Download Delirium In The ICU: Prevention And Treatment

Delirium In The ICU: Prevention And Treatment
From data presented at symposia and sessions held during the
Society of Critical Care Medicine’s 33rd (Orlando, FL) and 34th (Phoenix, AZ) Critical Care Congresses
Editorial
1
The Epidemiology & Pathophysiology Of Delirium
2
Diagnostic Tools, Treatment
Options, And Prevention Possibilities
5
Treatment And Prevention Of Delirium In The ICU
9
Costs Of Delirium In ICU Patients
14
Behavioral Effects Of ICU Medications
16
Identifying And Managing
Agitation And Delirium In The ICU
17
Adjuncts To IV Sedative Agents
18
GUEST EDITOR AND MEDICAL REVIEWER
CONTRIBUTING EDITORS
CONTINUING EDUCATION EDITOR
José R. Maldonado, MD, FAPM, FACFE
Gerald A. Maccioli, MD, FCCM
Eva Szabo, MD
Associate Professor of Psychiatry & Behavioral Sciences
Chief, Medical Psychiatry Section
Medical Director, Psychiatry Consultation Service
Faculty, Stanford Center for Biomedical Ethics
Stanford University School of Medicine, Stanford, CA
Director of Critical Care Medicine
Critical Health Systems, Inc.
Raleigh Practice Center
Medical Director, Medical/Surgical ICU
Nutrition Support and Respiratory Therapy
Rex Healthcare, Raleigh, NC
Assistant Professor
Department of Anesthesiology
University of New Mexico School of Medicine
Albuquerque, NM
Richard R. Riker, MD, FCCP
Department of Critical Care
Maine Medical Center, Portland, ME
Joseph F. Dasta, MSc, FCCM
Professor, The Ohio State University
College of Pharmacy, Columbus, OH
School of Pharmacy
Publication of this report was supported by
an unrestricted educational grant from
Hospira Worldwide, Inc.
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chlorpromazine
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fentanyl
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linezolid
lorazepam
midazolam
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propofol
quetiapine
sildenafil citrate
thioridazine hydrochloride
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valproate
voriconazole
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5001757
José R. Maldonado, MD, FAPM, FACFE
Associate Professor of Psychiatry & Behavioral Sciences
Chief, Medical Psychiatry Section
Medical Director, Psychiatry Consultation Service
Faculty, Stanford Center for Biomedical Ethics
Stanford University School of Medicine
Stanford, CA
Editorial
Delirium is the most common psychiatric syndrome found in the
general hospital setting. Its prevalence in certain patient populations is extremely high. Nationwide statistics suggest that delirium
may be found in up to 30% of general postsurgical patients, 25%
to 50% of hospitalized elderly patients, 28% to 63% of orthopedic elderly patients, 30% to 67% of postcardiotomy patients, and
between 30% and 80% of all patients in the ICU setting. Only
about a third of patients exhibiting significant symptoms of delirium are estimated to be adequately identified and treated. Similarly, preexisting cognitive impairment occurs in an estimated 20%
to 30% of medical patients but is recognized in only 13%.
Delirium has a far-reaching impact on patients’ long-term health
and is associated with high health care costs. The development of
delirium increases the risk of mortality, cognitive impairment, and
institutionalization. About 40% of patients with delirium develop
some form of chronic brain syndrome. The cost of delirium, especially when untreated, has been estimated at $28,000 per case.
In addition, a multivariate analysis of costs adjusting for several
variables suggests that delirium results in a 39% increase in ICU
costs and a 31% increase in hospital costs.
The pathophysiological mechanisms that lead to delirium are
poorly understood. Imbalances in several neurotransmitter systems have been implicated, including those involving acetylcholine, dopamine, serotonin, gamma-aminobutyric acid (GABA),
and beta-endorphins. The most compelling evidence seems to
implicate a derangement in neurotransmission caused by central cholinergic deficiency. Other suspects include infectious and
inflammatory processes, alterations in blood flow, and the activity
of receptors devoted to steroids and other substances.
The onset of delirium may be triggered by a number of physiological
processes, including metabolic derangement, infectious processes,
central nervous system pathology, and medication-induced side
effects. Among the reported risk factors for delirium are advanced
age, male gender, illness severity, fever, electrolyte abnormalities,
hypotension, preexisting cognitive and physical impairment, history of stroke, and history of alcohol abuse. In surgical patients,
who seem to have a higher incidence of delirium than medical
patients, additional risk factors include polypharmacy and fluid
and electrolyte imbalance. Medications commonly associated with
the development of delirium include benzodiazepines, narcotics,
and agents with high anticholinergic activity or side effects.
Several diagnostic tools can be used in an effort to identify ICU
patients with delirium. Some require patients to actively cooperate
and others do not. Patient participation is required for the Cognitive
Test for Delirium (DRS) and the Confusion Assessment Method for
the Intensive Care Unit (CAM–ICU), whereas the Delirium Screening Checklist requires little or no patient help.
Recommended strategies for addressing delirium include (1)
treating the reversible factors, such as infectious processes, drug
withdrawal, and medication toxicity, (2) adequately treating pain,
(3) correcting metabolic, nutritional, and endocrine disorders, and,
finally, (4) managing sleep deprivation. When adjunct medical
management is required, haloperidol is the drug used most often
to treat delirium. It may—depending on the syndrome’s etiology (eg,
CNS depressant withdrawal)—be combined with benzodiazepines
(such as lorazepam) to enhance efficacy. When benzodiazepine
agents are required, they should be combined with antipsychotic
medications in a precise ratio to prevent over- or undersedation
and minimize paradoxical disinhibition. The treatment goals are
to (1) control agitation, (2) prevent patients from harming themselves or their caretakers, and (3) restore a normal sleep-wake
cycle. Newer “atypical” antipsychotic agents such as olanzapine
and quetiapine have been used, but as yet no large, placebo-controlled studies have demonstrated their efficacy.
The alpha-2 receptor agonist dexmedetomidine is a relatively
selective agent currently approved for continuous intravenous
sedation in the ICU. Dexmedetomidine appears to promote a
sedative effect that is similar to sleep. Dexmedetomidine does
not depress the respiratory system and causes no extrapyramidal
side effects. Dexmedetomidine use has also been associated with
a decrease in the use of anesthesia and analgesia, a decrease
which by itself may reduce the incidence of delirium. Other benefits of dexmedetomidine include anxiolysis, blood pressure control
without tachycardia, a decreased oxygen demand, and a reduction
in shivering. Recent data indicate that dexmedetomidine may be
effective in treating delirium in ICU cardiac patients. In a new study
of patients undergoing cardiac surgery, subjects were randomized
to 1 of 3 arms of postoperative sedation. Preliminary data on the
first 60 patients showed an incidence of delirium of 5% (1/21) for
patients randomized to the dexmedetomidine arm, compared to
52% (12/23) for those on the propofol arm, and 50% (8/16) for
subjects on the midazolam arm.
At symposia and sessions held during the Society of Critical Care
Medicine’s 33rd Critical Care Congress in Orlando, Florida, and the
34th Critical Care Congress in Phoenix, Arizona, experts shared
information on various aspects of delirium in ICU patients. Their
presentations are summarized in this report.
1
The Epidemiology & Pathophysiology Of Delirium
Gerald A. Maccioli, MD, FCCM
Director of Critical Care Medicine, Critical Health Systems, Inc., Raleigh Practice Center, Medical Director
Medical/Surgical ICU, Nutrition Support and Respiratory Therapy, Rex Healthcare, Raleigh, NC
Epidemiology Of Delirium
Etiology Of Delirium
Delirium among hospitalized patients is common. Before admission, an estimated 10% to 38% of patients already suffer from
some form of delirium (Francis and Kapoor 1990, Levkoff et al
1992). After hospitalization, 25% to 60% of patients may develop
the condition (Francis and Kapoor 1990, Levkoff et al 1992).
Older patients, who have a high baseline risk at the time of hospitalization, have the highest risk of delirium—a reported prevalence
of 15% to 55% among patients aged 70 and older (Schor et al
1992, Johnson et al 1990, Francis et al 1990).
The causes of delirium are multifactorial and include metabolic,
infectious, central nervous system (CNS), and medication-related
adverse events.
Surgical patients have a higher risk for delirium than medical
patients. About 38% to 61% of surgical patients develop delirium
in the perioperative period (Gruber-Baldini et al 2003, Francis et
al 1990). These patients can be further subdivided into general
abdominal surgery patients, who have an incidence of 10% to
15% depending on the number of risk factors present at admission; open-heart surgery patients, who have an incidence of 30%;
and elective and emergent hip-fracture patients, who have an incidence greater than 50% (Gruber-Baldini et al 2003, Francis et al
1990).
Pathophysiology Of Delirium
The pathophysiology of delirium is poorly understood but thought
to result from the actions of multiple neurotransmitters. Delirium
can be considered a nonspecific manifestation of a widespread
reduction in cerebral metabolism and derangement of neurotransmission caused by a cholinergic deficiency. Thus, anticholinergic
activity is probably the most important cause of delirium; indeed,
plasma levels of anticholinergic activity appear to directly correlate with delirium. Dopamine, serotonin, GABA, and beta-endorphin pathways also appear to be involved in the pathophysiology
of delirium. Nonneurotransmitter phenomena—steroid and other
receptor activity, alterations of blood flow, and inflammation—also
have roles to play in the pathophysiology of delerium.
Pathways Involved In The Pathophysiology Of Delirium
•
•
•
•
•
2
Acetylcholine
– Anticholinergic drugs
– Increased serum anticholinergic activity
Dopamine
– Dopamine blockers are used for treatment
Serotonin
– Serotonin syndrome
Gamma Aminobutyric Acid (GABA)
– Hepatic encephalopathy—high glutamine
and glutamate levels
Beta-endorphin
– Glucocorticoids cause reduction in
beta-endorphin levels
– Others—antihistamine
Etiology Of Delirium
Metabolic Etiology
Hypernatremia
Hypercalcemia
Hypo- and hyperglycemia
Hyperosmolar states
Uremia (uremic encephalopathy)
Liver failure (hepatic encephalopathy)
••
••
••
••
•
•
••
••
••
Infectious Etiology
Urinary tract infection
Pneumonia
Sepsis
CNS Etiology
Alcohol withdrawal
(delirium tremens)—very agitated delirium
Barbiturate/benzodiazepine withdrawal (rare)
Postictal states
Increased intracranial pressure
Head trauma
Encephalitis/meningitis
Vasculitis
Medication Etiology
Anticholinergics
(benztropine mesylate, trihexyphenidyl hydrochloride)
Psychotropic medications (chlorpromazine,
thioridazine hydrochloride, tricyclic antidepressant
agents, paroxetine hydrochloride, benzodiazepines)
Lithium toxicity
Steroids
Narcotics
•
•
••
•
In particular, anticholinergic drugs, which are administered to many
surgical patients who undergo general anesthesia, are an important medication-related cause of delirium. This can be particularly
relevant in the elderly, since cholinergic transmission declines with
age. Decreased acetylcholine levels are associated with diminished
ability to perform activities of daily living; as acetylcholine levels
normalize, delirium resolves. Acetylcholine levels can be altered
as a result of many different types of medications in addition to
anticholinergic agents (Table 1). For instance, cimetidine—widely
used, inexpensive, and available over the counter—dramatically
influences anticholinergic levels.
