The Delirium Dilemma

Identification and Management of

Delirium in Hospitalized Patients

Megan Spence, PharmD

PGY1 Pharmacy Resident
Ascension St. Vincent Evansville

**I have no financial disclosure or conflicts of interest with the presented material in this presentation.
Objectives

1. Define delirium as it applies to hospitalized patients

2. Identify risk factors for development of delirium in the inpatient setting

3. Understand the role of antipsychotic medications in delirium management

4. Recognize a pharmacists’ role in patients with delirium

2
Definition and Risk Factors

3
Delirium

• Acute confusional state - acute brain dysfunction

• 15-50% in hospitalized patients

• Etiology largely contributed to a combination of factors

• May result in long-term cognitive impairment

European Delirium Association; American Delirium Society.BMC Med. 2014;12:141.

4
Diagnostic and
Statistical Manual
of Mental Disorders

• DSM - V Criteria

5
European Delirium Association; American Delirium Society.BMC Med. 2014;12:141.
Types of Delirium

van Velthuijsen EL, et. al.. Int J Geriatr Psychiatry. 2018;33(11):1521-1529.

6
Risk Factors - Non-modifiable

Richards, et al. Journal of Nursing Education and Practice. 6. 10.5430/jnep.v6n6p8.

Hein C, et al. J Am Med Dir Assoc. 2014;15(11):850.e11-850.e8.5E15. 7
Risk Factors - Modifiable
• Orientation to time and place

• Visual and/or hearing aids

• Family and friends

• Sleep disturbances

• Pain

• Electrolyte imbalances

• Restraints

Hsieh TT, et al. JAMA Intern Med 2015; 175: 512.

8
Medications Contributing to Delirium

Clegg A, et al. Age Ageing. 2011 Jan;40(1):23-9.

9
Biggest Offenders

• Benzodiazepines
• Higher doses increase risk
• Opioids
• Excess doses increase risk
• Uncontrolled pain causes higher risk of development
• Meperidine - highest risk of development
• Anticholinergics
• Antihistamines, tricyclic antidepressants
• Not an independent risk factor, but use may increase risk
• Corticosteroids
• Increase risk in critically ill patient settings
• Antibiotics
• First and third generation cephalosporins
• NOT cefepime or fluoroquinolones as originally thought

Swart LM, et al. Drugs Aging. 2017;34(6):437-443.

Egberts, A. J Am Med Dir Assoc. 2021;22(1):65-73.e4. 10
Crit Care Med. 2014;42(6):1480-1486
Crit Care. 2018;22(1):337.
Checkpoint #1

Case: ZM is a 67 year-old male admitted to the intensive care unit for respiratory
failure and declining clinical status. Reported past medical history includes
COPD, hypertension, and Type 2 diabetes mellitus. Which of the following
medications on ZM’s profile can be immediately addressed in an attempt to
prevent the development of delirium while in the ICU?

A. Aspirin 81 mg daily
B. Oxycodone SR 15 mg BID
C. Albuterol 2.5 mg nebulization every 4 hours
D. Atorvastatin 40 mg daily

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Evaluation

12
Richmond Agitation-Sedation Scale (RASS)
+4 COMBATIVE Combative, violent, immediate danger to staff

+3 VERY AGITATED Pulls to remove tubes or catheters; aggressive

+2 AGITATED Frequent non-purposeful movement, fights ventilator

+1 RESTLESS Anxious, apprehensive, movements not aggressive

0 ALERT & CALM Spontaneously pays attention to caregiver

-1 DROWSY Not fully alert; sustained awakening to voice (eye opening & contact > 10 sec)

-2 LIGHT SEDATION Briefly awakens to voice (eyes open & contact <10 sec)

-3 MODERATE SEDATION Movement or eye opening to voice (no eye contact)

-4 DEEP SEDATION No response to voice, but movement or eye opening to physical stimulation

-5 UNAROUSABLE No response to voice or physical stimulation

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Scoring Tools
Confusion Assessment Method for the ICU (CAM-ICU) Flowsheet

1. Acute Change or Fluctuating Course of Mental Status: NO

● Is there an acute change from mental status CAM-ICU negative
baseline? OR NO DELIRIUM
● Has the patient’s mental status fluctuated during
the past 24 hours?

