1. No category

Treatment of ICU Delirium:
Is It Time to Stop Being Typical?
http://www.cksinfo.com/medicine/cartoons/page3.html
G. Christina Caballero, Pharm.D.
PGY1 Pharmacy Resident
Department of Pharmacy, University Health System, San Antonio, TX
Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy
Pharmacotherapy Education and Research Center,
University of Texas Health Science Center at San Antonio
October 29, 2010
Learning Objectives:
o Define intensive care unit (ICU) delirium
o Describe the spectrum, incidence, and impact of ICU delirium
o Apply validated scales in the assessment of ICU delirium
o Evaluate available evidence for treatment using haloperidol vs. atypical antipsychotics
1|Page
BACKGROUND
I.
Overview of ICU Delirium
a. An acute, transient disturbance of consciousness and cognition in critically ill patients1
b. Common complication and independent predictor of adverse outcomes including mortality, long-term
cognitive impairment, and cost2-6
c. Recent survey of 1384 healthcare professionals revealed that delirium is considered a serious
complication, but only 16% use a validated assessment tool and treatment is extremely inconsistent7
d. Haloperidol is the treatment of choice, but atypical antipsychotics are gaining popularity8
II.
Spectrum of Delirium
a. Subtypes9-10
i. Hyperactive
1. Increased psychomotor activity with agitated behavior
ii. Hypoactive
1. Reduced psychomotor behavior and lethargy
iii. Mixed
1. Fluctuations between a hyperactive and hypoactive state
iv. Subsyndromal1
1. Restlessness, anxiety, irritability, distractibility, or sleep disturbance in days before onset
of overt delirium
2. Prodromal symptoms may progress to full-blown delirium over 1–3 days
III.
Incidence of Delirium
a. Far more common in ICU patients compared to patients on medical wards11
b. Incidence reported among medical and surgical ICU patients varies from 20% to more than 80%9
c. Subtypes
i. In a cohort of 375 medical ICU patients with delirium, 43.5% experienced hypoactive delirium,
54.9% experienced mixed delirium, and only 1.6% experienced hyperactive delirium12
ii. In a separate cohort of 100 mechanically ventilated surgical and trauma ICU patients, 62% had
hypoactive delirium, 7% had mixed delirium, and < 1% had hyperactive delirium13
iii. Subsyndromal delirium has been reported in 33.3% of patients admitted to ICU over a course of
1 year based on prospective chart review14
1. Associated with statistically significant increase in ICU and hospital length of stay and
mortality compared to no delirium
IV.
Impact of Delirium
a. Strong, independent predictor of prolonged hospital and ICU stay, reintubation, cost of care, long-term
cognitive impairment, discharge to non-home, and mortality2-6, 12
b. Ely et al found patients who developed ICU delirium had 3 times the risk of 6-month mortality2
i. Each additional day of delirium was associated with 10% increased risk of death
ii. Six-month survival in patients without delirium was 85% vs. 66% in those with delirium
2|Page
P = 0.008
Figure 1. Kaplan-Meier Analysis of Delirium in the ICU and 6-Month Survival2
c. Delirium in mechanically ventilated patients is associated with greater hospital costs
Figure 2. Median ICU and Hospital Cost per Patient from a Cohort of 275 Patients3
3|Page
PATHOPHYSIOLOGY AND RISK FACTORS
V.
Proposed Pathophysiology
a. Cerebral hypoperfusion, impaired oxidative metabolism, and atrophy9-10
i. Reduced oxidative metabolism results in an imbalance of neurotransmission
1. Studies evaluating delirious patients using electroencephalography (EEG) showed
diffuse slowing, a finding believed to represent reduced cerebral metabolism
b. Neurotransmitter imbalance9-10, 16
i. Multiple neurotransmitter systems have been implicated in pathophysiology of delirium
1. Dopamine
a. Increases in neuronal excitability; excess may be associated with delirium
b. Fluctuations have been implicated in other acute confusional states (e.g.
hallucinations, delusions)
2. Acetylcholine
a. Decreases neuronal excitability; depletion may be associated with delirium
b. Higher anticholinergic activity due to overuse of anticholinergic medications
may be associated with increased delirium symptom severity
c. Case studies have reported cessation of delirium symptoms upon anticholinergic
agent discontinuation
d. Higher serum anticholinergic activity (SAA), a biologic indicator to detect
anticholinergic processes, has been linked with the development of delirium
3. Imbalances in glutamate, gamma-aminobutyric acid (GABA), and monoamines
(serotonin, norepinephrine) may be associated with delirium
c. Alteration in transport of amino acids9-10, 16
i. Large neutral amino acids (LNAA) enter blood-brain barrier through the sodium-independent
large amino acid transporter-1 (LAT-1)
1. LAT-1 is a selective and highly saturable transport protein
2. Tryptophan, a precursor of serotonin, and phenylalanine compete with other LNAAs for
transport across blood-brain barrier
a. Decreased tryptophan will decrease available serotonin
b. Increased uptake of tryptophan and phenylalanine causes elevated levels of
dopamine and norepinephrine which have been implicated in delirium
10, 16
d. Sepsis
i. Inflammatory mediators produced during critical illness initiate a cascade of endothelial
damage, thrombin formation, and microvascular compromise which leads to decreased oxygen
and nutrient delivery to cerebral blood vessels
ii. Studies in animal models have shown these inflammatory mediators cross blood-brain barrier,
increase vascular permeability, and result in changes on EEG consistent with those seen in septic
patients with delirium
e. Apolipoprotein E (APOE)9-10, 17
i. APOE4 variant is known to be associated with higher susceptibility to Alzheimer’s disease and
has recently been implicated in increased duration of delirium in ICU patients
4|Page
VI.
