Delirium Management: Are You Pro- or “Anti ” Psychotic? › sites › ce.mayo.edu › files... · Antiparkinsonian agents Barbiturates Marcantonio ER. NEJM 2017;377:1456-66. ©2019

©2019 MFMER | slide-1

Delirium Management: Are You Pro- or “Anti-” Psychotic?

Abby Hendricks, PharmD PGY1 Pharmacy Resident Pharmacy Grand Rounds March 12, 2019


Objectives

• Identify risk factors for the development of delirium

• Discuss literature assessing the use of antipsychotics for delirium in various patient populations

• Describe treatment options for managing delirious patients


What is Delirium?

• Disturbance in attention and awareness

• Develops acutely

• Fluctuating severity

Assessment Scales

CAM-ICU

ICDSC

DRS-R-98

MDAS

NuDESC

Marcantonio ER. NEJM 2017;377:1456-66.

Attard A et al. CNS Drugs 2008;22(8):631-644.

Kalabalik J. JPP 2013;XX:1-13.


Classification

Hypoactive Hyperactive

M

I

X

E

D





Predisposing Risk Factors

70 YOM

PMH: HTN, DM, HFrEF,

dementia, alcohol abuse

70 YOM

PMH: HTN, DM, HFrEF,

dementia, alcohol abuse

135

3.8

103

25

37

1.5 126

135

3.8

103

25

37

1.5 126





Precipitating Risk Factors

Now s/p CABG x 3 following STEMI

Evidence of surgical site infection

Medications

Pain score: 9/10

IV

Last BM: 3 d ago

UOP

Zzzz.. Now s/p CABG x 3 following STEMI

Evidence of surgical site infection

130

3.3

103

25

34

1.5 126

130

3.3

103

25

34

1.5 126

7.6

29 15 250

7.6

29 15 250

Pain score: 9/10

Last BM: 3 d ago

Medications





Contributing Medications

Benzodiazepines Opioid analgesics Nonbenzodiazepine sedative hypnotics

Antihistamines Anticholinergics Anticonvulsants

Tricyclic antidepressants

Antiparkinsonian agents

Barbiturates



Audience Response Question #1

• JB is a 68 YOM admitted to the MICU for HAP

• PMH:

• CAD

• HTN

• Depression

135

3.2

103

25

37

1.5 126

Medications: • Aspirin 81 mg daily

• Lisinopril 20 mg daily

• Levofloxacin 750 mg daily

• Oxycodone 10 mg q4h prn



• Which of the following is a modifiable risk factor for the development of delirium?

• Age 68 years

• Oxycodone 10 mg q4h prn

• HTN

• Aspirin 81 mg daily


Management of Delirium

Provide supportive

care

Manage symptoms

Address modifiable risk factors


Throm RP et al. CCJM 2017;84(8):616-622.


Antipsychotics in ICU Delirium

2019

Devlin et al. Girard et al.

2013 SCCM Guideline

AAPs may reduce

duration of delirium

2010

2013

Page et al.

2018 SCCM Guideline

Suggest not routinely

using HAL or AAP to

treat delirium

2018

Girard et al.

2002 SCCM Guideline

HAL is preferred agent for

treatment of delirium in

critically ill patients

2004

Skrobik et al.

HAL – haloperidol, OLZ – olanzapine, QTP – quetiapine, ZPR – ziprasidone, PBO – placebo, AAP – atypical antipsychotic

Jacobi J et al. Crit Care Med 2002;30(1):119-41

Barr J et al. Crit Care Med 2013;41(1):263-306.

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

Skrobik et al. Intensive Care Med 2004;30:444-9.

Devlin et al. Crit Care Med 2010;38:419-27.

Girard et al. Crit Care Med 2010;38:428-37.

Page et al. Lancet Resp Med 2013;1:515-23.


Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness

Girard et al. NEJM 2018; 379: 2506-2516


Girard et al. 2018

N = 566

• ≥ 18 y.o.

• Medical/surgical ICU

• Ventilation, vasopressors,

or IABP

• Delirium (CAM-ICU)

Haloperidol 2.5 mg IV q12h

Max:10 mg/dose or 20 mg/d

Ziprasidone 5 mg IV q12h

Max: 20 mg/dose or 40 mg/d

Placebo

R

A

N

D

O

M

I

Z

E

1:1:1

Assessed

q12h using

CAM-ICU

• Positive for delirium, not at max dose = 2 x dose

• 2 consecutive assessments without delirium = ½ dose

• 4 consecutive assessments without delirium = dose held

IABP – intra-aortic balloon pump

Girard et al. NEJM 2018; 379: 2506-2516.


