14% of cases

o  Those cited in the critical review include:

§  Opioids

§  Corticosteroids

§  Benzodiazepines

o  Other medications mentioned but not consistently cited include:

§  Anticholinergics

§  NSAIDs

§  Chemotherapeutic agents

o  There are not many well designed studies examining drug-induced delirium

§  The studies have conflicting results

§  The studies vary in regards to design and analysis

§  Benzodiazepines and antipsychotics noted significant results in a study

§  Anticholinergics, anticonvulsants, antidepressants, antiemetics, antiparkinsonians, corticosteroids, H-2 antagonists, and NSAIDs were not significantly associated with delirium in any study noted in the critical review

§  These studies lack defined controls and numerous variables; therefore, results may not reliably be compared to infer significant findings.

o  Critical review conclusions: the currently available epidemiologic evidence of an association of psychoactive medications and delirium is rather weak.

High risk medications specific to the elderly (The Beers Criteria):

·  Why the Beers Criteria is important[iv]

o  The Beers criteria are based on expert consensus developed through extensive literature reviews identifying medications that may potentially inappropriate in older adults

o  Centers for Medicare and Medicaid (CMS) adopted the Beers Criteria in July 1999 for nursing home regulation.

o  Studies examining the use of medications found on the list indicate increased provider/facility costs and increased inpatient, outpatient and emergency visits.

o  The Beers Criteria was last update via an expert panel examining current literature and professional surveys in 2002

Information about this table- Medications Implicated in Drug-Induced Delirium i

·  This in not an all encompassing list; these are medications consistently mentioned in delirium literature

·  Just because a patient may be on one or more of these meds, it does not mean it is the absolute cause of delirium

·  Medication sensitivity and effect vary greatly from patient to patient, and delirium cases should encompass the patient’s entire medical picture (disease condition, environment, medications, etc.)

Table A- Medications Implicated in Drug-Induced Delirium

Medication Class / Medication
Benzodiazepines / Lorazepam
Diazepam
Clonazepam
Alprazolam
Triazolam
Clorazepate
Opioids / Fentanyl *
Meperidine *
Morphine *
Corticosteroids / Prednisone
NSAIDs / Diclofenac
Ibuprofen
Sulindac
Indomethacin
Salicylic acid
Ketoprofen
Antipsychotics / Clozapine * ª
Fluphenazine
Haloperidol
Loxapine
Olanzapine ª
Perphenazine
Quetiapine ª
Risperidone
Thioridazine ª
Ziprasidone
Antiarrhythmics / Amiodarone
Lidocaine
Quinidine
Tocainide
Antiasthmatics / Theophylline
Anticonvulsants / Phenytoin
Acetazolamide
Lamotrigine
Pregabalin
Valproic Acid*
Medication Class / Medication
Antidepressants / Amitriptyline ª
Desipramine ª
Doxepin ª
Imipramine ª
Protriptyline ª
Mirtazapine ª
Fluoxetine
Paroxetine
Sertraline
Dopaminergic Agents / Amantadine
Levodpa
Bromocriptine
Antihypertensives / Enalapril
Captopril
Lisinopril
Reserpine
Clonidine
Methyldopa
Nifedipine
Verapamil
Atenolol
Metoprolol
Propranolol
Anticholinergics / Atropine ª
Benztropine ª
Scopolamine ª
Tolterodine ª
Antimicrobials / Tobramycin
Bactrim
Linezolid
Other Agents / Digoxin
Alcohol withdrawl
Lithium *
* Documented incidence from clinical trials
ª Medications that have anticholinergic effects which can be associated with cognitive impairment

The Beer’s Criteria and fairly commonly medications iv,[v]

