Managing Acute Agitation in Medical Settings

 
The Medical Management of Acute Agitation
 
APM Resident Education Curriculum
 
Revised 2019: 
Ariadna Forray, MD, Naomi Schmelzer, MD
 
Original version: 
R. Scott Babe, M.D
., Clinical Assistant Professor of Psychiatry, Western University of Health Sciences,
Samaritan Mental Health, Corvallis, Oregon
Thomas W. Heinrich, MD
, Associate Professor of Psychiatry & Family Medicine, Chief, Psychiatric Consult Service at Froedtert Hospital,
Department of Psychiatry & Behavioral Medicine, Medical College of Wisconsin
 
Version of March 15, 
2019
 
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Identify the behavioral spectrum of agitation
Describe the broad differential diagnosis behind the symptoms of agitation and
aggression.
Apply non-pharmacologic and pharmacologic approaches to management of the
agitated patient in the general medical setting.
 
2
 
The Case
 
A 47 year-old male with a history of substance use disorder and bipolar disorder along with morbid
obesity, DM and COPD presents to the ED at 0200 after calling 911 and reporting chest pain.
He is cooperative in the ED, but observed to be mumbling to himself and staring at staff suspiciously.
He is given lorazepam 1mg PO to calm him.
Since arriving to the floor to rule out an MI, he has become increasingly restless, irritable, and
confrontational. He is increasingly uncooperative with medical care, then becomes verbally and
physically threatening to the staff.
His primary team calls a psychiatry consult for help managing these behaviors.
 
3
 
Definitions
 
Agitation
Excessive motor or verbal activity
“an emergent situation that is temporary, breaks the therapeutic alliance, and is in need of a
prompt and immediate intervention” (Garriga et al. 2016)
 
Aggression
Hostile, injurious, or destructive behavior. Can be verbal or physical.
 
Violence
Denotes physical aggression by people against other people
2 general types:
Impulsive/reactive
Instrumental/premeditated –goal-oriented violence
 
(Siever L. (2008) Neurobiology of aggression and violence. Am J Psychiatry 165: 429-42.
Garriga M., Pacchiarotti, I., Kasper, S. et al. (2016) Assessment and Management of Agitation in Psychiatry: Expert
consensus. World J Biol Psychiatry. 17, 170-185.)
 
4
 
Component Behaviors of Agitation
 
Nonaggressive behaviors
Restlessness (akathisia, fidgeting)
Wandering
Loud, excited speech
Pacing or frequently changing body positions
Inappropriate behavior (disrobing, intrusive, repetitive questioning)
Aggressive behaviors
Physical
Combativeness, punching walls
Throwing or grabbing objects, destroying items
Clenching hands into fists, posturing
Self-injury (repeatedly banging one’s head)
Verbal
Cursing
Screaming
 
5
 
Larkin GL. et al. Trends in US Emergency Department Visits for Mental Health Conditions, 1992-2001. Psychiatric Services, June 2005. 56; 671-677.
Marco, C. A., & Vaughan, J. (2005). Emergency management of agitation in schizophrenia. 
The American journal of emergency medicine
23
(6), 767-776.
 
There is little direct data on the prevalence, clinical impact, or financial consequences
of agitation
Behavioral emergencies responsible for 6% of all ED visits 
(Larkin et al 2005)
4.3 million psychiatric emergency visits/year 
(Marco and Vaughan, 2005)
21% (900,000) agitated patients with schizophrenia
13% (560,000) agitated patients with bipolar disorder
5% (210,000) agitated patients with dementia
 
 
6
 
Epidemiology
 
Epidemiology
 
Studies for health care workers
California:
465 assaults per 100,000 hospital workers vs. 82.5 assaults per 100,000 for all workers
(Peek-Asa et al 1997)
Minnesota Nurses Study 
(Gerberich et al 2004)
:
13.2 per 100 persons per year for physical assaults
38.8 per 100 persons per year for non-physical assaults
Greatest risk for persons working in/with:
Long term care facility
Intensive care
Psychiatric unit
Emergency department
Geriatric patients
 
7
 
Peek-Asa, C., Howard, J., Vargas, L., & Kraus, J. F. (1997). Incidence of non-fatal workplace assault injuries determined from employer's reports in California. 
Journal of
Occupational and Environmental Medicine
39
(1), 44-50.
Gerberich, S. G., Church, T. R., McGovern, P. M., Hansen, H. E., Nachreiner, N. M., Geisser, M. S., ... & Watt, G. D. (2004). An epidemiological study of the magnitude and
consequences of work related violence: the Minnesota Nurses’ Study. 
Occupational and environmental medicine
61
(6), 495-503.
 
Etiology of Agitation
 
A. Disease-related: three major categories
Psychiatric manifestations of general medical conditions
Substance intoxication/withdrawal
Primary psychiatric illness
B. Instrumental: unlikely to benefit from medical intervention (e.g., criminal
behavior)
Consider short trial of verbal de-escalation
Depending on severity, consider involving security or law enforcement
 
These are not mutually exclusive
 
 
8
 
Etiology of Agitation:  A Sample of the Varied Conditions
that may Present with Pathologic Agitation
Dementia
Huntington's disease
Brain injury or trauma
Delirium (Organic Brain Syndrome)
Korsakoff’s psychosis
Brain tumors
Seizure
Hypoglycemia
Stroke
Thyroid disease
Antisocial behavior
 
 
 
9
Substance intoxication or withdrawal
Bipolar disorder
Major Depressive Disorder
Psychosis
PTSD
Anxiety Disorders
Personality Disorders
Autism
Intellectual Disability
 
Etiology of Agitation: Medical Causes
Head trauma
Encephalitis, meningitis, other
infection
Encephalopathy (e.g., liver or renal
failure)
Environmental toxins
Metabolic abnormalities (sodium,
calcium, glucose)
 
 
10
Hypoxia
Thyroid disease
Seizure (including post-ictal state)
Toxic levels of medications
 
 
 
 
 
Nordstrom, K., Zun, L. S., Wilson, M. P., Stiebel, V., Ng, A. T., Bregman, B., & Anderson, E. L. (2012). Medical evaluation and triage of the agitated patient: consensus statement of the American Association for Emergency Psychiatry Project BETA Medical Evaluation
Workgroup. 
Western Journal of Emergency Medicine
13
(1), 3.
 
Etiology of Agitation: Delirium
 
Diagnostic Features
Disturbance of consciousness
A change in cognition or development of perceptual disturbance
Not accounted for by a dementia
Disturbance develops over a short period of time and tends to fluctuate
(“waxing and waning”)
Caused by a general medical condition
 
11
 
Etiology of Agitation: Substances
 
Substance intoxication –
Alcohol, cocaine, amphetamines, cannabis, ketamine, ecstasy, bath salts, inhalants
 
Substance withdrawal –
Alcohol withdrawal delirium/DTs
 
CNS effects of non-psychiatric medications (steroids)
 
12
 
Etiology of Agitation: Primary Psychiatric disorders
 
 
Schizophrenia
Bipolar Disorder
 Neurocognitive Disorder (Dementia)
Personality Disorders
Agitated depression
Anxiety disorder
Autism spectrum disorder
 
13
 
Etiology of Agitation: Common Triggers
 
Akathisia from antipsychotic or antidepressant use
Comorbid substance use or intoxication
Poor impulse control or other comorbid cognitive deficits
Chaotic or disruptive environment
Medical illness
Exacerbation of symptoms of primary illness
Psychosocial trigger
 
 
 
 
14
 
Garriga, M., Pacchiarotti, I., Bernardo, M., & Vieta, E. (2017). Psychiatric Causes of Agitation: Exacerbation of Mood and Psychotic Disorders. 
The Diagnosis and Management
of Agitation
, 126..
 
