treating agitation and de to an alphabet soup of potential options

Treating Agitation and Deto an Alphabet Soup of Potential Options

John W. Devlin, Pharm.D

Associate Professor

Northeastern University School of Pharmacy

Adjunct Associate Professor

Tufts University School of Medicine

Boston, MA

Delirium: Providing Clarity to an Alphabet Soup of Potential Options

Pharm.D., FCCP, FCCM,

Associate Professor

Northeastern University School of Pharmacy

Adjunct Associate Professor

Tufts University School of Medicine

Boston, MA

Before Considering a Pharmacologic

Treatment for Delirium…..

• Have the underlying causes of delirium been identified and reversed/treated whenever possible?



Have the underlying causes of delirium been identified and reversed/treated whenever possible?

Patient FactorsIncreased ageAlcohol useMale genderLiving aloneSmokingRenal disease

Less Modifiable

DELIRIUM

EnvironmentAdmission via ED or

through transferIsolationNo clockNo daylightNo visitorsNoiseUse of physical restraints

Inouye SK et al. JAMA 1996; 275: 852

Dubois MJ, et al. ICM 2001;27:1297

Ouimert S et al. ICM 2007; 33:66

Van Rompaey B et al. Crit Care 2009; 13:R77

More Modifiable

Predisposing DiseaseCardiac diseaseCognitive impairment

(e.g., dementia)Pulmonary disease

Acute IllnessLength of stayFever

Less Modifiable

DELIRIUMFeverMedicine service Lack of nutritionHypotensionSepsisMetabolic disorders Tubes/cathetersMedications:- anticholinergics- corticosteroids- benzodiazepines

Inouye SK et al. JAMA 1996; 275: 852

Dubois MJ, et al. ICM 2001;27:1297-1304

Ouimert S et al. ICM 2007; 33:66-73

Van Rompaey B et al. Crit Care 2009; 13:R77

More Modifiable



• Have the underlying causes of delirium been identified and reversed/treated whenever possible?

• Have non-pharmacologic treatment strategies been optimized?optimized?

• Does your patient have hyperactive delirium, hypoactive delirium or mixed hyperactivehypoactive delirium?



Have the underlying causes of delirium been identified and reversed/treated whenever possible?

pharmacologic treatment strategies been

Does your patient have hyperactive delirium, hypoactive delirium or mixed hyperactive-

Inouye SK et al N Engl J Med 1999

Mechanisms for ICU Delirium are Numerous and ComplexMechanisms for ICU Delirium are Numerous and Complex

Maldonado. Crit Care Clin 2008; 24:789

Fong TG et al. Nat Rev Neurol 2009; 5:210-220

American Psychiatric Association Guidelines (1999)• “Antipsychotic medications are often the pharmacologic

treatment of choice” (Grade I = recommended with substantial clinical confidence)

• “Haloperidol can be initiated at 1titrated to higher doses for patients who continue to be agitated. Patients who require multiple boluses, continuous infusion may be useful”

• “Some physicians have used the newer (atypical) • “Some physicians have used the newer (atypical) antipsychotics.”

SCCM Guidelines (2002)• Haloperidol is the preferred agent for the treatment of

delirium in critically ill patients.

American Psychiatric Association Guidelines (1999)“Antipsychotic medications are often the pharmacologic

(Grade I = recommended with substantial clinical confidence)

“Haloperidol can be initiated at 1-2mg every 2-4 hrs and titrated to higher doses for patients who continue to be agitated. Patients who require multiple boluses, continuous

“Some physicians have used the newer (atypical) “Some physicians have used the newer (atypical)

Haloperidol is the preferred agent for the treatment of delirium in critically ill patients. (Grade C recommendation)

Trzepacz P et al. APA 1999Jacobi J et al. Crit Care Med 2002; 30:119-141.

Use of haloperidol is an independent predictor for prolonged delirium

FDA ALERT [9/2007]: This Alert highlights revisions to the labeling for haloperidol (marketed as Haldol, Haldol Decanoate and includes WARNINGS stating that Torsadesbeen observed in patients receiving haloperidol, especially when the drug is administered intravenously or in higher doses than recommended.not approved for intravenous use.

