Improving delirium care in the intensive care unit: The design of a pragmatic study
Improving delirium care in the intensive care unit: The design of a pragmatic study
Noll L Campbell 0
Babar A Khan
Anthony J Perkins
Siu L Hui
Malaz A Boustani
0 Department of Pharmacy Practice, Purdue University School of Pharmacy , West Lafayette, IN , USA
Background: Delirium prevalence in the intensive care unit (ICU) is high. Numerous psychotropic agents are used to manage delirium in the ICU with limited data regarding their efficacy or harms. Methods/Design: This is a randomized controlled trial of 428 patients aged 18 and older suffering from delirium and admitted to the ICU of Wishard Memorial Hospital in Indianapolis. Subjects assigned to the intervention group will receive a multicomponent pharmacological management protocol for delirium (PMD) and those assigned to the control group will receive no change in their usual ICU care. The primary outcomes of the trial are (1) delirium severity as measured by the Delirium Rating Scale revised-98 (DRS-R-98) and (2) delirium duration as determined by the Confusion Assessment Method for the ICU (CAM-ICU). The PMD protocol targets the three neurotransmitter systems thought to be compromised in delirious patients: dopamine, acetylcholine, and gamma-aminobutyric acid. The PMD protocol will target the reduction of anticholinergic medications and benzodiazepines, and introduce a low-dose of haloperidol at 0.5-1 mg for 7 days. The protocol will be delivered by a combination of computer (artificial intelligence) and pharmacist (human intelligence) decision support system to increase adherence to the PMD protocol. Discussion: The proposed study will evaluate the content and the delivery process of a multicomponent pharmacological management program for delirium in the ICU. Trial Registration: ClinicalTrials.gov: NCT00842608
In 2005, approximately 2.7 million Americans aged 65
and older spent at least one day in the intensive care unit
(ICU) costing Medicare an estimated $27.5 billion [1-3].
It is estimated that up to 80% of these older ICU patients
had delirium during their hospital stay . Older adults
with delirium are more prone to falls, injuries, pressure
ulcers, restraints, mortality, institutionalization, and
dementia [4-8]. Delirium is considered an acute brain
failure that is most often unrecognized among older
adults in the ICU [9-14]. These patients may receive
potentially harmful medications such as anticholinergics
and benzodiazepines that are thought to cause or worsen
We conducted a systematic evidence review of the
existing literature to evaluate the efficacy and safety of
various pharmacological interventions . Of the four
studies focusing on delirium treatment, only one study
suggested a benefit of haloperidol and chlorpromazine
in reducing delirium severity, though no differences in
delirium incidence, duration, or hospital length of stay
were identified .
Despite the lack of evidence, clinicians that care for
these patients often use typical and atypical antipsychotics,
benzodiazepines, and other sedatives to manage the
symptoms of delirium [20,21]. This approach conflicts with our
current understanding of the neurotransmitter balance in
delirium. The available literature suggests a therapeutic
role for acetylcholine enhancement, gamma-aminobutyric
acid (GABA) reduction, and dopamine reduction
[9-12,15,22], which is reflected in available clinical practice
guidelines for delirium management . Therefore, this
neurotransmitter model supports a combination
intervention that includes avoiding or reducing the use of
benzodiazepines and anticholinergics, and the use of low dose
antipsychotics such as haloperidol [4,23-26]. However,
there have been no randomized controlled trials evaluating
the efficacy of this approach on reducing delirium severity,
duration, or complications [15-18].
Our primary objective is to test the efficacy of a
pharmacological intervention in reducing delirium severity
and duration among adults cared for in the ICU. Our
primary hypothesis is that, in comparison to usual care,
intervention patients will have (1) reduced delirium
severity at one week following randomization or hospital
discharge, and (2) fewer hospital days with delirium or
coma. The secondary hypothesis theorizes that the study
intervention will result in (1) shorter hospital lengths of
stay, (2) lower ICU, hospital, and 30-day mortality, and
(3) lower hospital-acquired complications related to
The study has been approved by the Institutional Review
Board (IRB) of Indiana University Purdue University
Indianapolis. Approval for enrollment in the study
requires informed consent provided by the potential
participants legally authorized representative.