Girard et al. 2018

0 2 4 6 8 10 12 14

ZPR

HAL

PBO

Adjusted median days (95% CI)

8.7 days

7.9 days

8.5 days

Primary

Efficacy

Days alive without delirium or coma during

14 day follow-up

P = 0.26

for overall effect

across trial groups

HAL – haloperidol, ZPR – ziprasidone, PBO – placebo

Girard et al. NEJM 2018; 379: 2506-2516.


Girard et al. 2018

• Secondary Efficacy

• Safety • Sedation most common ADE in all groups • QTc prolongation more common with ziprasidone

Endpoint Placebo Haloperidol Ziprasidone

Time to liberation from

ventilation, days 3 2 3

ICU discharge, days 5 5 6

Death at 30 days, n (%) 50 (27) 50 (26) 53 (28)

ADE – adverse drug effect

Girard et al. NEJM 2018; 379: 2506-2516.


Girard et al. 2018

• Limitations

• Composite endpoint

• Suboptimal ziprasidone dosing

• Haloperidol 11 mg IV = ziprasidone 660 mg PO

• Ziprasidone IV formulation not commercially available

• Conclusions

• No evidence for benefit of antipsychotics in critically ill patients with hypoactive delirium

Girard et al. NEJM 2018; 379: 2506-2516.



• On day 3 of hospitalization JB becomes confused and withdrawn. Nursing staff notes he is no longer following commands or cooperating with staff members.



• Based on results from the Girard et al trial, which of the following is the most appropriate management strategy:

• A: Initiate haloperidol 2.5 mg IV q12h

• B: Address modifiable contributors

• C: Initiate ziprasidone 20 mg IV q12h


Antipsychotics in Non-ICU Delirium

2019

2016

Grover et al.

2013

Maneeton et al.

2011

Grover et al.

2010

Tahir et al.

2006

Hu et al.

2017

Agar et al.

2004

Han & Kim

et al.

HAL – haloperidol, OLZ – olanzapine, QTP – quetiapine, ZPR – ziprasidone, PBO – placebo, AAP – atypical antipsychotic

Han et al. Psychosomatics 2004;45(4):297-301.

Hu et al. Chin J Clin Rehabil 2006;10(42):188-90.

Tahir et al. J Psychosom Res 2010;69(5):485-90.

Grover et al. J Psychosom Res 2011;71(4):277-81.

Maneeton et al. J Med Assoc Thai 2007;90(10):2158-63.

Grover et al. World J Psychiatry 2016;6(3):365-71.

Agar et al. JAMA 2017; 177(1):34-42


Efficacy of Oral Risperidone, Haloperidol, or Placebo for Symptoms of Delirium Among Patients in Palliative Care: A Randomized Clinical Trial

Agar et al. JAMA 2017; 177(1):34-42


Agar et al. 2017

N = 247

• ≥ 18 y.o.

• Hospice or palliative care

• Delirium diagnosed via DSM-

IV, MDAS score ≥ 7, with

target symptoms associated

with distress (NuDESC ≥ 1)

Risperidone

0.5 mg PO q12h

Haloperidol

0.5 mg PO q12h

Placebo

1:1:1

R

A

N

D

O

M

I

Z

E

Assessed

q8h using

NuDESC

score

• NuDESC score ≥ 1 = ↑ dose (max 4 mg/day)

• Adverse effects, MDAS score < 7, NuDESC < 1 = ↓ dose

>65 yo = ½ dose

MDAS – Memorial delirium assessment scale, NuDESC – Nursing delirium screening scale

Agar et al. JAMA 2017; 177(1):34-42


Agar et al. 2017

0 1 2 3

Time (days)

NuD

ES

C S

core

4

3

2

1

0

Placebo

Risperidone

Haloperidol

Agent NuDESC Scores

Study End Daily

Risperidone

(v. placebo)

+0.48 Units

(p=0.02)

+0.24 Units

(p<0.001)

Haloperidol

(v. placebo)

+0.24 Units

(p=0.009)

+0.21 Units

(p=0.002)

Primary

Efficacy

Improvement in mean NuDESC score

between baseline and day 3

NuDESC – Nursing delirium screening scale

Agar et al. JAMA 2017; 177(1):34-42


Agar et al. 2017

• Midazolam use (any antipsychotic vs. placebo)

• Day 1: 34.7% v 17.3% (p = 0.007)

• Day 2: 33.1% v 16.8% (p = 0.01)

• Day 3: 29.6% v 13.6% (p = 0.02)

Risperidone Haloperidol

Daily MDAS score

EPS

Median Survival

*Compared to placebo

MDAS – Memorial delirium assessment scale, EPS – extrapyramidal symptoms

Agar et al. JAMA 2017; 177(1):34-42


Agar et al. 2017

• Limitations

• Symptom and severity based outcomes

• PRN midazolam use

• Low doses?

