Crit Care Nurs Q

Vol. 40, No. 4, pp. 344–362

Copyright  c 2017 Wolters Kluwer Health, Inc. All rights reserved.

Oral Agents for the

Management of Agitation and
Agitated Delirium in Critically Ill
Patients
Qiu Min Yeo, PharmD, BCPS, BCCCP; Tessa L. Wiley, PharmD;
Melanie N. Smith, PharmD, BCPS;
Drayton A. Hammond, PharmD, MBA, BCPS, BCCCP

Agitation is one of the most common issues that critically ill patients experience. Medications used
to manage agitation are often administered intravenously or intramuscularly in the acutely agitated,
critically ill patient. However, a multimodal approach that utilizes multiple routes of administra-
tion may be appropriate. This review summarizes the available literature on oral antipsychotics,
clonidine, and valproic acid to manage agitation in critically ill patients while also focusing on their
pharmacology and appropriate monitoring. Despite inconclusive findings from different studies,
antipsychotics, clonidine, and valproic acid may provide benefit for specific patient populations.
As more evidence emerges, these agents may start playing a greater role in the management of
agitation, which is not amenable to first-line agents. As health care professionals, it is prudent
to be familiar with their dosing regimens, common adverse effects, and the monitoring required
to maximize patient benefits and minimize harms. Key words: antipsychotic agents, clonidine,
oral administration, psychomotor agitation, valproic acid

A GITATION is one of the most common

issues that critically ill patients experi-
ence, occurring in 59% to 71% of patients
who are admitted to the intensive care unit
(ICU).1,2 Although there is no consensus on
the definition of agitation, it may be de-
Author Affiliations: Department of Pharmacy,
Changi General Hospital, Singapore (Dr Yeo);
Department of Pharmacy, The University of
Mississippi Medical Center, Jackson (Dr Wiley);
Department of Pharmacy, Medical University of
South Carolina, Charleston (Dr Smith); and
Department of Pharmacy, Rush University Medical
Center, Chicago, Illinois (Dr Hammond).
The authors have disclosed that they have no signif-
icant relationships with, or financial interest in, any
commercial companies pertaining to this article.
Correspondence: Drayton A. Hammond, PharmD,
MBA, BCPS, BCCCP, Department of Pharmacy, Rush
University Medical Center, 1653 W. Congress Pkwy,
Chicago, IL 60612 (drayton.hammond@gmail.com).
DOI: 10.1097/CNQ.0000000000000172
344
scribed as a psychomotor disturbance char-
acterized by a marked increase in both mo-
tor and psychological activities, often but not
always accompanied by a loss of control of
action or disorganization of thoughts.3 It is
believed to be a manifestation of an under-
lying disorder in most instances. Agitation
has been associated with a significant impact
on patient outcomes, such as increased rates
of self-extubation, self-removal of catheters,
and of nosocomial infections; longer hospi-
tal lengths of stay; and greater utilization of
health care resources.4
ETIOLOGY
Critically ill patients may be agitated
for 1 or more reasons, which may be
grouped into 4 main categories: patient-
related causes, medication-related causes,
illness-related causes, and environmental
causes. Patient-related causes include medical