Table 1. Decrease In Acetylcholine Levels With Common Medications
Medication
Furosemide
Digoxin
Theophylline
Prednisolone
Cimetidine
Ranitidine
Opioids
Percentage Decrease In Acetylcholine
0.22
0.25
0.44
0.55
0.86
0.22
0.11
Risk Factors For Delirium
Multiple risk factors contribute to the onset of delirium.
Clinical Risk Factors For Delirium
Age (> 80 years)
Cognitive impairment
25% delirious are demented
40% demented in hospital are delirious
Male gender
Severe illness
Hip fracture
Fever or hypothermia
Hypotension
Malnutrition
••
Polypharmacy (> 3 meds)
Sensory impairment
Psychoactive medications
Use of lines and restraints
Metabolic disorders
Azotemia
Hypo- or hyperglycemia
Hypo- or hypernatremia
Depression
Alcoholism
Pain
••
•
In surgical patients, abdominal aortic aneurysm and noncardiac/
thoracic surgery are additional risk factors for delirium (Francis
and Kapoor 1990, Levkoff et al 1992).
Postoperative delirium is common, and models for predicting risk
have been developed. A study in hospitalized patients by Inoye
and Charpentier (1996) found that independent precipitating fac-
tors for delirium included use of physical restraints, malnutrition,
more than 3 medications administered, bladder catheter use, and
any iatrogenic event. Furthermore, as the number of risk factors
increased, so did the incidence of delirium. On a risk-factor point
scale, delirium risk was 3% for the low-risk group (0 points), 20%
for the intermediate-risk group (1-2 points), and 59% for the highrisk group (> 3 points) (PP < .001).
Marcantonio and colleagues also evaluated a clinical prediction
rule for postoperative delirium using data available to clinicians
preoperatively. Postoperative delirium occurred in 117 (9%) of
the 1341 patients undergoing major elective noncardiac surgery
(Marcantonio et al 1994). Independent correlates included age
70 years or older; self-reported alcohol abuse; poor cognitive
status; poor functional status; markedly abnormal preoperative
serum sodium, potassium, or glucose level; noncardiac thoracic
surgery; and aortic aneurysm surgery. From these 7 preoperative
factors, the researchers developed a simple predictive rule. The
rule stratified patients into groups with low (2%), medium (8%13%), and high (50%) rates of postoperative delirium. Patients
who developed delirium had higher rates of major complications,
longer lengths of hospital stay, and higher rates of discharge to
long-term care or rehabilitative facilities (Figure 1).
The Impact Of Delirium
Figure 1. Long-Term Cognitive Impairment
35%
40%
25%
Recovery
Permanent Cognitive Impairment
Mortality
Delirium has a far-reaching impact on patients’ long-term health
outcomes. One year from the diagnosis of delirium, 40% will have
recovered, but 25% of patients will have permanent cognitive
impairment and 35% will have died (Cole et al 2003). Furthermore, patients that do recover from delirium will have an increased
institutionalization rate and an annual incidence of dementia of
20%. Most importantly, patients who experience delirium during
their hospitalization have a 3- to 5-fold increase in mortality over
those who do not experience delirium, with an increasing mortality risk over time. The mortality rate for hospitalized patients with
delirium is 10% to 26% at baseline, 38% at 1 year, and 51% at
5 years.
In summary, delirium is a common disorder in both medical and
surgical patients but is typically underdiagnosed and undertreated.
There is a need to refine models that predict delirium and to find
ways to minimize the incidence. System-wide efforts should be
made to promptly identify patients with delirium and initiate treatment, avoiding drugs that will exacerbate the condition.
3
Key Points
•
•
•
•
•
The prevalence of delirium among hospitalized patients is high, and is greater among surgical patients than medical patients
Delirium can be thought of as a nonspecific manifestation of a widespread reduction in cerebral metabolism and derangement of neurotransmission due to cholinergic deficiency
Major pathways implicated in the pathophysiology of delirium include those involving acetylcholine, dopamine, serotonin,
GABA, and beta-endorphin. Other pathophysiologic factors include steroid and other receptor activity, alterations of blood
flow, and inflammation
Delirium has many causes, including ones related to metabolism, infection, the CNS, and medications
Delirium has a far-reaching impact on patients’ long-term health outcomes, including increased rates of mortality, cognitive
impairment, and institutionalization
References
Cole M, McCusker J, Dendukuri N, Han L. The prognostic significance of subsyndromal delirium in elderly medical inpatients. J Am Geriatr Soc. 2003 Jun;51(6):754-760.
Francis J, Kapoor WN. Delirium in hospitalized elderly. J Gen Intern Med. 1990 Jan-Feb;5(1):65-79.
Francis J, Martin D, Kapoor WN. A prospective study of delirium in hospitalized elderly. JAMA. 1990 Feb 23;263(8):1097-1101.
Gruber-Baldini AL, Zimmerman S, Morrison RS et al. Cognitive impairment in hip fracture patients: timing of detection and longitudinal follow-up. J Am Geriatr Soc. 2003 Sep;51(9):12271236.
Inouye SK, Charpentier PA. Precipitating factors for delirium in hospitalized elderly persons. Predictive model and interrelationship with baseline vulnerability. JAMA. 1996 Mar 20;275(11):852885.
Johnson JC, Gottlieb GL, Sullivan E, et al. Using DSM-III criteria to diagnose delirium in elderly general medical patients. J Gerontol. 1990 May;45(3):M113-119.
Levkoff SE, Evans DA, Liptzin B, et al. Delirium. The occurrence and persistence of symptoms among elderly hospitalized patients. Arch Intern Med. 1992 Feb;152(2):334-340.
Marcantonio ER, Goldman L, Mangione CM, et al. A clinical prediction rule for delirium after elective noncardiac surgery. JAMA. 1994 Jan 12;271(2):134-139.
Schor JD, Levkoff SE, Lipsitz LA, et al. Risk factors for delirium in hospitalized elderly. JAMA. 1992 Feb 12;267(6):827-831.
4
Diagnostic Tools, Treatment Options, And Prevention Possibilities
Richard R. Riker, MD, FCCP
Department of Critical Care, Maine Medical Center, Portland, ME
Despite the availability of several diagnostic tools for patients
with delirium, the condition remains underrecognized and underdiagnosed. Possible signs of delirium include sudden personality
changes, impaired thinking, or unusual anxiety or depression. A
patient with delirium may suddenly become agitated or uncooperative, or exhibit personality or behavioral changes, impaired
thinking, decreased attention span, or intense, unusual anxiety or
depression.
Delirium should be differentiated from depression and dementia,
which can have similar symptomatology. Delirium that manifests
as inactivity may appear to be depression. Likewise, delirium and
dementia can each cause disorientation and impaired memory,
thinking, and judgment. In elderly patients, dementia may often
present along with delirium, making the differential diagnosis more
difficult. Regular screening of the patient and monitoring of the
symptoms can help in the diagnosis.
Diagnostic tools for delirium in ICU patients can be classified into
those that require patient participation and those that do not.
ity in the similarity of their ratings of the patients via the CAMICU—with kappa statistics of 0.84, 0.79, and 0.95, respectively (P
< .001). Of the 38 patients studied (patients with dementia, psychosis, or neurologic disease were excluded), 33 (87%) developed
delirium as determined by the CAM-ICU; the mean duration of the
delirium was 4.2 ± 1.7 days. Sensitivity was 86% and specificity
77%. As with the CTD, patients were unable to complete the Attention Screening Examination (ASE) a significant proportion of the
time (49%).
The criteria and methods of the CAM-ICU were subsequently
refined, and the test was tailored for use by nonpsychiatrists
(Ely et al 2001a). For a positive diagnosis of delirium with the
revised test, 2 criteria must be present (acute onset of mental
status changes or fluctuation and the presence of inattention as
measured by the ASE) plus 1 of 2 additional criteria (either disorganized thinking or an abnormal level of consciousness, such as
agitation, lethargy, stupor, or coma).
Questions From The CAM-ICU
Tests For Evaluation Of Delirium In ICU Patients
•
•
Disorganized thinking: 2 or more incorrect
Requires Patient Participation
– Cognitive Test for Delirium
– Abbreviated Cognitive Test for Delirium
– CAM-ICU
No Patient Participation Required
– Delirium Screening Checklist
1. Will a stone float on water?
2. Are there fish in the sea?
3. Does 1 pound weigh more than 2 pounds?
4. Can you use a hammer to pound a nail?
Commands
1. Are you having unclear thinking?
2. Can you hold up this many fingers? (2 shown)
Cognitive Test For Delirium
The Cognitive Test For Delirium (CTD) developed by Hart et al
(1996) combines the Diagnostic and Statistical Manual of Mental
Disorders (DSM-III-R) criteria with verbal questioning, Mini-Mental
State Exam, and picture recognition to assess orientation, memory,
vigilance, comprehension, and attention span. The sensitivity of
the test was found to be 100% and the specificity 95%. In followup testing, however, a significant number of patients, 10 out of
43, were unable to complete the CTD. Many of these patients were
visually and hearing impaired, as are many patients seen in the
ICU. In 1997, the test was revised into an abbreviated form, and
key elements of the test were incorporated into the CAM-ICU.
The CAM–ICU
The CAM-ICU also requires patient participation. The test was
developed and evaluated in 2001 in a prospective cohort study of
38 patients who also received the gold standard, psychiatric evaluation (Ely et al 2001b). The patients were drawn from the adult
medical and coronary ICUs of a tertiary-care university-based
medical center. Two critical-care study nurses and an intensivist
who evaluated the patients demonstrated high inter-rater reliabil-
3. Now do it with the other hand (none shown)
Altered Level of Consciousness
Alert
Fully aware of environment, interacts appropriately
NOT Alert
••
••
Vigilant: hyperalert
Lethargic: drowsy but easily aroused, fully aware, and
appropriate with minimal prodding
Stupor: incompletely aware with prodding
Coma: unarousable
The revised CAM-ICU was evaluated in 96 intubated patients in
a prospective cohort study. Patients underwent 471 daily paired
evaluations. Compared with psychiatric evaluation, 2 study nurses
using the CAM-ICU obtained sensitivities of 93% to 100%, specificities of 98% to 100%, and high inter-rater reliability (kappa =
0.96; 95% CI, 0.92-0.99). Visual or auditory deficits were present
in 62% of the population. Despite these deficits, patients were
5
able to complete the visual attention assessment in 70% and the
auditory attention assessment in 73% of the evaluations, making
this instrument more useful than the original test for patients with
delirium.
ICU Delirium Screening Checklist
In studies of the CAM-ICU, patients with coma, psychosis, and
neurologic abnormalities were excluded, resulting in a higher
specificity than might otherwise have been observed. By comparison, a study that looked at the ICU Delirium Screening Checklist
evaluated a more inclusive group of ICU patients (Bergeron et al
2001). The researchers created the screening checklist of 8 items
based on DSM criteria and features of delirium: altered level of
consciousness, inattention, disorientation, hallucination or delusion, psychomotor agitation or retardation, inappropriate mood or
speech, sleep-wake cycle disturbance, and symptom fluctuation.