Etiology of Agitation: Schizophrenia
 
Patients may present to the ED with acute psychosis
Hallucinations
Delusions
Disorganized speech and/or behavior
Lack of insight
Bizarre behavior
Fertile conditions for the development of agitation
Psychosis and agitation have a reciprocal relationship
 
15
 
Etiology of Agitation: Schizophrenia
 
Patients at highest risk for violence
More suspicious and hostile
More severe hallucinations
Less insight into delusions
Greater thought disorder
Poor impulse control
Risk factors for being targeted for violence by person with schizophrenia
Parent or immediate family member
Cohabitation
Patient financially dependent on you
 
16
 
Sachs, G. S. (2006). A review of agitation in mental illness: burden of illness and underlying pathology. 
The Journal of clinical psychiatry
67
, 5-12.
 
Etiology of Agitation: Personality Disorders
 
 
Some personality disorders are more prone to agitation
Decreased stress tolerance
Poor impulse control
E.g., Borderline personality disorder, Antisocial personality disorder
 
17
 
Etiology of Agitation: Major Neurocognitive Disorder
 
Overall, the incidence of agitation is estimated to be between 60-80% (median 44%)
(Bartels et al 2003)
50% become frankly physically aggressive
24% become verbally aggressive
Burden of institutionalization
Residents with dementia complicated by agitation have the highest 3-month rate of ED visits and
greatest use of restraints 
(Sachs, 2006)
Despite use of restraints, over 40% receive no psychiatric medications
 
18
 
Bartels, S. J., Horn, S. D., Smout, R. J., Dums, A. R., Flaherty, E., Jones, J. K., ... & Voss, A. C. (2003). Agitation and depression in frail nursing home elderly patients with
dementia: treatment characteristics and service use. 
The American journal of geriatric psychiatry
11
(2), 231-238.
 
 Sachs, G. S. (2006). A review of agitation in mental illness: burden of illness and underlying pathology. 
The Journal of clinical psychiatry
67
, 5-12
 
Etiology of Agitation: Dementia
 
Agitation may be a final common pathway for the expression of…
Depression
Anxiety
Psychosis
Pain
Delirium
While agitation may be of multifactorial etiology in patients with dementia, it is
also true that many patients have only agitation as a target symptom for
treatment 
(Madhusoodanan,  2001)
 
19
 
 Madhusoodanan, S. (2001). Introduction: antipsychotic treatment of behavioral and psychological symptoms of dementia in geropsychiatric patients. 
The American Journal of
Geriatric Psychiatry
9
(3), 283-288
.
 
Etiology of Agitation: Psychodynamic Perspectives
 
A Psychodynamic framework can be used to complement treatment strategies
 
- Helps temper counter-transference
Psychodynamic perspectives of agitation and violence
-
In contemporary psychoanalytic thought, “the capacity for aggression is innate and universal,
aggressive behavior occurs in response to threats that the self perceives in relation to internal and
external objects.”
-
Crisis can be defined as an assault on the person’s sense of self 
(Bernstein 2007)
 
20
 
Yakeley, J. (2018). Psychodynamic approaches to violence. 
BJPsych Advances
24
(2), 83-92.
 
Back to the Case (continued)
 
Potential etiologies for our gentleman’s growing agitation
Substance intoxication or withdrawal
Delirium
Bipolar disorder
Personality disorder
 
21
 
Assessment of Agitation
 
Decisions regarding diagnostic tests must be made in the context of
available history and physical examination
Goal is to evaluate patient’s risk for medical comorbidities
Many questions involve forced decisions based on…
Assumptions
Information available
Diagnostic confidence
Patient’s individual risk factors
 
22
 
Assessment of Agitation
 
For a patient with known diagnosis of schizophrenia presenting with behavioral
features of typical decompensation:
Expectant management is appropriate
For patients with atypical features additional diagnostic tests may be required
Atypical presentations
Delirium
History of trauma
Overdose
Headache
Fever
Diagnostic tests to consider
Toxicology screens
CT of brain
BMP, CBC, and LFTs
Urinalysis
Endocrine tests
Lumbar puncture
 
23
 
The Case 
(continued)
 
Examination of the patient
The patient is febrile with normal vitals
Disheveled and malodorous
Heart, lungs and abdomen are benign
No tremor, diaphoresis, nystagmus or asterixis
Mental status examination reveals:
Appearance/behavior: middle-aged unkempt male in hospital johnny and socks,
uncooperative, pacing the room, poor eye contact, posturing with fists
Speech: spontaneous, loud, nonpressured, use of profane language
Mood: “I’m lousy!”, Affect: labile, irritable
TP: tangential, TC: paranoia towards hospital staff, no SI/HI, no perceptual
disturbances. Does not participate in formal cognitive exam questions.
 
 
 
 
 
 
24
 
The Case 
(continued)
 
Laboratory evaluation of the patient
CBC, BMP are normal except for a glucose of 211
LFTs are normal except for a low albumin
TSH, B12, Folate, and RPR are also normal
U/A is positive for glucose and trace ketones
CT of head is read as “negative”
EKG shows QTc < 400msec
UDS and serum toxicology are negative
Valproate, carbamazepine, and lithium levels are all negative
 
 
 
 
 
 
 
25
 
Before the Acute Intervention
 
The staff on Med/Surg units are often less informed about what feelings and
behaviors their actions may elicit in patients
Studies indicate that staff training and education can change this lack of appreciation
Psychiatric consultants should provide education about
Establishing goals from the patient’s perspective
Interventions that support a structured setting
Private or semi-private room
Establish clear set of expectations with a written schedule
Identify staff that are responsible for the patient’s care
Attempting to enlist the patient in the treatment, i.e. which route of medication has worked the
best in the past as a “choice” which retains some patient control
 
 
 
26
 
Goals of Intervention
 
Acute agitation or a violent patient modifies the normal caregiver-patient
relationship
The first goal of treatment is to do only what is necessary to assure the safety of the
patient and others while facilitating the resumption of more normal interpersonal
relations
Calming without over-sedation
 
27
 
Agitation Management
 
Medical evaluation and triage
Psychiatric evaluation
Verbal de-escalation
Environmental intervetions
Psychopharmacologic interventions
Use of seclusion/restraint
 
 
28
 
Holloman Jr, G. H., & Zeller, S. L. (2012). Overview of Project BETA: best practices in evaluation and treatment of agitation. 
Western Journal of Emergency Medicine
13
(1), 1
.
 