Risk Factors for ICU Delirium
a. Cited in literature9-10, 12, 18
Table 1. Patient and Iatrogenic Risk Factors for ICU Delirium
Patient Factors
Advanced age
Alcoholism
Smoking
Hypertension
Preexisting cognitive impairment
Depression
APOE4 polymorphism
Chronic illness
Severity of illness (APACHE II score)
Iatrogenic
Hypoxia
Metabolic disturbances or electrolyte imbalances
Dehydration or hypotension
Prolonged pain
Psychoactive medications
Sedatives and analgesics
Sleep deprivation
Respiratory disease or mechanical ventilation
Prolonged restraint use or immobility
Withdrawal syndromes
Severe sepsis or other infection
Hyperthermia
Head trauma or seizures
Vascular disorders or anemia
b. Risk associated with sedatives and analgesics in the ICU
i. Lorazepam19
1. 198 mechanically ventilated patients evaluated for probability of transitioning to
delirium as a function of lorazepam, midazolam, fentanyl, morphine, or propofol
administration
2. Lorazepam use had a dose-proportional increased risk for daily transition to delirium
%
Figure 3. Probability of Transition to Delirium
5|Page
DIAGNOSIS AND TREATMENT
VII.
Diagnosis
a. Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for delirium due to multiple
etiologies1:
i. Disturbance of consciousness with reduced ability to focus, sustain, or shift attention
ii. A change in cognition (such as memory deficit, disorientation, language disturbance) or
development of a perceptual disturbance is not better accounted for by a preexisting,
established, or evolving dementia
iii. The disturbance develops over a short period of time (usually hrs to days) and tends to fluctuate
during course of a day
iv. There is evidence from the history, physical examination, or laboratory finding that the delirium
has more than one etiology
b. Confusion Assessment Method for the ICU (CAM-ICU)10, 20
i. Full scale in Appendix A
ii. Applies a two-step approach to assessment
1. Level of consciousness evaluated with Richmond Agitation Sedation Scale (RASS)
a. RASS is a 10 point scale ranging from -5 to +4
i. -5 represents no response to voice or physical evaluation
ii. +4 represents overly combative, or violent patient
iii. 0 represents a calm and alert patient
b. RASS score of -4 or -5 cannot be assessed via CAM-ICU
2. Diagnostic criteria
a. Acute change or fluctuation in mental status
b. Accompanied inattention
c. Disorganized thinking OR altered level of consciousness (RASS score not 0)
iii. Sensitivity: 79-100%
iv. Specificity: 89-100%
c. Intensive Care Delirium Screening Check List (ICDSC) 10, 20
i. Full scale in Appendix B
ii. First evaluates the level of consciousness and if patient not comatose or stuporous they are
assessed
iii. Diagnostic criteria
1. Alterations in consciousness; inattention; disorientation; hallucinations, delusions, or
psychosis; inappropriate speech or mood; sleep/wake cycle disturbance; symptom
fluctuation
iv. Scores range from 0-8
v. Score ≥ 4 is diagnostic for delirium
vi. Sensitivity: 43-99%
vii. Specificity: 87-98%
6|Page
VIII.
Treatment Options
a. Nonpharmacologic21
i. Protocol-based measures have proven effective in reducing delirium in hospitalized patients
1. Orientation
a. Communication to reorient patient to surroundings
2. Cognitive stimulation
a. Discussion of current events, or word games
3. Sleep enhancement
a. Unit-wide noise reduction, schedule adjustment, relaxing music
4. Early mobilization
a. Ambulation or active range-of-motion exercises
5. Vision optimization
a. Visual aids (glasses, magnifying glasses), and adaptive equipment (large-print
books, illuminated keypad)
6. Hearing optimization
a. Provision of hearing aids, earwax disimpaction
7. Dehydration treatment
a. Recognition of dehydration and volume repletion
b. Pharmacologic
i. A survey on delirium and sedation practices of 1384 healthcare professionals at 41 North
American hospitals revealed that current treatment practices vary widely7
Figure 4. Prescribing Practices
ii. Haloperidol
1. Recommended first line treatment by Society of Critical Care Medicine and the
American Psychiatric Association8
a. Agent of choice for many years because of fewer anticholinergic side effects,
few active metabolites, and less propensity to cause sedation and hypotension
compared to other typical antipsychotics
2. Mechanism of action22-23
a. Centrally blocks action of dopamine by binding DA-2 receptors, and to a lesser
extent, DA-1 receptors
7|Page
3. Unlabeled dose22-23
a. 2-10 mg IV every 20-30 minutes until calm achieved then 25% of the maximum
dose every 6 hrs
b. Maximum 240 mg/24 hrs23
c. Once delirium is controlled, regularly scheduled doses (every 4 to 6 hrs) may be
continued for a few days; then tapered over several days8
4. Pharmacokinetics22-23
a. Oral bioavailability: 60-70%
b. Time to peak: 2-6 hr
c. Half-life: 18 hr
a. Metabolism: CYP3A4 (23%), glucuronidation
5. Adverse effects22-23
a. Sedation incidence: frequent
b. Akathisia incidence: frequent
c. EPS incidence: frequent
i. May be less frequent with IV administration25
d. Neuroleptic malignant syndrome (NMS) incidence: rare
e. Seizure incidence: rare
f. Incidence of QT prolongation and torsades de pointe is unknown but thought to
be small
i. More common with IV administration
ii. Majority of cases are in critically ill patients with cardiovascular disease
and high doses (> 50 mg/day)
iii. Monitor for electrocardiographic changes with therapy
6. History24-27
a. First used IV for treatment of delirious patients in 1960s
b. Protocol developed at two major cancer centers in US and Canada using IV
haloperidol, lorazepam, and hydromorphone titrated to response
i. Haloperidol 5 mg, lorazepam 0.5, hydromorphone 0.5 mg
ii. No response at 20 minutes: 10 mg haloperidol, 0.5-2 mg lorazepam
iii. No response in another 20 minutes: 10 mg of haloperidol, 0.5-2 mg
lorazepam q 30 minutes until patient is sedated
iv. Once sedated, double time between administration; 50% of haloperidol
dose, stop lorazepam, continue hydromorphone 0.5 mg q 3 hr
7. Trial data28
a. First double-blind, randomized comparison trial of pharmacotherapy for
management of delirium in medically ill AIDS patients evaluated haloperidol,
chlorpromazine, and lorazepam
i. Haloperidol and chlorpromazine were effective in reducing symptoms of
delirium, whereas lorazepam had treatment-limiting side effects and
was terminated early
8|Page
iii. Atypical antipsychotics
1. Differ from typical antipsychotics and one another in receptor binding,
pharmacokinetics, and side effect profile27-32
Table 2. Atypical Antipsychotics
Risperidone
Olanzapine
Quetiapine
Ziprasidone
Receptor Activity
Dopamine
Serotonin
Alpha adrenergic
Histaminic
Muscarinic
Dose
---
--
0.25-0.5 mg po BID
Bioavailability
Tablet, Solution,
ODT: 70%
Time to peak
1 hr
Half-life
Metabolism
3-24 hr
CYP2D6
Comments
Has not been
studied in ICU
patients
Sedation
EPS
NMS
Anticholinergic
Orthostasis
Hyperglycemia
QTc prolongation
++
+++*
+
+
++++
+
+
Dose and Pharmacokinetics
2.5-5 mg po q HS
25-50 mg po BID, increase
5-10 mg IM (subsequent
daily by 50 mg BID
doses 2-4 hrs apart)
Tablet, ODT: 40%
PO: 5-6 hr
IM: 15-45 min
20-70 hr
CYP1A2, CYP2D6
Tablet, solution: 100%
1 hr
7 hr
CYP3A4, CYP2D6
NG/enteral tube: hold tube
40% removed via first
feeds for 30 minutes;
pass metabolism
Start at 25 mg in hepatic
impairment
Adverse Effects
+++
+++
+++*
+
?
