Agitation

Etiology

Agitation can be multifactorial, reflecting the interaction between precipitating factors and patient characteristics.[8] In the emergency department, patients may be agitated due to reasons such as intoxication with alcohol or drugs, shock or other metabolic derangements, or exacerbation of psychiatric illness. Quick stabilization is essential to ensure patient and staff safety. In a study, almost 3% of patients presented to the emergency department with agitation, of whom 23% met the criteria for delirium.[9]

The most common conditions that lead to agitation in hospitalized patients are delirium, dementia, and acute psychosis. Delirium develops over a short period, is precipitated by an underlying medical cause or substance intoxication or withdrawal, and is characterized by fluctuations in attention and cognition.[10] One or several co-occurring medical conditions can cause delirium. Predisposing factors for delirium include male gender, older age, cognitive impairment, and metabolic derangements. Precipitating factors include medications such as anticholinergic or psychoactive substances, surgery, hypoxemia and hypoxia, acute pain, and infection.

Delirium is classified into 3 types—hyperactive, hypoactive, and mixed. Agitation in delirium is primarily associated with the hyperactive and mixed subtypes. These subtypes describe the individual's level of psychomotor activity. In hyperactive delirium, psychomotor activity is increased, while in mixed delirium, it fluctuates between increased and decreased (hypoactive) motor activity.[10]

Differentiating delirium from other neurocognitive disorders, such as Alzheimer disease or related dementias (ADRD), is important,  which are characterized by a gradual worsening of cognitive function. Delirium is characterized by rapidly fluctuating mental status with onset in hours to days, whereas dementia involves a gradual deterioration of cognitive function over months to years. Major neurocognitive disorder from ADRD is specified as with or without behavioral disturbances. When delirium and ADRD are comorbid, priority should be given to managing the delirium.

Other etiologies of agitation include traumatic brain injury (TBI), physical pain, acute psychosis or mania in schizophrenia or bipolar spectrum disorders, seizure disorders, autism spectrum disorder, anxiety disorders, acute stress disorder, personality disorders, and sleep-wake cycle disruption.[11][10] Many of these conditions are associated with frontal lobe dysfunction, which is believed to contribute to increased aggressive and agitated behavior.[12][13]

Epidemiology

The epidemiology of agitation varies by age group, etiology, environment, and severity. A large-scale prospective observational study conducted in an urban county emergency department in 2018 found the prevalence of agitation to be 2.6%. Of these patients, 23% met the criteria for delirium. Additionally, 84% of patients with agitation required physical restraint, and 72% required sedation with an intramuscular injection to allow for medical evaluation and to protect both the patient and medical providers from injury.[9] 

A study conducted in 2 urban settings in Germany studied the incidence of prehospital psychiatric emergency situations requiring a second-tier response by an emergency physician. In both urban settings, approximately 12% of all cases were psychiatric emergencies.[14] In one setting, 22.3% of psychiatric emergency calls were for agitation, while in the other setting, 30.1% of psychiatric emergency calls were for agitation. Agitation prevalence ranges from 30% to 50% in Alzheimer disease, 30% in Lewy body disease, 40% in frontotemporal degeneration, and 40% in vascular disease. In nursing homes, 80% of residents experience agitation.[15] A 2018 study in the Netherlands observed the progression of neuropsychiatric symptoms in patients with young-onset dementia, defined as the onset of symptoms before the age of 65, residing in nursing homes. Over the course of 2 years, 52% of young-onset dementia patients developed agitation.[16] 

The incidence of agitation in the ICU is estimated to be between 17.5% and 72%.[17][18][19] Agitation is associated with prolonged ICU stays, mechanical ventilation, unplanned venous catheter removals, unplanned extubations, and nosocomial infections. Independent risk factors for agitation in the ICU include the use of psychoactive drugs at the time of admission, a history of alcohol use disorder, abnormal sodium levels, sepsis, fever, and sedative administration in the ICU.[19] 

