Haloperidol vs Atypicals for ICU Delirium

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

Mechanisms 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

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; 5:132-148
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.
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.
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 1999
Jacobi 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 haloperidol
to treat delirium improves outcome
Millbrandt EB, et al. Crit Care Med 2005; 33: 226-229.

Use of haloperidol is an independent predictor for prolonged delirium

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

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.

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

Use of Atypical Antipsychotic Therapy is Increasing

2001

2007

Insert the 2008 Patel survey data

Ely EW et al. Crit Care Med 2004;32:106-12
Patel 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, 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?

Modifying the Incidence of Delirium (MINDS) Trial
• 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
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 Efficacy-related
• 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
Safety-related
• Clinically significant ventricular tachycardia
• Uncompensated class IV heart failure
• Refractory hypokalemia or hypomagnesemia


Haloperidol Placebo P value
N=35 N=36
Medical (%) 57 64

APACHE II score 26 (21-31) 26 (21-32)
Brain dysfunction on first study day
Coma (%) 35 32
Delirium (%) 47 49

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 haloperidol
Number of patients (%) 17 39 0.13
Dose (mg) 5 (3-24) 12.5 (5.5-50.2) 0.30
Ventilator-free days 7.8 (0-15) 12.5 (0-23) 0.25
21-day mortality (%) 11 17 0.81
Akathisia (%) 29 19 0.60
(severity of symptoms NS between groups)
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 twice
daily) vs Placebo
• PRN IV haloperidol protocolized and encouraged in each group
• Oversedation: hold study drug when SAS ≤ 2 (after holding sedation therapy)
• 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)

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

222 Excluded
46 Prior antipsychotic use within 30 days
38 Not receiving enteral nutrition
36 subjects randomized
28 Primary neurological condition
16 Encephalopathy or end-stage liver disease
12 Alcohol withdrawal
12 Inability to conduct ICDSC
11 No delirium
Quetiapine 50 mg NG twice daily Placebo 50 mg NG twice daily 11 Inability to obtain informed consent
(N=18) (N=18) 10 Moribund
8 Irreversible brain disease (e.g. dementia)
5 Baseline QTc interval ≥ 500msec
As needed haloperidol therapy, usual sedation and analgesia 5 Attending physician refusal for enrollment
therapy at the discretion of the subject’s physician 7 Other

Dose Titration
Increase 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 drug
1. Subject was deemed by the attending intensivist to be no longer
demonstrating signs of delirium, therefore, therapy no longer required
2. 10 days of therapy had elapsed
3. ICU discharge prior to 10 days of therapy
4. Serious adverse event potentially attributable to the study drug

Quetiapine Placebo
(n=18) (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)


Proportion of Patients with Delirium

Log-Rank p=0.001
Placebo

Quetiapine

Day During Study Drug Administration


Quetiapine Placebo P value
(n=18) (n=18)
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 22 44 0.29
after initial delirium resolution (%)
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 44 39 0.31
attending intensivist
10 days of therapy had elapsed 12 33
ICU discharge 44 28
Serious adverse drug event 0 0


Quetiapine Placebo P value
(n=18) (n=18)

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
Chronic care facility / another 11 44 0.06
acute care hospital / death

 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.


Ziprasidone Placebo P value
N=35 N=36
Medical (%) 67 64

APACHE II score 26 (23-32) 26 (21-32)
Brain dysfunction on first study day
Coma (%) 32 32
Delirium (%) 54 49

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 haloperidol
Number of patients (%) 30 39 0.13
Dose (mg) 10 (5-20) 12.5 (5.5-50.2) 0.30
Ventilator-free days 12.0 (0-18.6) 12.5 (0-23) 0.25
21-day mortality (%) 13 17 0.81
Akathisia (%) 20 19 0.60
(severity of symptoms NS between groups)
QTc ≥ 500 msec (n) 5 3 0.31


Methodological Differences Between MINDS and Quetiapine Studies

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

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

Receptor Adherence Differs Substantially Between Antipsychotics Studied

ά2-adrenergic H1-histaminic
5-HT2A serotonergic

ά1-adrenergic
D2 dopamine

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

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

• 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
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 Devlin JW et al. Intens Care Med 2007
Marquis F et al. Crit Care Med 2007
+ delirium, - not delirium, UA = unassessable Riker RR et al . Crit Care Med 2007
Robbins T et al . Crit Care Med 2008

• 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
• 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

P > 0.05
Mean
Delirium
Rating
Scale
(severity)

Day

Mean P > 0.05
Daily
Benzodiazepine
Dose

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

Olanzapine vs Haloperidol for ICU Delirium

Olanzapine Haloperidol
(N=28) (N=45)

Use of rescue IV 36 42 NS
haldol (%) (mostly day #1) (mostly day #1)

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

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

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 vs Atypicals for ICU Delirium

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