+
+++
++
+++
++
+++
++
?
?
10 mg IM every 2 hrs or 20
mg every 4 hrs;
40 mg po every 6 hrs
Capsule: 60%
PO: 5 hr
IM: 60 min
4-10 hr
Aldehyde oxidase, CYP3A4
Absorption doubled with
food;
No active metabolite
++
+
?
+
++
+
+++*
EPS: extrapyramidal symptoms; NMS: neuroleptic malignant syndrome; +:very low; ++:low; +++: moderate; ++++:high; +++++: very high;
?: uncertain; --:minimal or no activity; *Dose dependent
9|Page
CLINICAL EVIDENCE
IX.
Clinical trials in non-critically ill patient populations
i. Sipahimalani et al33
1. Open-label trial of 22 patients found haloperidol (n=11) and olanzapine (n=11) had similar
efficacy
2. Three patients in the haloperidol arm experienced EPS, 2 were excessively sedated, and 1 had
worsened symptoms
3. No side effects reported from patients on olanzapine
ii. Schwartz et al34
1. Retrospective chart review of 22 patients found haloperidol (n=11) and quetiapine (n=11) had
similar efficacy
2. Two patients in haloperidol arm developed EPS
3. Two patients in quetiapine arm experienced mild-to-moderate sedation, 1 of which required
discontinuation
35-36
iii. Hu et al
1. Randomized, placebo-controlled trial of 175 patients found haloperidol (n=72) and olanzapine
(n=74) had a statistically significant decrease in delirium symptoms compared to placebo
2. Efficacy between haloperidol and olanzapine not statistically different
3. Haloperidol arm experienced drowsiness (22.2%), dry mouth (16.7%), and dystonia (31.9%)
4. Olanzapine arm also experienced drowsiness (18.9%), dry mouth (2.7%), and dystonia (2.7%)
b. Clinical trials in mixed ICU and non-ICU patient population
i. Han et al37
1. Randomized double-blind trial of 24 patients found haloperidol (n=12) and risperidone (n=12)
effective in reducing symptoms of delirium
2. One patient in haloperidol arm experienced mild akathisia
c. Summary of findings
i. Atypical antipsychotics appear to be as effective as haloperidol in treatment of delirium in hospitalized
patients
ii. Haloperidol has a higher incidence of adverse events
10 | P a g e
d. Clinical trials with ICU-only populations
Skrobik YK, Bergeron N, Dumont M, et al. Olanzapine vs haloperidol: treating delirium in a critical care setting.
Intensive Care Med. 2004; 30:444-449.
Objective
To compare the safety and estimate the response profile of olanzapine, a second-generation antipsychotic, to
haloperidol in the treatment of delirium in the critical care setting
Design
Prospective, randomized, active-control trial conducted at a single academic hospital in Quebec, Canada
Population
Inclusion
o Ages 18-75 years, admission to medical-surgical ICU for more than 24 hrs, ICDSC ≥4 or clinical
manifestations of delirium as defined by DSM-IV criteria
Exclusion
o Pregnancy, antipsychotic medication within 10 days, GI dysfunction precluding enteral medication,
neurologic status not permitting evaluation, patients in whom haloperidol or olanzapine contraindicated
(Parkinson’s disease, oropharyngeal dysfunction, prolonged QT interval, hepatic or renal dysfunction)
Methods
Patients were randomized on an even/odd basis
o Haloperidol 2.5-5 mg po every 8 hrs (0.5-1 mg po if >60 yrs)
o Olanzapine 5 mg po daily (2.5 mg po if >60 yrs)
Dose titration based on clinical judgment
Treating physicians and nurses were not blinded to study drug
Agitation treated with IV haloperidol at the intensivist’s discretion
Patients screened for delirium 3 times daily over 5 days
Delirium index, Ramsay score, EPS symptom assessment performed daily
Delirium diagnosed using ICDSC (≥4) or clinical symptoms and was confirmed by a physician using DSM-IV criteria
Recorded all adjunct benzodiazepine use and converted to lorazepam equivalents
Outcome
Primary endpoint
o Delirium severity and benzodiazepine use
Secondary endpoints
o Rescue haloperidol, daily dose of antiparkinsonian medication, daily worst Ramsay score, EPS
Statistics
Fisher’s exact and Student’s t test used to compare medical and demographic characteristics
Analysis of variance for repeated measures used for group comparisons on DI severity scores and total
benzodiazepine dose based on a 2x5 mixed model
Sidaks multiple comparisons procedure used for post-hoc time-point comparisons
Results
1009 patients screened, 214 diagnosed with delirium, 103 eligible, informed consent obtained in 80
Baseline characteristics similar with exception of mean age which was higher in olanzapine arm (p=0.05)
Reduction in delirium index seen over time with no difference between therapies
Haloperidol IV rescue therapy was primarily used on the first day and was similar between groups
Daily dose
Number of rescue doses IV haloperidol day 1
Number of rescue doses IV haloperidol days 2-5
Rescue haloperidol dose, mg
Rescue haloperidol dose range, mg
Daily dose of antiparkinsonian medication
Daily worst Ramsay score
Patients experiencing EPS
Haloperidol (n=45)
6.5 mg (1-28 mg)
19
Olanzapine (n=28)
4.54 mg (2.5-13.5)
10
4
2.32 ± 1.32
1-5
0
1-3
1
2.92 ± 1.56
1-5
0
1-3
6
0
Values expressed in means (range)
Conclusions
Strengths
Limitations
Olanzapine is a safe alternative to haloperidol in delirious critical care patients
Delirium diagnosis confirmed by physician using DSM-IV criteria
Efficacy and safety assessed based on standardized scales
Small sample size, no placebo arm, lack of blinding, and extensive exclusion criteria
QT prolongation not assessed
Dose and route of administration not typical of current practices
11 | P a g e
Girard TD, Pandharipande PP, Carson SS, et al. Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: the
MIND randomized, placebo-controlled trial. Crit Care Med. 2010; 38(2):428-437
Objective
To demonstrate the feasibility of a placebo-controlled trial of antipsychotics for delirium in the ICU and test the
hypothesis that antipsychotics would improve days alive without delirium or coma
Design
