haloperidol is the “go to” drug for delirium: but are atypicals a better option?

Haloperidol is the “Go To” Drug for Delirium: But are Atypicals a Better Option?

John W. Devlin, Pharm.D., FCCP, FCCM,

Associate Professor

Northeastern University School of Pharmacy

Adjunct Associate Professor

Tufts University School of Medicine

Boston, MA

Maldonado. Crit Care Clin 2008; 24:789

Mechanisms for ICU Delirium are Numerous and Complex

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

Pharmacological Considerations When Treating Delirium

• Pharmacological therapy should be considered ONLY after underlying causes delirium are reversed/treated

• Pharmacological therapy should generally be reserved for patients with severe agitation that will affect patient/caregiver safety

• Delirium: ↓ acetylcholine and ↑ dopamine • “Positive” 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 consciousness)

• Number of delirium causes in ICU (n=11) > > non-ICU (n=1.5) • is delirium in the ICU more susceptible to antipsychotic therapy?

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

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

Pharmacological Considerations When Treating Delirium

• Substantial variability in receptor adherence properties between haloperidol and each atypical antipsychotic• While all conventional and atypical antipsychotics appear to be

equally efficacious in the treatment of psychosis, do they differ in their ability to treat delirium?

• A dose of haloperidol of 2-20mg/day is adequate to achieve the 60% binding to D2 receptors necessary for an antipsychotic effect to occur

• What is the most clinically relevant outcome to evaluate antipsychotic efficacy in ICU delirium?• Delirium resolution? • Time spent without delirium?• Delirium severity?• Longer-term outcomes? Trzepacz PT et al. Semin Clin Neuropsych 2000; 5:132-148.

Dubois 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.Kapur S et al. Am J Psych 1996; 153:948.

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 1-2mg every 2-4 hrs and titrated 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) antipsychotics.”

SCCM Guidelines (2002)• Haloperidol is the preferred agent for the treatment of delirium in critically ill

patients. (Grade C recommendation)

United Kingdom Delirium Guidelines (November, 2009 - draft)• “moderate quality evidence from a single RCT showing significant improvement

of delirium and lower severity of delirium with haloperidol vs no treatment at 7 days BUT some uncertainty surrounding this result.”

• “moderate quality evidence from a single RCT showing a significant recovery from delirium and lower severity of delirium vs. no treatment BUT much certainty with these results.”

• “there is low quality evidence from a meta-analysis of 2 studies (one RCT and one quasi-RCT) showing no difference in either recovery from delirium or severity of delirium between haloperidol and olanzapine”

Trzepacz P et al. APA 1999Jacobi J et al. Crit Care Med 2002; 30:119-141.National Clinical Guideline Center, NICE, UK, 2009 (draft)

While use of haloperidol is associated with lower mortality, it is unclear if use of haloperidolto treat delirium improves outcomeMillbrandt EB, et al. Crit Care Med 2005; 33: 226-229.

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 Haldol Lactate). The updated labeling includes WARNINGS stating that Torsades 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 not approved for intravenous use.

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

Potential Advantages of Atypical versus Conventional Antipsychotics

• Decreased extrapyramidal effects • Little effect on the QTc interval (with the exception of ziprasidone)• 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

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

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

Insert the 2008 Patel survey data

2001

2007

Few Prospective, Randomized Trials Have Evaluated Antipsychotic Therapy for Delirium Treatment in the ICU

• Pubmed search: • 1960 – December 2009

• antipsychotic: • haloperidol, olanzapine, quetiapine, risperidone, ziprasidone

• delirium

• critical care

• limited to prospective, randomized trial

• Results: 3 trials

Is there evidence from randomized-

controlled studies that supports the use of

haloperidol for the treatment of

delirium in the critically ill?

