1. Delirium and Its Management
Dimitry Davydow, MD, MPH
Assistant Professor
University of Washington
Department of Psychiatry and Behavioral Sciences

2. Disclosures:
- Nothing relevant to disclose
Objectives:
- To review important clinical aspects of delirium
- To discuss pharmacologic management strategies
for delirium
- To briefly discuss evidence-based
non-pharmacologic management strategies

3. Acute Brain Dysfunction AKA Delirium

4. Acute Brain Dysfunction AKA Delirium
Classical Definition: waxing and waning fluctuation in level of consciousness
Synonyms:
- Acute confusional state
- Toxic encephalopathy
- ICU psychosis
Can occur in all ages, though more common in the elderly
Onset is acute or subacute!

5. Acute Brain Dysfunction AKA Delirium
Motoric subtypes:
- Agitated/Hyperactive
- Lethargic/Hypoactive (most common in ICUs)
- Mixed (most common overall)
Signs and Symptoms:
- * Inattention
- Altered levels of consciousness
- Impaired memory and orientation
- Psychosis: Hallucinations, delusions, thought disorder
(Hallucinations and delusions only in about 1/3 of cases)
Lots of diagnostic and screening instruments available

6. Acute Brain Dysfunction AKA Delirium
Who is at greatest risk?
- The elderly
- Patients with “bad brains” (i.e., dementia,
TBI, prior strokes)
- Post-operative patients
- Patients with increasing comorbidities and
increasing numbers of medications
- Patients with a h/o depression1
- Patients with alcohol dependence (i.e., DTs)
McAvay GJ, Van Ness PH, Bogardus ST, et al. Depressive symptoms and the risk of incident delirium in older hospitalized adults. J Am Geriatr Soc 2007;55:

7. Acute Brain Dysfunction AKA Delirium
Why am I calling delirium “acute brain dysfunction?”
Because, delirium as a clinical syndrome is a CNS final common pathway of countless medical/surgical etiologic processes.
It’s like ARDS of the brain.

8. Acute Brain Dysfunction AKA Delirium
Why is it important to recognize and manage appropriately?
- Prolongs hospital length of stay.
- Accounts for > $7 billion of Medicare
inpatients expenditures.
- Associated with short and long-term
mortality.
- Agitated delirium interferes with patient care and
puts patients and staff at risk of harm.

9. Pathophysiology of Delirium
Not fully understood, though theories abound.
CNS contributing factors could be excessive neurotransmitter release and abnormal signal conduction, particularly excess striatal dopamine and underactivity of muscarinic neurons in the cortex, reticular activating system and hippocampus.
Pro-inflammatory cytokines crossing the blood-brain barrier are also thought to play a important role.

11. Most Important Management Aspects
Recognize the problem
Figure out what the underlying cause is (e.g., med,
infection, new stroke, electrolyte problem, profound anemia) and fix it

12. Common Pharmacologic Risk Factors
Anticholinergic medications:
- Diphenhydramine, Hydroxyzine
- Ipatropium
- Many tricyclic antidepressants (e.g., Amitriptyline)
- Paroxetine
- Many synthetic opioids (e.g., Fentanyl)
- Ranitidine/Cimetidine
- Oxybutynin
- Benztropine
- Prochlorperazine, Promethazine
- Cyproheptadine

13. Common Pharmacologic Risk Factors
More common anticholinergic medications:
- Digoxin
- Nifedipine
- Furosemide
- Dicyclomine
- Diphenoxylate atropine
- Chlorpromazine
- Olanzapine

14. Common Pharmacologic Risk Factors
Benzodiazepines
- Both intoxication and withdrawal
Opioids
Fluoroquinolone antibiotics
Corticosteroids

15. Other Toxin Risk Factors
Alcohol intoxication and withdrawal
Barbiturate intoxication and withdrawal
MDMA
Ketamine
PCP
LSD
Cocaine/Methamphetamines
Solvents

16. Other Etiologies of Delirium
Metabolic conditions  
- Electrolyte disturbances: hypoglycemia, hyperglycemia,
hyponatremia, hypernatremia, hypercalcemia,
hypocalcemia, hypomagnesemia  
- Hypothermia and hyperthermia 
- Dehydration and malnutrition
Respiratory failure: hypoxemia and hypercarbia 
Liver failure/hepatic encephalopathy
Renal failure/uremia

17. Other Etiologies of Delirium
Heart failure
Vitamin deficiencies: B12, thiamine (B1), folate, niacin (B3)
Anemia
Infections
- Systemic infections/sepsis
- Urinary tract infections (in elderly, dementias, TBI)
- Pneumonia
- Skin and soft tissue infections
- CNS infections: meningitis, encephalitis, brain abscess