Randomized, double-blind, placebo-controlled trial across 6 tertiary care medical centers in the US
Population
Inclusion
o Adults age 18 and older, mechanically ventilated in the medical or surgical ICU, who had an abnormal level
of consciousness or were receiving sedative or analgesic medications and CAM-ICU positive for delirium
Exclusion
o Pregnancy, continuous mechanical ventilation >60 hrs before screening, no plan for gastric access within 48
hrs, moribund state and/or withdrawal of life support, admission after drug overdose or suicide attempt,
ongoing outpatient neuroleptic use, allergy to haloperidol or ziprasidone, history of NMS, ongoing seizures,
stroke in the past 2 weeks, high risk for ventricular dysrhymthmias (including treatment with QTc
prolonging medication), previously diagnosed neurologic disease
Methods
Patients randomized in a 1:1:1 ratio to:
o Haloperidol 5 mg po q 12 for 24 hrs, followed by 5 mg po q 6 hrs
o Ziprasidone 40 mg po q 12 for 24 hrs, followed by 40 mg po q 6 hrs
o Placebo
st
Second dose of study medication administered 12 hrs after the 1 if QTc remained <500 msec
Blood levels of enterally administered drug were collected within 48 hrs of administration
Patients without gastric access received IM injection
Additional antipsychotic medications strongly discouraged but allowed for breakthrough delirium and agitation
Delirium evaluated twice daily
Patients not required to have a diagnosis of delirium; could be included if considered high risk for delirium
Therapy de-escalation
o Frequency reduced to every 8 hrs when patients were delirium/coma-free on 2 consecutive assessments
o Reduced to every 12 hrs when patients were delirium/coma-free on 3 consecutive assessments
o Discontinued when patients were delirium/coma-free on 4 consecutive assessments
o Recurrent delirium; study drug restarted or dosing frequency increased to previously effective regimen
o Frequency decreased in a similar manner if over-sedated despite discontinuation of sedatives and
analgesics and restarted upon resolution
Regardless of clinical status all study drugs were discontinued at 14 days
Presence of EPS was assessed daily using a modified Simpson-Angus Scale
o Elbow rigidity, wrist rigidity, glabella tap, tremor, salivation, and dystonia
Subjective akathisia assessed on days when not comatose or delirious using a visual analog scale
Study drug was discontinued:
o During administration of any drug known to prolong the QT interval, EPS, QTc prolongation, NMS, torsades
de pointes, ventricular tachycardia, or dystonia unresponsive to anticholinergic treatment
Outcomes
Primary endpoint
o Number of days patients were alive without delirium or coma
Secondary endpoints
o Daily delirium risk, duration of delirium, duration of coma, ventilator-free days, ICU and hospital length of
stay, all-cause 21-day survival
Statistics
Data analyzed using an intention-to-treat approach
At two-sided significance level of 2.5%, 29 patients in each group would have 80% power to detect a 25%
increase in delirium/coma-free days
Kruskal-Wallis used to compare continuous variables between the 3 treatment groups
Chi-square test to compare categorical variables
Time-to-event analysis used to compare effects of study drugs and placebo on ICU and hospital length of stay
Kaplan-Meier analyses used to determine medians and interquartile ranges
Markov regression model used to determine effect of treatment group on daily delirium risk
12 | P a g e
Results
3297 patients met inclusion criteria, 465 were eligible, 103 were enrolled, 97 completed the trial
Baseline characteristics were similar between groups
Antipsychotic Therapy
Days on drug
Average daily dose, mg
Patients receiving PRN IV haloperidol, n (%)
Total dose, mg
Average daily dose, mg
Patients receiving PRN atypical antipsychotics, n (%)
Haloperidol (n=35)
Ziprasidone (n=30)
Placebo (n=36)
p
7 (4-10)
15 (11-17)
6 (17)
4.5 (2.9-23.8)
4.5 (2.9-12.5)
1 (3)
4 (3-10)
113 (81-140)
9 (30)
10 (5-20)
5.7 (5-10)
2 (7)
5 (3-7)
NA
14 (39)
12.5 (5.5-50.2)
5 (10-11.9)
4 (11)
0.23
NA
0.13
0.30
0.65
0.39
Values expressed as median (interquartile range) unless otherwise specified
Clinical outcomes
o Neither haloperidol nor ziprasidone significantly increased the number of days patients were alive without
delirium or coma compared to placebo
Outcomes
Delirium/coma-free days
Delirium days
Resolution of delirium on study drug (%)
Coma days
Days accurately sedated (%)
Ventilator-free days
Length of stay, days
ICU
Hospital
21-day mortality (%)
Adverse effects (%)
Akathisia
EPS
QTc prolongation > 500 msec
Haloperidol (n=35)
14 (6-18)
4 (2-7)
24 (69)
2 (0-4)
70 (56-83)
7.8 (0-15)
Ziprasidone (n=30)
15 (9-18)
4 (2-8)
23 (77)
2 (0-4)
64 (50-94)
12.0 (0-18.6)
Placebo (n=36)
12.5 (1.2-17.2)
4 (2-6)
21 (58)
2 (0-5)
71 (53-92)
12.5 (0-23.3)
p
0.66
0.93
0.28
0.90
0.91
0.25
11.7 (4.6-15.7)
13.8
4 (11)
9.6 (3.8-14.5)
13.5
4 (13)
7.3 (4.7-12.3)
15.4
6 (17)
0.70
0.68
0.81
10 (29)
4 (11)
2
6 (20)
2 (7)
5
7 (19)
6 (17)
3
0.60
0.46
0.31
Values expressed as median(interquartile range) unless otherwise specified
Conclusions
Strengths
Limitations
Treatment with antipsychotics did not improve the number of days alive without delirium or coma
Randomized, double-blind, placebo-controlled trial
Included standardized assessment
Employed standardized de-escalation schedule
May have been significantly underpowered to demonstrate efficacy of the medications for many outcomes
Ten percent patients did not have a diagnosis of delirium
Baseline illness severity scores were higher
Haloperidol was given po instead of IV as is used in practice
Did not titrate drug to patient response
13 | P a g e
Devlin JW, Roberts RJ, Fong JJ, et al. Efficacy and safety of quetiapine in critically ill patients with delirium: a prospective,
multicenter, randomized, double-blind, placebo-controlled pilot study. Crit Care Med. 2010; 38(2)419-427.