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 Oral Agents for the Management of Agitation and Agitated Delirium
comorbidities (eg, psychiatric illness and re-
lated use of psychoactive drugs), cognitive
impairment, end-stage kidney and liver dis-
eases (by predisposing patients to metabolic
encephalopathy), and substance abuse disor-
ders (ie, nicotine, alcohol, opioids, and illicit
medications).5-7 Medications used to manage
acute or chronic illnesses can also be associ-
ated with agitation. Some examples of med-
ications commonly used in critically ill pa-
tients include antimicrobials (eg, acyclovir,
cephalosporins, and ciprofloxacin), corticos-
teroids, metoclopramide, and opioids. In
addition to recognizing newly prescribed
medications, it is important to note that
omission of a patient’s home psychoactive
medication(s) may also lead to agitation asso-
ciated with medication withdrawal.8 Acute ill-
nesses involving the central nervous system,
such as meningitis, encephalitis, traumatic
brain injury (TBI), stroke, and seizures, can
cause agitation. Mechanical ventilation and
electrolyte abnormalities, including hyperna-
tremia, hyponatremia, hypokalemia, and hy-
pomagnesemia, have also been implicated.6,9
Agitation can also be associated with hy-
peractive delirium when patients exhibit ag-
itation, an acute change in mental status,
inattention, and sometimes disorganized
thinking. Depending on the underlying cause,
different approaches may be required to man-
age agitation.9
SCALES USED IN MONITORING
AGITATION
There are many scales available for use to
assess for and monitor agitation. According
to the clinical practice guidelines for the
management of pain, agitation, and delirium
in adult patients in the ICU,10 the Richmond
Agitation-Sedation Scale (RASS) and Sedation-
Agitation Scale (SAS) are the most valid and
reliable sedation assessment tools for mea-
suring quality and depth of sedation in adult
ICU patients.11,12 Both yielded the highest
psychometric scores in terms of interrater
reliability and convergent or discriminant
validation and had a robust number of study
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345
participants. Ramsay Sedation Scale (Ramsay)
and Motor Activity Assessment Scale were
also assessed in this guideline and were found
to have a lower quality of evidence.10,13,14
Other scales have been used in special pop-
ulations, such as patients with brain injury
and pediatric patients. The Agitated Behavior
Scale can be used to assess the nature and
extent of agitation during the acute phase of
recovery from acquired brain injury.15 For pe-
diatric patients, the COMFORT scale is used
to assess pain and contains an embedded
component to assess agitation.16
GOALS OF THERAPY AND NEED
FOR ORAL MEDICATIONS
Goals of therapy when managing agitation
in the critically ill patient include the facilita-
tion of mechanical ventilation, prevention of
patient and caregiver injury, and avoidance
of psychological and physiological conse-
quences of inadequate treatment of agitation.
The first- and second-line sedatives recom-
mended for critically ill patients are usually
administered intravenously to allow for a
quicker time to onset and ease of titration.10
Antipsychotics used to manage agitation due
to delirium or underlying neuropsychiatric
disorders are often administered intramus-
cularly in the acutely agitated, critically ill
patient. Administering medications by the
intravenous and intramuscular routes has
the advantage of faster onset of action but
is accompanied by the risk of inadvertent,
iatrogenic needle injury. Conversely, oral
medications may be perceived as less co-
ercive than parenteral medications and,
therefore, lead to a less traumatic experience
for the patient.17 At the same time, not all ag-
itated patients can be adequately managed by
commonly used sedatives, depending on the
underlying cause of the agitation. As such,
a multimodal approach that utilizes multiple
routes of administration may be appropriate.
The objective of this review is to summarize
the available literature on specific, adjunctive
oral agents used to manage agitation in
critically ill patients while also focusing
346 CRITICAL CARE NURSING QUARTERLY/OCTOBER–DECEMBER 2017
on their pharmacology and appropriate
monitoring.
METHODS
Researchers searched MEDLINE using the
following strategy: “antipsychotic” or “cloni-
dine” or “valproic acid” and “agitation” and
“critical care” or “intensive care.” The search
was limited to case reports or series, obser-
vational studies, and clinical trials regarding
adult patients that were published in English.
References from identified articles were re-
viewed for relevant materials.
REVIEW OF ORAL AGENTS FOR
AGITATION AND AGITATED DELIRIUM
Data for the class of antipsychotics and in-
dividual agents clonidine and valproic acid
for the management of agitation and agitated
delirium were reviewed. Pharmacology clin-
ical pearls for all agents are summarized in
Table 1.
Antipsychotics
Loxapine
Loxapine is a dibenzoxazepine antipsy-
chotic with a similar structure to clozapine.18
It blocks postsynaptic mesolimbic D1 and
D2 receptors in the brain and possesses
serotonin 5-HT2 and adrenergic (α I) block-
ing activities.19 Loxapine is metabolized
to amoxapine, a tricyclic antidepressant.
It has a half-life of about 4 hours and a
time to peak concentration of 1 hour. It
is primarily indicated for the treatment of
schizophrenia and has an off-label indication
to manage psychosis or agitation associated
with dementia. The recommended starting
dosage for treatment of schizophrenia is
10 mg twice daily, although initial dosage
of up to 50 mg daily may be considered in
severe cases. Doses are increased until psy-
chotic symptoms are controlled. The usual
maintenance dose ranges from 60 to 100 mg
daily in divided doses 2 to 4 times daily.
The maximum recommended daily dosage
Copyright © 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
is 250 mg.20 Common side effects of oral
loxapine include parkinsonian-like symptoms
(eg, tremor, hypomimia, rigidity, akathisia),
drowsiness, dry mouth, constipation, and
weight changes, although it is also important
to monitor for rare but serious adverse effects
such as QT interval corrected prolongation.21
Sztrymf and colleagues22 evaluated the
short-term effects of loxapine on agitation,
breathing patterns, and hemodynamics in ag-
itated patients during weaning from mechan-
ical ventilation. They included patients who
were ventilated for greater than 48 hours and
met the criteria for ventilator weaning. These
patients were prospectively monitored at the
time of sedation (a combination of a benzo-
diazepine and an opiate) decrease or with-
drawal and were eligible for the study if they
exhibited agitation after sedation decrease or
removal, defined by RASS score of greater
than 1. Patients who could not receive med-
ications via the enteral route, had a known
allergy to loxapine, or a history of epilepsy
were excluded from the study. The first en-
teral administration of 150 mg of loxapine
was given via a nasogastric tube. If agita-
tion (defined by RASS score of >1) recurred
within 90 minutes, a second dose was given.
If the RASS score remained greater than 1 de-
spite a cumulative dose of 300 mg, conven-
tional sedation was resumed. The patient re-
mained eligible for a new evaluation during
the next attempt at sedation withdrawal.
A total of 19 patients were included, of
which 50% had a history of chronic alcohol
intake. Severe agitation was observed in all
of the patients after intravenous sedation
withdrawal, which was evident by marked in-
creases in both MASS and RASS and a similar
decrease in the Ramsay score. The agitation
was accompanied by increases in respiratory
rate, heart rate, and systemic systolic arte-
rial blood pressure. All patients exhibited
symptoms of opioid and/or benzodiazepine
withdrawal. Loxapine administration resulted
in a dramatic improvement in agitation in
17 of the 19 patients (89%). One of the 17
patients self-extubated 90 minutes after the
administration of the first loxapine dose.
 Table 1. Adjunctive Oral Agents for the Management of Agitation in Critically Ill Patients

Recommended
Mechanism Dosing Significant
Agent of Action Regimen Onset of Action Half-life Metabolism Adverse Effects Monitoring

Loxapine Blocks postsynaptic Starting dose: Within 30 min 4h Hepatically Tremor, QTc-interval
mesolimbic dopamine 10 mg twice metabolized to hypomimia, prolongation
D1 and D2 receptors daily amoxapine rigidity,
in the brain and Initial dosage of up akathisia,
possesses serotonin to 50 mg daily drowsiness, dry
5-HT2 and adrenergic may be mouth,
(alpha I) blocking considered in constipation,
activities severe cases and weight
Usual maintenance changes
dose: 60–100 mg
daily in divided
doses 2–4 times
daily
Maximum
recommended
daily dosage is
250 mg
Quetiapine Blocks serotonin 5-HT1A Starting dose: 7-14 d for Parent compound: Hepatically Drowsiness, QTc-interval
and 5-HT2 , dopamine 50 mg twice schizophrenic 6 h N-desalkyl metabolized by headache, prolongation
D1 and D2 , histamine daily symptoms quetiapine CYP 3A4 agitation,
H1 , and α 1 - and Dosage may be (active dizziness,
α 2 -adrenergic increased as metabolite): fatigue, and
receptors necessary daily 12 h extrapyramidal
in increments of side effects
50 mg bid to a
maximum daily
dose of 400 mg
Ziprasidone Blocks D2 , 5-HT2A , and No recommended Unknown Adults: 7 h Hepatically Drowsiness, QTc-interval
5-HT1D receptors and regimen for Children: 3.7 h metabolized extrapyramidal prolongation
acts as an agonist at indication side effects,
the 5-HT1A receptor Range of daily headache, and
Oral Agents for the Management of Agitation and Agitated Delirium

doses studied: dizziness

20-80 mg
(continues)

