1. Treating Agitation and De
Delirium: Providing Clarity
to an Alphabet Soup of Potential Options
John W. Devlin, Pharm.D FCCP, FCCM,
Pharm.D.,
Associate Professor
Northeastern University School of Pharmacy
Adjunct Associate Professor
Tufts University School of Medicine
Boston, MA

2. Before Considering a Pharmacologic
Treatment for Delirium…..
• Have the underlying causes of delirium been
identified and reversed/treated whenever possible?

3. Patient Factors Predisposing Disease
Increased age Less Modifiable Cardiac disease
Alcohol use Cognitive impairment
Male gender (e.g., dementia)
Living alone Pulmonary disease
Smoking
Renal disease
Acute Illness
DELIRIUM Length of stay
Fever
Medicine service
Environment Lack of nutrition
Admission via ED or Hypotension
through transfer Sepsis
Isolation Metabolic disorders
No clock Tubes/catheters
No daylight More Modifiable Medications:
No visitors - anticholinergics
Inouye SK et al. JAMA 1996; 275: 852
Noise Dubois MJ, et al. ICM 2001;27:1297
2001;27:1297-1304
- corticosteroids
Use of physical restraints Ouimert S et al. ICM 2007; 33:66
33:66-73 - benzodiazepines
Van Rompaey B et al. Crit Care 2009; 13:R77

4. Before Considering a Pharmacologic
Treatment for Delirium…..
• Have the underlying causes of delirium been
identified and reversed/treated whenever possible?
• Have non-pharmacologic treatment strategies been
pharmacologic
optimized?
• Does your patient have hyperactive delirium,
hypoactive delirium or mixed hyperactive
hyperactive-
hypoactive delirium?
Inouye SK et al N Engl J Med 1999

5. Mechanisms for ICU Delirium are Numerous and Complex
Maldonado. Crit Care Clin 2008; 24:789

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

7. 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 11-2mg 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)
Trzepacz P et al. APA 1999
Jacobi J et al. Crit Care Med 2002; 30:119-141.

8. 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.

9. 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

10. 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

11. 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
quetiapine,
• delirium
• critical care
• limited to prospective, randomized trial
• Results: 3 trials

12. Is there evidence from randomized
randomized-
controlled studies that supports the use of
haloperidol for the treatment of
delirium in the critically ill?

13. Modifying the Incidence of Delirium (MINDS) Trial
cidence
• Design: Double-blind, placebo-controlled randomized trial
controlled,
• 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
study
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
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]
Girard T et al. Crit Care Med Nov 2009 (ahead of press)

14. Modifying the Incidence of Delirium (MINDS) Trial
cidence
Inclusion Criteria:
• Mechanically ventilated adults with an abnormal level of consciousness or who
were receiving sedatives/analgesics
analgesics
Note: 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
Efficacy-related
• 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 Safety-related
• Clinically significant ventricular tachycardia
• Uncompensated class IV heart failure
• Refractory hypokalemia or hypomagnesemia
Girard T et al. Crit Care Med Nov 2009 (ahead of press)

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

16. 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
(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
Girard T et al. Crit Care Med Nov 2009 (ahead of press)

17. P = 0.66
Girard T et al. Crit Care Med Nov 2009 (ahead of press)

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

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

20. Is there evidence from randomized
randomized-
controlled studies that supports the use of
haloperidol for the treatment of
delirium in the critically ill?
No evidence from randomized, placebo
placebo-
controlled studies that haloperidol
improves outcome in ICU patents

21. Is there evidence from randomized
randomized-
controlled studies that supports the use of
an atypical antipsychotic agent for the treatment of
delirium in the critically ill?

22. • Design: Double-blind, placebo-controlled randomized trial
controlled,
• 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)
:
• Primary outcome:
• Time to first resolution of delirium (ie first 12 hour period when ICDSC ≤ 3)
ie.
Devlin JW et al. Crit Care Med Nov 2009 (ahead of press)

23. 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
Devlin JW et al. Crit Care Med Nov 2009 (ahead of press)

24. 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)
Devlin JW et al. Crit Care Med Nov 2009 (ahead of press)

25. Proportion of Patients with Delirium
Log-Rank p=0.001
Placebo
Quetiapine
Day During Study Drug Administration
Devlin JW et al. Crit Care Med Nov 2009 (ahead of press)

26. 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
Percent of time in study 3 (0-22) 21 (8-41) 0.03
Time spent deeply sedated (SAS ≤ 2)
Hours 0 (0-8) 0 (1-2) 0.54
Percent of time in study 0 (0-8) 0 (0-0) 0.39
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
Devlin JW et al. Crit Care Med Nov 2009 (ahead of press)

27. 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.
Devlin JW et al. Crit Care Med Nov 2009 (ahead of press)

28. 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
(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
(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
Girard T et al. Crit Care Med Nov 2009 (ahead of press)

29. Why did Patient Outcome Improve in Quetiapine
Study but not in MINDS Study?
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
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

30. Methodological Differences Between MINDS and Quetiapine Studies
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
ICU
• 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

31. Methodological Differences Between MINDS and Quetiapine Studies
Primary efficacy outcome differed:
MINDS: Days alive without delirium or coma Quetiapine: Time to first resolution of delirium
Number of days of ICU delirium/coma 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 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: 299299-307.

32. Methodological Differences Between MINDS and Quetiapine Studies
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

33. Methodological Differences Betwee MINDS and Quetiapine Studies
een
• 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

34. • Design: Prospective, randomized trial (even
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
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

35. 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

36. 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

37. Is there evidence from randomized
randomized-
controlled studies that supports the use of
an atypical antipsychotic agent for the treatment of
delirium in the critically ill?
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

38. Pharmacological Considerations When Treating Delirium
• “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)
• Does the number of delirium causes present affect responsiveness to
antipsychotic therapy?
• ICU (n=11) > > non-ICU (n=1.5)
ICU
• 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 dexmedetomidine?
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

39. 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