Drug / Concern / Severity Rating
Propoxyphene and combinations / Demonstrates analgesic effects similar to acetaminophen with adverse effects of narcotics / Low
Indomethacin / Produces most CNS effects of the NSAID class / High
Pentazocine / Narcotic with several CNS effects: confusion and hallucinations / High
Trimethobenzamide / Poor antiemetic effects; potential for EPS / High
Muscles relaxants and antispasmodics / Poorly tolerated in elderly; anticholinergic effects; increase fall risk / High
Flurazepam / Extremely long half-life cause prolonged side effects of sedation and falls / High
Amitriptyline / Potent anticholinergic; sedating / High
Doxepine / Potent anticholinergic; sedating
Meprobamate / Highly addictive anxiolytic / High
Specific dosing of benzodiazepines
·  Lorazepam > 3 mg
·  Oxazepam > 60 mg
·  Alprazolam > 2 mg
·  Temazepam > 15 mg
·  Triazolam > 0.25 mg / Doses ranging higher than those suggested demonstrate little benefit with increased side effects compared to smaller doses / High
Long-acting benzodiazepines
·  Chlordiazepoxide
·  Diazepam
·  Quazepam
·  Halazepam
·  Chlorazepate / Long half-life produces prolonged sedation and increased risk for falls / High
Disopyramide / Particular antiarrhythmic may induce heart failure in elderly; also anticholinergic effects / High
Digoxin / Closely monitor renal clearance and levels to prevent toxicity / Low
Short-acting dipyridamole / Potential for orthostatic hypotenstion; long-acting formulation only in those with prosthetic heart valves / Low
Methyldopa / Bradycardia; may potentiate depression / High
Reserpine > 0.25 mg / May induce depression, impotence, sedation, orthostatic hypotension / Low
Chlorpropamide / Long half-life may prolong hypoglycemia / High
GI antispasmodics
·  Dicyclomine
·  Hyoscyamine
·  Belladonna alkaloids
·  Clidinium-chlordiazapoxide / Increased anticholinergic effects; efficacy uncertain / High
Anticholinergics/Antihistamines
·  Chlorpheniarmine
·  Diphenhydramine
·  Hydroxyzine
·  Cyproheptadine
·  Promethazine / Potent anticholinergic / High
Diphenhydramine / Confusion and sedation; use lowest possible dose in allergic reactions / High
Ferrous Sulfate > 325 mg/day / High doses not dramatically absorbed; constipation greatly increased / Low
Barbiturates (except Phenobarbital) / Highly addictive; harmful side effects / High
Meperidine / Advantage over other analgesics questionable; increased side effects / High
Ticlopide / No more efficacious than aspirin for clots; more side effects / High
Ketorolac / Use (especially long-term) associated with GI side effects / High
Amphetamines / Addictive; Induce hypertension, angina, and myocardial infarction / High
Long-term use of NSAIDs / GI bleeds, renal failure, high blood pressure, heart failure / High
Bisacodyl / Long-term use may exacerbate bowel dysfunction / High
Amiodarone / May prolong QT interval; questionable efficacy in elderly / High
Fluoxetine (daily dosing) / Long half-life may prolong CNS stimulation, sleep disturbances, agitation / High
Nitrofurantoin / Renal impairment / High
Doxazosin / Hypotention; anticholinergic effects / Low
Methyltestosterone / Prostatic hypertrophy; cardiac issues / High
Short acting nifedipine / Hypotension; constipation / High
Clonidine / Hypotension; CNS effects / Low
Mineral oil / Risk for aspiration and other side effects / High
Cimitidine / Increased CNS effects (confusion); drug interactions / Low
Ethacrynic acid / Hypertension; fluid imbalances / Low
Estrogens only agents / Evidence of carcinogenic potential and lack of cardio-protective effects in elderly women / Low
Notes:
Abbreviations: CNS- central nervous system; NSAIDs- nonsteroidal anti-inflammatory drugs; EPS- extrapyramidal symptoms
Anticholinergic effects- may effect several different systems; most notable effects include: ataxia, dry mouth and eyes, blurred vision, constipation, tachycardia, light-headedness urinary retention, confusion, and agitation.

References:

[i] Borovick and Fuller. Drug-Induced Diseases: Prevention, Detection, and Management: 2nd ed. ASHP 2010; Chapter 15: Delirium.

[ii] Girard TD, et al. Crit Care 2008; 12(Suppl 3): S3

[iii] Gaudreau JD, et al. Psychosomatics 2005; 46(6): 302-316

[iv] Fick DM, et al. Arch Intern Med 2003; 163: 2716-2724

[v] PA-PSRS Patient Safety Advisory 2005; Vol 2(4)