YES

2. Inattention:
● “Squeeze my hand when I say the letter ‘A’”
S A V E A H A A R T or C A S A B L A N C A or A B A D B A D A A Y 0-2 Errors
CAM-ICU negative
● ERRORS: No squeeze with ‘A’ and squeeze on letter other
NO DELIRIUM
than ‘A’
● If unable to complete Letters → use pictures

> 2 Errors

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CAM-ICU Scoring Continued
RASS other
3. Altered level of consciousness
than zero CAM-ICU positive
● Current RASS level DELIRIUM PRESENT

RASS = zero
> 1 Error
4. Disorganized Thinking:
● Will a stone float on water?
● Are there fish in the sea?
● Does one pound weight more than two?
● Can you use a hammer to pound a nail? 0-1 error
● Command:
CAM-ICU negative
○ “Hold up this many fingers” NO DELIRIUM
○ “Now do the same thing with the other hand” OR
○ “Add one more finger”

15
16
Checkpoint #2

Question: ZM is now hemodynamically unstable and requiring vasopressor

support. Per the provider’s discretion, the decision was made to intubate. 48
hours later, the provider decides to attempt a spontaneous breathing trial, but
notices he becomes restless when sedation is weaned. Prior to intubation, ZM
was alert, calm, and agreeable to to treatment. RASS is determined to be +2
during the weaning trials. Based on the CAM-ICU tool, what is the next step for
this patient?

A. None; the patient does not have delirium based on the CAM-ICU
B. Test for disorganized thinking (e.g. ask “Is one pound greater than two?”)
C. Test for inattention (e.g. squeeze hands when prompted)
D. None; the patient has delirium based on the CAM-ICU

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Guideline-Directed Therapy

18
Clinical Practice Guidelines for the Prevention and
Management of Pain, Agitation/Sedation, Delirium,
Immobility, and Sleep Disruption in Adult Patients
in the ICU - 2018
• Society of Critical Care Medicine
• Extension of 2013 Guidelines
• Discusses importance of management, risk factors, possible outcomes,
prevention, and pharmacological and nonpharmacological treatment of
delirium in critically ill patients

Devlin JW, et al. Crit Care Med. 2018;46(9):e825-e873.

19
 Non-Pharmacological Treatment - FIRST LINE

ABCDE Intervention
A B C D E F

Assessment, Both Choice of Delirium Early mobility Family

prevention, and spontaneous sedation and assessment, and exercise engagement
management of awakening trials analgesia prevention, and and
pain and management empowerment
spontaneous
breathing trials

Devlin JW, et al. Crit Care Med. 2018;46(9):e825-e873.

20
Pharmacological Treatment

No significant evidence to routinely use

antipsychotics in delirium prevention or
management.

Devlin JW, et al. Crit Care Med. 2018;46(9):e825-e873.

21
Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness
Modifying the Impact of ICU-Induced Neurological Dysfunction - USA (MIND-USA)
New England Journal of Medicine, 2018

Study Type Randomized, double-blind, placebo-controlled; Multi-center

Objective Examine the effects of haloperidol or ziprasidone on delirium in critically ill patients

Patient Inclusion Criteria Exclusion Criteria

Population Admitted to intensive care unit with positive Baseline severe cognitive impairment, high
pressure ventilation, with vasopressor risk of side effects (e.g. history of QT
support, or an intraaortic balloon pump, prolongation), in a moribund state, rapidly
delirium based on the CAM-ICU resolving organ failure

Patient Baseline Characteristics: average 60 years, majority white males, ~90% hypoactive, <90%
Demographics requiring invasive ventilation

Girard TD, et al. N Engl J Med. 2018;379(26):2506-2516.

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MIND-USA Methods

566 Patients assigned 1:1:1 Subsequent Doses Evaluation

● < 70 years initial doses ● Given every 12 hours ● Used CAM-ICU and RASS
○ 0.5 mL placebo ● Doses doubled if: ○ Any day with at least
○ 2.5 mg haloperidol IV ○ Patient had delirium one positive CAM-ICU
○ 5 mg ziprasidone IV ○ Not yet receiving maximum dose score = delirium
● > 70 years initial doses ● Doses halved if: ○ If RASS >0 =
○ 0.25 mL placebo ○ No delirium present for two hyperactive delirium
○ 1.25 mg haloperidol IV consecutive assessments ○ If RASS < 0 =
○ 2.5 mg ziprasidone IV ○ Not currently receiving minimum hypoactive delirium
● Maximum doses dose
○ Haloperidol: 20 mg/day
○ Ziprasidone: 40 mg/day

Girard TD, et al. N Engl J Med. 2018;379(26):2506-2516.