Among patients with bipolar disorder and schizophrenia, a 2018 cross-sectional study conducted in Europe found that the majority of agitation episodes in the prior year were either mild or moderate in intensity (22.4% and 15.4%, respectively).[20] The intensity of episodes was characterized through self-report, using a predefined list of symptoms. Two-thirds of patients demonstrated insight and awareness of their agitation. The most commonly reported symptoms during an episode of agitation were feeling uneasy, restlessness, and nervousness.[20]

Between 2007 and 2016, about 8.4 million (8.3%) of 100.9 million emergency department visits in the United States were for psychiatric or substance-use–related diagnoses, with the percentage generally increasing over time.[21] Substance use is a significant risk factor for agitation. The lifetime prevalence of substance use disorders among patients with bipolar disorder is estimated to be 48% to 61%, and among patients with schizophrenia, it is estimated to be 47%.[22] The lifetime prevalence of a substance use disorder in the general community sample of this study was 17%. Substance use, including cannabis, stimulants, opioids, sedatives, and hallucinogens, is independently associated with an increased risk of violent behavior.[23] This risk has been estimated to be 4 to 10 times higher compared to the general population.

Agitation is reported in 20% to 41% of patients with TBIs in acute care units during the early recovery period, rising to 70% in rehabilitation settings.[24] The point prevalence of agitation in patients with intellectual disabilities is reported to be approximately 10%, with a remission rate of 25% at 2 years.[25] Increased risk of medium to high levels of aggression is associated with factors such as younger age, longer behavioral episodes, psychotropic medication use, pervasive developmental disorder, mood instability and irritability, increased contact with mental health professionals, and the need for home care. Several of these risk factors indirectly reflect the severity of the patient’s baseline condition. Personality disorders and longer length of behavioral episodes are associated with adverse clinical outcomes, along with agitation during behavioral episodes and more frequent contact with mental health professionals. In contrast, pervasive developmental disorder is associated with improved clinical outcomes.[25]

Pathophysiology

The neuroanatomy and neurophysiology of agitation involve several brain pathways and regions. Positron-emission tomography (PET) scans in patients with personality disorders and anxiety have highlighted frontal lobe dysfunction as a primary contributor to agitation.[26][27] Restlessness has been associated with disturbances in the limbic and striatal sensorimotor pathways, which leads to the excitation of prefrontal and sensorimotor cortices and the subsequent motor expression of restlessness in the form of agitation.[28] This bottom-up activation occurs in the setting of insufficient top-down inhibition and control normally exerted by higher cortical regions.[29] 

Insufficient amygdalar modulation by higher cortical regions and subsequent hyperactivity can lead to overestimating threats and misinterpreting environmental stimuli. External stress can contribute to the activation of these pathways by reducing inhibition from the prefrontal cortex. Additionally, disordered modulation between the prefrontal cortex and the locus coeruleus locus coeruleus has also been implicated, leading to increased tonic activity of the locus coeruleus and subsequent increased norepinephrine release.[29] 

Dementia may also lead to overactivity of norepinephrine due to compensatory mechanisms. In dementia, progressive loss of neurons in the locus coeruleus and the subsequent decrease in norepinephrine release are thought to lead to compensatory upregulation of adrenergic receptors and hypersensitivity.[15] Abnormal activation of the orbitofrontal cortex and anterior cingulate cortex has been observed in patients with Alzheimer dementia.[15] In postmortem studies of patients with Alzheimer dementia, tau pathology has been associated with neuropsychiatric symptoms, including aggressive behavior.