Wishard Memorial Hospital (WMH) serves as Indianas
only public acute care hospital for the indigent
population with 340 staffed beds, of which 51 are intensive
care unit beds. The ICU at WMH includes a medical
ICU (MICU), surgical ICU (SICU), coronary ICU
(CCU), and progressive ICU (PICU). In 2008, WMH
provided 88,502 patient days of care throughout all
hospital beds. The general population demographics of
patients admitted to WMH include 59%
African-Americans and 68% females . Demographics of patients
admitted to critical care units at WMH are included in
Enrollment and Eligibility
Patients admitted to the ICU for at least 24 hours will
be eligible for screening for the study. Screening
measures, further described below, will include a measure of
the level of sedation using the Richmond
AgitationSedation Scale (RASS)  and the Confusion
Assessment Method for the ICU (CAM-ICU) to evaluate for
delirium . Criteria for inclusion in the study consist
of: (1) patients admitted to any WMH ICU ward (SICU,
PICU, MICU, CCU) for 24 hours, (2) aged 18 years,
(3) score positive for delirium based on the RASS and
CAM-ICU on any day during the ICU stay, and (4) are
English-speaking. Patients are excluded for a history of
severe mental illness, admission with an alcohol-related
delirium, admission for an aphasic stroke, have a history
of allergic reaction or contraindication to haloperidol,
Table 1 Demographic summary of WMH ICU population
Average monthly admission
Mean length of ICU stay, days
*SICU = Surgical intensive care unit; MICU = Medical intensive care unit;
CCU = Coronary care unit; PICU = Progressive intensive care unit; ER =
are pregnant or nursing, or have previously been
enrolled in the study.
Patients meeting inclusion criteria will be pursued for
informed consent by contacting a legally authorized
representative. Figure 1 describes the flow of patients
through the screening and enrollment plans of the
study. As seen in Figure 1, we anticipate approaching
approximately 4700 patients for screening in order to
enroll 428 in the randomized controlled trial.
Design and Delivery of the Intervention
In 2005, we utilized the information technology
infrastructure at WMH to develop a patient-specific
computerized decision support system (CDSS). This system
targeted hospitalized older adults with cognitive
impairment (CI), including those with delirium. This study
was called enhancing care for hospitalized older adults
with memory problems (e-CHAMP). The intervention
was designed to: (1) alert the clinician of the presence of
CI in his/her patient at the time of ordering a diagnostic
or therapeutic order; (2) identify a medication order
with a moderate to severe central anticholinergic activity
and suggest an alternative medication; (3) identify the
presence of bladder catheterization and suggest an early
discontinuation; and (4) identify a physical restraint
order and suggest pharmacological alternatives using a
low dose of haloperidol .
This prior clinical trial experience revealed valuable
lessons that translated to the design of the current
Figure 1 Expected PMD recruitment flow chart. ICU: Intensive Care Unit; WMH: Wishard Memorial Hospital; RASS: Riker Agitation Sedation
Scale; CAM-ICU: Confusion Assessment Method for the Intensive Care Unit
CDSS in the intensive care setting. First, many alerts
were not routinely updated, and often presented
conflicting or confusing recommendations that were
outdated. Second, the end-users were bombarded with
numerous computer-generated alerts and reminders
during their routine care of hospitalized older adults
[31,32]. The reputation for the clinical relevance of
these computer-based alerts, warnings, and reminders
was poor amongst clinicians. Furthermore, the
endusers developed what was referred to as the F8 or
escape button reaction, where the end-user
automatically ignored the alerts. Thus, we know that
computerbased decision support may be a useful resource, but by
itself cannot change provider behavior in our institution.
In response to the e-CHAMP experience, we elected
to support the computerized delivery of the study
intervention with human intelligence in designing the
current trial, the Pharmacologic Management of
Delirium (PMD). Realizing the pace of care in the ICU
environment is rapid and changes quickly, the
constantly present computerized component described
below will be activated for each study patient enrolled
in the intervention arm. In addition, a clinical
pharmacist with training in cognitive impairment and delirium
(NLC) will review medication orders twice daily to
carry out the study intervention. The inclusion of a
clinical pharmacy specialist will allow for review of
medications that may be ordered prior to enrollment
in the study as well as identifying medications that
may be ordered outside of the capabilities of the
CDSS, such as non-formulary drugs. Additionally, the
inclusion of a human interaction will improve
adherence to study interventions as well as document
reasons for protocol deviations.
Infrastructure of the Computerized Intervention: The
Medical GOPHER Physician Order-Entry System
Since 1984, the Medical GOPHER system, a network of
computer workstations, has allowed physician order
entry and other direct interactions between computer
and physician . The Medical GOPHER system is
used by physicians to write all orders at WMH and is
linked to the Regenstrief Medical Record System
(RMRS). It allows the computer to push information to
providers as a CDSS. Furthermore, it can do this at the
critical time of clinical decision making, while the
physician is initiating an order or recording a diagnosis. The
study intervention will utilize the GOPHER system to
alert any practitioner entering an order (either original
or verbal) for any of twenty medications with definite or
strong anticholinergic properties that the patient is
enrolled in the study and the medication is not
recommended. Additionally, the intervention will provide a list
of alternatives to consider depending on the intended
use of each particular medication.
Regenstrief Medical Record System at WMH
The computerized Regenstrief Medical Record System
(RMRS) is the primary instrument for processing data
and monitoring patient and physician activity at WMH.