Environmental Interventions
 
Examples of effective non-pharmacological treatments
Clearing the room
Removing dangerous objects
Having staff available as a “show of force”
Close observation
Calm conversation
Decreasing sensorial stimulation
 
29
 
Communication/Behavioral Interventions
 
Nonverbal
Maintain a safe distance
Maintain a neutral posture
Do not stare; eye contact should convey sincerity
Do not touch the patient
Stay at the same height as the patient
Avoid sudden movements
Verbal
Speak in calm, clear tone
Personalize yourself
Avoid confrontation; offer to solve the problem
 
30
 
Onyike, C., & Lyketsos, C. (2011). Aggression and violence. 
Textbook of Psychosomatic Medicine: Psychiatric Care of the Medically
101
, 153-174..
 
Communication/Behavioral Interventions
 
Aligning Goals of Care
Acknowledge the patient’s grievance
Acknowledge the patient’s frustration
Shift the focus to discussion of how to solve the problem
Emphasize common ground
Focus on the big picture
Find ways to make small concessions
Monitoring Intervention Progress
Be acutely aware of progress
Know when to disengage
Do not insist on having the last word
 
31
 
Onyike, C., & Lyketsos, C. (2011). Aggression and violence. 
Textbook of Psychosomatic Medicine: Psychiatric Care of the Medically Ill
101
, 153-174
..
 
Back to the Case (continued)
 
You assist the team and the nursing staff:
Clear the room
Keep dangerous objects out of reach
Call security
You approach the patient using verbal de-escalation techniques that you have
learned and practiced
Despite these interventions the patient makes further threats, rips-off telemetry
lines, and starts to pace with clenched fists while mumbling incoherently
 
32
A little bit of history…
33
 
Serotonin-Dopamine Model of Regulation of Agitation
 
Dynamic interaction between the amygdala, nucleus accumbens, and the
prefrontal cortex
 
34
Nucleus
Accumbens
Amygdala
activation
Prefrontal Cortex
 
agitation
 
Suppression
 
Dopamine Released
 
Ryding et al. The role of dopamine and serotonin in suicidal behavior and aggression. Prog Brain Res 2008;172:307-15
Provides a basis for the response to certain medications
 
Goals of Intervention
 
Ideally pharmacotherapy for acute agitation should:
Be easy to administer, non-traumatic
Provide rapid tranquilization without excessive sedation
Have a fast onset of action and a sufficient duration of action
Have a low risk for significant adverse events and drug interactions
 
35
 
Goals of Intervention
 
Definition of psychopharmacologic treatment endpoint: 
rapid
tranquilization
Calming process separate from total sleep induction
Allows patient to participate in care
Enables clinician to gather history, initiate a work-up, and begin treatment of
unidentified conditions
Better therapeutic endpoint
Sleep is 
not
 the desired outcome
It conflicts with goal of patient participation
Has not been found to be essential to improvement in agitation or decrease in psychotic
symptoms
 
36
 
Vieta et al. 
Protocol for the management of psychiatric patients with psychomotor agitation. 
BMC Psychiatry
 
2017
;
17:328
 
Pharmacologic Considerations
 
Ease of preparation/administration
Rapid onset of action: IV > IM > PO
Sufficient duration of effect
Low risk of adverse reactions or drug interactions
 
What is known about the patient’s underlying condition(s)?
Age
Comorbid conditions
Medication/other substance exposure
 
 
37
 
Zeller et al. Systematic Reviews of Assessment Measures and Pharmacologic Treatments for Agitation. Clin Therapeutics 2010; 32:405-425
Pharmacologic Treatment
 
Most important factors in medication selection
Etiology of agitation
Acute effect on behavioral symptoms
Multiple means of administration
Limited side effects
Ease of administration
Patient preference
History of response
Goal is a balance between effectiveness and tolerability
 
38
Marder SR. A review of agitation in mental illness: treatment guidelines and current therapies. J Clin Psychiatry 2006;67:13-21
Pharmacologic Treatment
 
Route of administration
Oral (PO) administration
Preferred if patient accepts
Liquid or orally dissolving tablets
Intramuscular (IM) administration
Rapid elevation of plasma level
Higher transient concentration
Faster reduction in agitated behavior
39
Pharmacologic Treatment
 
Route of administration (continued)
Intravenous (IV) administration
Similar to IM but more rapid elevation of plasma level
Should be limited to when immediate tranquilization is essential
Requires appropriate monitoring of vital signs for respiratory depression and
cardiovascular compromise
40
Pharmacologic Treatment
 
Most studies of pharmacologic treatment in agitation were done in
patients with KNOWN psychiatric diagnosis
No randomized, controlled studies have examined the use of medications
in populations with…
Severe agitation
Drug-induced agitation
Significant medical comorbidity
Results difficult to extrapolate to the undifferentiated agitated patient in
the general ED or medical/surgical unit
41
 
Association for Emergency Psychiatry Recommendations
 
Undifferentiated Agitation/Suspected intoxication with stimulant or withdrawal from
alcohol/benzodiazepine
Oral benzodiazepines (e.g. lorazepam 1-2 mg)
Parenteral benzodiazepines (e.g. lorazepam 1-2 mg IM or IV)
 
Acute intoxication with CNS depressant (e.g., alcohol)
Avoid benzodiazepine if possible
1.
Oral 1
st
 generation antipsychotic (e.g. haloperidol 2-10 mg )
2.
Parenteral 1
st
 generation antipsychotic (e.g. haloperidol 2-10 mg IM)
 
Delirium (not associated with alcohol or benzodiazepine withdrawal)
1.
Oral 2
nd
 generation antipsychotic (e.g. risperidone 2 mg, olanzapine 5-10 mg)
2.
Oral 1
st
 generation antipsychotic (e.g. low dose haloperidol)
3.
Parenteral 2
nd
 generation antipsychotic (e.g. olanzapine 10 mg IM)
4.
Parenteral 1
st
 generation antipsychotic (e.g. haloperidol low dose IM or IV)
 
Schizophrenia or Mania
1.
Oral 2
nd
 generation antipsychotic alone (e.g. risperidone 2 mg, olanzapine 5-10 mg)
2.
Oral 1
st
 generation antipsychotic (e.g. haloperidol 2-10 mg with benzodiazepine)
3.
Parenteral 2
nd
 generation antipsychotic (e.g. olanzapine 10 mg IM)
4.
Parenteral 1
st
 generation antipsychotic (e.g. haloperidol 2-10 mg IM) along with benzodiazepine (e.g. lorazepam 1-2 mg)
 
42
 
Wilson M.P. et al. The Psychopharmacology of Agitation.  Consensus Statement of the
American Association for Emergency Psychiatry, Western J Emerg Med. 2012;13(1):26-34.
Benzodiazepines
 
Benzodiazepines (BZDs) act by facilitating the activity of GABA
GABA is a major inhibitory neurotransmitter
Therapeutic effects appears linked to decreased arousal
Little benefit for psychiatric symptoms other than anxiety
Long history of use in the management of acute agitation
Individually
Combination with antipsychotics (
except
 IM olanzapine)
Preferred in a patient in whom agitation is secondary to alcohol or sedative
withdrawal
43
Zaman et al. Benzodiazepines for psychosis-induced aggression or agitation. Cochrane Database Syst Rev. 2017;12:Cd003079
Benzodiazepines
 