Use of haloperidol is an independent predictor for prolonged delirium

Pisani MA et al. Crit Care Med 2009; 37: 177-183

This Alert highlights revisions to the labeling for haloperidol and Haldol Lactate). The updated labeling

de Pointes and QT prolongation have been observed in patients receiving haloperidol, especially when the drug is administered intravenously or in higher doses than recommended. Haloperidol is


Potential Advantages of Atypical versus Conventional Antipsychotics

• Decreased extrapyramidal effects

• Little effect on the QTc interval (with the exception of

• Less hypotension/fewer orthostatic effects

• Less likely to cause neuroleptic malignant syndrome

• Unlikely to cause laryngeal dystonia

• Lower mortality when used in the elderly to treat agitation related to dementia

Potential Advantages of Atypical versus Conventional Antipsychotics

interval (with the exception of ziprasidone)

Less hypotension/fewer orthostatic effects

malignant syndrome

dystonia

Lower mortality when used in the elderly to treat agitation related to dementia

Tran PV et al, J Clin Psychiatry 1997; 58:205-11Lee PE at al. J am Geriatr Soc 2005; 53:1374-1379Wang PS et al. N Engl J Med 2005; 353:2235-2341

Use of Atypical Antipsychotic Therapy is Increasing

2001

Insert the 2008 Patel survey data

2007

Use of Atypical Antipsychotic Therapy is Increasing

2001

Ely EW et al. Crit Care Med 2004;32:106-12Patel RP et al. Crit Care Med 2009; 37:825-832

Few Prospective, Randomized Trials Have Evaluated

Antipsychotic Therapy for Delirium Treatment in the ICU

• Pubmed search:

• 1960 – December 2009

• antipsychotic:

• haloperidol, olanzapine, quetiapine• haloperidol, olanzapine, quetiapine

• delirium

• critical care

• limited to prospective, randomized trial

• Results: 3 trials

Few Prospective, Randomized Trials Have Evaluated

Antipsychotic Therapy for Delirium Treatment in the ICU

quetiapine, risperidone, ziprasidonequetiapine, risperidone, ziprasidone

limited to prospective, randomized trial

Is there evidence from randomized

controlled studies that supports the use of

haloperidol for the treatment of haloperidol for the treatment of

delirium in the critically ill?

Is there evidence from randomized-


haloperidol for the treatment of haloperidol for the treatment of


• Design: Double-blind, placebo-controlled• Setting: 6 tertiary medical centers• Intervention:

• Haloperidol (5mg) vs ziprasidone (40mg) vs placebo (all as a max 14 days

• Q12h x 24 hrs then q6h for maximum 14 • ↓ q8h when CAM-ICU negative x 24hrs,• then ↓ q12h when negative x 36hrs,

Modifying the Incidence of

• then ↓ q12h when negative x 36hrs, • Could give IM if NPO up to max 8 doses• Oversedation: ↓study drug frequency when RASS

level (after holding sedation therapy)• If delirium reoccurred after d/c of study drug then restarted at last effective

dose (and weaned again as per above)• Primary outcome:

• Number of days patient alive without delirium or coma during the 21• Delirium = + CAM-ICU

• Coma = RASS (-4) [ie. responsive to physical but not verbal stimulation] or RASS (responsive to either]

controlled, randomized trial

(40mg) vs placebo (all as a clear liquid) x

q6h for maximum 14 daysx 24hrs,

x 36hrs, then d/c x 48hrs

cidence of Delirium (MINDS) Trial

x 36hrs, then d/c x 48hrsCould give IM if NPO up to max 8 doses

study drug frequency when RASS ≥2 levels above targeted level (after holding sedation therapy)If delirium reoccurred after d/c of study drug then restarted at last effective dose (and weaned again as per above)

Number of days patient alive without delirium or coma during the 21-day study period

. responsive to physical but not verbal stimulation] or RASS (-5) [ie. not

Girard T et al. Crit Care Med Nov 2009 (ahead of press)

Inclusion Criteria: • Mechanically ventilated adults with an

were receiving sedatives/analgesicsNote: Patients had brain dysfunction but did not necessarily have delirium at baseline

Exclusion Criteria:• Continuous mechanical ventilation > 60hrs at screening• No plan for gastric access within 48 hrs• Moribund state/withdrawal of life support expected