RMRS is a modular system, capable of recording
appointments, laboratory, pharmacy, and physician
ordering activity. This comprehensive database captures
all inpatient and outpatient data by date in a fully coded
form, making patient care data readily retrievable.
Additionally, RMRS contains death certificate information for
registered patients who die in, or outside of, Indiana.
The RMRS will be used to evaluate secondary study
outcomes such as length of stay and mortality.
Description of the Pharmacologic Intervention
The study intervention targets the imbalance of three
neurotransmitters believed to play a role in delirium.
Our intervention will focus on the pharmacologic
contribution of those neurotransmitter systems through a
combination of human and electronic activity. The
CDSS will be employed in reducing the role of
anticholinergic medications in delirium, whereas the human
interaction by the study pharmacist will execute
benzodiazepine monitoring, initiate haloperidol as described
below, and ensure adherence to anticholinergic
reduction recommendations provided by the CDSS.
Reduction of anticholinergic medications
Using lists of medications with central anticholinergic
activities identified from the medical literature well as
values of serum anticholinergic activity (SAA)
measurement, our interdisciplinary aging brain team developed
the Anticholinergic Cognitive Burden (ACB) scale. The
scale is intended to be a practical tool to identify the
severity of negative anticholinergic effects on cognition
of prescribed and over-the-counter medications. The
team established the following scoring system: drugs
with possible anticholinergic effects (as demonstrated by
the SAA or the in-vitro affinity to muscarinic receptors
but with no clinically relevant negative cognitive effects)
were given a score of 1. Drugs with established and
clinically relevant cognitive anticholinergic effects were
given the score of either 2 or 3, based on each drugs
blood-brain permeability and its association with the
development of delirium identified in available literature
Medications included in the ACB having a score of 2
or 3 will be the targeted medications for anticholinergic
burden reduction. Each order for a definite
anticholinergic will trigger a warning message to avoid its use in
patients with delirium, along with alternative
recommendations and prompts to discontinue the offending
agent. The definite anticholinergics targeted in our
study as well as suggested alternatives are available in
Withdrawal of benzodiazepines in intervention patients
will follow recommendations from the Society of Critical
Care Medicine (SCCM) guidelines regarding the use of
sedative and analgesic medications in critically ill patients
. Benzodiazepine reduction will occur cautiously but
deliberately, with constant communication with the
primary medical or surgical team and with close monitoring
for intolerable withdrawal reactions. Benzodiazepine dose
reductions will be initiated with 20-40% dose reduction
on day one, with subsequent reductions of 10-25% every
24 hours as tolerated. Safety and tolerability of the
weaning schedule will be evaluated through routine nursing
assessments of vital signs and behavior documented
every four hours.
Low-Dose Haloperidol course
During the ICU stay, every patient who consents to the
study, randomized into the intervention group, and is not
under mechanical ventilation will received an order of 0.5
to 1 mg haloperidol every 8 hours via oral or parental
route for a total of seven days or until discharge from the
hospital. Because of age-related pharmacokinetic
differences in metabolism and pharmacodynamic sensitivity,
patients under the age of 60 years will be given 1 mg/dose,
and those aged 60 years or older will be given 0.5 mg/
dose. This low dose of haloperidol is based on the critical
analysis of the data from the clinical trials that tested the
use of antipsychotics in delirium and the drug metabolism
of psychotropics in older adults. This low dose is not
intended to replace the sedative regimen used in patients
receiving mechanical ventilator.
Intravenous haloperidol use has been associated with a
higher risk of cardiovascular adverse outcomes,
specifically QT prolongation and Torsades de Pointe. However,
in a recent systematic review of case reports of
haloperidol-associated arrhythmias, a wide range of haloperidol
doses were used prior to the inciting events (2-1540 mg).
The onset of most events was typically within minutes to
hours following the cumulative doses of haloperidol
(range 15 minutes to 5 days). The authors concluded that
haloperidol given intravenously appears safe when given
in doses less than 2 mg. Patients enrolled in our study
will not be given haloperidol if they have: (1) a QT
prolongation of 500 milliseconds or above, (2) a history of
seizure disorders, or (3) an indication for seizure
prophylaxis (i.e., severe stroke or traumatic brain injury) as
haloperidol may decrease the seizure threshold .
Those randomized to the usual care group will receive no
electronic or human reminders for pharmacologic
management of delirium throughout their hospital stay. Study
participants in the usual care arm may receive
haloperidol as part of routine care in the ICU, without restriction
on the dose or frequency administered. Of note, study
participants will be randomized at the patient level,
therefore providers will care for patients enrolled in both
intervention and usual care arms of the study, exposing
the risk of cross-contamination. Study personnel will
continue to visit the patients twice daily to perform
delirium, safety, and adverse event assessments.