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347
 348

Table 1. Adjunctive Oral Agents for the Management of Agitation in Critically Ill Patients (Continued)

Recommended
Mechanism Dosing Significant
Agent of Action Regimen Onset of Action Half-life Metabolism Adverse Effects Monitoring

Clonidine Alpha-2 agonist 0.1-0.5 mg every 3-5 h 12-16 h Extensively Dry mouth, Blood pressure,
6-8 h hepatic to drowsiness, heart rate,
inactive dizziness, sedation
metabolites; constipation, scale
undergoes sedation, sinus
enterohepatic bradycardia
recirculation
Valproic Blocks voltage- 10-15 mg/kg/d Plasma levels Increased in Extensively Headache, Serum trough
acid dependent sodium 2-3 times daily, peak in 1-5 h, elderly, and hepatic via drowsiness, level
and calcium increase by 15 min to 2 h patients with glucuronide dizziness, 50-100 mg/L
channels; increases 5-10 mg/kg/d with syrup, liver conjugation insomnia, (goal con-
GABA synthesis, at weekly and impairment (30%-50% of nervousness, centration
activity at intervals; may immediately adults: 9-19 h administered alopecia, unknown for
receptors, and increase dose with dose) and 40% nausea, agitation)
blocks degradation. up to a intravenous via other vomiting,
Attenuates maximum of administra- oxidative abdominal
glutamate activity 60 mg/kg/d tion; same metabolic pain, diarrhea,
upon N-methyl-D- bioavailability pathways thrombocy-
CRITICAL CARE NURSING QUARTERLY/OCTOBER–DECEMBER 2017

aspartate for all dose topenia,

receptors forms infection,
tremor,
weakness

Abbreviations: GABA, γ -aminobutyric acid; QTc, corrected QT interval.