Lorazepam
Only BZD with complete and rapid IM absorption
No involvement of P450 system
IM or sublingual administration
60-90 minutes until peak plasma concentration
8-10 hour duration of effect
12-15 hour elimination half-life
Studies suggest that lorazepam 2 mg is at least as effective as haloperidol in
controlling acute agitation
1-2
44
1
Allen MH. Managing the agitated psychotic patient: a reappraisal of the evidence. J Clin Psychiatry 2000;61(S14):S1-S20
2
Battaglia et al. Haloperidol, lorazepam, or both for psychotic agitation? A multicenter, prospective, double-blind,
emergency department study. Am J Emerg Med 1997;15:335–340
Benzodiazepines
 
Side effects
Excessive sedation
Additive with other CNS depressants
Respiratory depression
BZDs avoided in patients at risk for CO
2
 retention
Paradoxical disinhibition
More likely with high doses in patients with structure brain damage, mental
retardation or dementia
Ataxia
45
Typical Antipsychotics
 
Dopamine antagonist
Positive
Antipsychotic
Anti-agitation
Negative
Extrapyramidal symptoms (EPS)
Neuroleptic Malignant Syndrome (NMS)
Many authors consider typical antipsychotics the treatment of choice in acute
agitation, especially in the setting of delirium
46
Typical
 
Antipsychotics
 
Low potency
Not recommended
High potency - 
Haloperidol
Virtually no anticholinergic properties
Little risk of hypotension
Does not suppress respiration
Can be given IV
Not FDA approved
Fast acting
Onset of action: 30 minutes
Duration of action up to 12-24 hours
47
Powney et al. Haloperidol for psychosis-induced aggression or agitation (rapid tranquillisation). Cochrane Database of Systematic Reviews 2012;11:CD009377
Typical
 
Antipsychotics
 
Side effects
Extrapyramidal symptoms
Dystonia
Akathisia
Parkinson-like effects
QTc prolongation
Rare at low doses
Haloperidol and droperidol with “Black Box” warnings
Lower seizure threshold
Low-potency > high-potency antipsychotics
48
Powney et al. Haloperidol for psychosis-induced aggression or agitation (rapid tranquillisation). Cochrane Database of Systematic Reviews 2012;11:CD009377
 
Typical Antipsychotics
 
Loxapine
5 – 10 mg, inhaled
Inhaled Loxapine has been recently endorsed by FDA for treatment for agitation in
Bipolar I disorder
Efficacy supported in multiple trials when compared to placebo, has not been
compared to other active medication
Need to monitor for bronchospasm, especially in patients with asthma
 
49
 
Owen RT. Inhaled loxapine: a new treatment for agitation in schizophrenia or bipolar disorder. Drugs of Today.  49(3):195-201, 2013
Garriga et al. Assessment and management of agitation in psychiatry: expert consensus. World J Biol Psychiatry 2016;17:86-128
Atypical Antipsychotics
 
Major advance in psychiatry
Broader spectrum of response
Different side effect profile
Less EPS and akathisia
QTc concern remains
Metabolic syndrome
No randomized, controlled studies have examined the use of
medications in populations with…
Severe agitation
Drug-induced agitation
Significant medical comorbidity
50
 
Atypical Antipsychotics
 
Olanzapine
Intramuscular
Oral tablet
Oral tablet, disintegrating
Aripiprazole
Oral solution
Oral tablet
Oral tablet, disintegrating
Intramuscular (immediate-release no longer available in US)
Risperidone
Oral solution
Oral tablet
Oral tablet, disintegrating
Quetiapine
Oral tablet
Ziprasidone
Intramuscular
Oral tablet
 
51
Atypical Antipsychotics
 
Olanzapine
IM dose range of 5-10mg
Maximum of 30mg/day
15-45 minutes until peak plasma concentration
21-54 hour elimination half-life
PO dose range 5-10mg
Flexible dose up to 40 mg/day better than fixed 10 mg/day dose
24-54 hour elimination half-life
1-3 hours until peak plasma concentration, but benefits often occur in less
time
52
Garriga et al. Assessment and management of agitation in psychiatry: expert consensus. World J Biol Psychiatry 2016;17:86-128
Atypical Antipsychotics
 
Olanzapine
Adverse events
Concern of orthostasis
Long-term use has been associated with the development of metabolic
syndrome
IM olanzapine should NOT be administered with BZDs or CNS depressants
given reports of adverse events and 8 deaths in Europe
Patients were also suffering from medical comorbidities
Cardiopulmonary depression, hypotension, and bradycardia reported
53
Garriga et al. Assessment and management of agitation in psychiatry: expert consensus. World J Biol Psychiatry 2016;17:86-128
 
Atypical Antipsychotics
 
Risperidone
2 - 6 mg PO or ODT
Oral risperidone concentrate 2mg + oral lorazepam 2mg equivalent to IM
haloperidol 5mg + IM lorazepam 2mg
Oral risperidone 2 mg equally effective as oral haloperidol 5 mg
Overall not thought to be superior to other antipsychotics
 
54
 
Garriga et al. Assessment and management of agitation in psychiatry: expert consensus. World J Biol Psychiatry 2016;17:86-128
Atypical Antipsychotics
 
Aripiprazole
It is unique in that it is a partial dopamine agonist
Decreases dopamine in hyper-dopaminergic areas of the brain
Increases dopamine in hypo-dopaminergic areas of the brain
Oral aripiprazole 15 mg as effective as oral olanzapine 20 mg
Low risk for QT interval prolongation (<1%)
Immediate-release IM aripiprazole is effective in the management of agitation in
psychiatric illness; recommended IM dose is 9.75mg (discontinued in the US)
55
Kinon BJ, et al., J Clin Psychopharmacology. 28(6):601-607, 2008
Gonzalez D,  et al. Current Medical Research & Opinion.  29(3):241-50, 2013
Atypical Antipsychotics
 
Quetiapine
1-3 hours to peak plasma concentrations
Very low risk of EPS
Sedation and orthostasis are side effects
Superior to placebo in 3 randomized trials, but not more efficacious when
compared to haloperidol
56
Garriga et al. Assessment and management of agitation in psychiatry: expert consensus. World J Biol Psychiatry 2016;17:86-128
Atypical Antipsychotics
 
Ziprasidone
First atypical with an IM formulation
IM dose range of 10-20mg
10mg q2 hour; 20mg q4 hour; maximum of 40mg IM/day
30-40 minutes to peak plasma concentrations (9x faster than PO); 2-4 hour
elimination half-life; 4-6 hour duration of effect
Adverse events: QTc interval prolongation
Appears to prolong the QT to a greater degree than haloperidol, risperidone,
or olanzapine; no clinically relevant ECG changes observed in agitation studies
57
Garriga et al. Assessment and management of agitation in psychiatry: expert consensus. World J Biol Psychiatry 2016;17:86-128
 
Combination Therapy
 
Individual medications can be targeted to the different components of
agitation
Anxiety and arousal 
 benzodiazepine
Psychosis 
 antipsychotic
Combining medications at low doses may reduce individual side effects
(decrease Cmax), while obtaining desired effect
 
 
 