Nurses assigned 1 point to each symptom they had observed in
the previous 8 hours. A total of 93 patients were evaluated with the
checklist, and the checklist score was compared to a psychiatric
evaluation. Delirium was diagnosed in 15 patients, 14 (93%) of
whom had a score of 4 points or more. A score of 4 or more points
was also present in 15 (19%) patients without delirium, of whom
14 had a known psychiatric illness, dementia, a structural neurological abnormality, or encephalopathy. Sensitivity of the test was
estimated at 99% and specificity was 64%. Thus, the ICU Delirium
Screening Checklist has a high sensitivity, making it an effective
screening tool, especially since it does not require patient participation. The specificity is poor, however, when an unscreened general ICU population is studied.
Recognizing Preexisting Cognitive Impairment
It is important to recognize risk factors for delirium, including the
presence of preexisting cognitive impairment, which occurs in 20%
to 30% of medical patients but is recognized only about half the
time. Pisani and colleagues (2003) interviewed a proxy for each of
183 elderly ICU patients and found that 63 (38%) had preexisting
cognitive impairment, but physicians had diagnosed the condition
in only 29 of these 63 (46%) and in 7 of 102 patients (6.8%) not
identified by the proxy as being impaired. Severe cases were more
often detected than mild cases: 13/23 (57%) with severe impairment compared with 3/12 (12%) with mild impairment and 7/14
(50%) with moderate impairment. Better strategies are needed
to detect preexisting cognitive impairment, especially among the
elderly.
intervention group compared to 15.0% of the usual-care group
(matched odds ratio, 0.60; 95% CI, 0.39-0.92). The total number
of days with delirium (105 vs 161, P = .02) and the total number of episodes (62 vs 90, P = .03) were significantly lower in
the intervention group, but the severity of delirium and recurrence
rates did not differ significantly.
Delirium Treatment Options
The first approach in treating delirium is to address the reversible
factors, such as drug withdrawal or toxicity, pain, metabolic and
endocrine issues, and sleep deprivation (Jacobi et al 2002). Pharmacologic intervention is usually done with haloperidol, but this is
a level C recommendation. Newer antipsychotics, such as olanzapine and quetiapine, have been tested only in small studies.
Haloperidol does not suppress respiratory drive and is largely nonsedating. However, many controversies exist about the proper dosing strategy for haloperidol, including whether a dose-response
ceiling exists at 10 or 20 mg, whether low doses are more effective
than high doses, and whether benzodiazepines are antagonistic or
synergistic. It is generally administered in a 2- to 5-mg intravenous
push, with a doubling of the dose every 30 minutes as necessary.
Continuous infusions are occasionally used.
Studies have shown the efficacy of haloperidol alone and in combination with other drugs. One study in 20 agitated patients found
that the combination of haloperidol and lorazepam was superior to
that of lorazepam alone (Bieniek et al 1998). Another study of 180
alcohol-dependent trauma ICU patients found that hallucinations
and cardiac complications were increased with a flunitrazepamclonidine regimen and pneumonia and prolonged mechanical
ventilation were associated with chlormethiazole-haloperidol treatment. Thus, flunitrazepam-haloperidol may be a preferable combination in patients with cardiac or pulmonary risk factors (Spies et
al 1996).
Alpha-2 Receptor Agonists
Alpha-2 receptor agonists are a class of agents that, unlike most
other sedatives, do not act via the GABA receptor (Figure 2).
Figure 2. Alpha-2 Receptor Activity
Synaptic
Vesicle
Negative
Feedback
Preventing Delirium
Attempts to prevent delirium in patients at risk can be rewarding,
although not all problems can be averted according to a study by
Inouye et al (1999), who evaluated the efficacy of a multicomponent prevention strategy. A total of 852 non-ICU patients 70 years
or older underwent an intervention of standardized protocols for
the management of 6 risk factors for delirium: cognitive impairment, sleep deprivation, immobility, visual impairment, hearing
impairment, and dehydration. Delirium developed in 9.9% of the
6
α² receptor
NOREPINEPHRINE
Alpha²
receptor
Alpha¹ receptor
α² receptor
α¹ receptor
Alpha²
receptor
In the norepinephrine alpha-2 receptor pathway, preformed vesicles of norepinephrine are released across the synapse once the
action potential travels down the nerve. Norepinephrine binds
preferentially at the alpha-2 receptor both at the presynaptic and
postsynaptic locations with great specificity for the alpha-2 receptor (Table 2).
Table 2. Specificity Of Select Alpha-2 Receptor Agonists
Alpha-2 Receptor Agonist
Alpha-2/Alpha-1 Selectivity
Dexmedetomidine
Medetomidine
Clonidine
1600
1200
220
When norepinephrine binds at a presynaptic receptor, negative
feedback inhibits its further release. This sympatholytic effect
blunts the tachycardia and hypertension commonly seen during
times of stress, and alpha-2 receptor binding in the locus coeruleus and dorsal region of the spinal cord results in sleeplike calming and analgesic effects.
The alpha-2 receptor agonist dexmedetomidine allows patient
arousability and has minimal effect on respiratory drive, even at
high doses and with deep sedation. Administration of dexmedetomidine can reduce recall compared to recall before dosing with
this drug. Pharmacokinetic characteristics of dexmedetomidine
are listed below.
Pharmacokinetic Characteristics Of Dexmedetomidine
•
•
•
•
•
Rapid onset of action - short distribution t½
Elimination half life 2 hours
Metabolized by liver - metabolites inactive
Decreased drug clearance with hepatic and cardiac
dysfunction
Onset 5 to 15 minutes, offset 1 hour, return to baseline in 4 hours
Recent clinical studies of dexmedetomidine suggest that it is a
useful sedative in various ICU settings. The USA Cardiac Surgery
Study examined dexmedetomidine-based vs propofol-based sedation regimens for ICU sedation after coronary artery bypass graft
surgery (Herr et al 2003). A total of 295 patients were randomized
to receive 1.0 µg/kg of dexmedetomidine over 20 minutes and
then 0.2 to 0.7 µg/kg/h to maintain a Ramsay sedation score of
3 or more during assisted ventilation and 2 or more after extubation. Patients could be given propofol for additional sedation if
necessary. The remaining patients received propofol-based care
according to each investigator’s standard practice. Only 28% of
the dexmedetomidine patients required morphine for pain relief
while ventilated vs 69% of propofol-based patients (PP < .001).
In addition, the use of nonsteroidal anti-inflammatory analgesics,
beta-blockers, antiemetics, epinephrine, and diuretics was significantly reduced in the dexmedetomidine group.
Similarly, the USA Long-Term ICU Study compared dexmedetomidine with midazolam for long-term infusions for ICU sedation
(Riker et al 2001). The study was an open-label, randomized trial
conducted in 10 centers for patients requiring sedation during
mechanical ventilation lasting 24 hours to 7 days (168 hours).
Dexmedetomidine was administered at a dose of 1 µg/kg loading dose and then at a dose of 0.2-0.7 µg/kg/h. Midazolam was
administered at a dose of 0.01 to 0.05 mg/kg loading dose, followed by 0.02 to 0.1 mg/kg/h. The target sedation range was a
Ramsay score of 2 to 4. The time in the target Ramsay score range
was greater in the dexmedetomidine group vs the midazolam
group, especially after the first 24 hours (91% of time vs 67% of
time for dexmedetomidine vs midazolam). In addition, after extubation, dexmedetomidine patients transferred out of the ICU more
quickly than midazolam patients, although the difference was not
statistically significant (PP < .31).
Dexmedetomidine And Sleep
Activation of noradrenergic pathways via the alpha-2 receptor may
reproduce what happens during sleep. One study by Nelson et al
(2003) evaluated the effects of dexmedetomidine in a rat model
and found that endogenous sleep pathways may be causally
involved in dexmedetomidine-induced sedation. Dexmedetomidine’s sedative mechanism was believed to involve the inhibition
of the locus coeruleus, leading to disinhibition of the ventrolateral
preoptic (VLPO) nucleus firing. The increased release of GABA at
the terminals of the VLPO nucleus then inhibits tuberomammillary
nucleus firing, which is required for the arousal response. As a
result, the investigators concluded that these and other alpha-2
receptor agonists may promote a sedative effect that is more akin
to sleep than agents that act at the GABA receptor.
In conclusion, preexisting cognitive impairments are common
among ICU patients and are rarely identified. In these patients
and in those who develop delirium while in the ICU, several validated scales can be used in diagnosis. Timely diagnosis allows
for earlier treatment, which first involves an attempt to reverse the
factors that may be inducing delirium, such as pain, drug and alcohol withdrawal, metabolic disturbances, and drug toxicity. While
haloperidol remains the drug most often recommended to treat
delirium, it is associated with many side effects. Alpha-2 receptor
agonists, such as dexmedetomidine and clonidine, reduce analgesic and GABA-sedative requirements, preserve respiratory drive,
activate sleep-like pathways, and may represent a novel alternative
for the prevention of delirium.
7
Key Points
•
•
•
•
•
•
Diagnostic tools for delirium in ICU patients can be classified into those that require patient participation and those that do
not
Tests that require patient participation include the Cognitive Test for Delirium and the follow-up form, the abbreviated Cognitive Test for Delirium. The third test is the Confusion Assessment Method for the Intensive Care Unit (CAM–ICU). In contrast,
the Delirium Screening Checklist does not involve patient participation
Preexisting cognitive impairment occurs in an estimated 20% to 30% of medical patients, but it is recognized in only 13% of
patients. Attempting to prevent delirium in patients with risk factors for it may be a useful approach in the effort to influence
outcomes
Recommended strategies for the treatment of delirium include first treating reversible factors such as drug withdrawal, toxicity, pain, metabolic and endocrine issues, and sleep deprivation
Haloperidol is the most widely used treatment for delirium, but has drawbacks. Newer antipsychotics, such as olanzapine and
quetiapine, have been tested in small studies only
Alpha-2 receptor agonists include clonidine and dexmedetomidine, and may allow for arousability and promote a sedative
effect that is more akin to sleep than agents that act at the GABA receptor
References
Bergeron N, Dubois MJ, Dumont M, Dial S, Skrobik Y. Intensive Care Delirium Screening Checklist: evaluation of a new screening tool. Intensive Care Med. 2001 May;27(5):859-64.
Bieniek SA, Ownby RL, Penalver A, Dominguez RA. A double-blind study of lorazepam versus the combination of haloperidol and lorazepam in managing agitation. Pharmacotherapy. 1998 JanFeb;18(1):57-62.
Ely EW, Inouye SK, Bernard GR, et al. Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA. 2001a
Dec 5;286(21):2703-2710.
Ely EW, Margolin R, Francis J, et al. Evaluation of delirium in critically ill patients: validation of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Crit Care Med. 2001b
Jul;29(7):1370-1379.
Hart RP, Levenson JL, Sessler CN, Best AM, Schwartz SM, Rutherford LE. Validation of a cognitive test for delirium in medical ICU patients. Psychosomatics. 1996 Nov-Dec;37(6):533-546.
Herr DL, Sum-Ping ST, England M. ICU sedation after coronary artery bypass graft surgery: dexmedetomidine-based versus propofol-based sedation regimens. J Cardiothorac Vasc Anesth. 2003
Oct;17(5):576-584.
Inouye SK, Bogardus ST Jr, Charpentier PA, et al. A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med. 1999 Mar 4;340(9):669-676.