Objective
To compare the efficacy and safety of scheduled quetiapine to placebo for the treatment of delirium in critically ill
patients requiring as-needed haloperidol
Design
Prospective, randomized, double-blind, placebo-controlled trial at 3 academic hospitals in the US and Canada
Population
Inclusion
o Age 18 years or older, admission to medical or surgical ICU, delirium diagnosed by primary care team, order
for as-needed haloperidol, ability to tolerate enteral nutrition
Exclusion
o History of irreversible cognitive dysfunction, primary neurologic condition or injury, history of hepatic
encephalopathy or ESLD, actively withdrawing from alcohol, antipsychotic agent within 30 days, treatment
with dexmedetomidine or a neuromuscular blocker, treatment with an agent that affects quetiapine
concentrations or increases QTc, baseline QTc interval ≥500 msec, pregnancy, non-English speaking,
prognosis considered hopeless
Methods
Patients were randomized in a 1:1 ratio to:
o Quetiapine 50 mg po or NG/enteral tube twice daily (n=18)
o Placebo po or NG/enteral tube twice daily (n=18)
Titrated daily by 50 mg every 12 hrs to 200 mg every 12 hrs based on PRN haloperidol during previous 24 hrs
Allowed IV haloperidol 1-10 mg every 2 hrs on PRN basis
Scheduled IV haloperidol, oral PRN haloperidol, or other antipsychotics not allowed during study period
Delirium assessments conducted at baseline and by bedside nurse every shift for a total of 10 days
ICDSC ≥ 4 diagnostic for delirium
Sedation assessed using the Sedation-Agitation Scale (SAS)
o Deeply sedated defined as SAS ≤2
o Agitation defined as SAS ≥5
o Somnolence was defined as decrease in SAS ≥1, in patients with SAS ≤4, in the absence of sedatives
QTc was measured every 12 hrs
o Prolongation defined as >60 msec increase above baseline or >450 msec for males and >470 for females
Signs of EPS monitored daily and if thought to be present were evaluated by one of the investigators within 1 hr,
then every 12 hrs
Study drug was continued until: patient was deemed to no longer have signs of delirium by attending intensivist,
10 days of therapy, ICU discharge, or medication-induced adverse event
Outcomes
Primary endpoint
o Time to first resolution of delirium
Secondary endpoints
o Total hrs in delirium, total hrs spent deeply sedated or agitated, episodes of subject-initiated device
removal, use of haloperidol, use of sedatives and analgesics, duration of study drug administration, average
daily and maximum study drug dose, length of mechanical ventilation, duration of both ICU and hospital
stay and hospital mortality
Statistics
Data analyzed using an intention-to-treat approach
At a two-sided significance level of 0.05%, 24 patients in each group would have 80% power to detect significant
difference
Kaplan-Meier survival curves were used to compare time to first resolution of symptoms
Mann-Whitney U test used to compare outcomes
Fisher’s exact tests were used for categorical data with rare events
14 | P a g e
Results
256 patients screened, 36 randomized
Baseline characteristics not statistically different
Medication Use Outcomes
Study drug
Daily dose, mg
Maximum daily dose, mg
Haloperidol
Daily dose, mg
Days when ≥ 1 dose administered, %
Sedative
Daily dose in midazolam equivalents, mg
Fentanyl
Daily dose, mcg
Quetiapine (n=18)
Placebo (n=18)
p
110 (88-191)
200 (100-313)
NA
NA
NA
NA
1.9 (0.8-3.8)
44 (40-100)
4.3 (1.2-6.1)
60 (33-80)
0.26
0.7
5.3 (0-42)
26.5 (0.3-74)
0.32
0 (0-65)
170 (0-7)
0.02
Quetiapine (n=18)
1 (0.5-3.0)
Placebo (n=18)
4.5 (2-7)
p
0.001
36 (12-87)
53 (16-67)
22
120 (60-195)
69 (58-100)
44
0.006
0.02
0.29
6 (0-38)
3 (0-22)
36 (11-66)
21 (8-41)
0.02
0.03
0 (0-8)
0 (0-8)
0 (1-2)
0 (0-0)
0.54
0.39
8
17
11 (3-19)
16 (10-22)
24 (11-33)
11
10
22
11 (4-29)
16 (13-32)
26 (17-49)
17
0.79
1.0
0.67
0.28
0.32
1.0
Placebo (n=18)
2 (11)
2 (11)
0
0
34 (44)
8 (28)
p
0.39
0.56
0.79
1.0
0.7
1.0
Values expressed as median(interquartile range) unless otherwise specified
Clinical Outcomes
Time to first resolution of delirium, days
Time in delirium
Hours
Percent
Delirium recurrence, %
Time spent agitated
Hours
Percent
Time spent deeply sedated
Hours
Percent
Subject-initiated device removal
Number of episodes
Number of subjects with episode, %
Duration of mechanical ventilation, days
Duration of ICU stay, days
Duration of hospitalization, days
Hospital mortality, %
Values expressed as median(interquartile range) unless otherwise specified
Percentages are expressed as % of time subject was administered study drug
Safety Outcomes
Study drug-related adverse events, %
Episodes of somnolence, %
Episodes of hypotension, %
Episodes of EPS
Episodes of QTc interval >60 msec above baseline, %
Episodes of QTc interval >500 msec, %
Quetiapine (n=18)
6 (28)
5 (22)
1 (6)
0
20 (39)
8 (22)
All values are expressed as median (interquartile range)
Percentages are expressed as % of time subject was administered study drug
Conclusions
Strengths
Limitations
Quetiapine added to as-needed haloperidol results in faster delirium resolution, and less agitation
Prospective, randomized, double-blind, placebo-controlled trial
Dose was titrated to patient response
Adverse effects evaluated regularly
Extensive exclusion criteria do not represent most ICU patients
Study was only powered to reliably assess the primary outcome
Upon completion of therapy treatment revealed to physician which may have biased future patient treatment
Discontinuation was based on physician discretion and may have been early in some cases
15 | P a g e
X.