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 Oral Agents for the Management of Agitation and Agitated Delirium
Two remaining patients required resump-
tion of intravenous sedation to control the
agitation.
The mean (± standard deviation) time
between loxapine administration and a
significant decrease in RASS scores was
62 ± 39 minutes, during which, if neces-
sary, gentle physical restraints and verbal reas-
surance were provided while waiting for the
medication to take effect. While RASS scores
after loxapine administration returned to
those observed before agitation, both Motor
Activity Assessment Scale and Ramsay scores
indicated that patients were calm and coop-
erative but less sedated than before agitation
occurred. No side effects from loxapine were
observed in this study. The authors concluded
that loxapine seems to be safe and effective
for treating acute agitation after withdrawal of
sedative infusions during weaning from me-
chanical ventilation. While the findings from
this study were positive, the sample size was
too small for it to be conclusive or general-
izable. However, the authors mentioned that
they have been using loxapine for many years
without noticing adverse effects. More well-
designed studies are required to better char-
acterize the use of loxapine in critically ill pa-
tients, but it is a potential option for agitated
patients who are candidates for being weaned
off mechanical ventilation.
Quetiapine
Quetiapine is a dibenzothiazepine atyp-
ical antipsychotic thought to mediate its
antipsychotic actions by acting as an an-
tagonist at both dopamine type 2 (D2 ) and
serotonin type 2 (5-HT2 ) receptors. It has
low binding properties at D2 receptors,
which appear to be favorable in delirium
management.23,24 Its antagonistic actions at
multiple neurotransmitter receptors in the
brain (serotonin 5-HT1A and 5-HT2 , dopamine
D1 and D2 , histamine H1 , and α 1 - and
α 2 -adrenergic receptors) may explain some
of the adverse effects observed with its use.
Common adverse effects include drowsiness,
headache, agitation, dizziness, fatigue, and
extrapyramidal side effects. Quetiapine has
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349
been associated with QTc-interval prolon-
gation; hence, it is prudent for all health
care team members to review concurrent
medications for others that increase the risk
of QTc-interval prolongation.24
Quetiapine is indicated for the treatment
of schizophrenia and bipolar disorder. It also
has off-label indications for the treatment of
delirium in critically ill patients, obsessive
compulsive disorder, delusional parasitosis,
generalized anxiety disorder, posttraumatic
stress disorder, psychosis or agitation as-
sociated with dementia, and psychosis in
Parkinson disease. The recommended dosage
for the treatment of delirium in critically
ill patients is 50 mg orally twice daily. The
dosage may be increased as necessary on
a daily basis in increments of 50 mg twice
daily to a maximum daily dose of 400 mg.
Quetiapine is rapidly absorbed following oral
administration with a time to peak plasma
concentration of about 1.5 hours in adults
and a half-life of 6 hours (and 12 hours for its
active metabolite, N-desalkyl quetiapine). It
is metabolized in the liver by CYP3A4
enzymes and excreted in the urine.24
There is some evidence that quetiapine
may be useful for agitation due to delir-
ium. Devlin and colleagues25 conducted
a prospective, randomized, double-blind,
placebo-controlled study in 3 medical centers
to compare the efficacy and safety of sched-
uled quetiapine to placebo for the treatment
of delirium in critically ill patients requir-
ing as-needed haloperidol. Thirty-six adult
ICU patients with delirium (defined as In-
tensive Care Delirium Screening Checklist
score of ≥4), tolerating enteral nutrition, and
without a complicating neurologic condition
were included. They were randomized to re-
ceive quetiapine 50 mg every 12 hours or
placebo. The total daily dose of quetiapine
was increased by 50 mg every 24 hours to
a maximum of 400 mg if more than 1 dose
of haloperidol were given in the previous
24 hours. Quetiapine was provided until the
ICU team discontinued it because of delirium
resolution, therapy for 10 or more days, or
ICU discharge. Baseline characteristics were
350 CRITICAL CARE NURSING QUARTERLY/OCTOBER–DECEMBER 2017
similar between the quetiapine (n = 18) and
placebo (n = 18) groups. Quetiapine was
associated with a shorter time to first res-
olution of delirium (1.0 [interquartile range
(IQR), 0.5-3.0 vs 4.5 days (IQR, 2.0-7.0), P =
.001]), reduced duration of delirium (36 [IQR,
12-87] vs 120 hours [IQR, 60-195], P = .006),
and less time agitated (SAS score of ≥5)
(6 [IQR, 0-38] vs 36 hours [IQR, 11-66],
P = .02). Mortality (11% quetiapine vs 17%)
and ICU length of stay (16 quetiapine vs
16 days) were similar, but subjects treated
with quetiapine were more likely to be dis-
charged home or to rehabilitation (89% que-
tiapine vs 56%, P = .06). Subjects treated
with quetiapine also required fewer days
of as-needed haloperidol (3 [IQR, 2-4] vs
4 days [IQR, 3-8], P = .05). The incidence
of QTc-interval prolongation and extrapyra-
midal symptoms was similar between groups,
but numerically more somnolence was ob-
served with quetiapine (22% vs 11%, P =
.66). The authors concluded that quetiapine
added to as-needed haloperidol resulted in
faster delirium resolution, less agitation, and
a greater rate of transfer to home or reha-
bilitation. This was a well conducted study
but the sample size was too small to reliably
detect differences in important clinical out-
comes. In addition, open-label, as-needed an-
tipsychotics were used by the clinical team,
which may have further minimized potential
differences between groups.26
Interestingly, the post hoc analysis of this
study provided a contradictory result.27 The
authors extracted data for 10 delirium symp-
toms from the intensive care delirium screen-
ing checklist previously collected for 29 study
patients and compared patients who received
quetiapine with those who received placebo.
Among patients with the delirium symptoms
at baseline, use of quetiapine led to a shorter
time (days) to first resolution of symptom
fluctuation (4 vs 14, P = .004), inattention (3
vs 8, P = .10), and disorientation (2 vs 10, P
= .10) but a longer time to first resolution of
agitation (3 vs 1, P = .04) and hyperactivity (5
vs 1, P = .07). However, the authors pointed
out that nearly twice as much “as needed”
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haloperidol was administered on average to
the placebo group, which may account for
the faster resolution of agitation in this group.
It is unclear whether quetiapine improves ag-
itation in critically ill patients with delirium.
In addition, a retrospective case series by
Wan and colleagues28 included 17 critically
ill patients with hyperactive or mixed delir-
ium identified by a validated chart review and
an RASS score persistently greater than 1 for
48 hours despite therapy. Patients taking que-
tiapine for a preexisting psychiatric condition
were excluded. The mean patient age was
59 years, and 15 patients were male. Eight pa-
tients had a history of drug or alcohol abuse,
which was not believed to be the cause of
delirium as viewed by the attending clinician.
All patients had been taking 4 or 5 agents
to control their delirium and agitation be-
fore quetiapine was started and had a median
RASS score of 3 along with consistent doc-
umentation of an acute confused state. The
median time until delirium onset was 5 days
from ICU admission, and the median dura-
tion of refractory hyperactive or mixed delir-
ium was 15 days prior to the introduction
of quetiapine. Quetiapine was initiated by ei-
ther the oral or enteral route at a daily dose
of 25 mg (normally administered in 12-hourly
divided doses) for all patients, and the dose
was titrated by the attending clinician. The
median total daily dose prescribed was 50
mg, with a range between 12.5 and 400 mg.
Following the introduction of quetiapine, pa-
tients had a reduced need for other antiagita-
tion medications and experienced resolution
of refractory hyperactive or mixed delirium
within a median of 4 days. Adverse effects
(ie, QTc-interval prolongation, excessive som-
nolence, and transient hypotension) were ex-
perienced by 4 patients. No extrapyrami-
dal symptoms were observed. The authors
concluded that commencement of quetiap-
ine treatment might be temporally associated
with the resolution of hyperactive and mixed
delirium and a reduction in sedative require-
ments. Unfortunately, the lack of a control
group prevented meaningful comparisons to
be made. Nonetheless, the study described
 Oral Agents for the Management of Agitation and Agitated Delirium
improved agitation from refractory hyperac-
tive or mixed delirium with initiation of queti-
apine and provided useful information on the
low adverse effect event occurrence in these
patients.
Ziprasidone
Ziprasidone is a benzylisothiazolylpiper-
azine antipsychotic with high affinity for D2 ,
D3 , 5-HT2A , 5-HT1A , 5-HT2C , 5-HT1D , and α 1 -
adrenergic receptors and moderate affinity
for histamine H1 receptors. It functions as an
antagonist at the D2 , 5-HT2A , and 5-HT1D re-
ceptors and as an agonist at the 5-HT1A recep-
tor. It is indicated for the treatment of bipolar
disorder, schizophrenia, and acute agitation
associated with schizophrenia. It is also used
off-label or delusional parasitosis and major
depressive disorder as an adjunct to antide-
pressants. Ziprasidone is well absorbed and
has a bioavailability of 60% after oral admin-
istration. It is extensively metabolized by the
liver and has a half-life of 7 hours in adult and
3.7 hours in children. Common adverse ef-
fects include drowsiness, extrapyramidal side
effects, headache, and dizziness. Similar to
quetiapine, it can also increase the risk of
QTc-interval prolongation.29 Ziprasidone has
been investigated for the treatment of agita-
tion after TBI. There is one case series con-
sisting of adult patients and one of pediatric
patients.30,31
Five adult patients with a mean age of
26.8 ± 9.8 years with a severe TBI were
included in the study. All the patients had
a Glasgow Coma Scale score of less than 8.
The mean length of coma was 16 days and
mean length of posttraumatic agitation was
62.4 days. Agitation was assessed by the
Agitated Behavior Scale prior to the admin-
istration of ziprasidone, after 2 weeks of
ziprasidone treatment, and at ziprasidone dis-
continuation. The authors found a decrease
in Agitated Behavior Scale total score from
27.2 ± 3 to 18 ± 1.2 after 2 weeks of
treatment. The same decrease also existed
in each of the subscales (disinhibition, ag-
gressiveness, and lability). The mean dose of
ziprasidone was 52.8 mg (range: 20-80 mg)
Copyright © 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
351
and was administered for a mean of 48.2 ±
14.8 days.30
Another case series study was performed
at a university hospital and pediatric trauma
center. Over an 18-month period, all patients
who presented to the pediatric ICU with TBI
and later developed agitation and/or aggres-
sion were treated with ziprasidone as the
sole intervention. Pre- and posttreatment SAS
scores were recorded. Twenty children re-
ceived ziprasidone for agitation and/or ag-
gression during the immediate recovery pe-
riod from TBI. The median patient age was
8 years (range: 9 months to 17 years). They
were stratified into 4 age groups: less than
2 years of age (group 1), 2 to 6 years of age
(group 2), 7 to 12 years of age (group 3),
and 13 years of age or older (group 4). Com-
pared with baseline, there was a significant
reduction in the SAS score 24 hours after
the initiation of ziprasidone (P < .001) in
all age groups. The initial ziprasidone doses
for groups 1 to 4 were 1.7, 0.9, 0.7, and
0.6 mg/kg, respectively, with final doses of
1.8, 1.5, 1.7, and 0.07 mg/kg, respectively.
The durations of therapy for groups 1 to 4
were 5, 8, 6, and 3 days, respectively. In both
case series, no adverse events due to ziprasi-
done were reported. Based on limited data,
ziprasidone appears to be safe and effective
in adult and pediatric patients with agitation
after TBI.31 (Table 2).
Antipsychotics and QTc-interval
prolongation
Prolongation of the QTc-interval is a rare
but serious event as it can precipitate tor-
sades de pointes—a serious ventricular ar-
rhythmia that may result in sudden cardiac
death.32,33 The mechanism of medication-
induced QTc-interval prolongation is thought
to involve the inhibition of the delayed potas-
sium rectifier current IKr (rapid). The ma-
jority of patients who develop medication-
induced QTc-interval prolongation also have
multiple risk factors, including heart dis-
ease or cardiac abnormalities, age more than
65 years, female sex, receipt of more than
1 QTc-interval prolonging agent, increased
352 CRITICAL CARE NURSING QUARTERLY/OCTOBER–DECEMBER 2017