Following the eligibility and screening assessments,
informed consent will be obtained from the participants
legally authorized representative. Randomization of
eligible patients providing consent will occur in a 1:1 ratio
between intervention and usual care groups. The
computerized order entry system (GOPHER) is capable of
performing this process and will conduct randomization in
random blocks of four to encourage even distribution of
patients between the intervention and usual care groups.
Delirium Recognition: In accordance with national
guidelines , the study will identify delirium by using the
RASS and the CAM-ICU on all patients who are
admitted directly from the emergency room or
transferred from other services to the ICU. Such assessment
will be performed after 24 hours of ICU admission and
twice daily until discharge from the hospital. As an initial
step in conducting the CAM-ICU, the interviewer must
assess the patients sedation status to assure a valid
CAM-ICU result. The CAM-ICU was validated using the
RASS, and therefore this will be the sedation scale
utilized for our study evaluation. RASS has excellent
interrater reliability among adult medical and surgical ICU
patients and has excellent validity when compared to a
visual analogue scale and other selected sedation scales
. The RASS requires 30-60 seconds to perform with
minimal training and has been used by our local ICU
team. The RASS is a 10-point scale that reflects the
patient level of sedation as determined by their responses
to verbal versus physical stimulation. A RASS score of -5
indicates a comatose state with lack of response to verbal
or physical stimuli, a score of 0 represents alert and calm,
and a score of +4 indicates a state of combative, violent
behavior with immediate danger to staff, self, or others.
A patient with a RASS score of -3 to +4 will be
considered eligible to be assessed by the CAM-ICU to
determine the presence of delirium .
The CAM-ICU will detect delirium among patients
receiving ICU care at both the time of ICU admission
and during their ICU stay. The CAM-ICU was chosen
because of its practical use in the ICU wards, its
acceptable psychometric properties, and based on the
recommendation of national guidelines [4,35]. The CAM-ICU
score is determined by examining the patient for (a)
acute and fluctuating changes in mental status, (b)
inattention, (c) disorganized or incoherent thinking, and (d)
altered level of consciousness. A CAM-ICU score is
considered to be positive if the patient displays both a and b,
plus c and/or d. The CAM-ICU diagnosis of delirium
was validated against the DSM-III-R delirium criteria
determined by a psychiatrist and found to have a
sensitivity of 97% and a specificity of 92% . The CAM-ICU
has been developed, validated and applied into ICU
settings and multiple investigators have used the same
method to identify patients with delirium [36-38].
Delirium Severity: Since the CAM-ICU does not
evaluate delirium severity, we selected the Delirium Rating
Scale revised-1998 (DRS-R-98) [39,40] developed by Dr.
Paula Trzepacz and colleagues. The DRS-R-98 was
designed to evaluate the breadth of delirium symptoms
for phenomenological studies in addition to measuring
symptom severity with high sensitivity and specificity. It
has been used in treatment, phenomenological and
pathophysiological studies and has been translated into
12 languages. Characteristic symptoms include
impairments of attention, short and long-term memory,
visuospatial ability and orientation, perceptual and sleep-wake
cycle disturbances, abnormalities of language and
thought process and content, motor agitation and
retardation, and mood lability. The DRS-R-98 is a 16-item
clinician-rated scale with anchored items descriptions
corresponding to both symptoms and temporal aspects
of delirium. The severity scale has 13 items each rated
from 0 to 3 where the sum has a maximum of 39 points,
with higher scores indicating greater severity of delirium.
Three additional items (rated from 0 to either 2 or 3)
capture temporal course and attribution to an underlying
etiology and when added to the sum of the 13 symptom
items produce the DRS-R-98 total score that ranges from
0 to 46. The DRS-R-98 has excellent inter-rater reliability
(intra-class correlation 0.97) and internal consistency
(Cronbachs alpha 0.94) [39,40].
The study will collect demographic and baseline
functional information from the patients legally authorized
representative and/or caregivers. Cognitive function
status will be obtained by interviewing the patients legally
authorized representative using the Informant
Questionnaire on Cognitive Decline in the Elderly (IQCODE).
IQCODE is a questionnaire that can be completed by a
relative or other caregiver to determine whether that
person has declined in cognitive functioning. The
IQCODE lists 26 everyday situations where a person has
to use their memory or intelligence. Each situation is
rated by the informant for amount of change over the
previous 10 years, using a Likert scale ranging from
1much improved to 5-much worse. The IQCODE has a
sensitivity between 69% to 100% and specificity of 80%
to 96% for dementia .
Utilizing the electronic medical record system
(RMRS), we will collect several data points of interest at
baseline and throughout the study period. First, RMRS
will allow us to collect reason for admission, severity of
illness (APACHE II) , and the number of comorbid
conditions (Charlson Comobidity Index)  for each
patient enrolled in the study. We will also collect length
of stay (both ICU and total hospital stay), mortality rate,
and hospital-related consequences. We have previously
defined hospital-related consequences to include: the
number of patients with documented falls, use of
physical restraints, injuries such as pulling out IV lines or
urinary catheters, any ordered or observed re-intubation,
and pressure ulcers. These will be assessed using the
RMRS, direct daily observation, and retrospective review
of the electronic medical record. This definition of
delirium-related hospital complications has been previously
used and published [44,45].