Summary of Findings
a. Mortality, cost, hospital stay, and long-term cognitive impairment have been associated with delirium in
the critically ill and this disease should not go without proper assessment and treatment
b. Standardized screening eliminates delay in therapy
c. Randomized, placebo-controlled trials evaluating haloperidol and antipsychotic treatment are possible
d. Large randomized, placebo-controlled trials with a characteristic ICU population are needed for
definitive evidence of efficacy of atypical antipsychotics
e. Based on the available evidence atypical antipsychotics appear to be as effective as haloperidol
XI.
Recommendations
a. Screening for delirium
i. At least daily in all ICU patients using a validated assessment tool such as ICDSC or CAM-ICU
b. Pharmacologic treatment
i. Scheduled atypical antipsychotics
1. Start at lower end of dosage range and titrate based on objective assessment of patient
response
2. Patients older than 65 should receive 50% of usual starting dose
ii. Haloperidol IV should be used for breakthrough agitation and delirium
1. May be used as a measure of need for atypical dose escalation
iii. Special populations
1. Cardiac conduction abnormalities or concurrent QTc prolonging therapy
a. Scheduled atypical antipsychotics
i. Although not studied in these patients, less incidence of QTc
prolongation
ii. Monitor EKGs at baseline and routinely
iii. Discontinue in patients with QTc >500 msec
2. Neurologic deficits
a. Scheduled atypical antipsychotics
i. Although not studied in these patients, less incidence of neurologic
adverse effects
ii. Monitor for signs EPS, akathisias, and NMS
iii. Discontinue in patients experiencing these symptoms
16 | P a g e
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
American Psychiatric Associated Workgroup on Delirium. Practice guideline for the treatment of patients with delirium. 1999
Ely EW, Shintani A, Truman B. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004; 291:17531762.
Milbrandt EB, Deppen S, Harrison PL, et al. Costs associated with delirium in mechanically ventilated patients. Crit Care Med. 2004;32(4): 955-962.
Thomason JW, Shintani A, Peterson JF, et al. Intensive care unit delirium is an independent predictor of longer hospital stay: a prospective analysis of 261
non-ventilated patients. Critical Care. 2005; 9:R375-R381.
Ely EW, Gautam S, Margolin R, et al. The impact of delirium in the intensive care unit on hospital length of stay. Intensive Care Med. 2001;27:1892-1900.
Girard T, Jackson JC, Pandharipande PP, et al. Delirium as a predictor of long-term cognitive impairment in survivors of critical illness. Crit Care Med.
2010;38(7):1513-1520.
Patel RP, Gambrell M, Speroff T, et al. Delirium and sedation in the intensive care unit: survey of behaviors and attitudes of 1384 healthcare professionals.
Crit Care Med. 2009;37(3):825-830.
Jacobi J, Fraser GL, Coursin DB, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med.
2002; 30:119-141
Morandi A, Jackson JC, Ely EW. Delirium in the intensive care unit. Int Rev Psychiatry. 2009; 21(1):43-58.
Girard TD, Pandharipande PP, Ely EW. Delirium in the intensive care unit. Critical Care. 2008;12:S3:1-9.
Rea RS, Battistone S, Fong JJ, et al. Atypical antipsychotics versus haloperidol for treatment of delirium in acutely ill patients. Pharmacotherapy.
2007;27(4)588-594.
Pun BT, Ely EW. The importance of diagnosing and managing ICU delirium. CHEST. 2007; 132(2):624-636.
Peterson JF, Pun BT, Dittus RS, et al. Delirium and its motoric subtypes: a study of 614 critically ill patients. J Am Geriatr Soc. 2006;54:479-484.
Pandharipande P, Cotton BA, Shintani A, et al. Motoric subtypes of delirium in mechanically ventilated surgical and trauma intensive care unit patients.
Intensive Care Med. 2007;33:1726-1731.
Ouimet S, Riker R, Bergeon N, et al. Subsyndromal delirium in the ICU: evidence for a disease spectrum. Intensive Care Med. 2007;1007-1013.
Gunther ML, Morandi A, Ely EW. Pathophysiology of delirium in the intensive care unit. Crit Care Clin. 2008;24:45-65
Ely EW, Girard TD, Shintani AK, et al. Apoliprotein E4 polymorphism as a genetic predisposition to delirium in critically ill patients. Crit Care Med.
2007;35(1):112-117.
Ouimet S, Kavanagh BP, Gottfried SB, et al. Incidence, risk factors, and consequences of ICU delirium. Intensive Care Med. 2007;33:66-73.
Pandiharipande P, Shintani A, Peterson J, et al. Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients.
Anesthesiology; 2006:104:21-26.
van Eijk MMJ, van Marum RJ, Klijn IAM, et al. Comparison of delirium assessment tools in a mixed intensive care unit. Critical Care Med. 2009;37(6):18811885.