Modifying the Incidence of

• Moribund state/withdrawal of life support expected• Admission with drug overdose or suicide• Previously diagnosed neurologic disease (e.g., dementia) • Ongoing neuroleptic use at admission• Ongoing seizures• Stroke or MI in past 2 weeks• High risk for ventricular dysrhythmias• Clinically significant ventricular tachycardia • Uncompensated class IV heart failure• Refractory hypokalemia or hypomagnesemia

an abnormal level of consciousness or whoanalgesics

Note: Patients had brain dysfunction but did not necessarily have delirium at baseline

Continuous mechanical ventilation > 60hrs at screeningNo plan for gastric access within 48 hrsMoribund state/withdrawal of life support expected

cidence of Delirium (MINDS) Trial

Efficacy-relatedMoribund state/withdrawal of life support expectedAdmission with drug overdose or suicidePreviously diagnosed neurologic disease (e.g., dementia)

use at admission

dysrhythmiasClinically significant ventricular tachycardia Uncompensated class IV heart failure

hypomagnesemiaGirard T et al. Crit Care Med Nov 2009 (ahead of press)

Safety-related

Efficacy-related

Haloperidol

Medical (%)

APACHE II score

Brain dysfunction on first study dayComa (%)

Delirium (%)

Delirium/coma-free days

Delirium (days)

Coma (days)

Days accurately sedated (%)Days accurately sedated (%)

Days on study drug

Average daily dose (mg) 4.5 (2.9

Additional haloperidolNumber of patients (%)

Dose (mg)

Ventilator-free days

21-day mortality (%)

Akathisia (%)(severity of symptoms NS between groups)

QTc ≥ 500 msec (n)

HaloperidolN=35

PlaceboN=36

P value

57 64

26 (21-31) 26 (21-32)

35

47

32

49

14 (6-18) 12.5 (1.2-17) 0.66

4 (2-7) 4 (2-6) 0.93

2 (0-4) 2 (0-5) 0.90

70 7170 71

7 (4-10) 5 (3-7) 0.23

4.5 (2.9-23.8) - -

17

5 (3-24)

39

12.5 (5.5-50.2)

0.13

0.30

7.8 (0-15) 12.5 (0-23) 0.25

11 17 0.81

29 19 0.60

2 3 0.31



P = 0.66



haloperidol for the treatment of


No evidence from randomized, placebocontrolled studies that haloperidol improves outcome in ICU patents



haloperidol for the treatment of


No evidence from randomized, placebo-controlled studies that haloperidol improves outcome in ICU patents



an atypical antipsychotic agent an atypical antipsychotic agent




an atypical antipsychotic agent for the treatment of an atypical antipsychotic agent for the treatment of


• Design: Double-blind, placebo-controlled• Setting: 3 academic medical centers• Intervention:

• Quetiapine 50mg PO/NGT twice dailydaily) vs Placebo

• PRN IV haloperidol protocolized and encouraged in each group• Oversedation: hold study drug when SAS

• Primary outcome:• Time to first resolution of delirium (ie

controlled, randomized trial

daily titrated to a maximum of 200mg twice

and encouraged in each group: hold study drug when SAS ≤ 2 (after holding sedation therapy)

ie. first 12 hour period when ICDSC ≤ 3)

Devlin JW et al. Crit Care Med Nov 2009 (ahead of press)

36 subjects randomized

Quetiapine 50 mg NG twice daily(N=18)

Placebo 50 mg NG twice daily(N=18)

As needed haloperidol therapy, usual sedation and analgesiatherapy at the discretion of the subject’s physician

258 patients with delirium (ICDSC ≥ 4) tolerating enteral nutrition

Dose TitrationIncrease quetiapine or placebo dose by 50 mg every 12 hours on a daily basis if the subject received ≥ 1 dose of as needed haloperidol in the previous 24 hours.(Maximum dose=200 mg every 12 hours)

Discontinuation of study drug1. Subject was deemed by the attending intensivist to be no longerdemonstrating signs of delirium, therefore, therapy no longer required2. 10 days of therapy had elapsed3. ICU discharge prior to 10 days of therapy4. Serious adverse event potentially attributable to the study drug

222 Excluded46 Prior antipsychotic use within 30 days38 Not receiving enteral nutrition 28 Primary neurological condition16 Encephalopathy or end-stage liver disease12 Alcohol withdrawal12 Inability to conduct ICDSC11 No delirium 11 Inability to obtain informed consent 10 Moribund

8 Irreversible brain disease (e.g. dementia)5 Baseline QTc interval ≥ 500msec5 Attending physician refusal for enrollment7 Other

Placebo 50 mg NG twice daily(N=18)

As needed haloperidol therapy, usual sedation and analgesia

4) tolerating enteral nutrition

Increase quetiapine or placebo dose by 50 mg every 12 hours on a daily basis 1 dose of as needed haloperidol in the previous 24 hours.