Use of all medications, including focused
interventionrelated medications (anticholinergics, benzodiazepines,
and haloperidol) will be monitored through the GOPHER
computerized order entry system, as well as the McKesson
medication administration system. The McKesson system
is used at the patients bedside and collects the
administration of each medication. Additionally, McKesson is able to
monitor medications administered as continuous infusions
by documenting start times, stop times, and drip rates
throughout the administration period.
In our study an adverse event will be defined as any
untoward medical occurrence in a subject without
regard to the possibility of a causal relationship. Adverse
events will be collected after the subject has provided
consent and enrolled in the study. If a subject
experiences an adverse event after the informed consent
document is signed (entry) but the subject has not started to
receive study intervention, the event will be reported as
not related to study drug. All adverse events occurring
after entry into the study and until hospital discharge
will be recorded. An adverse event that meets the
criteria for a serious adverse event (SAE) between study
enrollment and hospital discharge will be reported to
the local IRB as an SAE. If haloperidol is discontinued
as a result of an adverse event, study personnel will
document the circumstances and data leading to
discontinuation of treatment. A serious adverse event for this
study is any untoward medical occurrence that is
believed by the investigators to be causally related to
study-drug and results in any of the following:
Lifethreatening condition (that is, immediate risk of death);
severe or permanent disability, prolonged
hospitalization, or a significant hazard as determined by the Data
Safety Monitoring Board. Serious adverse events
occurring after a subject is discontinued from the study will
NOT be reported unless the investigators feels that the
event may have been caused by the study drug or a
protocol procedure. Investigators will determine relatedness
of an event to study drug based on a temporal
relationship to the study drug, as well as whether the event is
unexpected or unexplained given the subjects clinical
course, previous medical conditions, and concomitant
Although haloperidol is widely used in treatment of
delirium, it is not approved by the FDA for such use, and
its efficacy in such treatment is not clear. Although our
study employs a low dose (1.5 mg per day) of haloperidol
for a short period of time (seven days), its potential
adverse effects of QT prolongation and extrapyramidal
symptoms (EPS) will be monitored during the study. The
study will monitor for the following movement-related
adverse effects daily through patient examination and
chart review: dystonia, akathisia, pseudoparkinsonism,
akinesia, and neuroleptic malignant syndrome. Study
personnel will use the Simpson-Angus  and Barnes Akathisia
 scales to monitor movement-related effects.
We will conduct intention-to-treat analyses to test the
intervention effects on the primary outcomes. No
interim analysis is planned for early termination due to
efficacy. To formally test for potential harm due to the
intervention, 3 interim analyses will be performed using
the proposed primary analysis methods after the
completion of 0.25, 0.5 and 0.75 of the projected 428
evaluable subjects, using the OBrien-Fleming boundary, for
an overall significance level of 0.05 at study completion.
To test the intervention effect on severity of delirium,
we will use the primary outcome of DRS-R-98 severity
score on day 8 post-randomization. The primary
analysis to test the intervention effect on day-8 DRS-R-98
severity score will be analysis-of-covariance (ANCOVA)
with the baseline score as a covariate, after testing and
removing any intervention-by-baseline score interaction.
If there is a significant interaction, we will test the
intervention effect at the mean of the baseline DRS-R-98
severity score. We will use the last observed DRS-R-98
forward to Day 8 as the primary outcome in one
analysis. For sensitivity analyses, we will use different
methods to impute the missing data. For example, we will
impute the missing Day 8 DRS-R-98 severity scores with
their worst score on record for patients who have been
discharged with delirium or died before day 8. For
patients who were hospitalized but could not be
evaluated for whatever reason on day 8, we could also
interpolate their previous and subsequent DRS-R-98 severity
scores to estimate the missing Day 8 score.
We will also test the intervention effect on the
repeated measures of DRS-R-98 severity scores using a
mixed-effects model. An appropriate contrast for the
day 8 effect will be used to corroborate the results of
the ANCOVA in the primary analyses. This analysis will
provide additional information on the time course of
the severity of delirium from its onset in the ICU, with
or without intervention.
To test the intervention effect on duration of delirium,
we will compare between groups the number of
comafree and delirium-free days in the first 8 days
post-randomization using a two-sample t-test corroborated with
the Wilcoxon rank sum test. The intervention effect will
be further tested while controlling for patient
characteristics using multiple regression. Patients who die before
day 8 will have all subsequent days counted as not
coma-free or delirium-free. We will impute all days
post-discharge as coma-free and delirium-free.