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 Jan;30(1):119-141.
Pisani MA, Redlich C, McNicoll L, Ely EW, Inouye SK. Underrecognition of preexisting cognitive impairment by physicians in older ICU patients. Chest. 2003 Dec;124(6):2267-2274
Nelson LE, Lu J, Guo T, Saper CB, Franks NP, Maze M. The alpha2-adrenoceptor agonist dexmedetomidine converges on an endogenous sleep-promoting pathway to exert its sedative effects.
Anesthesiology. 2003 Feb;98(2):428-436.
Riker et al. Long-Term Dexmedetomidine Infusions for ICU Sedation: A Pilot Study. ASA Annual Meeting Abstracts. Anesthesiology. 2001;95:A383.
Spies CD, Dubisz N, Neumann T et al. Therapy of alcohol withdrawal syndrome in intensive care unit patients following trauma: results of a prospective, randomized trial. Crit Care Med. 1996
Mar;24(3):414-422.
8
Treatment And Prevention Of Delirium In The ICU
José R. Maldonado, MD, FAPM, FACFE
Associate Professor of Psychiatry & Behavioral Sciences, Chief, Medical Psychiatry Section, Medical Director,
Psychiatry Consultation Service, Faculty, Stanford Center for Biomedical Ethics, Stanford University School of Medicine, Stanford, CA
The incidence of delirium in the subacute medical-surgical ward
was found to be 14% in one retrospective chart review (Maldonado
and Wise 2003). In addition, only about a third of patients exhibiting significant symptoms of delirium were adequately identified or
treated. The average delirious patient remained hospitalized nearly
10 days longer (ie, twice the length of hospital stay) than nondelirious patients suffering from similar medical problems.
The study also found a high economic cost for delirium, especially
for untreated cases; the total average cost for nontreated delirious patients during the index period was $28,000 extra per case
compared to similar nondelirious patients, or $980,000 for the 35
delirious patients in the study over a 2-month period. This translated to nearly $15.5 million per year when the computation was
made for all such cases in the hospital.
Treatment Of Delirium And Outcome
Haloperidol remains the best medication for the treatment of agitated delirium, either alone or in combination with lorazepam. Maldonado et al (2003a) conducted a prospective study evaluating
the efficacy of haloperidol combined in an appropriate ratio with
lorazepam and found benefits for this approach and also identified disparities in the diagnosis and treatment of delirium in the
hospital. A total of 225 ICU patients were studied over a 6-month
period until they were discharged from the hospital or died. Of the
225 patients admitted to the ICU, 41 (18%) were identified as
delirious. Patients’ average age was 68 years; 129 were surgical
and 96 were medical patients. Delirium was accurately diagnosed
by the surgical or medical staff only about half the time. In fact, a
total of 30% of patients suffering from delirium were misdiagnosed
as being anxious or depressed by the primary team. On average,
surgical teams consulted the psychiatry service 2.8 days after the
onset of delirium symptoms, while medical services waited 4.2
days.
The pharmacological management of the patients varied significantly among the surgical, medical, and psychiatric services. Medical and surgical services managed delirious patients with varying
combinations of medications, including opiates, benzodiazepines,
propofol, and neuroleptics, usually on an as-needed basis. In contrast, the psychiatry service used flexible doses of haloperidol and
lorazepam, usually in dosing regimens adjusted on 24-hour intervals and maintained a haloperidol:lorazepam ratio of at least 2:1
(the H2A protocol). The results of the study suggest that the use of
the H2A protocol shortened the length of stay; the average length
of stay using the medical-surgical approach to treating delirium vs
the psychiatry service protocol was 15 vs 11 days (Figure 3).
Figure 3. Average Length Of Stay (Days)
15
15
12
11
9
Days
Delirium is the most common psychiatric syndrome found in the
general hospital setting and its presence has broad and long-lasting effects on morbidity, mortality, and hospital costs. Ely et al
(2001) conducted a study of patients admitted to the ICU, 50%
of whom were receiving mechanical ventilation, and found that
81.3% of the patients developed delirium. As expected, the duration of delirium was associated with length of stay in the ICU (r
= 0.65, P = .0001) and in the hospital (r = 0.68, P < .0001).
Multivariate analysis demonstrated that delirium was the strongest
predictor of length of stay in the hospital (PP = .006), even after
adjusting for severity of illness, age, gender, race, and days of benzodiazepine and narcotic drug administration. Newman and colleagues (2001) demonstrated that patients who were cognitively
impaired at the time of discharge continued to experience cognitive decline for months and years later. According to the report, the
incidence of cognitive decline was 53% at discharge, 36% at 6
weeks, 24% at 6 months, and 42% at 5 years. Furthermore, cognitive function at discharge was a significant predictor of long-term
function (PP < .001).
6
3
0
Med/Surg
Psychiatry
Similarly, the total duration of delirium was 13 vs 6 days, and the
percentage of time delirious was 86% vs 58% in the medicalsurgical services vs the psychiatry service, respectively. Rapid and
dramatic improvements in cognitive functioning, as assessed using
9
Delirium Rating Scale (DRS) scores, were observed in patients
treated with the H2A protocol (Figure 4).
Figure 4. Cognitive Functioning Over Time By Delirium Treatment Protocol (Psychiatry, Blue Vs Med/Surg, Light Blue)
DRS Score
(above 10 suggests delirium)
25
Similar results have been described by Sipahimalani et al (1998)
using olanzapine. They followed 11 patients with delirium, using
an average dose of 5 to 12 mg/d with a reported effectiveness >
50%. Finally, Schwartz and Masand (2000) reported on 11 delirious subjects treated with quetiapine at an average dose of 200
mg/d and a reported effectiveness > 50%. There are no reports on
the use of ziprasidone for the treatment of delirium.
20
15
10
5
0
1
2
3
4
5
6
7
8
9
10
11
12
13 14 15
Hospital Day
In addition, the complete resolution of delirium at the time of discharge home was 14% in the medical-surgical group vs 90% in
the psychiatry group.
The study indicated that haloperidol combined in an appropriate
ratio with lorazepam was effective for the treatment of delirium.
However, lorazepam is not recommended for routine use in delirium and, when it is employed, the lowest dose should be administered. The H2A protocol implies that the dose of lorazepam should
never exceed half the haloperidol dose.
While the H2A protocol is intended to treat delirium, it is also
designed to minimize over- or undersedation. Even at optimal doses,
haloperidol poses some risk for significant adverse side effects
(eg, extrapyramidal symptoms, akathisia, neuroleptic malignant
syndrome, torsades de pointes) or dose-dependent oversedation.
There has clearly been a need for medications that may more safely
achieve tranquilization-sedation and potentially prevent delirium,
and the alpha-2 agonists help to accomplish these goals.
Due to the stigma and potential side effects associated with typical antipsychotic agents (eg, haloperidol), atypical agents have
been used recently in the management of all psychiatric symptoms
associated with agitation and psychosis, including delirium. Large
studies, particularly head-to-head comparisons between atypical
agents and haloperidol, are lacking. A study by Bender et al (2004)
suggested that atypical agents may have a greater incidence of
adverse effects than typical agents, excluding extrapyramidal symptoms (EPS). There is also evidence that some atypical agents (eg,
clozapine, olanzapine) may aggravate or cause delirium, probably
due to their anticholinergic potential (Bender et al 2004). Results
on most atypical agents are limited to small case reports.
Horikawa et al (2003) reported on the use of risperidone in 10
patients with delirium. The average dose of risperidone was 0.5 to
2 mg/d. The reported effectiveness of risperidone was 80%. Side
effects included sedation in 30% and EPS in 10% of subjects.
Mittal et al (2004), using a mean daily dose of 0.75 mg, also
reported similar results using risperidone in another 10 subjects
10
suffering from delirium. The largest risperidone study was reported
by Parellada et al (2004). They recruited 64 delirious patients and
started them all on risperidone at the time of diagnosis. There was
no comparison group. They reported improvements on all measures
(ie, DRS, CGI, and the Foldstein Mini-Mental Status Examination
[MMSE]) after 7 days of treatment.
The only published randomized study (Han and Kim 2004) looked
at 28 patients with delirium who were randomly assigned to receive
a flexible-dose regimen of haloperidol or risperidone over a 7-day
treatment period. The severity of delirium was assessed by using
MMSE scores. The authors found no significant difference in the
efficacy or response rate between haloperidol and risperidone in
the treatment of delirium. In addition, there was no significant difference in the frequency of response to the drugs between the 2
groups. Similarly, there were no clinically significant side effect differences between treatment groups.
The use of antipsychotic agents addresses the theory of dopamine
excess associated with delirium. Even though benzodiazepines are
commonly used as adjunct therapy in the treatment of delirium,
there is reason to believe that their use may aggravate or perpetuate delirium, as they all have some anticholinergic load. Similarly,
benzodiazepines can cause disinhibition at the lower doses usually
given for “sundowning” or elderly patients.
Therefore, clinicians have continued to search for other pharmacological alternatives for the treatment of delirium. The logic behind
the potential use of alpha-2 agonist agents became apparent
when it was observed that many patients who “fail” on the H2A
protocol become “responders” when alpha-2 agonists are added
to the combination. Alpha-2 agonists exert anxiolysis and sedation
without significant respiratory depression, with a diminished need
for anesthesia and analgesia. They also provide blood pressure
control without significant tachycardia, with a decreased oxygen
demand, and with a reduction in shivering. The achievement of
sedation without the use of benzodiazepines is another attractive
feature of these drugs, given the high correlation between benzodiazepines and delirium. Alpha-2 agonists used in clinical practice
include clonidine, dexmedetomidine, and mivazerol.
A recent meta-analysis (Wijeysundera et al 2003) found that
alpha-2 agonists may reduce mortality and myocardial infarction
following vascular surgery. The study reviewed 23 randomized trials
comparing preoperative, intraoperative, or postoperative administration of clonidine, dexmedetomidine, or mivazerol vs controls.
During cardiac surgery, the use of alpha-2 agonists was associated
with reduced ischemia (RR = 0.71; 95% CI, 0.54-0.92; P = .01),
with trends toward lower mortality (RR = 0.49; 95% CI, 0.12-1.98;
P = .3) and a reduced risk of myocardial infarction (RR = 0.83;
95% CI, 0.35-1.96; P = .7).
Dexmedetomidine In Postcardiotomy Patients
The new, highly selective alpha-2 agonist dexmedetomidine has
demonstrated clinical efficacy in the ICU setting. It appears to
eliminate or reduce opiate requirements and lessen hypertension
and tachycardia without causing respiratory depression. In addition, patients receiving dexmedetomidine are uniquely arousable
and responsive. Recent studies suggest there are benefits in using
dexmedetomidine in cardiac surgery patients, up to 80% of whom
may experience postoperative delirium (van der Mast and Roest
1996, Smith and Dimsdale 1989). A prospective, randomized
trial by Maldonado et al (2003b) evaluated dexmedetomidine in
patients undergoing elective cardiac surgery, including mitral valve
repair or replacement, aortic valve repair or replacement, ascending aortic replacements with aortic valve preservation, and aortic
aneurysm repair. All participants underwent a battery of neuropsychiatric tests before surgery. In addition, each patient received a
similar combination of inhalation agents, intravenous sedatives,
and opioids according to a cardiac anesthesia protocol.