Table 2. Oral Antipsychotics in Agitation and Agitated Delirium

Author(s) Study Design Patient Population Intervention Results

Sztrymf et al22 Case series n = 19 mechanically Loxapine r RASS decreased from

ventilated patients 2 ± 0 to −1.1 ± 2.3;
with marked agitation P < .05
after sedation r MASS decreased from
withdrawal 5.4 ± 0.5 to 2.7 ± 1.6;
P < .05
r Ramsay score
increased from 1.0 ±
0 to 3.5 ± 1.5; P < .05
r Respiratory rate
decreased from 31.2 ±
7.2 to 23.4 ± 7.8;
P < .05 without
hemodynamic adverse
events
Sixteen (84%) patients
were successfully
managed with
loxapine, sedation
was resumed in 2
others, and 1 patient
self-extubated without
having to be
reintubated
Devlin Randomized n = 36 adult ICU Quetiapine Quetiapine was
et al.25 controlled patients with delirium, associated with
pilot study tolerating enteral r a shorter time to first
nutrition, and without resolution of delirium
a complicating (1.0 [IQR], 0.5-3.0 vs
neurologic condition 4.5 d [IQR, 2.0-7.0;
P = .001]);
r reduced duration of
delirium (36 [IQR,
12-87] vs 120 h [IQR,
60-195; P = .006]);
r less time agitated (SAS
score of ≥5) (6 [IQR,
0-38] vs 36 h [IQR,
11-66; P = .02])
Wan et al28 Case series n = 17 adult patients Quetiapine Quetiapine
with refractory commencement was
hyperactive and associated with a
mixed delirium and a reduction in the need
RASS score for other medications
persistently greater (within 0-6 d) and
than 1 for 48 h despite resolution of delirium
therapy within a median of 4 d
(continues)

Copyright © 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
 Oral Agents for the Management of Agitation and Agitated Delirium 353

Table 2. Oral Antipsychotics in Agitation and Agitated Delirium (Continued)

Author(s) Study Design Patient Population Intervention Results

Scott et al31 Case series n = 20 pediatric Ziprasidone Significant reduction in

patients with TBI SAS score after
who subsequently initiation of
developed agitation medication (P < .001)
and/or aggression in
the immediate
postinjury recovery
period
Noe et al30 Case series n = 5 adult patients Ziprasidone Reduction in ABS total
with severe TBI and score from 27.2 ± 3 to
were in the phase of 18 ± 1.2 after 2 wk of
posttraumatic amnesia treatment

Abbreviations: ABS, Agitated Behavior Scale; ICU, intensive care unit; IQR, interquartile range; MAAS, Motor Activity
Assessment Scale; RASS, Richmond Agitation Sedation Scale; SAS, Riker Sedation-Agitation Scale; TBI, traumatic brain
injury.

concentration of an offending agent, elec- agents, as it does not produce respiratory

trolyte abnormalities (ie, hypokalemia and/or
hypomagnesemia), bradycardia, and congen-
ital QT syndrome.34 Of the 3 antipsychotics
discussed in this review article, loxapine is
not associated with QTc-interval prolonga-
tion, according to a study conducted us-
ing an aerosol formulation.35 Conversely,
ziprasidone caused QTc-interval increases of
15.9 ms and 9.6 ms in 2 separate trials.36,37
However, a post hoc analysis of phase II
to IV trials involving 4306 subjects taking
ziprasidone reported a mean increase in QTc-
interval of only 3.6 ms.38 It is unclear whether
quetiapine may prolong the QTc-interval due
to the presence of underlying risk factors for
the patients studied.39 Regardless, in patients
who are initiated on these agents, it is pru-
dent to monitor an electrocardiogram and
heart rate regularly and to minimize the use
of concurrent medications that can increase
the risk of QTc-interval prolongation.
Clonidine
Clonidine is an α-2 partial agonist that
stimulates presynaptic α-2 adrenorecep-
tors within the brainstem, decreasing
norepinephrine release while enhancing
parasympathetic activity.40 Clonidine’s seda-
tive properties offer advantages over other
depression, decreases the dose requirements
of other sedatives, facilitates opiate with-
drawal, and can be administered orally.41
Clonidine has excellent bioavailability (75%-
88%) and a low drug acquisition cost, making
it an attractive option for the treatment
of agitation. It has a time to peak plasma
concentration of 3 to 5 hours and a half-life
of 12 to 16 hours, which increases to 41
hours in severe renal impairment.42 It has
a Food and Drug Administration–labeled
indication for the treatment of hypertension
but is used off-label for opioid withdrawal,
pain management, attention deficit hy-
peractivity disorder, and agitation. When
used for opioid withdrawal, the dose is 0.1
to 0.3 mg every 6 to 8 hours (maximum
1.2 mg/d).43 The most frequent adverse
effects are dry mouth, drowsiness, dizziness,
constipation, and sedation, although cases
of sinus bradycardia have been reported
as well.42
Evidence supporting the use of clonidine
as a sedative agent in the critically ill re-
mains scarce, and the 2013 Pain, Agitation,
and Delirium guidelines provided no recom-
mendation on its use.10 The use of cloni-
dine as an agent to reduce agitation and delir-
ium has been extrapolated from the trials