For secondary outcomes, binary measures, e.g.
mortality and complications, logistic regression will be used to
test the intervention effect, controlling for covariates
when appropriate. Highly skewed outcomes such as
hospital and ICU length of stay will be compared between
groups using nonparametric tests, such as Wilcoxons
rank sum test, and semiparametric survival analyses
which can control for covariates.
Data Safety Monitoring Board
A data safety monitoring board (DSMB) consisting of
five members having no participation in the planning or
execution of the study will be assembled. The DSMB
will be responsible for the oversight of the safety of
study patients and to ensure an appropriate sample is
collected throughout the study period. The board will
review relevant safety data after the completion of data
collection of 25%, 50%, and 75% of the planned study
sample. During these safety analyses, the DSMB will
make recommendations to continue or terminate the
progress of the study based on the observed effects of
the study intervention.
There are limitations within our study that are worth
addressing. First, the potential for contamination exists
by randomizing study subjects at the patient level.
Physicians may care for patients in both groups and
therefore may change behavior based on exposure to the
study recommendations. Second, we did not design the
study to determine which of the three pharmacologic
interventions contributed most significantly to the
outcome. Based on our previous experience with
eCHAMP and that of other delirium trials that revealed a
small effect size, we chose to evaluate only the impact
of the combined pharmacologic intervention. Finally, the
impact of the study intervention may be limited by the
use of a low dose of haloperidol and the absence of an
absolute restriction on anticholinergic and
benzodiazepine use. The use of a low dose of haloperidol is a result
of our interpretation of the available literature on
delirium treatment .
Despite these limitations, our study will add valuable
information to the scant literature about the hospital
care for adults with delirium. First, it provides a focused
intervention aimed at the current theory of
neurotransmitter imbalances thought to occur during delirium.
Second, it provides an opportunity to study the impact
of a multi-component intervention not only on delirium
duration, but also delirium severity, which few studies
have reported until recently. Third, the intervention
uses a novel delivery method that provides
recommendations at the time of order entry, which is most
practical in the ICU environment when the pace of care is at
The proposed intervention may result in several
benefits considering the impact of delirium on acute and
long-term outcomes. It might lead to the development
of a universal computerized order entry program that
might improve the safety of the current health care
system in caring for hospitalized adults with delirium. Our
intervention might also decrease health care utilization
and cost of the current health care system by reducing
days with delirium. Additionally, a successful delirium
intervention may also help physicians deliver better care
for their patients and increase their trust in the use of
information technology as a tool to help their patients.
List of abbreviations
ICU: intensive care unit; GABA: gamma-aminobutyric acid; IRB: institutional
review board; WMH: Wishard Memorial Hospital; MICU: medical intensive
care unit; SICU: surgical intensive care unit; CCU: coronary intensive care
unit; PICU: progressive intensive care unit; RASS: Richmond
AgitationSedation Scale; CAM-ICU: confusion assessment method for the intensive
care unit; CDSS: computerized decision support system; eCHAMP: enhancing
care of hospitalized older adults with memory problems; PMD:
Pharmacologic Management of Delirium; RMRS: Regenstrief Medical Record
System; SAA: serum anticholinergic activity; ACB: anticholinergic cognitive
burden; SCCM: Society of Critical Care Medicine; DRS-R-98: Delirium Rating
Scale revised 1998; IQCODE: Informant questionnaire on cognitive decline in
the elderly; APACHE: acute physiology and chronic health evaluation; SAE:
serious adverse event; EPS: extrapyramidal symptom; ANCOVA: analysis of
covariance; DSMB: data safety monitoring board; ER: emergency room
Acknowledgements and Funding
The trial is funded through the National Institutes of Health grant
R01AG054205-02. The funding agency had no role in the development of
the study design, collection, analysis, interpretation of data, manuscript
development, or the decision to submit the manuscript for publication.
All authors have read and approved the manuscript. All authors were
involved in study design and manuscript development.
1. Cooper LM , Lindle-Zwirble TW : Medicare Intensive Care Unit Use: Analysis of incidence , cost, and payment. Crit Care Med 2004 , 32 : 2247 - 2253 .
2. National Hospital Discharge Survey: Public use data file documentation . U. S. Department of Health and Human Services. Centers for Disease Control and Prevention. National Center for Health Statistics. Division of Health Care Statistics. Hospital Care Statistics Branch; 2005 [http://www.cdc. gov/nchs/about/major/hdasd/nhds.htm], (accessed May 8 , 2007 ).
3. DeFrances CJ , Podgornik MN : 2004 National Hospital Discharge Survey . Advance data from vital and health statistics . National Center for Health Statistics Hyattsville, MD; 2006 , no 371 .
4. Jacobi J , Fraser GL , Coursin DB , Riker RR , Fontaine D , Wittbrodt ET , Chalfin DB , Masica MF , Bjerke HS , Coplin WM , Task Force of the American College of Critical Care Medicine (ACCM) of the Society of Critical Care Medicine (SCCM), American Society of Health-System Pharmacists (ASHP), American College of Chest Physicians , et al: Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult . Crit Care Med 2002 , 30 ( 1 ): 119 - 141 .