Patients were randomized to receive 1 of 3 postoperative sedation
protocols: dexmedetomidine (loading dose 0.4 µg/kg, followed
by 0.2-0.7 µg/kg/h), propofol (25-50 µg/kg/min), or fentanylmidazolam (50-150 µg/h and 0.5-2 mg/h, respectively). In all
cases, sedation protocols were started intraoperatively at the time
of sternal closure. Patients were followed for the development of
delirium using DSM-IV-TR criteria and the Delirium Rating Scale
and neurocognitive deficits using the Foldstein Mini-Mental Status
Examination (MMSE) and the Trail Making A & B test.
Table 3. Mean ± One Standard Error Of The Mean For Selected
Demographic And Surgical Variables By Postoperative Sedation
Group.
Dexmedetomidine
(n = 21)
Although the study was not powered to detect a statistical difference in length-of-stay variables, patients receiving dexmedetomidine appeared to spend less time in the ICU and to have a
shorter average hospital stay than patients receiving propofol or
midazolam (Table 4). In addition, the use of pain medication was
similar between the dexmedetomidine and the propofol groups and
was significantly lower than that of the midazolam group. This suggests that the difference in the observed “delirium-sparing” effect
of dexmedetomidine was not caused by the previously reported
decrease in opioid consumption, but more likely was the result of
some inherent characteristic of the medication. Finally, no difference in the use of antinausea medication was observed among the
3 treatment groups.
Midazolam
(n = 15)
Demographics
Age
56.4 ± 16.9
57.3 ± 18.5
58.2 ± 16.9
Sex (male)
14/21 (67%)
15/23 (65%)
8/16 (50%)
ASA score
3.4 ± 0.5
3.5 ± 0.5
3.6 ± 0.5
MMSE†
29.5 ± 0.9
29.2 ± 0.9
29.2 ± 0.9
Clamp time
112.9 ± 46.7
117.5 ± 40.7
103.1 ± 34.5
Bypass time
160.3 ± 68.3
161.5 ± 58.2
143.0 ± 46.3
*
Surgical Variables
Lowest temp (˚C)
28.8 ± 1.7
28.7 ± 1.6
29.8 ± 3.1
Anesthesia time
405.4 ± 118.9
424.5 ± 96.0
410.8 ± 98.1
Surgery time
300.2 ± 113.4
308.1 ± 103.7
308.7 ± 101.4
ASA score, developed by the American Society of Anesthesiologists, assigns a
preoperative risk score based on the presence of comorbidities at the time of
surgery (0-5).
*
Mini-Mental Status Exam (MMSE) is a cognitive function assessment scored
from 0 to 30. A normal score is 24 or higher.
†
Figure 5. Incidence (%) Of Delirium By Postoperative Sedation
Group
60
**
Demographic and baseline measures were similar among treatment groups. The authors reported on the first 60 patients in
the study, 37 of whom (62%) were male and 23 (38%) female.
Patients’ average age was 57 (Table 3).
The patients all had an MMSE score greater than 29 upon enrollment. A total of 21 subjects (35%) developed delirium in the first
3 postoperative days, including only 1/21 (5%) receiving dexmedetomidine vs 12/23 (52%) receiving propofol and 8/16 (50%)
given midazolam (Figure 5). These numbers are consistent with
national averages for these types of surgical cases.
Propofol
(n = 23)
50
*
40
30
%
20
10
0
Dexmedetomidine
Propofol
Midazolam
*Statistically significant at P < .05 adjusted for multiple comparisons.
**Statistically significant at P < .01 adjusted for multiple comparisons.
11
Table 4. Mean ± One Standard Error Of Measured Outcome
Variables
Dexmedetomidine
(n = 21)
Propofol
(n = 23)
Midazolam
(n = 15)
1/21 (5%)
12/23 (52%)‡
8/16 (50%)**
2.0
2.5 ± 2.9
5.9 ± 6.8
0.09 ± .42
1.3 ± 2.4
2.7 ± 5.4
Total hospital
7.5 ± 2.5
9.7 ± 8.4
8.5 ± 4.9
ICU
2.1 ± 1.2
2.8 ± 2.1
3.2 ± 4.3
Incubation (hours)
13.4 ± 6.5
12.2 ± 8.3
15.7 ± 15.7
Fentanyl (µg)
414 ± 512
373 ± 402
984 ± 758**
Oxycodone (5 mg)
6.3 ± 4.6
6.0 ± 4.9
6.5 ± 5.0
Hydrocodone (5
mg)
3.5 ± 3.8
2.2 ± 3.9
0.9 ± 1.5
Total morphine Eq
59.9 ± 53.5
53.3 ± 43.8
113.9 ± 78.4**
Antinausea (mg)
16.2 ± 19.3
16.1 ± 23.2
20.5 ± 24.3
Delirium
% Delirious
Length of delirium
# Days delirious
Length of Stay (days)
In this study, the type of postoperative sedation appeared to be
the most important predictor of delirium, even after adjusting for
age, sex, and ASA risk score. The absolute risk reduction in the
dexmedetomidine group was 47%, suggesting that only 2 patients
would need to be treated with dexmedetomidine to prevent 1 additional case of postoperative delirium.
The “delirium-sparing” effects may be attributed to dexmedetomidine’s specific and unique pharmacological profile, including its
action on a single receptor type, promotion of a physiologic sleepwake cycle, absence of anticholinergic side effects, and potential
neuroprotective properties. Future studies of dexmedetomidine
and other alpha-2 agonists are needed to elucidate their role in
preventing postoperative delirium.
PPN Medications*
†
Total over first 3 postoperative days
Combination of medications taken for nausea, Anzemet and Phenergan (mg)
**
Versus dexmedetomidine, P < .05, adjusted for comparing multiple group
means
‡
Versus Dexmedetomidine, P < .01, adjusted for comparing multiple group
means.
*
†
Key Points
•
•
•
•
•
•
•
12
Delirium is the most common psychiatric syndrome found in the general hospital setting but only about a third of patients
exhibiting significant symptoms of delirium are adequately identified
The effects of delirium may be broad and long-lasting. Failure to recognize delirium may lead to increased morbidity and
mortality and prolonged hospital stays. About 40% of delirium patients develop some form of chronic brain syndrome
Haloperidol remains the best medication for the treatment of agitated delirium, either by itself or combined in an appropriate
ratio with lorazepam. The combination should be administered in a precisely calibrated ratio in order to avoid over- or undersedation
Unlike other standard sedative and tranquilizing agents, alpha-2 agonists allow for effective sedation, anxiolysis, tranquilization, and management of agitation without causing significant respiratory depression
Dexmedetomidine is associated with lower requirements of other anesthesic and analgesic agents, control of blood pressure
without producing tachycardia, and reductions in oxygen demand and shivering
Nationwide, between 50% and 80% of cardiac surgery patients may experience postoperative delirium
Recent data indicate that dexmedetomidine may be effective in treating delirium in ICU cardiac patients. In preliminary studies of patients undergoing cardiac anesthesia, postoperative delirium developed in 50% of patients randomized to propofol
or midazolam compared with only 5% receiving dexmedetomidine
References
Bender S, Grohmann R, Engel RR, Degner D, Dittmann-Balcar A, Ruther E. Severe adverse drug reactions in psychiatric inpatients treated with neuroleptics. Pharmacopsychiatry. 2004 Mar;37
Suppl 1:S46-53.
Ely EW, Gautam S, Margolin, et al. The impact of delirium in the intensive care unit on hospital length of stay. Intensive Care Med. 2001 Dec;27(12):1892-900.
Han CS, Kim YK. A double-blind trial of risperidone and haloperidol for the treatment of delirium. Psychosomatics. 2004 Jul-Aug;45(4):297-301.
Horikawa N, Yamazaki T, Miyamoto K, et al. Treatment for delirium with risperidone: results of a prospective open trial with 10 patients. Gen Hosp Psychiatry. 2003 Jul-Aug;25(4):289-92.
Maldonado JR, Dhami N, Wise L. Clinical implications of the recognition and management of delirium and in general medical wards. Psychosomatics. 2003a;44[2]:157-158.
Maldonado JR, van der Starre PJ, Wysong A. Post-Operative Sedation and the Incidence of ICU Delirium in Cardiac Surgery Patients. ASA Annual Meeting Abstracts. Anesthesiology. 2003b;99:
A465.
Maldonado JR, Wise L. Clinical and Financial Implications of Timely Recognition and Management of Delirium in the Acute Medical Wards. J Psychosom Res. 2003;55:151.
Mittal D, Jimerson NA, Neely EP, et al. Risperidone in the treatment of delirium: results from a prospective open-label trial. J Clin Psychiatry. 2004 May;65(5):662-667.
Newman MF, Kirchner JL, Phillips-Bute B, et al. Longitudinal assessment of neurocognitive function after coronary-artery bypass surgery. N Engl J Med. 2001 Feb 8;344(6):395-402.
Parellada E, Baeza I, de Pablo J, Martinez G. Risperidone in the treatment of patients with delirium. J Clin Psychiatry. 2004 Mar;65(3):348-53.
Schwartz TL, Masand PS. Treatment of Delirium With Quetiapine. Prim Care Companion J Clin Psychiatry. 2000 Feb;2(1):10-12.
Sipahimalani A, Masand PS. Olanzapine in the treatment of delirium. Psychosomatics. 1998 Sep-Oct;39(5):422-30.
Smith LW, Dimsdale JE. Postcardiotomy delirium: conclusions after 25 years? Am J Psychiatry. Apr 1989;146(4):452-458.
van der Mast RC, Roest FH. Delirium after cardiac surgery: a critical review. J Psychosom Res. Jul 1996;41(1):13-130.
Wijeysundera DN, Naik JS, Beattie WS. Alpha-2 adrenergic agonists to prevent perioperative cardiovascular complications: a meta-analysis. Am J Med. 2003 Jun 15;114(9):742-752.
13
Costs Of Delirium In ICU Patients
Joseph F. Dasta, MSc, FCCM
Professor, The Ohio State University, College of Pharmacy, Columbus, OH
The ICU consumes enormous resources in the hospital, contributing to approximately 33% of inpatient costs, yet the ICU contains
fewer than 10% of hospital beds. The cost of the average patient’s
ICU stay in one study was $19,725; however, this value will vary
according to type of illness, complications, and length of stay.
Some of the well-documented illnesses associated with higher ICU
costs include acute renal failure; decompensated congestive heart
failure; infectious conditions, such as sepsis and ventilator-associated pneumonia; and thrombosis (Dasta et al 2005).
Length of stay is considered the major driver of the increased costs
of ICU care. One large database whose information relates to 250
hospitals revealed that the average cost per day in the ICU after
the third day was $3500, a figure that remained relatively constant
over the course of the ICU stay (Table 5; Roberts et al 2003).
Table 5. Breakdown Of ICU Costs Per Day
Variable
Trauma ICU
Surgical ICU
Medical ICU
Mechanical ventilation
Average Cost Per Day ($)
3700
3600
3000
1522*
*Incremental cost
Drugs administered in the ICU are a substantial component of the
cost of care. One academic medical center study found that the
drugs given in the ICU accounted for 38% of total drug costs and
increased in cost 12% per year compared to an only 6% yearly
increase in non-ICU drug costs (Weber et al 2003). However, when
assessing the costs of pharmacotherapy, one must consider more
than just the acquisition price of a drug. An effective drug therapy,
even if expensive, can minimize the development of the disease,
reduce the stay in the ICU or the duration of mechanical ventilation
in ICU patients, and be a cost-effective approach to patient care
(Chalfin 2001).