1. Subject was deemed by the attending intensivist to be no longerdemonstrating signs of delirium, therefore, therapy no longer required

4. Serious adverse event potentially attributable to the study drug


Age (years)

Male (%)

APACHE II (on admission to ICU)

Medical (%)

ICU days prior to enrollment

Intubated at study entry (%)

Sedation Agitation Scale (SAS) at study entry (%)

3 or 4

≥ 5

ICDSC score at study entry

Quetiapine(n=18)

Placebo(n=18)

62.4 ± 14 63.6 ± 15.3

56 56

19.7 ± 5.3 21.4 ± 9.2

72 78

5 (2-8) 7 (3-11)5 (2-8) 7 (3-11)

72 89

72 67

28 33

5 (4-6) 5 (4-6)


Pro

po

rtio

n o

f P

ati

en

ts w

ith

De

liri

um

Pro

po

rtio

n o

f P

ati

en

ts w

ith

De

liri

um

Day During Study Drug Administration

Placebo

Quetiapine

Log-Rank p=0.001

Day During Study Drug Administration


Time of study drug administration (hours)

Time in delirium

Hours

Percent of time in study

Number of subjects experiencing delirium recurrence after initial delirium resolution (%)

Time spent agitated (SAS ≥ 5)

Hours


Time spent deeply sedated (SAS ≤ 2)

Hours Hours


Subject-initiated device removal

Number of episodes

Number of subjects with ≥ 1 episode (%)

Reason for discontinuation of study drug (%)

Therapy felt to be no longer required by subject’s

attending intensivist

10 days of therapy had elapsed

ICU discharge

Serious adverse drug event

Quetiapine(n=18)

Placebo(n=18)

P value

102 (84-168) 186 (108-228) 0.04

36 (12-87) 120 (60-195) 0.006

53 (16-67) 69 (58-100) 0.02

22 44 0.29

6 (0-38) 36 (11-66) 0.02

3 (0-22) 21 (8-41) 0.03

0 (0-8) 0 (1-2) 0.540 (0-8) 0 (1-2) 0.54

0 (0-8) 0 (0-0) 0.39

8 10 0.79

17 22 1.0

44 39 0.31

12 33

44 28

0 0


Duration of mechanical ventilation (days)

Duration of ICU stay (days)

Duration of hospitalization (days)

Hospital mortality (%)

Delirium in the 14 day period after study drug discontinued (or until subject discharged/transferred from hospital)

Subjects with ≥ 1 day of delirium (%)

Time spent in delirium (%)

Subject placement after hospital discharge (%)

� Five episodes of somnolence and one episode of hypotension were observed that were felt to be possibly related to the administration of quetiapine.

� No episodes of EPS were experienced during the study drug period.

� The number of subjects with QTc prolongation as determined by a > 60 msec increase from baseline (39 vs. 44%, p=0.74), QTc > 500 msec (22 vs. 28%, p=1.0), or other CPMP definitions (50 vs. 72%, p=0.31) was similar between the quetiapine and placebo groups.

Home / rehabilitation center

Chronic care facility / another

acute care hospital / death

Quetiapine(n=18)

Placebo(n=18)

P value

11 (3-19) 11 (4-29) 0.67

16 (10-22) 16 (13-32) 0.28

24 (11-33) 26 (17-49) 0.32

11 17 1.0

Delirium in the 14 day period after study drug discontinued (or until subject discharged/transferred from hospital)

20 56 0.09

0 (0-0) 14 (0-47) 0.05

Five episodes of somnolence and one episode of hypotension were observed that were felt to be possibly related to the administration of quetiapine.

No episodes of EPS were experienced during the study drug period.

The number of subjects with QTc prolongation as determined by a > 60 msec increase from baseline (39 vs. 44%, p=0.74), QTc > 500 msec (22 vs. 28%, p=1.0), or other CPMP definitions (50 vs. 72%, p=0.31) was similar between the quetiapine and placebo groups.