5. Jackson JC , Gordon SM , Hopkins RO , et al: The association between delirium and cognitive decline: A review of the empirical literature . Neuropsychol Rev 2004 , 14 : 87 - 98 .
6. Saravay SM , Kaplowitz M , Kurek J , et al: How do delirium and dementia increase length of stay of elderly general medical inpatients? Psychosomatics 2004 , 45 : 235 - 42 .
7. Chelluri L , Pinsky MR , Donahoe MP , et al: Long-term outcome of critically ill older patients requiring intensive care . JAMA 1993 , 269 : 3119 - 3123 .
8. Witlox J , Eurelings JS , de Jonghe JF , et al: Delirium in elderly patients and the risk of post-discharge mortality, institutionalization and dementia: a meta-analysis . JAMA 2010 , 304 ( 4 ): 443 - 451 .
9. Pandharipande PP , Pun BT , Herr DL , et al: Effect of sedation with dexmedetomidine vs. lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial . JAMA 2007 , 298 ( 22 ): 2644 - 2653 .
10. Gunther ML , Morandi A , and Ely EW : Pathophysiology of delirium in the intensive care unit . Crit Care Clin 2008 , 24 : 45 - 65 .
11. Inouye SK , Ferrucci L : Elucidating the pathophysiology of delirium and the interrelationship of delirium and dementia . Journals of Gerontology Series A-Biological Sciences & Medical Sciences 2006 , 61 ( 12 ): 1277 - 80 .
12. Marcantonio ER , Rudolph JL , Culley D , Crosby G , Alsop D , Inouye SK : Serum biomarkers for delirium . Journals of Gerontology Series A-Biological Sciences & Medical Sciences 2006 , 61 ( 12 ): 1281 - 6 .
13. Gunther ML , Jackson JC , Ely EW : The cognitive consequences of critical illness: practical recommendations for screening and assessment . Critical Care Clinics 2007 , 23 ( 3 ): 491 - 506 .
14. Hopkins RO , Jackson JC : Long-term neurocognitive function after critical illness . Chest 2006 , 130 ( 3 ): 869 - 78 .
15. Boustani M , Campbell N , Munger S , Maidment I , Fox C : Impact of anticholinergics on the aging brain: a review and practical application . Aging Health 2008 , 4 : 311 - 320 .
16. Campbell NL , Ayub A , Fox GC , Munger SL , Ott C , Guzman O , Farber M , Ademuyiwa A , Singh R : Pharmacological Management of Delirium in Hospitalized Adults-A Systematic Evidence Review . J Gen Intern Med 2009 , 24 ( 7 ): 848 - 853 .
17. Boustani M , Buttar A : Delirium in hospitalized older adults . In Primary Care Geriatrics, A Case-Based Approach Edited by: R Ham, P Sloane, G Warshaw , 5 2007 , 15 : 210 - 218 .
18. Weber JB , Coverdale JH , Kunik ME : Delirium: current trends in prevention and treatment . Intern Med J 2004 , 34 ( 3 ): 115 - 121 .
19. Breitbart W , Marotta R , Platt MM , et al: A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients . Am J Psychiatry 1996 , 153 ( 2 ): 231 - 237 .
20. Ely EW , Stephens RK , Jackson JC , Thomason JW , Truman B , Gordon S , Dittus RS , Bernard GR : Current opinions regarding the importance, diagnosis, and management of delirium in the intensive care unit: a survey of 912 healthcare professionals . Crit Care Med 2004 , 21 ( 1 ): 106 - 112 .
21. Inouye SK : Delirium in older persons . N Engl J Med 2006 , 354 ( 11 ): 1157 - 1165 .
22. Trzepacz PT : Is there a final common neural pathway in delirium? Focus on acetylcholine and dopamine . Semin Clin Neuropsychiatry 2000 , 5 ( 2 ): 132 - 148 .
23. Fick DM , Cooper JW , Wade WE , Waller JL , Maclean JR , Beers MH : Updating the Beers criteria for potentially inappropriate medication use in older adults: results of a US consensus panel of experts . Arch Intern Med 2003 , 163 : 2716 - 2724 .
24. Maccioli GA , Dorman T , Brown BR , mazuski JE , McLean BA , Kuszaj JM , Rosenbaum SH , Frankel LR , Devlin JW , Govert JA , Smith B , Peruzzi WT : Clinical practice guidelines for the maintenance of patient physical safety in the intensive care unit: use of restraining therapies-American College of Critical Care Medicine Task Force2001-2002 . Crit Care Med 2003 , 31 ( 11 ): 2665 - 2676 .