• Conclusions

• No evidence for benefit of antipsychotics in reducing symptoms of hyperactive/mixed delirium in palliative care patients

• May be harmful?

Agar et al. JAMA 2017; 177(1):34-42


Antipsychotics – Yes or No?

X X

? ?

Hypoactive

Hyperactive

ICU Non-ICU


Delirium

Address

Modifiable

Risk Factors

Provide

Supportive

Care

Non-pharmacologic

Interventions

Antipsychotics

Alternative

Agents

Non-pharmacologic

Interventions

Antipsychotics




Non-Pharmacologic Interventions

• Reduce duration of delirium, LOS, and mortality

Cognition/

Orientation

• Cognitive stimulation activities

• Reorient to time, place, and person

Early mobility • Ambulation and active range-of-motion exercises

• Minimize use of physical restraints

Hearing • Encourage use of hearing aids or portable amplifiers

• Special communication techniques as indicated

Vision • Encourage use of eyeglasses and/or magnifying lenses

• Utilize adaptive equipment (i.e. large print books)

Sleep-wake

cycle

• Implement non-pharmacologic nighttime sleep protocol

• Minimize unnecessary awakenings

Hydration/

Feeding

• Encourage fluids

• Monitor dietary intake and provide assistance as needed

Hshieh TT et al. JAMA Intern Med 2015 1;175(4):512–20.




Antipsychotic Selection

Agent D2 a1 H1 M1

Haloperidol +++ --- --- ---

Olanzapine ++ + +++ +++

Risperidone +++ ++ + +/-

Quetiapine + + ++ ++

Ziprasidone ++ +/- + ---

Receptor

profile

a1 H1

5-HT2A

M1

D2

Effectiveness Safety

Farah A. Prim Care Companion J Clin Psychiatry 2005;7:268-74.


Riviere J et al. Psychosomatics 2019;60:18-26.


Antipsychotic Selection Agent Dose

Equivalence*

QTc

Prolongation

Comments

Haloperidol 2

IV – High

PO - Low

Only IV option

IV to PO is 1:2

Risperidone

1 Low

EPS > 6 mg

Orthostasis

Olanzapine

5 Low

ODT - must swallow

Avoid IM with IV/IM BZD

Quetiapine

75 Low

Sedation – qHS dosing

Suppository form (MCR)

Ziprasidone 60 High Give PO with food

*PO equivalent doses listed; EPS – extrapyramidal symptoms, BZD - benzodiazepines

Patel MX et al. Schizophrenia Research 2013;149:141-48.





• On day 5 of hospitalization JB’s mental status changes and he becomes acutely agitated, starts pulling out his IV lines, and endorses hallucinations.



• Which of the following is associated with the highest risk of QTc prolongation?

• A: Quetiapine

• B: Olanzapine

• C: Risperidone

• D: Ziprasidone


Summary

• Recent evidence demonstrates lack of benefit for the use of antipsychotics in hypoactive delirium

• Antipsychotic use may be warranted for acutely agitated delirious patients

• Consider adverse effect profiles and dose equivalence when selecting a regimen

• Non-pharmacologic strategies remain the cornerstone of delirium management


Delirium Management: Are You Pro- or “Anti-” Psychotic?

Abby Hendricks, PharmD PGY1 Pharmacy Resident Pharmacy Grand Rounds March 12, 2019


Antipsychotic Dosing (TDD) Agent Schizophrenia

Delirium Suggested

Dosing

Haloperidol 5-20 0.5-10 5-20

Risperidone 4-8 0.25-4 2.5-4

Olanzapine 10-20 1-20 10-20

Quetiapine 400-800 12.5-200 150-400

Ziprasidone 80-160 5-160 80-160

TDD – Total Daily Dose

Documents

Delirium Management: Are You Pro- or “Anti ” Psychotic? › sites › ce.mayo.edu › files... · Antiparkinsonian agents Barbiturates Marcantonio ER. NEJM 2017;377:1456-66. ©2019