89 56

0.0611 44


Ziprasidone

Medical (%)

APACHE II score

Brain dysfunction on first study dayComa (%)

Delirium (%)

Delirium/coma-free days 15 (9.1

Delirium (days)

Coma (days)

Days accurately sedated (%)Days accurately sedated (%)

Days on study drug

Average daily dose (mg)

Additional haloperidolNumber of patients (%)

Dose (mg)

Ventilator-free days 12.0 (0

21-day mortality (%)

Akathisia (%)(severity of symptoms NS between groups)

QTc ≥ 500 msec (n)

ZiprasidoneN=35

PlaceboN=36

P value

67 64

26 (23-32) 26 (21-32)

32

54

32

49

15 (9.1-18.0) 12.5 (1.2-17) 0.66

4 (2-8) 4 (2-6) 0.93

2 (0-4) 2 (0-5) 0.90

64 7164 71

4 (4-10) 5 (3-7) 0.23

113 (81-140) - -

30

10 (5-20)

39

12.5 (5.5-50.2)

0.13

0.30

12.0 (0-18.6) 12.5 (0-23) 0.25

13 17 0.81

20 19 0.60

5 3 0.31


Patient populations studied very different:• Delirium at study entry:

• MINDS: 47-54%

• Quetiapine: 100%

• Coma at study entry:

• MINDS: 32-40% • Are patients in coma delirious or simply oversedated

Why did Patient Outcome Improve in Study but not in MINDS Study?

• Are patients in coma delirious or simply oversedated

• ~ 10% of patients never developed delirium over the course of the study

• Quetiapine: 0%

• Active alcohol withdrawal:

• MINDS: included

• Quetiapine: excluded

• Time course in ICU stay when randomized:

• MINDS: patients excluded if mechanically ventilated

• Quetiapine: Time from ICU admission to randomization = median of 6 days

Patient populations studied very different:

oversedated?

Why did Patient Outcome Improve in QuetiapineStudy but not in MINDS Study?

oversedated?

~ 10% of patients never developed delirium over the course of the study

Time course in ICU stay when randomized:

MINDS: patients excluded if mechanically ventilated ≥ 2.5 days

: Time from ICU admission to randomization = median of 6 days

Pisani MA et al. Arch Intern Med 2007; 167:1629-1634

Was a placebo truly used in either study?• Additional antipsychotic use in placebo groups substantial

• MINDS: • 39% received haloperidol (median = 12.5mg )

• 11% received atypical antipsychotic

• Quetiapine:

• All patients received at least one haloperidol dose before entry

• Haloperidol given on 60% of study days (median 4.3 mg per day)

Method of antipsychotic discontinuation

Methodological Differences Between MINDS and

• MINDS:

• D/C when CAM-ICU negative for > 48hrs ; could continue up to max of 14 days

• Median duration: • Haloperidol: 7 (4-10) days

• Ziprasidone: 4 (3-10) days

• Placebo: 5 (3-7) days

• Quetiapine:

• Attending MD felt delirium resolved (44%/39%); 10 days of therapy (12%/33%); ICU discharge (44%/28%)

• Median duration:

• Quetiapine: 4.3 (3.5-7) days

• Placebo: 7.8 (4.5-9.5) days

Additional antipsychotic use in placebo groups substantial

All patients received at least one haloperidol dose before entry

Haloperidol given on 60% of study days (median 4.3 mg per day)

Methodological Differences Between MINDS and Quetiapine Studies

ICU negative for > 48hrs ; could continue up to max of 14 days

Attending MD felt delirium resolved (44%/39%); 10 days of therapy (12%/33%); ICU discharge


Primary efficacy outcome differed:

MINDS: Days alive without delirium or coma


Number of days of ICU delirium/coma significantly associatedwith time to death within 1 yr (HR, 1.10; 95% CI 1.02-1.18)

Pisani MA et al. Days of delirium are associated with 1Am J Respir Crit Care Med 2009; 180: 1092-7.Trzepacz PT et al. Designing clinical trials for the treatment of delirium. J Psychosomatic Res 2008; 65: 299

• Median age ranged from 51-56 therefore most

patients < 60 yrs old

• Neither number of delirium/coma-free days, days

of delirium nor number of patients where delirium

resolved differed between the 3 groups

Quetiapine: Time to first resolution of delirium


“the primary end point…..delirium resolution

or response (measured as a predefined decrease

in delirium symptoms below a specified value)….”

• Percent of time spent in delirium during time study

MA et al. Days of delirium are associated with 1-year mortality in an older intensive care unit population.