25. American Psychiatric Association : Practice guidelines for the treatment of patients with delirium . American Psychiatric Association. Am J Psychiatry 1999 , 156 ( 5 Suppl): 1 - 20 .
26. Chow TW , MacLean CH : Quality indicators for dementia in vulnerable community-dwelling and hospitalized elders . Ann Intern Med 2001 , 135 : 668 - 676 .
27. Boustani M , Baker MS , Campbell N , Munger S , Hui S , Castellucio P , Farber M , Guzman O , Ademuyiwa A , Miller D , Callahan C : Impact and recognition of cognitive impairment among hospitalized elders . J Hosp Med 2010 , 5 ( 2 ): 69 - 75 .
28. Sessler CN , Gosnell MS , Grap MJ , Brophy GM , O'Neal PV , Keane KA , Tesoro EP , Elswick RK : The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients . Am J Respir Crit Care Med 2002 , 166 ( 10 ): 1338 - 44 , Nov 15.
29. Ely EW , Margolin R , Francis J , May L , Truman B , Dittus R , 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 2001 , 29 : 1370 - 1379 .
30. Boustani MA , Munger S , Beck R , Campbell N , Weiner M : A gero-informatics tool to enhance the care of hospitalized older adults with cognitive impairment . Clin Interv Aging 2007 , 2 ( 2 ): 247 - 253 .
31. Cash JJ : Alert Fatigure . Am J Health Syst Pharm 2009 , 66 ( 23 ): 2098 - 2101 .
32. Ash JS , Sittig DF , Campbell EM , Guappone KP , Dykstra RH : Some unintended consequences of clinical decision support systems . AMIA Annu Symp Proc 2007 , 26 - 30 .
33. Dexter PR , Perkins S , Overhage JM , Maharry K , Kohler RB , McDonald CJ : A computerized reminder system to increase the use of preventive care for hospitalized patients . N Engl J Med 2001 , 345 : 965 - 70 .
34. Meyer-Massetti C , Cheng CM , Sharpe BA , Meier CR , Guglielmo BJ : The FDA extended warning of intravenous haloperidol and Torsades de Pointes: how should institutions respond ? J Hosp Med 2010 , 5 : E8 - E16 .
35. Ely EW , Truman B , Shintani A , Thomason JW , Wheeler AP , Gordon S , Francis J , Speroff T , Gautam S , Margolin R , Sessler CN , Dittus RS , Bernard GR : Monitoring sedation status over time in ICU patients: reliability and validity of the Richmond Agitation-Sedation Scale (RASS) . JAMA 2003 , 289 ( 22 ): 2983 - 91 .
36. Ely EW , Inouye SK , Bernard GR , Gordon S , Francis J , May L , et al: Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU) . JAMA 2001 , 286 : 2703 - 2710 .
37. Cole MG , McCusker J , Bellavance F , et al: Systematic detection and multidisciplinary care of delirium in older medical inpatients: a randomized trial . CMAJ 2002 , 167 : 753 - 9 .
38. Cole MG , McCusker J , Dendukuri N , Han L : Symptoms of delirium among elderly medical inpatients with or without dementia . J Neuropsychiatry Clin Neurosci 2002 , 14 : 167 - 75 .
39. Trzepacz PT , Baker RW , Greenhouse J : A symptom rating scale for delirium . Psychiatry Res 1988 , 23 : 89 - 97 .
40. Trzepacz PT , Mittal D , Torres R , et al: Validation of the Delirium Rating Scale-revised-98. J Neuropsychiatry Clin Neurosci 2001 , 13 ( 2 ): 229 - 242 .
41. Jorm AF : The Informant Questionnaire on cognitive decline in the elderly (IQCODE): a review . Int Psychogeriatr 2004 , 16 ( 3 ): 275 - 93 .
42. Knaus WA , Zimmerman JE , Wagner DP , et al: APACHE-Acute physiology and chronic health evaluation: A physiologically based classification system . Crit Care Med 1981 , 9 : 591 - 597 .
43. Charlson ME , Pompei P , Ales KL , et al: A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987 , 40 : 373 - 383 .
44. Ely EW , Gautam S , Margolin R , Francis J , May L , Speroff T , Truman B , Dittus R , Bernard R , Inouye SK : The impact of delirium in the intensive care unit on hospital length of stay . Intensive Care Med 2001 , 27 : 1892 - 1900 .
45. Pandharipande P , Shintani A , Peterson J , Pun BT , Wilkinson GR , Dittus RS , Bernard GR , Ely EW : Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients . Anesthesiology 2006 , 104 ( 1 ): 21 - 6 .
46. Simpson GM , Angus JW : A rating scale for extrapyramidal side effects . Acta Psychiatr Scand Suppl 1970 , 212 : 11 - 9 .
47. Barnes TR : A rating scale for drug-induced akathisia . Br J Psychiatry 1989 , 154 : 672 - 676 .