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

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

• Q12h x 24 hrs then q6h for maximum 14 days• ↓ q8h when CAM-ICU negative x 24hrs,• then ↓ q12h when negative x 36hrs, then d/c x 48hrs• Could give IM if NPO up to max 8 doses• Oversedation: ↓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)• Primary outcome:

• Number of days patient alive without delirium or coma during the 21-day study period• Delirium = + CAM-ICU • Coma = RASS (-4) [ie. responsive to physical but not verbal stimulation] or RASS (-5) [ie. not

responsive to either]

Modifying the Incidence of Delirium (MINDS) Trial

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

Inclusion Criteria: • Mechanically ventilated adults with an abnormal level of consciousness or who

were receiving sedatives/analgesics

Exclusion Criteria:• Continuous mechanical ventilation > 60hrs at screening• No plan for gastric access within 48 hrs• 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

Modifying the Incidence of Delirium (MINDS) Trial


Safety-related

Efficacy-related

HaloperidolN=35

PlaceboN=36

P value

Medical (%) 57 64

APACHE II score 26 (21-31) 26 (21-32)

Brain dysfunction on first study dayComa (%)Delirium (%)

3547

3249

Delirium/coma-free days 14 (6-18) 12.5 (1.2-17) 0.66

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

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

Days accurately sedated (%) 70 71

Days on study drug 7 (4-10) 5 (3-7) 0.23

Average daily dose (mg) 4.5 (2.9-23.8) - -

Additional haloperidolNumber of patients (%)Dose (mg)

175 (3-24)

3912.5 (5.5-50.2)

0.130.30

Ventilator-free days 7.8 (0-15) 12.5 (0-23) 0.25

21-day mortality (%) 11 17 0.81

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

29 19 0.60

QTc ≥ 500 msec (n) 2 3 0.31



P = 0.66

Is there evidence from randomized-

controlled studies that supports the use of

an atypical antipsychotic agent for the treatment of

delirium in the critically ill?

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

• Quetiapine 50mg PO/NGT twice daily titrated to a maximum of 200mg twicedaily) vs Placebo

• PRN IV haloperidol protocolized and encouraged in each group• Oversedation: hold study drug when SAS ≤ 2 (after holding sedation therapy)

• Primary outcome:• Time to first resolution of delirium (ie. first 12 hour period when ICDSC ≤ 3)

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

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

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

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)

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

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


Quetiapine(n=18)

Placebo(n=18)

Age (years) 62.4 ± 14 63.6 ± 15.3

Male (%) 56 56

APACHE II (on admission to ICU) 19.7 ± 5.3 21.4 ± 9.2

Medical (%) 72 78

ICU days prior to enrollment 5 (2-8) 7 (3-11)

Intubated at study entry (%) 72 89

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

3 or 4 72 67

≥ 5 28 33

ICDSC score at study entry 5 (4-6) 5 (4-6)


Placebo

Quetiapine

Pro

po

rtio

n o

f P

atie

nts

wit

h D

elir

ium

Day During Study Drug Administration


Log-Rank p=0.001

Quetiapine(n=18)

Placebo(n=18)

P value

Time of study drug administration (hours) 102 (84-168) 186 (108-228) 0.04

Time in delirium

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

Percent of time in study 53 (16-67) 69 (58-100) 0.02

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

22 44 0.29

Time spent agitated (SAS ≥ 5)

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


Time spent deeply sedated (SAS ≤ 2)

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


Subject-initiated device removal

Number of episodes 8 10 0.79

Number of subjects with ≥ 1 episode (%) 17 22 1.0

Reason for discontinuation of study drug (%)

Therapy felt to be no longer required by subject’s

attending intensivist

44 39 0.31

10 days of therapy had elapsed 12 33

ICU discharge 44 28

Serious adverse drug event 0 0


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.