Copyright © 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
354 CRITICAL CARE NURSING QUARTERLY/OCTOBER–DECEMBER 2017
of dexmedetomidine, an intravenous α-2 ago-
nist, which showed reduced incidence of ag-
itation and delirium when compared with lo-
razepam and midazolam.44,45 Currently, much
of the recent literature addresses the transi-
tion from dexmedetomidine to enteral cloni-
dine in the ICU.46,47
Kariya and colleagues48 published one of
the first reports of enteral clonidine use for
agitation management in a 52-year-old burn
patient. The patient remained agitated with
a Ramsay scale score of 1 despite midazolam,
buprenorphine, and ketamine continuous in-
fusions. On hospital day 5, clonidine was ad-
ministered at 10 μg/kg/d (0.65 mg/d) divided
into 3 doses. By hospital day 5, hemodynam-
ics normalized; midazolam, buprenorphine,
and ketamine infusions were discontinued;
and the agitation resolved as evidenced by
a Ramsay scale score of 3. Oral clonidine
was gradually decreased and discontinued
on the seventeenth hospital day with ICU
discharge.
Two studies have investigated the transition
from dexmedetomidine to enteral clonidine
for agitation management.46,47 Gagnon and
colleagues46 conducted a single-center,
prospective, observational, pilot study in
20 adult patients with or without agitation
who received dexmedetomidine for sedation.
Patients were mostly male with a median
age of 62 years and 65% were mechanically
ventilated. Sixty percent of the patients were
on dexmedetomidine for agitation. Clonidine
was administered every 6 hours at doses be-
tween 0.2 and 0.5 mg. Doses were initiated
at 0.2 mg for patients on dexmedetomidine
doses less than 0.7 μg/kg per hour, body
mass less than 100 kg, or older patients, and
0.3 mg for patients on dexmedetomidine
doses of 0.7 μg/kg per hour or more, body
mass of 100 kg or more, or younger patients.
The dexmedetomidine dose was reduced by
25% from baseline within 6 hours of each
clonidine dose if no agitation occurred, and
clonidine doses were adjusted to maintain
a target SAS score of 3 to 4. Clonidine was
tapered off when agitation resolved by
extending the dosing interval every 24 to
Copyright © 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
48 hours. Successful transition from dex-
medetomidine to clonidine occurred in
50% of patients within 24 hours and 75%
within 48 hours. No significant differences
were seen between the dexmedetomi-
dine and clonidine maintenance phases
as measured by an occurrence of SAS
out of the target range of 3 to 4 (25% vs
50%), confusion assessment method for the
intensive care unit (CAM-ICU) positivity
(40% vs 50%), or the use of benzodi-
azepines (1.4-mg lorazepam equivalents vs
3-mg lorazepam equivalents) or antipsy-
chotics (60% vs 35%). in addition, no
differences were seen in hemodynamic
adverse events (25% vs 40%). The authors
estimated that the use of clonidine in place
of dexmedetomidine generated a drug cost
avoidance during the 3-month study of
$15 359 to $52 138. This study suggests
that transitioning from dexmedetomidine
to clonidine may be a safe, effective, and
less costly method for providing α-2 agonist
therapy for agitation.
In a retrospective analysis, Terry and
colleagues47 evaluated 26 patients for
dexmedetomidine discontinuation within
8 hours of enteral clonidine administration
and the rates of dexmedetomidine reinitiation
in patients who failed clonidine transition.
Patients were mostly male with a mean age of
54.4 years. Most patients (80.7%) were admit-
ted to the cardiac ICU but only 14.8% were
mechanically ventilated. Dexmedetomidine
discontinuation occurred in 65.4% of patients
within 8 hours of clonidine administration
and no patients required dexmedetomidine
reinitiation. The median time to success-
ful dexmedetomidine discontinuation was
1 hour. Enteral clonidine administration
was not protocolized; the most common
dosing strategy was 0.1 mg titrated every 6 to
8 hours to achieve a specified RASS goal.
The median clonidine exposure was 0.35 mg
per ICU day in patients who discontinued
dexmedetomidine and 0.5 mg per ICU day in
those who did not (P = .036). Both groups
had a median RASS score of 0 and similar
rates of CAM-ICU positivity (17.6% vs 44.4%).
 Oral Agents for the Management of Agitation and Agitated Delirium
Similar to the study by Gagnon et al,46 no
difference was found in the rates of rescue
sedation (94% vs 100%) or hemodynamic
adverse events (35.5% vs 44.4%) between the
groups. They did observe that unintentional
use of clonidine beyond ICU and hospital
discharge was as high as 76.9%; however,
the process for weaning enteral clonidine
was not studied. The authors concluded that
clonidine may be a safe and effective adjuvant
to facilitate transitioning sedated patients
off dexmedetomidine, but clinicians should
critically evaluate the need for clonidine at
ICU and hospital discharge.
A prospective, randomized, double-blind,
placebo-controlled study by Farasatinasab and
colleagues49 was designed to assess the im-
pact of clonidine on sedative agent use in me-
chanically ventilated patients. Forty adult pa-
tients on mechanical ventilation for 3 days or
more were randomized into 2 equal groups
of clonidine and placebo. The clonidine arm
received enteral clonidine 0.1 mg 3 times
daily and escalated to 0.2 mg 3 times daily
on the second day if hemodynamics remained
stable. Both arms received usual sedation
with intravenous opioids, benzodiazepines,
or propofol. Patients were mostly male with
a mean age of 57 years. There were no differ-
ences between the groups in sedative agent
regimens, but the number of patients with
drug abuse was higher in the intervention
group than in the control group (50% vs 15%,
P = .018). Mean daily morphine dosing equiv-
alents (mg per day) during the study period
were reduced by 27.5 ± 14.36 in the cloni-
dine arm and increased by 1.96 ± 18.78 in
the placebo arm (P = .006). The mean daily
midazolam use (mg per day) during the study
period was reduced by 1.87 ± 1.63 in the
clonidine arm and increased by 0.41 ± 0.64
in the placebo arm (P = .005). Linear regres-
sion analysis, which included variables such
as history of drug abuse and higher propo-
fol use in the intervention arm, found a re-
duction in opioid requirement in the cloni-
dine arm by 79.6 mg per day (P = .005)
and a reduction in benzodiazepine require-
ment in the clonidine arm by 5.41 mg per day
Copyright © 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
355
(P = .05). There were no significant differ-
ences in hemodynamic adverse events. The
effect of clonidine on attainment of seda-
tion goals was not assessed. The authors con-
cluded that clonidine is an attractive option at
reducing opioid and benzodiazepine use for
sedation in mechanically ventilated patients.
Based on the available literature, clonidine ap-
pears to be a safe and effective option for se-
dation and treatment of agitation in the ICU,
especially as an adjunct agent to help with
weaning intravenous sedatives. Although this
use of clonidine is well documented in the
pediatric literature, future studies, including
larger randomized controlled trials, would be
helpful to characterize the use of clonidine
for the adult patient population with agitation
(Table 3).
Valproic acid
Valproic acid is an emerging treatment
for ICU agitation because it allows patients
to interact with their caregivers; may be
administered outside of the ICU; has multiple
formulations; has a low drug acquisition cost;
and has not been associated with respiratory
depression, hemodynamic derangements, or
delirium. Valproic acid is a histone deacety-
lase inhibitor that blocks voltage-dependent
sodium and calcium channels, increases
γ -aminobutyric acid synthesis, potentiates
γ -aminobutyric acid activity at postsynaptic
receptors, blocks γ -aminobutyric acid degra-
dation, and attenuates the activity of gluta-
mate upon N-methyl-D-aspartate receptors.50
Approved indications include migraine
prevention and resolution and prevention
of simple and complex absence seizures,
complex partial seizures, and mania. Off-label
uses include diabetic neuropathy and status
epilepticus. Valproic acid is available as an
immediate release tablet, capsule, and oral
solution; a delayed release capsule, tablet,
and capsule sprinkle; a 24-hour extended
release tablet; and intravenous solution. Val-
proic acid distributes into the cerebral spinal
fluid at concentrations similar to unbound
concentrations in the blood. It is highly pro-
tein bound (80%-90%), and concentrations
 356
Table 3. Oral Clonidine in Agitation and Agitated Delirium