23
 MIND-USA Results

Primary Days alive without delirium or coma during 14 day

Endpoint follow-up - Composite outcome

Efficacy Median number of days alive without delirium or

Endpoint coma
● Placebo: 8.5 (95% CI, 5.6-9.9)
● Haloperidol: 7.9 (95% CI, 4.4-9.6)
● Ziprasidone: 8.7 (95% CI, 5.9-10.0)

Conclusion The use of haloperidol or ziprasidone did not have

an effect on delirium in patients with hypoactive
delirium in the intensive care unit as compared to
placebo.

Girard TD, et al. N Engl J Med. 2018;379(26):2506-2516.

24
MIND-USA Discussion

• Strengths
• Large sample size
• Broad inclusion criteria
• Double-blinded
• Uses CAM-ICU score

• Limitations
• Enrollment not limited to delirium
• Lacked sufficient power
• Composite endpoint
• Ziprasidone dose not equivalent to haloperidol

Girard TD, et al. N Engl J Med. 2018;379(26):2506-2516.

25
Pharmacological Treatment

May use dexmedetomidine in mechanically

ventilated patients where agitation is
precluding weaning/extubation.

Devlin JW, et al. Crit Care Med. 2018;46(9):e825-e873.

26
Dexmedetomidine

• Mechanism of action: selective ɑ2-agonist reducing norepinephrine release

• Causes sedation and/or relaxation

• Dosing
• 0.2-1.5 mcg/kg/hr
• Doses >1.5 mcg/kg/hr show no additional efficacy

• Side effects
• Bradycardia
• Hypotension
• Hyperthermia

Biomed Res Int. 2015;2015:635737.

27
 Effect of Dexmedetomidine Added to Standard Care on Ventilator-Free
Time in Patients with Agitated Delirium
Dexmedetomidine to Lessen Intensive Care Unit (ICU) Agitation (DahLIA)
The Journal of the American Medical Association, 2016

Study Type Double-blind, placebo-controlled, randomized clinical trial

Objective Determine effectiveness of dexmedetomidine when added to standard care in

patients with agitated delirium receiving mechanical ventilation

Patient Inclusion Criteria Exclusion Criteria

Population Mechanical ventilation required Pregnant or breastfeeding, dementia, head
due to severe agitation injury, already receiving dexmedetomidine,
known contraindications

Patient Average age 57 years, > 70% male

Demographics

Outcomes Ventilator-free hours in 7 days following randomization 28

Reade MC,et al. JAMA. 2016;315(14):1460-1468.
DahLIA Methods and Results

39 Patients 32 Patients ● Median difference =

PLACEBO 17.0 hours
DEXMEDETOMIDINE
(Normal Saline) ● 95% CI, 4.0-33.2
hours, P = 0.01
0.5 mcg/kg/h 0.5 mcg/kg/h ● Addition of
→ →
0-1.5 mcg/kg/hr
dexmedetomidine
0-1.5 mcg/kg/hr
resulted in more
ventilator-free
hours at 7 days
Median 144.8 hours of Median 127.5 hours of
ventilator-free time ventilator-free time

Reade MC,et al. JAMA. 2016;315(14):1460-1468.

29
DahLIA Discussion

• Using dexmedetomidine as TREATMENT rather than sedation

• Dexmedetomidine group • Hierarchical modeling to

• Lower rate and volume on adjust for imbalanced
days 1 and 2 characteristics
• Less patients received
antipsychotic medications
• Lower quantities of
sedatives and opioids

• Post-hoc analysis: Reduction in the prevalence of delirium from 95.5% to 68.7%

Reade MC,et al. JAMA. 2016;315(14):1460-1468.

30
Pharmacological Treatment

Lack of robust clinical trials

determining use of pharmacological
agents in patients with delirium.