PT et al. Designing clinical trials for the treatment of delirium. J Psychosomatic Res 2008; 65: 299-307.

• Percent of time spent in delirium during time study

drug administered was greater in placebo group

69% vs. 53%, p=0.02)

• Delirium recurred in more placebo than quetiapine

patients (44% vs. 22%, p=0.29)

ά1-adrenergic

H1-histaminic

D2 dopamine


Receptor Adherence Differs Substantially Between Antipsychotics Studied

ά2-adrenergic

Median doses of haloperidol, ziprasidone and Median doses of haloperidol, ziprasidone and

Equivalent dose (mg)

Median study dose per day (mg)

Median study dose per day in HEs (mg)

Median PRN haloperidol per day (mg)

Total median dose of haloperidol per day (mg)

5-HT2A serotonergic


Receptor Adherence Differs Substantially Between Antipsychotics Studied

and quetiapine administered not equivalent

Schotte A, et al. Pyschopharmacology (Berlin) 1996: 124: 57-73.

Woods SW et al. J Clin Psychiatry 2003 Jun;64:6:663-7

and quetiapine administered not equivalent

Haloperidol Ziprasidone Quetiapine

2 60 75

15 113 110

15 3.8 2.9

4.5 5.7 1.9

19.5 9.5 4.8

Methodological Differences Betwee

• While both CAM-ICU and ICDSC are both highly valid

DSM-IV criteria) and reliable, they are very different scales with respect to the

characteristics of delirium they evaluate and the

• The two scales identify hypoactive delirium very differently….

• was the proportion of patients with hypoactive delirium (less likely to respond

to antipsychotic therapy) the same between the two studies?

• The two scales account for level of sedation and the interaction between sedation

CAM-ICU vs ICDSC Agreement: 71%, kappa 0.54 (0.46

DSC + DSC -

CAM-ICU + 73 11

CAM-ICU - 48 96

CAM-ICU UA 14 2

135 109

+ delirium, - not delirium, UA = unassessable

• The two scales account for level of sedation and the interaction between sedation

and delirium quite differently

een MINDS and Quetiapine Studies

highly valid (vs. psychiatrists using

, they are very different scales with respect to the

and the duration of time that is evaluated.

The two scales identify hypoactive delirium very differently….

was the proportion of patients with hypoactive delirium (less likely to respond

to antipsychotic therapy) the same between the two studies?

The two scales account for level of sedation and the interaction between sedation

Agreement: 71%, kappa 0.54 (0.46 – 0.63)

DSC UA

7 91

1 145

36 52

44 288 Devlin JW et al. Intens Care Med 2007Marquis F et al. Crit Care Med 2007Riker RR et al . Crit Care Med 2007Robbins T et al . Crit Care Med 2008

The two scales account for level of sedation and the interaction between sedation

• Design: Prospective, randomized trial (even• Setting: 1 academic medical center• Intervention:

• Olanzapine 5mg PO/NGT daily vs haloperidoldaily

• ↓ dose by 50% in elderly• dose not titrated in either arm• dose not titrated in either arm

• PRN IV haloperidol and IV benzodiazepines allowed for agitation• Primary outcome:

• Severity of delirium (delirium rating scale) • Subjects:

• Inclusion: ICDSC ≥4 or clinical symtoms• All delirium confirmed by psychiatrist using DSM

• Exclusion: Use of antypsychotic in previous 10 days, coma or stupor, GI dysfunction precluding drug administration, patients with safety concerns to study medication: parkinson’s disease, QTc interval, hepatic or renal dysfunction

even/odd days assignment)

haloperidol 2.5-5mg PO/NGT three times

PRN IV haloperidol and IV benzodiazepines allowed for agitation

Severity of delirium (delirium rating scale)

symtoms of deliriumAll delirium confirmed by psychiatrist using DSM-IV criteria

in previous 10 days, coma or stupor, GI dysfunction precluding drug administration, patients with safety concerns to

disease, oropharyngeal dysfunction, prolonged interval, hepatic or renal dysfunction

Skrobik YK et al. Intensive Care Med 2004; 30:444-49

Mean DeliriumRating Scale

(severity)

Day

P > 0.05

Day

Day

Mean Daily

BenzodiazepineDose

P > 0.05


Olanzapine vs Haloperidol for ICU Delirium

Olanzapine

(N=28)