Author(s) Study Design ICU Population Interventions Results

Kariya et al48 Case report Adult burn Clonidine 10 μg/kg/d in Resolution of agitation and effective
3 divided doses discontinuation of intravenous
sedatives
Gagnon et al46 Single-center Mixed medical, Clonidine 0.2-0.5 mg Successful wean of DEX in 75% of
prospective surgical, every 6 h titrated to patients at 48 h
observational neurologic SAS of 3-4 used to No difference in achievement of SAS
wean DEX target, delirium, sedative use, or
hemodynamic adverse events
found in the clonidine vs DEX
maintenance phases
Terry et al47 Single-center Primarily cardiac Clonidine 0.1 mg every Successful wean of DEX in 65.4% of
retrospective 6-8 h titrated to RASS patients at 8 h
or until hemodynamic No difference was found in RASS
parameters prohibited goal, delirium, sedative use, or
titration used to wean hemodynamic adverse events
DEX found in those successfully
weaned in 8 hours versus not
Farasatinasab Randomized, General Clonidine 0.1-0.2 mg Clonidine initiation resulted in a
et al49 double-blind, every 8 h titrated to reduction in opioid requirement
placebo-controlled Ramsay score of 3-4 in by 79.6 mg/d (P = .005) and a
addition to usual reduction in benzodiazepine
CRITICAL CARE NURSING QUARTERLY/OCTOBER–DECEMBER 2017

sedation with requirement by 5.41 mg/d

fentanyl, midazolam, No significant differences in
morphine, or propofol hemodynamic adverse events but
effect of clonidine on attainment
of sedation goals was not assessed

Abbreviations: DEX, dexmedetomidine; ICU, intensive care unit; RAAS, Richmond Agitation-Sedation Scale; SAS, Sedation-Agitation Scale.