What about hyperactive delirium?

Devlin JW, et al. Crit Care Med. 2018;46(9):e825-e873.

31
Efficacy of Oral Risperidone, Haloperidol, or Placebo for Symptoms of
Delirium Among Patients in Palliative Care: A Randomized Clinical Trial
The Journal of the American Medical Association, 2016

Study Type Double-blind, parallel-arm, dose-titrated, randomized clinical trial

Objective Determine efficacy of risperidone or haloperidol in relieving target symptoms

of delirium associated with distress among patients in palliative care

Patient Inclusion Criteria Exclusion Criteria

Population Delirium diagnosed based on Delirium due to substance withdrawal,
DSM-IV criteria, MDAS >7, history of neuroleptic malignant syndrome,
target symptoms of distress regular use of antipsychotic drugs

Patient Average age 75 years, > 60% male, > 80% cancer diagnosis
Demographics

Outcome Improvement in mean group difference of delirium symptom score at baseline

and at day 3 32
Agar MR, et al. JAMA Intern Med. 2017;177(1):34-42.
 Risperidone and Haloperidol in Delirium

Methods ● 247 patients randomized in a 1:1:1

fashion
● < 65 years - 0.5 mg initial dose; q12h;
max 4 mg/day
● > 65 years - maximum dose halved
● Assessments every 8 hours

Results Patients receiving antipsychotics had

significantly increased delirium symptom
scores than those receiving placebo

Conclusions Risperidone and haloperidol may potentially

worsen symptoms in patients with
hyperactive delirium at end-of-life

Agar MR, et al. JAMA Intern Med. 2017;177(1):34-42.

33
Need for Delirium Management

• Delirium is associated with:

Devlin JW, et al. Crit Care Med. 2018;46(9):e825-e873.

34
Checkpoint #3

Question: After ZM was noted to be agitated, sedation was increased. The

provider would like to start considering extubation. Which medication not
currently ordered can be recommended to help ZM with this transition?

A. Haloperidol 5 mg IV BID
B. Risperidone 1 mg PO BID
C. Ziprasidone 10 mg IV BID
D. Dexmedetomidine 0.5 mcg/kg/hr continuous infusion

35
Pharmacist Role

36
Clinical Pharmacist Impact on Intensive Care Unit Delirium: Intervention
and Monitoring
Hospital Pharmacy, 2019

Study Type Single-center, before and after

Objective If clinical pharmacists using a clinical decision support system (CDSS)

would decrease the incidence of delirium

Patient Population 61 adult patients admitted to a trauma intensive care unit

Outcomes Primary: incidence of delirium; Secondary: hospital length of stay, ICU

length of stay, ventilator duration, delirium - potentiating medications

Lightfoot M, et al.. Hosp Pharm. 2019;54(3):180-185.

37
Clinical Pharmacist Intervention in Delirium Results

28 Patients in Pre-intervention group 33 Patients in Intervention group

9 (33%) Developed delirium 7 (24%) Developed delirium

No difference found in delirium incidence

P = 0.45

Majority of patients were male, < 65

years, many on Clinical Institute
Withdrawal Assessment protocol

Lightfoot M, et al.. Hosp Pharm. 2019;54(3):180-185.

38
Lightfoot M, et al.. Hosp Pharm. 2019;54(3):180-185.
39
40
Additional of Antipsychotics

41
Antipsychotic Agents for Delirium - Considerations

• Second generation antipsychotics may cause less extrapyramidal symptoms

than haloperidol

• Second generation antipsychotics have black box warning for increased

mortality in elderly patients with dementia-related psychosis

• Choice of antipsychotic has no effect on:

• Hospital length of stay
• Delirium duration
• Mortality
• Cardiac outcomes

Ann Intern Med. 2019;171(7):485-495.

42
QTc Prolongation

Lowest Risk

Highest Risk

US Pharm. 2015;40(11):HS34-HS40
43
Additional Trials

44
Checkpoint #4

Question: It has been determined that ZM may require antipsychotic medication

for his delirium. QTc is 487 ms. Which antipsychotic medication has the lowest
risk of QTc prolongation and may be considered for treatment in ZM?