Use of rescue IV

haldol (%)

36

(mostly day #1)

Extrapyramidal NoneExtrapyramidal

Symptoms

None

Olanzapine vs Haloperidol for ICU Delirium

Haloperidol

(N=45)

42

(mostly day #1)

NS

6 pts with possible episodes NS6 pts with possible episodes

but all rated very low on

Simpson-Angus Scale

NS




an atypical antipsychotic agent


Pilot study data suggests that the addition of

to “as needed” haloperidol may improve delirium resolution

and other patient outcomes; however,

does not appear to improve patient outcome in

patients with acute brain dysfunction



an atypical antipsychotic agent for the treatment of


Pilot study data suggests that the addition of quetiapine

to “as needed” haloperidol may improve delirium resolution

and other patient outcomes; however, ziprasidone

does not appear to improve patient outcome in

patients with acute brain dysfunction

Pharmacological Considerations When Treating Delirium

• “Positive” signs of delirium (i.e., agitation, hallucinations) more likely to respond to antipsychotic therapy than “hypo activity, inattention, disordered cognition, depressed level of consciousness)

• Does the number of delirium causes present affect responsiveness to antipsychotic therapy?

• ICU (n=11) > > non-ICU (n=1.5)

• Does the underlying cause (s) of the delirium influence response to • Does the underlying cause (s) of the delirium influence response to antipsychotic therapy?

• Receptor adherence properties appear to affect responsiveness of therapy between haloperidol and each atypical antipsychotic

• Adrenergic mechanism appears to influence delirium far more than serotonergic or dopaminergic mechanism

• Is this consistent to the effects we see with

Pharmacological Considerations When Treating Delirium

” signs of delirium (i.e., agitation, hallucinations) more likely to respond to antipsychotic therapy than “negative” signs of delirium (i.e., hypo activity, inattention, disordered cognition, depressed level of

Does the number of delirium causes present affect responsiveness to

ICU (n=1.5)

Does the underlying cause (s) of the delirium influence response to Does the underlying cause (s) of the delirium influence response to

Receptor adherence properties appear to affect responsiveness of therapy between haloperidol and each atypical antipsychotic

Adrenergic mechanism appears to influence delirium far more than mechanism

Is this consistent to the effects we see with dexmedetomidine?

Inouye SK. N Engl J Med 2006; 354:1157-65.Trzepacz PT et al. Semin Clin Neuropsych 2000; 5:132-148Dubois MJ et al. Intensive Care Med 2001; 27:1297-1304. Girard T et al. Crit Care Med Nov 2009 (ahead of press) Skrobik Y et al. Crit Care Clinics 2009 25:585-587.Platt, MM etal. J Neuropsychiatry Clin Neurosci 1994; 10:188-90

Conclusions• No high quality data to support the administration of haloperidol alone in

treating delirium

• Pilot study data suggests that the addition of haloperidol may improve delirium resolution and other patient outcomes

• Future studies investigating antipsychotic therapy in the ICU should:

• Ensure that underlying causes of delirium are addressed/reversed in a systematic

fashion prior to randomization

• Use a placebo group that receives no antipsychotic therapy given the very small • Use a placebo group that receives no antipsychotic therapy given the very small

placebo effect seen in delirium studies

• Stratify drug assignment based on:• presence of “positive” and “negative” delirium symptoms

• Hyperactive vs. hypoactive delirium

• Account for the influence of level of sedation and sedative choice on detection of

delirium

• Less restrictive exclusion criteria

• Large enough to evaluate key patient outcomes

• Evaluate patient outcome(s) and dependency after ICU discharge

ConclusionsNo high quality data to support the administration of haloperidol alone in

Pilot study data suggests that the addition of quetiapine to “as needed” haloperidol may improve delirium resolution and other patient outcomes

Future studies investigating antipsychotic therapy in the ICU should:

Ensure that underlying causes of delirium are addressed/reversed in a systematic

Use a placebo group that receives no antipsychotic therapy given the very small Use a placebo group that receives no antipsychotic therapy given the very small

placebo effect seen in delirium studies

presence of “positive” and “negative” delirium symptoms

Account for the influence of level of sedation and sedative choice on detection of

Large enough to evaluate key patient outcomes

Evaluate patient outcome(s) and dependency after ICU discharge

treating agitation and de to an alphabet soup of potential options

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