The Cost Of Delirium In ICU Patients
The cost of managing agitated ICU patients is not well characterized. In a study of mechanically ventilated medical ICU patients,
Woods and colleagues (2004) recently identified, over a 5-month
period, those who were severely agitated (totaling 16% of the population) and noted that they averaged a 7-day-longer confinement
in the ICU than nonagitated patients. Assuming an average medical ICU cost of $3000/day, the severely agitated patients would
generate an increased cost of $21,000 per patient.
It has been estimated that delirium occurs in over 2.3 million older
hospitalized patients, culminating in 17 million hospital days at a
cost of over $4 billion (1994 dollars) per year (Ely et al 2001).
Patients developing delirium have longer lengths of hospital stay,
higher mortality rates, and a greater likelihood of being discharged
14
to a nursing home (Franco et al 2001). Out of 500 patients undergoing elective surgery, 11% experienced postoperative delirium,
and for those patients, total direct and indirect costs and pharmacy costs were higher compared to those of patients who did not
develop delirium (Franco et al 2001).
Delirium in ICU patients is increasingly recognized as a major public health problem, yet not enough is being done about it. According to a recent survey, most ICU clinicians believe delirium to be a
common and significant problem in critical care, but only 40% routinely screen for the condition. Of the respondents, 66% reported
using the standard-of-care, haloperidol, to treat delirium, but 12%
reported using lorazepam, although benzodiazepines are believed
to cause or exacerbate delirium (Ely et al 2004b). Identification
of delirium and appropriate treatment, therefore, are both areas
of concern.
Delirium appears to be an independent predictor of higher mortality and longer hospital stay. In a study of 224 mechanically ventilated medical ICU patients, 82% developed delirium, which was
associated with multiple negative outcomes (Ely et al 2004a).
Delirious patients had a 10-day increase in median length of stay
and a 2-fold increased risk of remaining hospitalized. In fact, each
day spent in the ICU with delirium resulted in a 20% increased
risk of remaining hospitalized. Moreover, patients with ICU delirium
were 9 times more likely to be discharged with cognitive impairment. Most importantly, delirium was associated with increased
mortality 6 months after discharge: 34% vs 15%. Although daily
and cumulative doses of propofol, morphine, and fentanyl were
higher in the delirium patients, only lorazepam doses were statistically different.
Milbrandt et al (2004) also recently found associations between
delirium in the ICU, increased length of stay, and higher costs. In
their study, delirium was diagnosed in 82% of patients admitted
to medical and coronary ICUs at an academic medical center.
These patients had longer ICU stays (median 8 vs 5 days) and
hospital lengths of stay (21 vs 11 days) than those who did not
develop delirium and incurred an average ICU cost of $22,346
compared to $13,332 for patients without delirium—a difference
of over $9000. Hospital costs averaged $41,836 and $27,106,
respectively—nearly a $15,000 difference.
Higher costs in delirium patients have also been observed in subcategories of expenditures such as pharmacy, laboratory, and bed
expenses. For example, in the study by Milbrandt et al, the increase
in pharmacy costs averaged $1652 for delirium patients although
the average cost per day was similar in the 2 patient groups, suggesting that length of stay in the ICU was the primary cost driver
in these patients.
Both hospital and ICU costs appear to increase linearly as the
severity of delirium increases (Milbrandt et al 2004). Multivariate
analysis of costs adjusted for several variables found delirium to be
associated with a 39% increase in ICU costs and a 31% increase
in hospital costs. If these data are extrapolated to all mechanically
ventilated patients who develop delirium, health care costs would
rise to between $6.5 and $20.4 billion. Assuming a 20% increase
in delirium-related expenditures, the annual attributable health
care cost is still staggering—$300 million to $4 billion.
Pharmacoeconomic Implications Of Delirium Treatment
The pharmacoeconomic implications of delirium treatment were
demonstrated in a recent study of 73 ICU patients with delirium
who had been randomized to receive oral haloperidol or olanzapine (Skrobik et al 2004). Response, measured by a decrease in
the delirium index score, was similar between the 2 drugs. However,
no patients experienced adverse effects with olanzapine, whereas
6 patients receiving oral haloperidol experienced extrapyramidal
manifestations. On the basis of equal efficacy, a cost minimization
model approach would recommend the use of the least expensive
agent; however, this model does not take into account the costs
of adverse reactions to haloperidol. It should also be noted that
haloperidol is the drug most widely used to treat delirium in the
ICU, but the data to support such a practice are sparse. The Society for Critical Care Medicine (SCCM) guidelines recommend haloperidol with only a level C rating (evidence based on studies with
weak methods or observational studies; Jacobi et al 2002). Given
the lack of data, economic assessment of various treatments from
properly powered randomized controlled trials is needed to determine the most cost-effective approach for treating and preventing
ICU delirium.
Ely et al (2004a) report a 20% increased risk of remaining in
the hospital for each day spent with delirium in the ICU, so cost
savings are realized from a shorter hospital stay. Thus, preliminary
data suggest considerable cost savings in postoperative valve
patients receiving dexmedetomidine. However, economic assessment of treatment in randomized controlled trials is needed to
determine the most cost-effective approach for treating and preventing ICU delirium.
Key Points
•
•
•
•
•
The ICU contributes 33% of inpatient costs yet contains fewer than 10% of hospital beds
The cost of the average patient’s ICU stay in one study was $19,725; however, this value will vary according to type of illness, complications, and length of stay
Delirium is a common problem in ICU patients and appears to be an independent predictor of higher mortality and longer
hospital stay
Delirium extends the length of an ICU stay by 3 days, and, in multivariate analyses, results in a 39% increase in ICU costs
and a 31% increase in hospital costs
When evaluating drugs for delirium on a pharmacoeconomic basis, the cost of adverse drug reactions and other factors
should be considered
References
Chalfin DB. Pharmacoeconomic investigations in intensive care. Curr Opin Crit Care. 2001 Dec;7(6):460-463.
Dasta et al. Pharmacoeconomics in Critical Care. In: Grenvik A (ed). Textbook of Critical Care. 5th ed. WB Saunders; 2005:1732-1739.
Ely EW, Siegel MD, Inouye S. Delirium in the intensive care unit: an under-recognized syndrome of organ dysfunction. Sem Respir Crit Care Med. 2001;22:115-126.
Ely EW, Shintani A, Truman B, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004a Apr 14;291(14):1753-1762.
Ely EW, Stephens RK, Jackson JC, et al. Current opinions regarding the importance, diagnosis, and management of delirium in the intensive care unit: a survey of 912 healthcare professionals.
Crit Care Med. 2004b Jan;32(1):106-112.
Franco K, Litaker D, Locala J, Bronson D. The cost of delirium in the surgical patient. Psychosomatics. 2001 Jan-Feb;42(1):68-73.
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 Jan;30(1):119-141.
Milbrandt EB, Deppen S, Harrison PL, et al. Costs associated with delirium in mechanically ventilated patients. Crit Care Med. 2004 Apr;32(4):955-962.
Roberts C, Dasta J, Kim SR, McLaughlin TP, Mody S, Piech CT. Incremental daily cost of mechanical ventilation in patients receiving treatment in an Intensive Care Unit. Crit Care Med. 2003;31:
A26.
Skrobik YK, Bergeron N, Dumont M, Gottfried SB. Olanzapine vs haloperidol: treating delirium in a critical care setting. Intens Care Med. 2004 Mar;30(3):444-449.
Weber RJ, Kane SL, Oriolo VA, Saul M, Skledar SJ, Dasta JF. Impact of intensive care unit (ICU) drug use on hospital costs: a descriptive analysis, with recommendations for optimizing ICU pharmacotherapy. Crit Care Med. 2003 Jan;31(1 Suppl):S17-24.
Woods JC, Mion LC, Connor JT, et al. Severe agitation among ventilated medical intensive care unit patients: frequency, characteristics and outcomes. Intensive Care Med. 2004 Jun;30(6):10661072.
15
Behavioral Effects Of ICU Medications
Gil Fraser, PharmD
Associate Professor of Medicine, University of Vermont, Burlington, VT
In the “pharmacologically rich” setting of the ICU, the typical patient
receives 6 to 9 medications a day. Particularly in the elderly, there
is a relationship between the number of medications and the risk
of adverse drug reactions and delirium. Delirium risk is increased
9-fold when patients receive over 5 medications daily or receive
3 new medications. The American philosophy may espouse “a pill
for every ill,” but the opposite is true: there is almost certainly “an
ill in every pill.”
Many of the medications commonly administered in the ICU will
readily derange the delicate balance between dopamine and acetylcholine. At baseline, the elderly may already have a dopaminergic-cholinergic imbalance. They also have a diminished ability to
clear drugs; thus, standard doses have superpharmacologic activity. The frail elderly cannot withstand these “pharmacologic jolts,”
yet they are likely to receive any number of medications that have
the potential to induce psychiatric reactions. According to Micromedex 2004 (www.micromedex.com), delirium is associated with
103 medications, confusion is associated with 338, agitation with
177, and insomnia with 414.
Antidepressants And Neuroleptics
The number and type of medications administered to ICU patients
are very important to the degree of risk for delirium. Both treatment with and withdrawal from the selective serotonin reuptake
inhibitors (SSRIs) can produce behavioral symptoms. In about
20% of patients, abrupt withdrawal can produce dizziness, anxiety, insomnia, intense dreams, headache, nausea and vomiting,
and/or sweating. Treatment with SSRIs can produce psychomotor
restlessness, which can be interpreted as agitation. SSRIs can also
produce “serotonin syndrome,” usually within 24 hours of dosing,
which includes mental status changes, restlessness, myoclonus,
diaphoresis, shivering, and diarrhea.
Neuroleptics can produce neuroleptic malignant syndrome, which
can include changed mental status, rigidity, rhabdomyolysis, and
hyperthermia. This syndrome has been seen with atypical antipsychotics as well, although in such cases it produces less rigidity and
blunting of the temperature curve. Benzodiazepines and opiates
are deliriogenic and can increase time spent on mechanical ven-
tilation. A study by Pandharipande et al (2005) showed that the
use of lorazepam in the previous 24 hours was associated with a
3-fold increased risk for transitioning to delirium. Benzodiazepines
are intended for sedation, but patients may have paradoxical reactions, including rage. Patients with a history of heavy alcohol consumption or psychiatric illness may be especially prone to such
reactions.
Antibiotics, Steroids, And Other Agents
Antibiotics can also cause behavioral changes, including mania,
serotonin syndrome, and confusions/hallucinations. The risk for
serotonin syndrome is especially high with linezolid, particularly
in combination with an SSRI; this combination should be avoided.
Mania is occasionally seen with macrolides, particularly clarithromycin and the quinolones (Abouesh et al 2002). Hallucinations
and confusion have been observed in 9% of patients receiving
voriconazole (Walsh et al 2002). Mania is associated with steroid use; doses > 80/day actually produced psychosis in 18% of
patients in one study (Abouesh et al 2002).