Quetiapine(n=18)

Placebo(n=18)

P value

Duration of mechanical ventilation (days) 11 (3-19) 11 (4-29) 0.67

Duration of ICU stay (days) 16 (10-22) 16 (13-32) 0.28

Duration of hospitalization (days) 24 (11-33) 26 (17-49) 0.32

Hospital mortality (%) 11 17 1.0

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

Subjects with ≥ 1 day of delirium (%) 20 56 0.09

Time spent in delirium (%) 0 (0-0) 14 (0-47) 0.05

Subject placement after hospital discharge (%)

Home / rehabilitation center 89 56

0.06Chronic care facility / another acute care hospital / death

11 44


ZiprasidoneN=35

PlaceboN=36

P value

Medical (%) 67 64

APACHE II score 26 (23-32) 26 (21-32)

Brain dysfunction on first study dayComa (%)Delirium (%)

3254

3249

Delirium/coma-free days 15 (9.1-18.0) 12.5 (1.2-17) 0.66

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

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

Days accurately sedated (%) 64 71

Days on study drug 4 (4-10) 5 (3-7) 0.23

Average daily dose (mg) 113 (81-140) - -

Additional haloperidolNumber of patients (%)Dose (mg)

3010 (5-20)

3912.5 (5.5-50.2)

0.130.30

Ventilator-free days 12.0 (0-18.6) 12.5 (0-23) 0.25

21-day mortality (%) 13 17 0.81

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

20 19 0.60

QTc ≥ 500 msec (n) 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?

• ~ 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 ≥ 2.5 days

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

Methodological Differences Between MINDS and Quetiapine Studies

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• 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


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

Primary efficacy outcome differed:

MINDS: Days alive without delirium or coma Quetiapine: Time to first resolution of delirium


Pisani MA et al. Days of delirium are associated with 1-year mortality in an older intensive care unit population. Am 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: 299-307.

“the primary end point…..delirium resolutionor response (measured as a predefined decreasein delirium symptoms below a specified value)….”

• 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

• 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 quetiapinepatients (44% vs. 22%, p=0.29)

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

5-HT2A serotonergic

ά1-adrenergic

H1-histaminic

D2 dopamine


Receptor Adherence Differs Substantially Between Antipsychotics Studied

ά2-adrenergic

Schotte A, et al. Pyschopharmacology (Berlin) 1996: 124: 57-73.Woods SW et al. J Clin Psychiatry 2003 Jun;64:6:663-7

Median doses of haloperidol, ziprasidone and quetiapine administered not equivalent

Haloperidol Ziprasidone Quetiapine

Equivalent dose (mg) 2 60 75

Median study dose per day (mg) 15 113 110

Median study dose per day in HEs (mg) 15 3.8 2.9

Median PRN haloperidol per day (mg) 4.5 5.7 1.9

Total median dose of haloperidol per day (mg) 19.5 9.5 4.8

CAM-ICU vs ICDSC Agreement: 71%, kappa 0.54 (0.46 – 0.63)

DSC + DSC - DSC UA

CAM-ICU + 73 11 7 91

CAM-ICU - 48 96 1 145

CAM-ICU UA 14 2 36 52

135 109 44 288

+ delirium, - not delirium, UA = unassessable

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


• While both CAM-ICU and ICDSC are both highly valid (vs. psychiatrists using DSM-IV criteria) and reliable, they are very different scales with respect to the characteristics of delirium they evaluate 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 and delirium quite differently

• Design: Prospective, randomized trial (even/odd days assignment)• Setting: 1 academic medical center• Intervention:

• Olanzapine 5mg PO/NGT daily vs haloperidol 2.5-5mg PO/NGT three times daily

• ↓ dose by 50% in elderly• 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 of delirium• All delirium confirmed by psychiatrist using DSM-IV criteria

• 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, oropharyngeal dysfunction, prolonged QTc interval, hepatic or renal dysfunction

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


Mean DeliriumRating Scale

(severity)

Day

Day

Mean Daily

BenzodiazepineDose

P > 0.05

P > 0.05

Olanzapine vs Haloperidol for ICU Delirium

Olanzapine

(N=28)

Haloperidol

(N=45)

Use of rescue IV haldol (%)

36

(mostly day #1)

42

(mostly day #1)

NS

Extrapyramidal Symptoms

None 6 pts with possible episodes but all rated very low on Simpson-Angus Scale

NS


Cost-effectiveness of Haloperidol vs Olanzapine

National Clinical Guideline Center, NICE, UK, 2009 (draft)

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

treating delirium

• 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

fashion prior to randomization

• 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

haloperidol is the “go to” drug for delirium: but are atypicals a better option?

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