58
Combination Therapy
 
Most common combination
Haloperidol 5mg IM
Lorazepam 2mg IM
Benefits
Faster reduction in agitation
Less injections required
Simple to administer
Lower incidence of EPS
59
Garriga et al. Assessment and management of agitation in psychiatry: expert consensus. World J Biol Psychiatry 2016;17:86-128
Wilson et al. A comparison of the safety of olanzapine and haloperidol in combination with benzodiazepines in emergency department patients with acute
agitation. J Emerg Med 2012;43(5):790-7
Combination Therapy
 
Side effects
Overall, very well tolerated
Side effect profiles of both the BZDs and antipsychotics apply
Excess sedation most common adverse reaction
However, recent studies suggest sedation rates appear similar to lorazepam
treatment alone
60
Garriga et al. Assessment and management of agitation in psychiatry: expert consensus. World J Biol Psychiatry 2016;17:86-128
 
Onset of Action
 
61
 
Adapted from Zun LS. J Emergency Medicine. 54(3):364-74, 2018
 
Summary for Acute Term
 
62
 
Adapted from Allen M, Currier G, Carpenter D: The expert consensus guideline series: treatment of behavioral emergencies, J Psychiatr Pract 11:1-112, 2005
 
Summary for Acute Term (cont.)
 
63
 
Adapted from Allen M, Currier G, Carpenter D: The expert consensus guideline series: treatment of behavioral emergencies, J Psychiatr Pract 11:1-112, 2005
 
Cost
 
64
Disposition
 
Disposition depends on etiology of agitation and current condition
Delirium 
 General medical hospital
Psychosis 
 Psychiatric admission
Don’t have a clue 
 General medical hospital to determine cause of agitation
65
Riker RR, Fraser GL. The new practice guidelines for pain, agitation, and delirium. Am J Critical Care. 22(2):153-7, 2013
 
Special Population:  ICU patients
 
Mechanically ventilated ICU patients: analgesia and sedation are
recommended
Dexmedetomidine, rather than benzodiazepines
No evidence haloperidol decreases the duration of delirium
Atypical antipsychotics may decrease the duration of delirium in ICU
patients
 
66
 
Riker RR, Fraser GL. The new practice guidelines for pain, agitation, and delirium. Am J Critical Care. 22(2):153-7, 2013
 
Special Population: Weaning of Ventilation
 
Dexmedetomidine (alpha 2 adrenergic sedative)
Better than midazolam (  hypertension and tachycardia,  time intubated)
1
Better than haloperidol (  time intubated,   length of stay)
2
 
 
67
 
1
Ricker et. al, JAMA.2009;301(5):489–499
2
Reade et. al, Critical Care 2009;13:R75
 
Recommended Readings
 
Garriga M, Pacchiarotti I, Kasper S, et al. Assessment and management of agitation in
psychiatry: Expert consensus. World J Biol Psychiatry 2016;17:86-128.
Marder SR.
  
A review of agitation in mental illness: treatment guidelines and current
therapies. J Clin Psychiatry. 2006;67 (Suppl 10):13-21.
Ryding E, Lindström M, Träskman-Bendz L. The role of dopamine and serotonin in
suicidal behaviour and aggression.  Prog Brain Res. 2008;172:307-15.
Wilson M.P. et al. The Psychopharmacology of Agitation.  Consensus Statement of the
American Association for Emergency Psychiatry, Western J Emerg
Med. 2012;13(1):26-34.
 
68
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This resource discusses the medical management of acute agitation, covering the behavioral spectrum, differential diagnosis, non-pharmacologic and pharmacologic approaches, and case scenarios. Definitions of agitation, aggression, and violence are provided along with descriptions of component behaviors of agitation. A case study illustrates a patient's escalating agitation in a medical setting.

  • Agitation management
  • Behavioral spectrum
  • Medical settings
  • Pharmacologic approaches
  • Acute care

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  1. The Medical Management of Acute Agitation APM Resident Education Curriculum Revised 2019: Ariadna Forray, MD, Naomi Schmelzer, MD Original version: R. Scott Babe, M.D., Clinical Assistant Professor of Psychiatry, Western University of Health Sciences, Samaritan Mental Health, Corvallis, Oregon Thomas W. Heinrich, MD, Associate Professor of Psychiatry & Family Medicine, Chief, Psychiatric Consult Service at Froedtert Hospital, Department of Psychiatry & Behavioral Medicine, Medical College of Wisconsin Version of March 15, 2019 ACADEMY OF CONSULTATION-LIAISON PSYCHIATRY Psychiatrists Providing Collaborative Care Bridging Physical and Mental Health

  2. Objectives Identify the behavioral spectrum of agitation Describe the broad differential diagnosis behind the symptoms of agitation and aggression. Apply non-pharmacologic and pharmacologic approaches to management of the agitated patient in the general medical setting. Academy of Consultation-Liaison Psychiatry 2

  3. The Case A 47 year-old male with a history of substance use disorder and bipolar disorder along with morbid obesity, DM and COPD presents to the ED at 0200 after calling 911 and reporting chest pain. He is cooperative in the ED, but observed to be mumbling to himself and staring at staff suspiciously. He is given lorazepam 1mg PO to calm him. Since arriving to the floor to rule out an MI, he has become increasingly restless, irritable, and confrontational. He is increasingly uncooperative with medical care, then becomes verbally and physically threatening to the staff. His primary team calls a psychiatry consult for help managing these behaviors. 3 Academy of Consultation-Liaison Psychiatry

  4. Definitions Agitation Excessive motor or verbal activity an emergent situation that is temporary, breaks the therapeutic alliance, and is in need of a prompt and immediate intervention (Garriga et al. 2016) Aggression Hostile, injurious, or destructive behavior. Can be verbal or physical. Violence Denotes physical aggression by people against other people 2 general types: Impulsive/reactive Instrumental/premeditated goal-oriented violence (Siever L. (2008) Neurobiology of aggression and violence. Am J Psychiatry 165: 429-42. Garriga M., Pacchiarotti, I., Kasper, S. et al. (2016) Assessment and Management of Agitation in Psychiatry: Expert consensus. World J Biol Psychiatry. 17, 170-185.) 4 Academy of Consultation-Liaison Psychiatry

  5. Component Behaviors of Agitation Nonaggressive behaviors Restlessness (akathisia, fidgeting) Wandering Loud, excited speech Pacing or frequently changing body positions Inappropriate behavior (disrobing, intrusive, repetitive questioning) Aggressive behaviors Physical Combativeness, punching walls Throwing or grabbing objects, destroying items Clenching hands into fists, posturing Self-injury (repeatedly banging one s head) Verbal Cursing Screaming 5 Academy of Consultation-Liaison Psychiatry

  6. Epidemiology There is little direct data on the prevalence, clinical impact, or financial consequences of agitation Behavioral emergencies responsible for 6% of all ED visits (Larkin et al 2005) 4.3 million psychiatric emergency visits/year (Marco and Vaughan, 2005) 21% (900,000) agitated patients with schizophrenia 13% (560,000) agitated patients with bipolar disorder 5% (210,000) agitated patients with dementia Larkin GL. et al. Trends in US Emergency Department Visits for Mental Health Conditions, 1992-2001. Psychiatric Services, June 2005. 56; 671-677. Marco, C. A., & Vaughan, J. (2005). Emergency management of agitation in schizophrenia. The American journal of emergency medicine, 23(6), 767-776. 6 Academy of Consultation-Liaison Psychiatry