Inouye SK, Bogardus ST, Charpenter PA, et al. A multicomponent intervention to prevent delirium in hospitalized older patients. N Eng J Med.
1999;340(9):669-676.
DRUGDEX® System (electronic version), Thomson Reuters (Healthcare) Inc., Greenwood Village, Colorado, USA. Available at: http://www.thomsonhc.com
Accessed October 11, 2010.
Lexi-Comp Online™ *database online+. Hudson, OH: Lexi-Comp, Inc.; 2010. Available at:
http://online.lexi.com.ezproxy.lib.utexas.edu/crlsql/servlet/crlonline. Accessed October 11, 2010.
Adams F. Emergency intravenous sedation of the delirious, medically ill patient. J Clin Psychiatry. 1988;49:12(Suppl):22-27.
Gelfand SB, Indelicato J, Benjamin J. Using intravenous haloperidol to control delirium. Hosp Community Psychiatry. 1992;43(3):215.
Levenson JL. High-dose intravenous haloperidol for agitated delirium following lung transplantation. Pscyhomatics. 1993;36(1):66-68.
Menza MA, Murray GB, Holmes VF. Decreased extrapyramidal symptoms with intravenous haloperidol. [Abstract] J Clin Psychiatry. 1987; 48(7):278-80.
Breibart W, Marotta R, Platt MM, et al. A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized
AIDS patients. Am J Psychiatry. 1996; 153(2):231-237.
Stahl SM. Describing an atypical antipsychotic: receptor binding and its role in pathophysiology. Primary Care Companion J Clin Psychiatry. 2003;5(suppl
3):9-13.
Karan RS, Pandhi P. D2 and 5HT2 Receptors: relevance to antipsychotic drugs. Indian Journal of Pharmacology. 2000;32:187-191.
Markowitz JS, Brown CS, Moore TR. Atypical antipsychotics part I: pharmacology, pharmacokinetics, and efficacy. Ann Pharmacother. 1999; 33:73-85.
Brown CS, Markowitz JS, Moore TR, et al. Atypical antipsychotics part II: adverse effects, drug interactions, and costs. 1999;33:210-217.
Sipahimalani A, Masand PS. Olanzapine in the treatment of delirium. Psychosomatics. 1998; 39(5):422-430.
Schwartz TL, Masand PS. Treatment of delirium with quetiapine. Primary Care Companion J Clin Psychiatry. 2000; 2(1):10-12.
Hu H, Deng W, Yang H. A prospective random control study comparison of olanzapine and haloperidol in senile delirium. [Abstract] Chongging Medical
Journal 2004;8:1234–7.
Lonergan E, Britton AM, Luxenberg J. Antipsychotics for delirium. Cochrane Database of Systematic Reviews. 2007;2:1-15.
Han CS, Kim YK. A double-blind trial of risperidone and haloperidol for the treatment of delirium. Psychosomatics. 2004; 45(4):297-301.
Skrobik YK, Bergeron N, Dumont M, et al. Olanzapine vs haloperidol: treating delirium in a critical care setting. Intensive Care Med. 2004; 30:444-449.
Girard TD, Pandharipande PP, Carson SS, et al. Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: the MIND randomized,
placebo-controlled trial. Crit Care Med. 2010; 38(2):428-437.
Devlin JW, Roberts RJ, Fong JJ, et al. Efficacy and safety of quetiapine in critically ill patients with delirium: a prospective, multicenter, randomized, doubleblind, placebo-controlled pilot study. Crit Care Med. 2010; 38(2):419-427.
icudelirium.org. RASS and CAM-ICU Worksheet. Available at: http://icudelirium.org/index.html. Accessed September 15, 2010.
icudelirium.org. Intensive Care Delirium Screening Checklist. Worksheet. Available at: http://icudelirium.org/index.html. Accessed September 15, 2010.
Positive Aging Resource Center. The Delirium Index. Available at: http://www.positiveaging.org/provider/pdfs/deliriumdi.pdf Accessed October 1, 2010
Asian Intensive Care Research meeting. Sedation scales. Available at:http://www.aic.cuhk.edu.hk/web8/sedation20scale.htm. Accessed October 1, 2010
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Appendix A. Confusion Assessment Method for the Intensive Care Unit (CAM-ICU)41
Step 1: Sedation Assessment
The Richmond Sedation Agitation Scale (RASS)
Score
Term
Description
+4
Combative
Overtly combative, violent, immediate danger to staff
+3
Very agitated
Pulls or removes tube(s) or catheter(s); aggressive
+2
Agitated
Frequent non-purposeful movement, fights ventilator
+1
Restless
Anxious but movements not aggressive vigorous
0
Alert and calm
-1
Drowsy
Not fully alert, but has sustained awakening (eye-opening/eye contact) to voice (≥10 seconds)
-2
Light sedation
Briefly awakens with eye contact to voice (<10 seconds)
-3
Moderate sedation
Movement or eye opening to voice but no eye contact
-4
Deep sedation
No response to voice, but movement or eye opening to physical stimulation
-5
Unarousable
No response to voice or physical stimulation
Step 2: Delirium Assessment
Feature 1: Acute onset or fluctuating course
Positive if you answer “yes” to either 1A or 1B
Positive
Negative
1A: Is the patient different than his/her baseline mental status?
Or
2A: Has the patient had any fluctuation in mental status in the past 24 hours as evidenced by fluctuation on a sedation
scale (e.g. RASS), GCS, or previous delirium assessment?
Yes
No
Feature 2: Inattention
Positive if either score for 2A or 2B is less than 8
Positive
Negative
Attempt the ASE letters first. If the patient is able to perform this test and the score is clear, record this score and
move to Feature 3. If the patient is unable to perform this test or the score is unclear, then perform the ASE Pictures.
If you perform both tests, use the ASE Pictures’ results to score the Feature.
2A: Attention Screening Exam (ASE) Letters: record score (enter NT for not tested)
Score (out of 10):
______
Directions: Say to the patient, “I am going to read you a series of 10 letters. Whenever you hear the letter ‘A’ indicate by
squeezing my hand.” Read the following letters aloud:
SAVEAHAART
Scoring: Errors are counted when a patient fails to squeeze on the letter “A” or when the patient squeezes on a letter other
than “A”.