A number of other agents have been associated with delirium,
including but not limited to dopamine, nitroprusside (delirium is
avoided by adding thiosulfate to the infusion), and H2 antagonists
(particularly cimetidine, which crosses the blood-brain barrier
and has anticholinergic activity). Diphenhydramine (Benadryl) is
powerfully deliriogenic in the elderly, raising the risk for behavioral
disturbances over 5-fold (Agostini et al 2001). Global amnesia
has been associated with sildenafil, which is sometimes used for
pulmonary hypertension.
Use Of Alternatives
There are strategies for dealing with delirium that exclude the use
of benzodiazepines and opiates, and these should be employed
whenever possible, using alternative agents such as dexmedetomidine, melatonin, valproate, and others. Simple approaches such
as reorienting patients, stimulating patients, providing glasses and
hearing aids, limiting catheters and tubings, and using nondrug
sleep protocols can also be quite beneficial.
Key Points
•
•
•
Many of the medications commonly administered in the ICU will derange the delicate balance between dopamine and acetylcholine
A vast number of agents typically used in the ICU are associated with delirium and other behavioral changes. Especially in
the elderly, these agents should be avoided
Strategies for dealing with delirium should involve agents other than benzodiazepines and opiates, when possible
References
Abouesh A, Stone C, Hobbs WR. Antimicrobial-induced mania (antibiomania): a review of spontaneous reports. J Clin Psychopharmacol. 2002 Feb;22(1):71-81.
Agostini JV, Leo-Summers LS, Inouye SK. Cognitive and other adverse effects of diphenhydramine use in hospitalized older patients. Arch Intern Med. 2001 Sep 24;161(17):2091-2097.
Pandharipande PP, Shintani A, Peterson J, Ely W. Sedative and analgesic medications are independent risk factors in ICU patients for transitioning into delirium. Society of Critical Care Medicine 34th
Critical Care Congress; Phoenix, AZ/January 15-19, 2005. Abstract 75.
16
Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med. 2002
Jan 24;346(4):225-234.
Identifying And Managing Agitation And Delirium In The ICU
William Peruzzi, MD
Professor of Anesthesiology and Chief, Section of Critical Care Medicine, Northwestern University School of Medicine, Chicago, IL
Agitation and delirium share a number of characteristics and can
therefore be difficult to distinguish from each other. Agitation is
a mental state of extreme emotional disturbance—the feeling of
being agitated and not calm. Delirium is a floridly abnormal mental state characterized by disorientation, irritability, fear, misperceptions of sensory stimuli, and sometimes visual hallucinations. It is
a disturbance of consciousness that is accompanied by changes
in cognition that are not accounted for by preexisting dementia.
Delirium typically is marked by agitation, it is important to note
the existence of the quiet, hypoactive delirious state as well as a
mixed state of delirium that includes both hypoactive and hyperactive behaviors. The hypoactive delirious patient is one who is quiet
and unable to pay attention. This behavior may herald a worsening
process.
Various factors contribute to the development of agitation and
delirium, including environmental disturbances that enhance
stimulation, particularly lack of sleep; emotional and psychological
feelings of loss of control; and the administration of certain drugs,
including benzodiazepines. Underlying the disorder is a chemical or
physiological imbalance that contributes to an inflammatory state.
The development of delirium has a broad impact on outcomes. It
increases mortality 3- to 5-fold, doubles length of hospital stay,
and increases nursing home placements. Ely et al (2004) found
delirium in 18% of 224 mechanically ventilated patients, who were
more likely to remain in a coma, to stay an average of 10 days longer in the hospital, to have twice the rate of cognitive impairment at
discharge (55% vs 27%), and to have twice the risk of dying (34%
vs 15%) 6 months later. The study found that delirious patients
received much higher doses of lorazepam, propofol, morphine, and
fentanyl—conceivably as part of the treatment strategy, but possibly
contributing to the development or severity of delirium as well.
The study by Ely et al used the Richmond Agitation Sedation Scale
(RASS) for diagnosis and assessment (Sessler et al 2002). This
is a useful scoring system that addresses the whole mental spectrum, from unarousable to combative, in a single 10-point scale
and helps determine sedation needs. The RASS scoring mechanism is further described at www.icudelirium.org.
Richmond Agitation-Sedation Scale
+4 Combative
-1 Drowsy
+3 Very agitated
-2 Light sedation
+2 Agitated
-3 Moderate sedation
+1 Restless
-4 Deep sedation
0 Alert and calm
-5 Unarousable
In the scoring of alert patients, for example, +2 indicates a patient
who has frequent nonpurposeful movements or fights the ventilator, while +1 describes a patient who is anxious and apprehensive,
but whose movements are not aggressive or vigorous. Sedated
patients who can be prompted to open their eyes and maintain
eye contact for > 10 seconds are scored as -1, while those with
contact for < 10 seconds are scored -2; patients who move when
spoken to but do not maintain eye contact are scored -3.
Standardizing The Approach To Sedation
A number of studies have demonstrated that issues of sedation
in the ICU are best addressed by using a standardized approach.
A University of Chicago study (Kress et al 2000) of 128 mechanically ventilated patients found that daily interruptions of sedative-drug infusions resulted in significant decreases in time spent
on mechanical ventilation and in the ICU compared to control
patients receiving standard nonprotocol care. Median days on
mechanical ventilation were 4.9 in the intervention group vs 7.3 in
the control group (PP = .004), and ICU length of stay was 6.4 days
vs 9.9, respectively (PP = .02). Another nurse-managed algorithm
that implemented sedation upon the first signs of delirium showed
a significant decrease in ICU and hospital lengths of stay and a
trend for decreased tracheostomies (Brook et al 1999).
When sedation is properly managed using a standardized protocol, clinical outcomes are improved.
Key Points
•
•
•
Agitation and delirium share a number of characteristics and can therefore be difficult to distinguish from one another
When sedation is properly managed using a standardized protocol, clinical outcomes are improved
Delirium typically is marked by agitation, but it is important to note the existence of the quiet, hypoactive delirious state as
well as a mixed state of delirium that includes both hypoactive and hyperactive behaviors
References
Brook AD, Ahrens TS, Schaiff R, et al. Effect of a nursing-implemented sedation protocol on the duration of mechanical ventilation. Crit Care Med. 1999 Dec;27(12):2609-2615.
Ely EW, Shintani A, Truman B, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004 Apr 14;291(14):1753-1762.
Kress JP, Pohlman AS, O’Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. New Engl J Med. 2000 May 18;342(20):1471-1477.
Sessler CN, Gosnell MS, Grap MJ, et al. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med. 2002 Nov 15;166(10):13381344.
17
Adjuncts To IV Sedative Agents
Staffan Wahlander, MD
Associate Clinical Professor of Anesthesiology and Associate Chief, Division of Critical Care, Columbia University Medical Center, New York, NY
Adequate sedation is a balancing act. Patients can be “controlled”
with propofol or anesthetizing doses of midazolam but can’t be
expected to awake with normal brain function after 2 to 3 weeks in
this state. Better approaches are needed.
Newer sedatives manage what once were the most common side
effects: hemodynamic instability and respiratory depression. The
challenge is dealing with prolonged sedation/oversedation and
ICU delirium—associated with more ICU and mechanical ventilator
time; both can lead to complications in those already quite ill.
Agitation in ICU patients has many causes, not all should be treated
by inducing coma. Sedation should aim for calm, not coma. Treatment should target agitation’s cause. Keep in mind: (1) Traditional
sedatives do not effectively treat pain or delirium and can cause
or exacerbate delirium. (2) Metabolic derangements should not
be treated with sedatives. (3) Anxiety should be treated with anxiolytics and sedatives. (4) Pain should be treated with drugs that
have minimal sedative effects. (5) Delirium probably should not be
treated with agents that act on GABA receptors; sedation can mask
pain but this doesn’t get at the real problem.
Pain isn’t controlled by high doses of sedatives or anesthetics.
For mostly visceral pain, opioids are preferred. Fentanyl causes
little sedation and is most effective. Peripheral pain is most often
adequately treated with acetaminophen, nonsteroidal anti-inflammatory agents, and COX-2 inhibitors (although COX-2s are controversial). Local anesthetics can be useful, including epidural, spinal,
and axillary infusions. A multimodal analgesic approach using
lower doses of drugs is often ideal to avoid side effects.
To treat anxiety, reduce patient exposure to the agents acting on
the GABA receptor, avoiding oversedation and the development
of delirium: provide adequate analgesia; reduce environmental
stress; intervene therapeutically to allow for more interaction; use
daily interruptions; follow goal-oriented sedation protocols; and
administer new agents that are less sedating.
Encouraging a normal sleep pattern/circadian rhythm can reduce
stress: turn off lights and limit night-time interventions; limit stressful activities; position patients properly; eliminate physical irritants
(eg, adjust bandages and tubing); offer massage, music, and other
forms of relaxation; and reassure patients.
Goal-directed sedation minimizes the risk of overdosing. It involves
setting a sedation goal using a validated scale, such as the Ramsay scale, and monitoring the sedative effect. EEG-derived monitoring is of questionable value for intermediate levels of sedation
because it lacks sensitivity and it does not demonstrate delirium.
Daily interruptions of sedative infusions are recommended; the staff
is forced to reassess sedation need regularly. Time on mechanical
ventilation, days in the ICU, and hospital stay are reduced. Despite
vigilance and proper management of ICU patients, delirium often
occurs. Agents now entering the clinical setting will help reduce
the risk of oversedation with traditional agents such as propofol
and midazolam. Atypical antipsychotics can be used with traditional GABA-adrenergic agents to lower the doses of these drugs,
or to replace them. More data on their efficacy and safety are
needed.
The alpha-2 agonists, unlike most other neuroleptics, do not act
via the GABA receptor. Dexmedetomidine is a relatively selective
alpha-2 agonist—much more selective than clonidine, which has
unwanted alpha-1 cardiovascular effects. Dexmedetomidine produces sedation and analgesia and decreases need for opioids
(which helps: opioids are implicated in causing delirium). Dexmedetomidine produces a different kind of delirium than that seen
with propofol and midazolam in that patients are arousable when
stimulated, then fall back to sleep. This fosters interaction with the
patient, which is helpful to the medical team.
Wahlander et al (2004) compared dexmedetomidine + low-dose
bupivacaine to low-dose bupivacaine + fentanyl infusion in postthoracotomy patients. Dexmedetomidine improved pain control,
and heart rate slowed to the desirable range. Patients getting
bupivacaine + fentanyl had greater pain and more tachycardia.
Dexmedetomidine also had a more beneficial effect on respiratory
function in these compromised patients, producing a consistently
lower PaCO2.
Maldonado et al (2003) reported that dexmedetomidine was
associated with a reduction in delirium in postcardiotomy patients
compared to other conventional protocols. If new agents can
reduce the incidence of delirium, their use should be considered.
Key Points
•
•
•
•
Achieving adequate sedation often requires a multimodal approach that balances between over- and undersedation
Pain is not controlled by high doses of sedatives or anesthetics
Efforts should be made to reduce ICU stressors, such as bright lights, night-time interruptions, and discomfort
Compared to conventional strategies, the use of dexmedetomidine was shown to reduce delirium among postcardiotomy
patients and, in postthoracotomy patients, to have greater benefits on pain, heart rate, and respiratory function
References
Maldonado JR, van der Starre PJ, Wysong A. Post-Operative Sedation and the Incidence of ICU Delirium in Cardiac Surgery Patients. ASA Annual Meeting Abstracts. Anesthesiology. 2003;99:
A465.