  7. Epidemiology Studies for health care workers California: 465 assaults per 100,000 hospital workers vs. 82.5 assaults per 100,000 for all workers (Peek-Asa et al 1997) Minnesota Nurses Study (Gerberich et al 2004): 13.2 per 100 persons per year for physical assaults 38.8 per 100 persons per year for non-physical assaults Greatest risk for persons working in/with: Long term care facility Intensive care Psychiatric unit Emergency department Geriatric patients Peek-Asa, C., Howard, J., Vargas, L., & Kraus, J. F. (1997). Incidence of non-fatal workplace assault injuries determined from employer's reports in California. Journal of Occupational and Environmental Medicine, 39(1), 44-50. Gerberich, S. G., Church, T. R., McGovern, P. M., Hansen, H. E., Nachreiner, N. M., Geisser, M. S., ... & Watt, G. D. (2004). An epidemiological study of the magnitude and consequences of work related violence: the Minnesota Nurses Study. Occupational and environmental medicine, 61(6), 495-503. Academy of Consultation-Liaison Psychiatry 7

  8. Etiology of Agitation A. Disease-related: three major categories Psychiatric manifestations of general medical conditions Substance intoxication/withdrawal Primary psychiatric illness B. Instrumental: unlikely to benefit from medical intervention (e.g., criminal behavior) Consider short trial of verbal de-escalation Depending on severity, consider involving security or law enforcement These are not mutually exclusive 8 Academy of Consultation-Liaison Psychiatry

  9. Etiology of Agitation: A Sample of the Varied Conditions that may Present with Pathologic Agitation Substance intoxication or withdrawal Bipolar disorder Major Depressive Disorder Psychosis PTSD Anxiety Disorders Personality Disorders Autism Intellectual Disability Dementia Huntington's disease Brain injury or trauma Delirium (Organic Brain Syndrome) Korsakoff s psychosis Brain tumors Seizure Hypoglycemia Stroke Thyroid disease Antisocial behavior 9 Academy of Consultation-Liaison Psychiatry

  10. Etiology of Agitation: Medical Causes Head trauma Encephalitis, meningitis, other infection Encephalopathy (e.g., liver or renal failure) Environmental toxins Metabolic abnormalities (sodium, calcium, glucose) Hypoxia Thyroid disease Seizure (including post-ictal state) Toxic levels of medications Nordstrom, K., Zun, L. S., Wilson, M. P., Stiebel, V., Ng, A. T., Bregman, B., & Anderson, E. L. (2012). Medical evaluation and triage of the agitated patient: consensus statement of the American Association for Emergency Psychiatry Project BETA Medical Evaluation Workgroup. Western Journal of Emergency Medicine, 13(1), 3. 10 Academy of Consultation-Liaison Psychiatry

  11. Etiology of Agitation: Delirium Diagnostic Features Disturbance of consciousness A change in cognition or development of perceptual disturbance Not accounted for by a dementia Disturbance develops over a short period of time and tends to fluctuate ( waxing and waning ) Caused by a general medical condition 11 Academy of Consultation-Liaison Psychiatry

  12. Etiology of Agitation: Substances Substance intoxication Alcohol, cocaine, amphetamines, cannabis, ketamine, ecstasy, bath salts, inhalants Substance withdrawal Alcohol withdrawal delirium/DTs CNS effects of non-psychiatric medications (steroids) 12 Academy of Consultation-Liaison Psychiatry

  13. Etiology of Agitation: Primary Psychiatric disorders Schizophrenia Bipolar Disorder Neurocognitive Disorder (Dementia) Personality Disorders Agitated depression Anxiety disorder Autism spectrum disorder 13 Academy of Consultation-Liaison Psychiatry

  14. Etiology of Agitation: Common Triggers Akathisia from antipsychotic or antidepressant use Comorbid substance use or intoxication Poor impulse control or other comorbid cognitive deficits Chaotic or disruptive environment Medical illness Exacerbation of symptoms of primary illness Psychosocial trigger Garriga, M., Pacchiarotti, I., Bernardo, M., & Vieta, E. (2017). Psychiatric Causes of Agitation: Exacerbation of Mood and Psychotic Disorders. The Diagnosis and Management of Agitation, 126.. Academy of Consultation-Liaison Psychiatry 14

  15. Etiology of Agitation: Schizophrenia Patients may present to the ED with acute psychosis Hallucinations Delusions Disorganized speech and/or behavior Lack of insight Bizarre behavior Fertile conditions for the development of agitation Psychosis and agitation have a reciprocal relationship 15 Academy of Consultation-Liaison Psychiatry

  16. Etiology of Agitation: Schizophrenia Patients at highest risk for violence More suspicious and hostile More severe hallucinations Less insight into delusions Greater thought disorder Poor impulse control Risk factors for being targeted for violence by person with schizophrenia Parent or immediate family member Cohabitation Patient financially dependent on you Sachs, G. S. (2006). A review of agitation in mental illness: burden of illness and underlying pathology. The Journal of clinical psychiatry, 67, 5-12. 16 Academy of Consultation-Liaison Psychiatry

  17. Etiology of Agitation: Personality Disorders Some personality disorders are more prone to agitation Decreased stress tolerance Poor impulse control E.g., Borderline personality disorder, Antisocial personality disorder 17 Academy of Consultation-Liaison Psychiatry

  18. Etiology of Agitation: Major Neurocognitive Disorder Overall, the incidence of agitation is estimated to be between 60-80% (median 44%) (Bartels et al 2003) 50% become frankly physically aggressive 24% become verbally aggressive Burden of institutionalization Residents with dementia complicated by agitation have the highest 3-month rate of ED visits and greatest use of restraints (Sachs, 2006) Despite use of restraints, over 40% receive no psychiatric medications Bartels, S. J., Horn, S. D., Smout, R. J., Dums, A. R., Flaherty, E., Jones, J. K., ... & Voss, A. C. (2003). Agitation and depression in frail nursing home elderly patients with dementia: treatment characteristics and service use. The American journal of geriatric psychiatry, 11(2), 231-238. Sachs, G. S. (2006). A review of agitation in mental illness: burden of illness and underlying pathology. The Journal of clinical psychiatry, 67, 5-12 18 Academy of Consultation-Liaison Psychiatry

  19. Etiology of Agitation: Dementia Agitation may be a final common pathway for the expression of Depression Anxiety Psychosis Pain Delirium While agitation may be of multifactorial etiology in patients with dementia, it is also true that many patients have only agitation as a target symptom for treatment (Madhusoodanan, 2001) Madhusoodanan, S. (2001). Introduction: antipsychotic treatment of behavioral and psychological symptoms of dementia in geropsychiatric patients.The American Journal of Geriatric Psychiatry, 9(3), 283-288. 19 Academy of Consultation-Liaison Psychiatry

  20. Etiology of Agitation: Psychodynamic Perspectives A Psychodynamic framework can be used to complement treatment strategies - Helps temper counter-transference Psychodynamic perspectives of agitation and violence - In contemporary psychoanalytic thought, the capacity for aggression is innate and universal, aggressive behavior occurs in response to threats that the self perceives in relation to internal and external objects. - Crisis can be defined as an assault on the person s sense of self (Bernstein 2007) Yakeley, J. (2018). Psychodynamic approaches to violence. BJPsych Advances, 24(2), 83-92. Academy of Consultation-Liaison Psychiatry 20