2B: ASE Pictures: record score (enter NT for not tested)
Feature 3: Disorganized Thinking
Positive if the combined score is less than 4
3A: Yes/No questions
Positive
Alternate between Set A and Set B (Patient earns one point for each correct answer)
Set A
3.
4.
5.
6.
Will a stone float on water?
Are there fish in the sea?
Does 1 pound weigh more than 2 pounds?
Can you use a hammer to pound a nail?
Negative
Combined score (3A
and 3B):_________
Set B
1. Will a leaf float on water?
2. Are there elephants in the sea?
3. Do 2 pounds weigh more than 1 pound?
4. Can you use a hammer to cut wood?
3B: Command
Say to patient: “Hold up this many fingers” (Examiner holds two fingers in front of patient) “Now do the same thing with
the other hand” (Not repeating the number of fingers) *If the patient is unable to move both arms, for the second part of
the command as the patient to “add one finger”.
Feature 4: Altered Level of Consciousness
Positive if the actual RASS score is anything other than zero
Overall CAM-ICU Delirium (Features 1 and 2, and either 3 or 4 indicate a positive score)
Positive
Negative
Positive
Negative
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Appendix B. Intensive Care Delirium Screening Checklist (ICDSC)42
Patient Evaluation
Day 1
Day 2
Day 3
Day 4
Altered level of consciousness
If A or B do not complete patient evaluation for the period
Inattention
Disorientation
Hallucination – delusion – psychosis
Inappropriate speech
Sleep/wake cycle disturbance
Symptom fluctuation
Total Score (0-8)
Scoring System:
This scale is completed based on information collected from each 8-hour shift or from the previous 24 hours. Obvious
manifestation of an item = 1 point; no manifestation of an item or no assessment possible = 0 points. The score of each item is
entered into the corresponding empty box and is 0 or 1.
1.
Altered level of consciousness:
A) No response or B) the need for vigorous stimulation in order to obtain any response signified a severe alteration in
the level of consciousness precluding evaluation. If there is coma (A) or stupor (B) most of the time period then a
dash (-) is entered and there is no further evaluation during that period.
C) Drowsiness or requirement of a mild to moderate stimulation for a response implies an altered level of consciousness
and score 1 point.
D) Wakefulness or sleeping state that could easily be aroused is considered normal and scores no point.
E) Hypervigilance is rated as an abnormal level of consciousness and scores 1 point.
2.
Inattention: Difficulty in following a conversation or instructions. Easily distracted by external stimuli. Difficulty in shifting
focuses. Any of these scores 1 point.
3.
4.
Disorientation: Any obvious mistake in time, place or person scores 1 point.
Hallucination, delusion or psychosis: The unequivocal clinical manifestation of hallucination or of behavior probably due to
hallucination (e.g. trying to catch a non-existent object) or delusion. Gross impairment in reality testing. Any of these
scores 1 point.
5.
Psychomotor agitation or retardation: Hyperactivity requiring the use of additional sedative drugs or restraints in order to
control potential dangerousness (e.g. pulling out IV lines, hitting staff). Hypoactivity or clinically noticeable psychomotor
slowing. Any of these scores 1 point.
Inappropriate speech or mood: Inappropriate, disorganized or incoherent speech. Inappropriate display of emotion
related to events or situation
6.
7.
8.
Sleep/wake cycle disturbance: Sleeping less than 4 hours or waking frequently at night (do not consider wakefulness
initiated by medical staff or loud environment). Sleeping during most of the day. Any of these scores 1 point.
Symptom fluctuation: Fluctuation of the manifestation of any item or symptom over 24 hours (e.g. from one shift to
another) scores 1 point.
19 | P a g e
Appendix C. Delirium Index43
Inattention
Attentive
Generally attentive but makes at least one error spelling “world” backwards
Questions can generally be answered but subject is distractible and at times has difficulty in shifting
attention to new questions or questions may have to be repeated several times
Either unresponsive or totally unable to keep track of or answer questions; great difficulty focusing
Cannot assess
Disorganized Thinking
Responses are logical, coherent and relevant
Responses are vague or unclear
Thought is occasionally illogical, incoherent or irrelevant
Either unresponsive or thought is fragmented, illogical, incoherent, and irrelevant
Cannot assess
Altered Level of Consciousness
Normal
Hypervigilant or hypovigilant
Drowsy/sleepy; responds only to simple loud questions
Unresponsive or comatose
Disorientation
Knows date and name of hospital
Either does not know date or hospital
Either does not know month or year or that he/she is in the hospital
Either unresponsive or does not know name or birth date
Cannot assess
Memory Impairment
Recalls 3 words or details of hospitalization
Either cannot recall 1 of the words or has difficulty recalling details of hospitalization
Either cannot recall 2 of 3 words or recalls very few details of hospitalization
Either unresponsive or cannot recall any of the three words or any details of hospitalization
Cannot assess
Perceptual Disturbances
Unresponsive, no perceptual disturbances observed, cannot assess
Misinterprets stimuli
Occasional non-threatening hallucinations
Frequent, threatening hallucinations
Motor Disturbances
Normal
Responds well to questions but either moves frequently or is lethargic/sluggish
Moves continuously or very slow with little spontaneous movement
Agitated, difficult to control or no voluntary movement
0
1
2
3
9
0
1
2
3
9
0
1
2
3
0
1
2
3
9
0
1
2
3
9
0
1
2
3
0
1
2
3
Appendix D. Sedation-Agitation Scale (SAS)44
Level of Sedation-Agitation
Dangerous agitation
Very agitated
Agitated
Calm and cooperative
Sedated
Very sedated
Unarousable
Response
Pulling at ET tube, thrashing, climbing over bed rails
Does not calm, requires restraints, bites ET tube
Attempts to sit up but calms to verbal instructions
Obeys commands
Difficult to rouse; obeys simple commands
Rouses to stimuli; does not obey commands
Minimal or no response to noxious stimuli
Score
7
6
5
4
3
2
1
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