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 Oral Agents for the Management of Agitation and Agitated Delirium
are increased in populations with decreased
protein binding, such as neonates, the elderly
patients, and those with hepatic and/or renal
impairment(s). The half-life is between 9 and
19 hours in adults and may be prolonged
in the elderly and patients with hepatic im-
pairment. Oral maintenance doses are 10 to
15 mg/kg per day for complex partial seizures
and 15 mg/kg per day for simple and com-
plex absence seizures; both have a maximum
approved dose of 60 mg/kg per day.51
The literature investigating the use of val-
proic acid for agitation in critically ill pa-
tients is growing.52-56 One retrospective study
by Gagnon and colleagues52 evaluated 53
critically ill patients admitted to 2 academic
medical centers between December 2012
and February 2015. Information on valproic
acid prescribing practices and safety was col-
lected as well as incidence of agitation, delir-
ium, and concomitant psychoactive medica-
tion use compared between valproic acid day
1 and valproic acid day 3. Valproic acid was
initiated on ICU day 7 (IQR: 4-10) and was
continued for a median of 7 (IQR: 4-10) days.
The median maintenance dose was 1500 mg
per day (23 [IQR: 15-31] mg/kg per day). Al-
most all patients (96%) were agitated on the
day valproic acid was initiated. On day 3 of
therapy, 61% remained agitated (P < .0001).
In addition, fewer patients were experienc-
ing delirium on day 3 of valproic acid ther-
apy (68% vs 49%, P = .012). Fewer patients
received opioids (77% vs 65%, P = .02) and
dexmedetomidine (47% vs 24%, P = .004)
between days 1 and 3 of therapy; however,
these decreases may have included reasons
other than valproic acid usage (eg, resolu-
tion of underlying pathophysiology, extuba-
tion). In mixed-models analyses, daily require-
ments for concomitant sedative and analgesic
medications were decreased as well (fentanyl:
185 μg per day, P = .0003; lorazepam: 2.1 mg
per day, P = .0004; dexmedetomidine:
0.15 μg/kg per hour per day, P < .0001;
propofol: 5 μg/kg/min per day, P = .003). Hy-
perammonemia (19%) and thrombocytopenia
(13%) were the most commonly observed ad-
verse effects. Hyperammonemia resulted in
valproic acid discontinuation in 4 patients
Copyright © 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
357
(7.5%); however, a dose-response effect was
not observed. The authors concluded that
valproic acid therapy was associated with
a reduction in agitation, delirium, and con-
comitant psychoactive medication use within
48 hours of initiation.
Bourgeois and colleges53 described val-
proic acid use in 6 patients with past medical
histories significant for psychiatric diseases
who were actively experiencing agitation and
delirium. Half of the patients were critically
ill and the other half were acutely ill; all were
seen by a consultation-liaison service to man-
age their delirium and/or psychotic agitation
because they had experienced a suboptimal
response and/or significant adverse effects
from conventional therapy with benzodi-
azepines and/or antipsychotic agents. All pa-
tients received valproic acid (1162.5-1533.3
mg per day) alongside other psychoactive
agents (ie, haloperidol, lorazepam). Two
patients received the intravenous formulation
of valproic acid and 4 received the oral liquid
formulation through a nasogastric tube. The
average serum valproic acid concentration
was 44.6 mg/L. All 6 patients experienced
resolution or improvement in their agitation
and delirium symptoms within 3 to 5 days.
No adverse effects were observed with
valproic acid therapy. In patients with a
history of psychiatric disease, valproic acid
may have a role in management of agitated
delirium; however, further evaluation is
necessary to determine the likelihood of
success with this intervention and a target
serum concentration, if one exists.
Sher and colleagues54 performed a single
center, retrospective cohort study of 15
patients who experienced 16 episodes of ag-
itation associated with hyperactive delirium
(diagnosed by a psychiatrist according to
Diagnostic and Statistical Manual of Mental
Disorders [Fourth Edition, Text Revision]
[DSM-IV-TR] criteria and liptzin criteria). All
episodes except for one were refractory to
conventional antipsychotic-based therapy.
Most patients were treated in the ICU. After
initiation of valproic acid, complete reso-
lution of delirium according to DSM-IV-TR
criteria was documented in 13 (81.3%)

Table 4. Oral Valproic Acid in Agitation and Agitated Delirium
Study Design ICU Population
Gagnon et al52 Retrospective cohort 53 patients representing 522
study patient-days of valproic acid
therapy. Respiratory failure
(26%), trauma (22%), and
acute stroke (15%) were the
most common reasons for
ICU admission.
Bourgeois Case series 6 separate patient cases; all
et al53 patients were male, the
average age was 47 y
(range = 40-63 y)
Copyright © 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
358
Interventions Results
Critically ill patients Incidence of agitation was 96% for
treated with valproic day 1 of therapy vs 61% for day 3
acid for agitation for (P < .0001) and delirium was 68%
≥2 d while in the ICU vs 49% (P = .012)
Treatment with opioids (77% vs 65%,
P = .02) and dexmedetomidine
(47% vs 24%, P = .004) also
decreased by day 3
Valproic acid was associated with
reduced fentanyl equivalents
(−185 μg/d, P = .0003) and
lorazepam equivalents (−2.1 mg/d,
P = .0004)
Hyperammonemia and
thrombocytopenia were the most
common adverse effects
Valproic acid used The average daily dose of valproic
because of suboptimal acid was between 1162.5 mg and
responses and/or 1533.3 mg per day and the average
concerning side serum valproic acid level was
effects from 44.6 mg/L
CRITICAL CARE NURSING QUARTERLY/OCTOBER–DECEMBER 2017
conventional therapy In all 6 cases, valproic acid combined
with benzodiazepines with conventional antidelirium
and/or antipsychotics medications resulted in improved
control of behavioral symptoms
without significant side effects
(continues)
 Table 4. Oral Valproic Acid in Agitation and Agitated Delirium (Continued)
Study Design ICU Population
Sher et al54 Retrospective chart 15 patients with 16 total
analysis episodes of hyperactive
delirium, 14 patients were
male, and the average age
was 51.8 y (range = 25-
87 y); 12 out of 16 episodes
were treated in the ICU,
1 treated in the CCU,
3 treated on the floor
Abbreviations: CCU, critical care unit; ICU, intensive care unit.
Copyright © 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Interventions Results
Valproic acid was started Complete resolution of delirium was
after multiple documented in 13 cases
medications were The average time from valproic acid
tried in an attempt to initiation to delirium resolution
control agitation was 6.2 d (SD = 8.0, range = 1-30)
associated with The average dose of valproic acid on
hyperactive delirium days 1 through 4 was 1133-
1258 mg per 24 h (SD = 480-625),
administered in 2-3 divided daily
doses
There were no statistical differences
in laboratory findings and no other
adverse effects attributable to
valproic acid
Oral Agents for the Management of Agitation and Agitated Delirium
359
360 CRITICAL CARE NURSING QUARTERLY/OCTOBER–DECEMBER 2017
episodes. The mean time from valproic acid
initiation to delirium resolution was 6.2 days
(SD = 8.0, range = 1-30). Excluding the out-
lier of 30 days, the mean number of days to
delirium resolution was 4.2 days (SD = 3.8).
All study patients, including the 3 patients
whose delirium incompletely resolved, expe-
rienced discernible improvement in agitation
and behavioral management as reflected by
documented mini-mental state evaluations;
an ability to discontinue restrains; reports of
decreased impulsivity, restlessness, and ag-
gression; and a decreased need for sedation.
The mean valproic acid daily dose during the
first 4 days of therapy was 1133 to 1258 mg
(SD = 480-625), administered twice or thrice
daily. Other than 2 cases of thrombocytope-
nia, there were no adverse effects attributed
to valproic acid. There appeared to be a
significant improvement in hyperactive delir-
ium symptoms in the majority of patients
with the initiation of valproic acid following
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