  21. Back to the Case (continued) Potential etiologies for our gentleman s growing agitation Substance intoxication or withdrawal Delirium Bipolar disorder Personality disorder 21 Academy of Consultation-Liaison Psychiatry

  22. Assessment of Agitation Decisions regarding diagnostic tests must be made in the context of available history and physical examination Goal is to evaluate patient s risk for medical comorbidities Many questions involve forced decisions based on Assumptions Information available Diagnostic confidence Patient s individual risk factors 22 Academy of Consultation-Liaison Psychiatry

  23. Assessment of Agitation For a patient with known diagnosis of schizophrenia presenting with behavioral features of typical decompensation: Expectant management is appropriate For patients with atypical features additional diagnostic tests may be required Atypical presentations Delirium History of trauma Overdose Headache Fever Diagnostic tests to consider Toxicology screens CT of brain BMP, CBC, and LFTs Urinalysis Endocrine tests Lumbar puncture 23 Academy of Consultation-Liaison Psychiatry

  24. The Case (continued) Examination of the patient The patient is febrile with normal vitals Disheveled and malodorous Heart, lungs and abdomen are benign No tremor, diaphoresis, nystagmus or asterixis Mental status examination reveals: Appearance/behavior: middle-aged unkempt male in hospital johnny and socks, uncooperative, pacing the room, poor eye contact, posturing with fists Speech: spontaneous, loud, nonpressured, use of profane language Mood: I m lousy! , Affect: labile, irritable TP: tangential, TC: paranoia towards hospital staff, no SI/HI, no perceptual disturbances. Does not participate in formal cognitive exam questions. 24 Academy of Consultation-Liaison Psychiatry

  25. The Case (continued) Laboratory evaluation of the patient CBC, BMP are normal except for a glucose of 211 LFTs are normal except for a low albumin TSH, B12, Folate, and RPR are also normal U/A is positive for glucose and trace ketones CT of head is read as negative EKG shows QTc < 400msec UDS and serum toxicology are negative Valproate, carbamazepine, and lithium levels are all negative 25 Academy of Consultation-Liaison Psychiatry

  26. Before the Acute Intervention The staff on Med/Surg units are often less informed about what feelings and behaviors their actions may elicit in patients Studies indicate that staff training and education can change this lack of appreciation Psychiatric consultants should provide education about Establishing goals from the patient s perspective Interventions that support a structured setting Private or semi-private room Establish clear set of expectations with a written schedule Identify staff that are responsible for the patient s care Attempting to enlist the patient in the treatment, i.e. which route of medication has worked the best in the past as a choice which retains some patient control Academy of Consultation-Liaison Psychiatry 26

  27. Goals of Intervention Acute agitation or a violent patient modifies the normal caregiver-patient relationship The first goal of treatment is to do only what is necessary to assure the safety of the patient and others while facilitating the resumption of more normal interpersonal relations Calming without over-sedation 27 Academy of Consultation-Liaison Psychiatry

  28. Agitation Management Medical evaluation and triage Psychiatric evaluation Verbal de-escalation Environmental intervetions Psychopharmacologic interventions Use of seclusion/restraint Holloman Jr, G. H., & Zeller, S. L. (2012). Overview of Project BETA: best practices in evaluation and treatment of agitation. Western Journal of Emergency Medicine, 13(1), 1. Academy of Consultation-Liaison Psychiatry 28

  29. Environmental Interventions Examples of effective non-pharmacological treatments Clearing the room Removing dangerous objects Having staff available as a show of force Close observation Calm conversation Decreasing sensorial stimulation 29 Academy of Consultation-Liaison Psychiatry

  30. Communication/Behavioral Interventions Nonverbal Maintain a safe distance Maintain a neutral posture Do not stare; eye contact should convey sincerity Do not touch the patient Stay at the same height as the patient Avoid sudden movements Verbal Speak in calm, clear tone Personalize yourself Avoid confrontation; offer to solve the problem Onyike, C., & Lyketsos, C. (2011). Aggression and violence. Textbook of Psychosomatic Medicine: Psychiatric Care of the Medically, 101, 153-174.. 30 Academy of Consultation-Liaison Psychiatry

  31. Communication/Behavioral Interventions Aligning Goals of Care Acknowledge the patient s grievance Acknowledge the patient s frustration Shift the focus to discussion of how to solve the problem Emphasize common ground Focus on the big picture Find ways to make small concessions Monitoring Intervention Progress Be acutely aware of progress Know when to disengage Do not insist on having the last word Onyike, C., & Lyketsos, C. (2011). Aggression and violence. Textbook of Psychosomatic Medicine: Psychiatric Care of the Medically Ill, 101, 153-174.. 31 Academy of Consultation-Liaison Psychiatry

  32. Back to the Case (continued) You assist the team and the nursing staff: Clear the room Keep dangerous objects out of reach Call security You approach the patient using verbal de-escalation techniques that you have learned and practiced Despite these interventions the patient makes further threats, rips-off telemetry lines, and starts to pace with clenched fists while mumbling incoherently 32 Academy of Consultation-Liaison Psychiatry

  33. A little bit of history 33 Academy of Consultation-Liaison Psychiatry

  34. Serotonin-Dopamine Model of Regulation of Agitation Dynamic interaction between the amygdala, nucleus accumbens, and the prefrontal cortex Provides a basis for the response to certain medications Amygdala activation Serotonin Nucleus Accumbens Suppression Dopamine Released Prefrontal Cortex agitation Ryding et al. The role of dopamine and serotonin in suicidal behavior and aggression. Prog Brain Res 2008;172:307-15 34 Academy of Consultation-Liaison Psychiatry

  35. Goals of Intervention Ideally pharmacotherapy for acute agitation should: Be easy to administer, non-traumatic Provide rapid tranquilization without excessive sedation Have a fast onset of action and a sufficient duration of action Have a low risk for significant adverse events and drug interactions 35 Academy of Consultation-Liaison Psychiatry

  36. Goals of Intervention Definition of psychopharmacologic treatment endpoint: rapid tranquilization Calming process separate from total sleep induction Allows patient to participate in care Enables clinician to gather history, initiate a work-up, and begin treatment of unidentified conditions Better therapeutic endpoint Sleep is not the desired outcome It conflicts with goal of patient participation Has not been found to be essential to improvement in agitation or decrease in psychotic symptoms Vieta et al. Protocol for the management of psychiatric patients with psychomotor agitation. BMC Psychiatry 2017;17:328 36 Academy of Consultation-Liaison Psychiatry

  37. Pharmacologic Considerations Ease of preparation/administration Rapid onset of action: IV > IM > PO Sufficient duration of effect Low risk of adverse reactions or drug interactions What is known about the patient s underlying condition(s)? Age Comorbid conditions Medication/other substance exposure Zeller et al. Systematic Reviews of Assessment Measures and Pharmacologic Treatments for Agitation. Clin Therapeutics 2010; 32:405-425 Academy of Consultation-Liaison Psychiatry 37