18. Other Etiologies of Delirium
Endocrine conditions  
- Hyperthyroidism/hypothyroidism  
- Hyperparathyroidism  
- Adrenal insufficiency
Cerebrovascular disorders  
- Global hypoperfusion states  
- Hypertensive encephalopathy  
- Focal ischemic strokes and hemorrhages: especially
nondominant parietal and thalamic lesions

19. Other Etiologies of Delirium
Autoimmune disorders
- CNS vasculitis  
- CNS Lupus
Seizure-related disorders  
- Nonconvulsive status epilepticus  
- Intermittent seizures with prolonged post-ictal states
Neoplastic disorders  
- Diffuse metastases to the brain  
- Gliomatosis cerebri  
- Carcinomatous meningitis
- Hematologic malignancies

20. Other Etiologies of Delirium
Hospitalization (or other environmental change in demented)
Severe insomnia
Severe pain
Constipation
Terminal end-of-life delirium

21. Reminder: Most Important Management Aspects
Recognize the problem
Figure out what the underlying cause is (e.g., med,
infection, new stroke, electrolyte problem, profound anemia) and fix it

22. Pharmacologic Management Strategies
Antipsychotics
Other:
- Dexmedetomidine
- Melatonin
- Benzodiazepines ?

23. Antipsychotics for Delirium

24. Important Consideration
Treating delirium with a medication means treating symptoms
No evidence that antipsychotics make a delirious patient “not delirious”
Only figuring out the underlying cause and fixing it will make a delirious patient “not delirious”
Antipsychotic management is temporary

25. Haloperidol

26. Haloperidol Butyrophenone derivative
Mechanism of action: blockade of D2 receptors in mesocortex and limbic system
“High potency” antipsychotic
Available PO/IM/IV
IV form is treatment of choice for agitated delirium
IV haloperidol: onset within seconds; duration 4-6 hours
Hepatically metabolized; renal and biliary excretion

27. Haloperidol Unfortunately, no RCTs w/ IV haloperidol in delirium
Best haloperidol delirium study to date:
- 244 delirious patients with HIV/AIDS randomized
(double-blind) to haloperidol (PO) vs. chlorpromazine (PO)
vs. lorazepam (PO); only haloperidol group improved
while other 2 worsened1
Breitbart W, Marotta R, Platt MM, et al. A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. Am J Psychiatry 1996;153:

28. Haloperidol
Side effects/Adverse events:
- EPS: less common w/ IV than PO/IM; akathesia is a concern:
- Avoid in patients w/ Parkinson’s disease
- QTc prolongation and Torsades Des Pointes:
- QTc prolongation is a class-related phenomenon
- Most patients w/ QT prolongation and Torsades while on IV haloperidol
have additional risk factors for these cardiac events1
- Check baseline EKG and monitor frequently w/ regular use; replete
Mg++ and K+
- Neuroleptic Malignant Syndrome:
- Typically in high doses w/ rapid escalation of dosing
Meyer-Massetti C, Cheng CM, Sharpe BA, Meier CR, Guglielmo BJ. The FDA extended warning for intravenous haloperidol: how should institutions respond? J Hosp Med 2010;5:E8-E16

29. Haloperidol Dosing considerations: - No evidence-base
- Dosing based on patient size, age, history of
antipsychotic exposure
- Begin 1-2mg IV q 4 hrs PRN
- If requiring frequent PRNs, schedule dosing
- If severely agitated and minimal other risk factors, can
give 5mg IV q minutes over 1 hour, then schedule
q 6 hrs
- Have a ceiling: 100mg/24 hrs is a pretty good one

30. Atypical Antipsychotics
Quetiapine

31. Quetiapine Lowest potency atypical antipsychotic
Mechanism of action: less potent blockade of D2 receptors, also blocks 5HT receptors; also blocks α1 and H1 receptors
Only available PO
Half-life: 6 hours
Hepatically metabolized; renally excreted

32. Quetiapine One double-blind RCT of quetiapine for delirium:1
- Found its “safe and effective”
- Only 36 patients
- Doses beginning at 50mg q 12 hrs up to 200mg q 12 hrs
- Both groups got IV haloperidol as “rescue”
Dosing considerations:
- No evidence base
- If using, would begin at 50mg q 12 hrs w/ 50mg q 4 hrs PRN
(adjust if elderly, renal failure)
Devlin JW, Roberts RJ, Fong JJ, et al. Efficacy and safety of quetiapine in critically ill patients with delirium: a prospective, multicenter. Randomized, double-blind, placebo controlled pilot study. Crit Care Med 2010;38:

33. Quetiapine Side effects/Adverse Events: Other issues: - Expensive
- Sedation
- Orthostatic hypotension
- At high doses (800mg per day), has significant anticholinergic
effects
- QTc prolongation and NMS are still concerns
Other issues:
- Expensive
- At doses below 50mg, primarily only an H1 blocker

34. Atypical Antipsychotics
Risperidone

35. Risperidone
Mechanism of action: highest potency atypical D2 blocker; also blocks 5HT receptors
Available PO as tablet, dissolvable tablet, liquid
Half-life is 3-20 hours depending on formulation
Hepatically metabolized; renally excreted

36. Risperidone
One very small RCT found risperidone equal to haloperidol PO for delirium in the ICU1
Dosing considerations:
- No evidence base
- If using, can start at 0.5-1mg PO q 12 hrs w/ 0.5mg q 4 hrs
PRN (adjust for elderly, renal failure)
Side effects/Adverse Events:
- EPS
- Sedation
- QTc prolongation; NMS
1. Han CS, Kim YK. A double-blind trial of risperidone and haloperidol for the treatment of delirium. Psychosomatics 2004;45:

37. Other Atypical Antipsychotics
Olanzapine:
- Available PO as tablet or dissolvable tab; also IM
- Problem: highly anticholinergic once going over 15 mg total
Ziprasidone:
- Problem: greatest risk of QTc prolongation
Aripiprazole:
- Problem: half-life 75 hours
All are expensive
Data for use in delirium minimal to none

38. Antipsychotics for Delirium
Is there evidence that antipsychotics can prevent delirium?
- 3 studies with elective hip surgery patients; 2 studies w/
haloperidol and 1 w/ olanzapine pre-op; mixed results
- Jury is still out

39. Antipsychotics for Delirium – Final Thoughts
Treating the symptoms:
- Agitated, hyperactive delirium
- Hypoactive delirium but psychotic symptoms present that
are bothering the patient
Class-related issues:
- QTc prolongation, NMS, FDA black box warning for risk of
death due to cerebrovascular events in elderly w/ dementia
Temporary measure:
- Have a taper schedule

40. Other Pharmacologic Agents for Delirium

41. Dexmedetomidine
Sedative agent for intra-operative and ICU sedation while intubated
Mechanism of action: central α2 agonist
IV only
Half-life: 3 hours
Hepatically metabolized; renally excreted

42. Dexmedetomidine
No RCT evidence to support use to treat delirium in ICU settings
- One open label study showed promising results for dex drip
vs. haloperidol drip in intubated, delirious ICU patients1
Can consider for agitated, delirious, critically ill patients refractory to other agents
Dosing:
- Loading infusion of up to 1mcg/kg/min over 10 min
- Maintenance: mcg/kg/hr
- Adjust downward in elderly
Reade MC, O’Sullivan K, Bates S, et al. Dexmedetomidine vs. haloperidol in delirious, agitated, intubated patients: a randomised open-
label trial. Crit Care 2009;13:R75

43. Dexmedetomidine Side effects/Adverse events: - Bradycardia
- Hypotension
- Transient hypertension
Other issues:
- Cost: ($55 per 100mcg/mL in 2mL vial VS. $5 per 5mg
midazolam vial)

44. Melatonin Insomnia may play an important role in potentiating delirium
Disturbance in metabolism of tryptophan-derived compounds may play role in delirium
Emerging evidence to support use of melatonin 0.5mg at bedtime for treatment and possible prevention of delirium1
Larger-scale RCTs are needed
Al-Aama T, Brymer C, Gutmanis I, et al. Melatonin decreases delirium in elderly patients: a randomized, placebo-controlled trial. Int J Geriatr Psychiatry 2011;26:

45. Benzodiazepines?
Only use benzos for delirium if it’s DTs or benzodiazepine withdrawal-related delirium
Otherwise, you will make it worse
In patients w/ cirrhosis or other hepatic insufficiency and DTs, use lorazepam or oxazepam (no active hepatic metabolite)
For barbiturate withdrawal-related delirium, use phenobarbitol (initial loading dose than taper)

46. Non-pharmacologic Management of Delirium
3 Rs (Reorientation, Reassurance, Reinforce normal sleep-wake cycle)
Restraints if necessary to keep patient and staff safe
1:1 observer
Enlist family to help with 3 Rs as much as possible
Early mobilization

47. Summary
The keys to managing delirium are to recognize it and fix the underlying problem
Antipsychotics may treat symptoms (e.g., agitation, psychosis), but they won’t cure delirium
Consider non-pharmacologic options to help manage delirious patients

48. The End