A. Haloperidol
B. Ziprasidone
C. Olanzapine
D. Quetiapine

45
ICU Manual for Pain/Agitation/Delirium

• Assess CAM-ICU at every shift

• Follow ABCDEF Scheduling Medications:

• Follow delirium protocol QUIET AT NIGHT INITIATIVE

• Multidisciplinary approach

Ascension St. Vincent Evansville ICU Manual for Pain/Agitation/Delirium. May 2020.
46
Conclusions

As initial prevention, Work with a multidisciplinary Should a patient need

pharmacists can address team to address modifiable antipsychotic
resuming home and non-modifiable risk medications, review
medications and limiting factors, focusing on patient information to
inpatient medications medication administration determine which may be
which may be and management. the most appropriate.
contributing to the
development of delirium.

47
Future Directions

Ethical considerations in managing patients with delirium

Robust trials determining pharmacological treatment

Evaluate clinically meaningful outcomes

Treatment duration after initiation

Devlin JW, et al. Crit Care Med. 2018;46(9):e825-e873.

48
References
1. European Delirium Association; American Delirium Society. The DSM-5 criteria, level of arousal and delirium diagnosis: inclusiveness is
safer. BMC Med. 2014;12:141. Published 2014 Oct 8. doi:10.1186/s12916-014-0141-2
2. van Velthuijsen EL, Zwakhalen SMG, Mulder WJ, Verhey FRJ, Kempen GIJM. Detection and management of hyperactive and hypoactive
delirium in older patients during hospitalization: a retrospective cohort study evaluating daily practice. Int J Geriatr Psychiatry.
2018;33(11):1521-1529. doi:10.1002/gps.4690
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2018;379(26):2506-2516. doi:10.1056/NEJMoa1808217
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10.1093/ageing/afq140. Epub 2010 Nov 9. PMID: 21068014.
6. Reade MC, Eastwood GM, Bellomo R, et al. Effect of Dexmedetomidine Added to Standard Care on Ventilator-Free Time in Patients With
Agitated Delirium: A Randomized Clinical Trial [published correction appears in JAMA. 2016 Aug 16;316(7):775]. JAMA.
2016;315(14):1460-1468. doi:10.1001/jama.2016.2707
7. Agar MR, Lawlor PG, Quinn S, et al. Efficacy of Oral Risperidone, Haloperidol, or Placebo for Symptoms of Delirium Among Patients in
Palliative Care: A Randomized Clinical Trial [published correction appears in JAMA Intern Med. 2017 Feb 1;177(2):293]. JAMA Intern Med.
2017;177(1):34-42. doi:10.1001/jamainternmed.2016.7491
8. Lightfoot M, Sanders A, Burke C, Patton J. Clinical Pharmacist Impact on Intensive Care Unit Delirium: Intervention and Monitoring. Hosp
Pharm. 2019;54(3):180-185. doi:10.1177/0018578718778226
9. Hsieh TT, Yue J, Oh E, et al. Effectiveness of multicomponent nonpharmacologial delirium interventions: a meta-analysis. JAMA Intern
Med 2015; 175: 512.
10. Devlin JW, Skrobik Y, Gélinas C, et al. Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation,
Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Crit Care Med. 2018;46(9):e825-e873.
doi:10.1097/CCM.0000000000003299
11. Ascension St. Vincent Evansville ICU Manual for Pain/Agitation/Delirium. May 2020.

49
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12. Hein C, Forgues A, Piau A, Sommet A, Vellas B, Nourhashémi F. Impact of polypharmacy on occurrence of delirium in elderly emergency
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13. Swart LM, van der Zanden V, Spies PE, de Rooij SE, van Munster BC. The Comparative Risk of Delirium with Different Opioids: A
Systematic Review. Drugs Aging. 2017;34(6):437-443. doi:10.1007/s40266-017-0455-9
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Am Med Dir Assoc. 2021;22(1):65-73.e4. doi:10.1016/j.jamda.2020.04.019
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50
The Delirium Dilemma
Identification and Management of
Delirium in the Hospitalized Patients

Megan Spence, PharmD

megan.spence@ascension.org
PGY1 Pharmacy Resident
Ascension St. Vincent Evansville

**I have no financial disclosure or conflicts of interest with the presented material in this presentation.