  38. Pharmacologic Treatment Most important factors in medication selection Etiology of agitation Acute effect on behavioral symptoms Multiple means of administration Limited side effects Ease of administration Patient preference History of response Goal is a balance between effectiveness and tolerability Marder SR. A review of agitation in mental illness: treatment guidelines and current therapies. J Clin Psychiatry 2006;67:13-21 38 Academy of Consultation-Liaison Psychiatry

  39. Pharmacologic Treatment Route of administration Oral (PO) administration Preferred if patient accepts Liquid or orally dissolving tablets Intramuscular (IM) administration Rapid elevation of plasma level Higher transient concentration Faster reduction in agitated behavior 39 Academy of Consultation-Liaison Psychiatry

  40. Pharmacologic Treatment Route of administration (continued) Intravenous (IV) administration Similar to IM but more rapid elevation of plasma level Should be limited to when immediate tranquilization is essential Requires appropriate monitoring of vital signs for respiratory depression and cardiovascular compromise 40 Academy of Consultation-Liaison Psychiatry

  41. Pharmacologic Treatment Most studies of pharmacologic treatment in agitation were done in patients with KNOWN psychiatric diagnosis No randomized, controlled studies have examined the use of medications in populations with Severe agitation Drug-induced agitation Significant medical comorbidity Results difficult to extrapolate to the undifferentiated agitated patient in the general ED or medical/surgical unit 41 Academy of Consultation-Liaison Psychiatry

  42. Association for Emergency Psychiatry Recommendations Undifferentiated Agitation/Suspected intoxication with stimulant or withdrawal from alcohol/benzodiazepine Oral benzodiazepines (e.g. lorazepam 1-2 mg) Parenteral benzodiazepines (e.g. lorazepam 1-2 mg IM or IV) Acute intoxication with CNS depressant (e.g., alcohol) Avoid benzodiazepine if possible 1. Oral 1st generation antipsychotic (e.g. haloperidol 2-10 mg ) 2. Parenteral 1st generation antipsychotic (e.g. haloperidol 2-10 mg IM) Delirium (not associated with alcohol or benzodiazepine withdrawal) 1. Oral 2nd generation antipsychotic (e.g. risperidone 2 mg, olanzapine 5-10 mg) 2. Oral 1st generation antipsychotic (e.g. low dose haloperidol) 3. Parenteral 2nd generation antipsychotic (e.g. olanzapine 10 mg IM) 4. Parenteral 1st generation antipsychotic (e.g. haloperidol low dose IM or IV) Schizophrenia or Mania 1. Oral 2nd generation antipsychotic alone (e.g. risperidone 2 mg, olanzapine 5-10 mg) 2. Oral 1st generation antipsychotic (e.g. haloperidol 2-10 mg with benzodiazepine) 3. Parenteral 2nd generation antipsychotic (e.g. olanzapine 10 mg IM) 4. Parenteral 1st generation antipsychotic (e.g. haloperidol 2-10 mg IM) along with benzodiazepine (e.g. lorazepam 1-2 mg) Wilson M.P. et al. The Psychopharmacology of Agitation. Consensus Statement of the American Association for Emergency Psychiatry, Western J Emerg Med. 2012;13(1):26-34. 42 Academy of Consultation-Liaison Psychiatry

  43. Benzodiazepines Benzodiazepines (BZDs) act by facilitating the activity of GABA GABA is a major inhibitory neurotransmitter Therapeutic effects appears linked to decreased arousal Little benefit for psychiatric symptoms other than anxiety Long history of use in the management of acute agitation Individually Combination with antipsychotics (except IM olanzapine) Preferred in a patient in whom agitation is secondary to alcohol or sedative withdrawal Zaman et al. Benzodiazepines for psychosis-induced aggression or agitation. Cochrane Database Syst Rev. 2017;12:Cd003079 43 Academy of Consultation-Liaison Psychiatry

  44. Benzodiazepines Lorazepam Only BZD with complete and rapid IM absorption No involvement of P450 system IM or sublingual administration 60-90 minutes until peak plasma concentration 8-10 hour duration of effect 12-15 hour elimination half-life Studies suggest that lorazepam 2 mg is at least as effective as haloperidol in controlling acute agitation1-2 1Allen MH. Managing the agitated psychotic patient: a reappraisal of the evidence. J Clin Psychiatry 2000;61(S14):S1-S20 2Battaglia et al. Haloperidol, lorazepam, or both for psychotic agitation? A multicenter, prospective, double-blind, emergency department study. Am J Emerg Med 1997;15:335 340 44 Academy of Consultation-Liaison Psychiatry

  45. Benzodiazepines Side effects Excessive sedation Additive with other CNS depressants Respiratory depression BZDs avoided in patients at risk for CO2 retention Paradoxical disinhibition More likely with high doses in patients with structure brain damage, mental retardation or dementia Ataxia 45 Academy of Consultation-Liaison Psychiatry

  46. Typical Antipsychotics Dopamine antagonist Positive Antipsychotic Anti-agitation Negative Extrapyramidal symptoms (EPS) Neuroleptic Malignant Syndrome (NMS) Many authors consider typical antipsychotics the treatment of choice in acute agitation, especially in the setting of delirium 46 Academy of Consultation-Liaison Psychiatry

  47. TypicalAntipsychotics Low potency Not recommended High potency - Haloperidol Virtually no anticholinergic properties Little risk of hypotension Does not suppress respiration Can be given IV Not FDA approved Fast acting Onset of action: 30 minutes Duration of action up to 12-24 hours Powney et al. Haloperidol for psychosis-induced aggression or agitation (rapid tranquillisation). Cochrane Database of Systematic Reviews 2012;11:CD009377 47 Academy of Consultation-Liaison Psychiatry

  48. TypicalAntipsychotics Side effects Extrapyramidal symptoms Dystonia Akathisia Parkinson-like effects QTc prolongation Rare at low doses Haloperidol and droperidol with Black Box warnings Lower seizure threshold Low-potency > high-potency antipsychotics Powney et al. Haloperidol for psychosis-induced aggression or agitation (rapid tranquillisation). Cochrane Database of Systematic Reviews 2012;11:CD009377 48 Academy of Consultation-Liaison Psychiatry

  49. Typical Antipsychotics Loxapine 5 10 mg, inhaled Inhaled Loxapine has been recently endorsed by FDA for treatment for agitation in Bipolar I disorder Efficacy supported in multiple trials when compared to placebo, has not been compared to other active medication Need to monitor for bronchospasm, especially in patients with asthma Owen RT. Inhaled loxapine: a new treatment for agitation in schizophrenia or bipolar disorder. Drugs of Today. 49(3):195-201, 2013 Garriga et al. Assessment and management of agitation in psychiatry: expert consensus. World J Biol Psychiatry 2016;17:86-128 Academy of Consultation-Liaison Psychiatry 49

  50. Atypical Antipsychotics Major advance in psychiatry Broader spectrum of response Different side effect profile Less EPS and akathisia QTc concern remains Metabolic syndrome No randomized, controlled studies have examined the use of medications in populations with Severe agitation Drug-induced agitation Significant medical comorbidity 50 Academy of Consultation-Liaison Psychiatry

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