18
Wahlander S, Wagener G, Playford H, Saldana-Ferretti B, Sladen R. Intravenous Dexmedetomidine Can Replace Epidural Fentanyl as a Supplement to Low-Dose Epidural Bupivacaine for Postthoracotomy Pain Control. Presented at: 78th International Anesthesia Research Society Clinical and Scientific Congress; March 27-31, 2004; Tampa, FL.
Delirium In The ICU:
Prevention And Treatment
GUEST EDITOR AND MEDICAL REVIEWER
José R. Maldonado, MD, FAPM, FACFE, Associate Professor of Psychiatry and Behavioral Science;
Chief, Medical Psychiatry Section; Medical Director, Psychiatric Consultation Service; Faculty,
Stanford Center for Biomedical Ethics, Stanford University School of Medicine, Stanford, CA
CONTRIBUTING EDITORS
Richard R. Riker, MD, Department of Medicine, Maine Medical Center, Portland, ME
Joseph F. Dasta, MSc, Professor, College of Pharmacy, The Ohio State University, Columbus, OH
Gerald A. Maccioli, MD, FCCM, Director of Critical Care Medicine, Critical Health Systems, Inc,
Raleigh Practice Center; Medical Director, Medical/Surgical ICU, Nutrition Support and Respiratory
Therapy, Rex Healthcare, Raleigh, NC
CONTINUING EDUCATION EDITOR
Eva Szabo, MD, Assistant Professor, Department of Anesthesiology, University of New Mexico School
of Medicine, Albuquerque, NM
NEEDS ASSESSMENT
Delirium is the most common psychiatric syndrome found in the general hospital setting. Its prevalence among certain patient populations is extremely high. Nationwide, between 50% and 80% of
cardiac surgery patients may experience postoperative delirium. Nevertheless, it has been estimated
that only about a third of patients exhibiting significant symptoms of delirium are adequately identified and treated. Similarly, preexisting cognitive impairment occurs in an estimated 20% to 30%
of medical patients but is recognized in only 13%. Delirium has a far-reaching impact on patients’
long-term health and is associated with high health care costs. The pathophysiological mechanisms
that lead to delirium are also poorly understood. Recommended strategies for addressing delirium
include treating the reversible factors, such as drug withdrawal and medication toxicity, adequately
treating pain, correcting metabolic and endocrine disorders, and finally, managing sleep deprivation.
The treatment goals are to control agitation, prevent patients from harming themselves or their caretakers, and restore a normal sleep-wake cycle. Many physicians want to be educated on the most
recent advances in treating delirium.
EDUCATIONAL OBJECTIVES
After completion of this program, participants should be able to do the following:
Understand the epidemiology and pathophysiology of delirium
Discuss the risk factors and impact of delirium
Evaluate the delirium diagnostic tools, treatment options, and prevention possibilities
Discuss the latest advances in treating delirium
Discuss the management of delirium in the ICU setting
••
••
•
TARGET AUDIENCE
Anesthesiologists, Intensivists, and Pharmacists
CONTINUING MEDICAL EDUCATION ACCREDITATION
This activity has been planned and implemented in accordance with the Essential Areas and Policies
of the Accreditation Council for Continuing Medical Education (ACCME) through the co-sponsorship
of the University of New Mexico School of Medicine and Rogers Medical Intelligence Solutions. The
University of New Mexico School of Medicine Office of Continuing Medical Education is accredited by
the ACCME to provide continuing medical education for physicians.
The University of New Mexico School of Medicine Office of Continuing Medical Education designates this educational activity for a maximum of 1.0 Category 1 credit toward the AMA Physician’s
Recognition Award. Each physician should claim only those credits that he/she actually spent in the
activity.
CONTINUING PHARMACY EDUCATION ACCREDITATION
Extension Services in Pharmacy, School of Pharmacy at the University of Wisconsin
Madison, is accredited by the Accreditation Council on Pharmacy Education (formerly the
American Council on Pharmaceutical Education) as a provider of continuing pharmaceutical education. Pharmacists are required to complete the attached final examination and evaluation
form. Statements of credit for continuing pharmaceutical education participation will be mailed within
one month of receipt of this form. Extension Services in Pharmacy at the University of Wisconsin
School of Pharmacy designates 1.0 hour or 0.1 continuing education unit (CEU) for this activity. ACPE
number: 073-999-05-050-H01.
Each pharmacist should claim only those hours of credit actually spent in this educational activity.
DATE OF ORIGINAL RELEASE
March 2005. Approved for a period of 18 months for CME and CEU credit.
CONFLICT OF INTEREST AND FINANCIAL DISCLOSURES
In accordance with the Essential Areas and policies of the ACCME relating to commercial support,
which require the disclosure of the existence of any significant financial interest or any other relationship a faculty member, physician participant, author, or sponsor has with manufacturer(s) of
any commercial product(s) discussed in an educational presentation, the following interests and
relationships are reported:
José R. Maldonado, MD, FAPM, FACFE, has received grant/research support from Hospira Worldwide,
Inc, and Abbott Laboratories; he has also served on the speakers’ bureaus of Eli Lilly and Company,
School of Pharmacy
Forest Pharmaceuticals, Hospira Worldwide, Inc, and Pfizer Inc. Richard R. Riker, MD, has received
grant/research support from Eli Lilly and Company, Chiron, Amphastar, AstraZeneca, GlaxoSmithKline,
Abbott Laboratories, Altana Pharma AG, and Johnson & Johnson. He has served as a consultant
for Hospira Worldwide, Inc, Aspect Medical Systems, and GlaxoSmithKline. He has also served on
the speakers’ bureaus for Eli Lilly and Company, Abbott Laboratories, Hospira Worldwide, Inc, and
Aspect Medical Systems. Joseph F. Dasta, MSc, has received grant/research support from Abbott
Laboratories and Aspect Medical Systems and has served as a consultant to Abbott Laboratories,
ESP Pharma, Fujisawa Healthcare, Ortho Biotech, and Xanodyne. He has also served on the speakers’
bureaus of ESP Pharma and Ortho Biotech. Gerald A. Maccioli, MD, FCCM, has served as a consultant to Hospira Worldwide, Inc. Eva Szabo, MD, has nothing to disclose.
COMMERCIAL SUPPORT
The University of New Mexico School of Medicine, the University of Wisconsin School of Pharmacy,
and Rogers Medical Intelligence Solutions gratefully acknowledge the unrestricted educational grant
provided by Hospira Worldwide, Inc.
Should you need additional CME information, please call (505) 272-3942.
Should you need additional ACPE information, please call (608) 262-3130.
MEDIA
Printed report
ESTIMATED TIME TO COMPLETE ACTIVITY
1 hour
METHOD OF PARTICIPATION
Read the report, take the quiz, and compete the evaluation form.
For continuing medical education credit: Please complete the posttest and send or fax it to The
University of New Mexico School of Medicine for scoring. A score of 70% is required to qualify for
CME credit.
Mail to:
The University of New Mexico School of Medicine
Office of Continuing Medical Education
MSC09 5370
1 University of New Mexico
Albuquerque, NM 87131-0001
Fax to:
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PLEASE TURN OVER FOR CME QUIZ AND EVALUATION
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Delirium In The ICU: Prevention And Treatment
Please complete the test and evaluation form and send or fax it to the University of New Mexico School of Medicine for CME credit,
or the University of Wisconsin School of Pharmacy for CEU credit. A score of 70% is required for CME and CEU credit.
Name:_____________________________________________________________________________
(Please print)
1. The most important cause of delirium appears to be derangement of neurotransmission due to:
a. Dopaminergic deficiency
b. Cholinergic deficiency
c. Alterations in serotonin uptake
2. In hospitalized patients aged 70 and older, the prevalence of delirium exceeds
50% in some reports.
a. True
b. False
3. Which medications are not implicated as potential causes of delirium?
a. Anticholinergic agents
b. Benzodiazepines
c. Aspirin
d. Steroids
e. Narcotics
4. Which is not a risk factor for delirium:
a. Polypharmacy
b. Hip fracture
c. Metabolic disorders
d. Cognitive impairment
e. All are risk factors
5. Patients who develop delirium have worse outcomes, including higher rates, of
which of the following?
a. Permanent cognitive impairment
b. Mortality
c. Prolonged hospitalization
d. Institutionalization
e. All of the above
6. Delirium can be prevented in some patients who are at risk for developing it.
a. True
b. False
10. Characteristics of the alpha-2 receptor agonist dexmedetomidine include all of
the following, except:
a. Ability to more easily arouse patients
b. Minimal effect on respiratory drive
c. Some risk of tachycardia
d. Sedative effect that is akin to sleep
e. Reduction in oxygen demand and shivering
11. A recent study by Maldonado et al in postcardiotomy patients found a high rate
of delirium for patients receiving propofol or midazolam, but for patients receiving dexmedetomidine the rate was only:
a. 5%
b. 10%
c. 13%
12. Both treatment with and withdrawal from selective serotonin reuptake inhibitors
(SSRIs) can result in behavioral changes in hospitalized patients.
a. True
b. False
13. Patients with delirium are never calm and quiet.
a. True
b. False
14. The use of a standardized approach to sedation, such as daily interruptions of
sedation, has been shown to:
a. Reduce time on mechanical ventilation
b. Reduce ICU length of stay
c. Reduce mortality
d. a and b
15. Traditional sedatives are not effective in treating pain or delirium and, in fact,
can even cause or exacerbate delirium.
a. True
b. False
EVALUATION
7. The first approach in treating delirium is:
a. Sedate the patient
b. Give benzodiazepines
c. Look for and treat any reversible causes
Do you feel that the content of this report was fair, balanced, and free of commercial bias?
a. YES
b. NO
If no or maybe, please indicate which presentation:
_______________________________________________________________________
Were alternate treatments presented in a fair and balanced fashion?
Do you feel that the educational objectives were met?
8. While it has its drawbacks, haloperidol is usually the first approach used to treat
delirium:
a. True
b. False
9. Alpha-2 receptor agonists, like other neuroleptics, act via the gamma aminobutyric acid (GABA) receptor.
a. True
b. False
a. YES
a. YES
b. NO
b. NO
If no, please state the reasons:________________________________________________
Did you find the content of this report valuable to your practice?
a. YES
b. NO
Comments: ______________________________________________________________
What other topics are you interested in?
_______________________________________________________________________
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This report and CME activity/enduring material are co-sponsored by the University of New Mexico School of Medicine, the University of Wisconsin School of Pharmacy and
Rogers Medical Intelligence Solutions.
PRESENTATIONS IN FOCUS™ is published by Rogers Medical Intelligence Solutions, an independent provider of clinical information services. Reports are based on research
presented at medical meetings or other venues, on information gathered from physicians, and on findings published in medical literature. Reports are supported by
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Solutions makes no warranties as to the accuracy of content or the findings presented. Publication of this report was supported by an unrestricted educational grant from
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©2005 Rogers Medical Intelligence Solutions
5001757
Publication of this report was supported by an unrestricted educational grant
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