Multiple neurotransmitters have been postulated to be associated with aggression. Norepinephrine is implicated in aggression, as it is thought to be involved in the hyperactivation of the amygdala and other pathways involved in the "fight-or-flight" response. In addition to norepinephrine, dysregulation of dopaminergic, serotonergic, cholinergic, androgenic, and γ-aminobutyric acid (GABA) systems has also been implicated in aggression.[29] Low levels of 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of serotonin, in the cerebrospinal fluid have been associated with aggressive personality traits as well as suicide attempts using more violent means.[30][31] A meta-analysis from 2020 showed that testosterone was associated with aggression, and it also found a small but statistically significant association between higher endogenous testosterone levels and aggression in men, but not in women.[32]

The neurotransmitters involved in agitation can vary depending on the diagnosis.[28] In psychosis and substance use, particularly stimulant-induced psychosis, agitation is often associated with a hyperdopaminergic state, with increased norepinephrine and reduced GABAergic tone. Dysregulated glutaminergic neurotransmission has also been implicated in agitation in psychosis, as glutamine is considered to modulate dopamine neurotransmission.

Akathisia can lead to agitation and is believed to be modulated by increased dopamine blockade in striatal neurons due to antipsychotic medications, which also elevate central norepinephrine and further antagonize dopamine function.[33] Increased norepinephrine tone and decreased GABAergic inhibition have been proposed as contributing factors to agitation in panic disorder and generalized anxiety disorder. Agitation in these conditions is closely related to anxiety, which may be secondary to heightened hypothalamic-pituitary-adrenal axis activity.

Two different serotonin models of agitation have been proposed in affective disorders.[28] The "serotonin-sensitive" model applies to agitated depression or mania, where high catecholamine levels correspond with low serotonin levels. The "serotonin-resistant" model is characterized by extremely high arousal that drives aggression and agitation, associated with decreased GABAergic function and increased noradrenergic activity. GABA and serotonin pathways, which develop together, are involved in top-down modulation of the limbic system from the cortex, influencing agitation and other dysphoric reactions to the environment.[29]

History and Physical

Before evaluating a patient with agitation, clinicians should ensure the environment is safe. They should ensure they can access the room's exit without interference. Staff should remain nearby while the clinician examines the patient in case of behavioral escalation. Clinicians should maintain a safe distance of at least 1 to 2 arm's length from the patient. Maintaining a calm demeanor and empathic approach may help reduce the risk of aggression.[34][35][36]

Obtaining a history from an agitated individual can be difficult, as patients may be physically or verbally aggressive. Early recognition of risk is important, as are interventions targeted to the etiology of the agitation. The history and physical examination may first require nonpharmacological interventions (such as verbal de-escalation, changes in environment, and psychoeducation), medications, or physical restraint.

Before considering physical restraints or medications, clinicians should first ensure the safety of the surroundings and attempt verbal de-escalation. If possible, they should move the patient to a quiet room with lower stimuli and dimmer lights and away from loud areas.[37] Verbal de-escalation can be aided by using a calm and even tone of voice, respecting personal space, using one person with one message, naming feelings, and appealing to the patient's wants or needs. In addition, setting limits and reinforcing appropriate behavior may be necessary. If medications are required, offering a choice to patients regarding medications or route of administration may increase their sense of control and reduce anxiety. Some patients may respond to verbal de-escalation alone. After de-escalation, clinicians can attempt a focused evaluation, continuously monitoring for potential sudden outbursts of aggression during this process. They should avoid leading questions or making assumptions and initially focus on identifying the probable cause of the agitation.

If patients do not respond to verbal de-escalation, oral medication should be offered next if patient or staff safety is not threatened. Oral medication can help engage the patient in their care and reduce a sense of coercion. If possible, collateral information should be obtained from any accompanying family member, friend, or witness while the medication takes effect and the patient is given time and space. If the patient remains agitated despite oral medication, a locked or unlocked seclusion room may provide an additional reduction in stimuli. Physical restraint and intramuscular medication may be necessary if safety remains a concern. When using seclusion, physical restraint, or intramuscular medication, the patient should be monitored closely and reassessed when it is safe to complete the evaluation and treatment plan. 

In 2012, the American Association of Emergency Psychiatry Project BETA (Best Practices in the Evaluation and Treatment of Agitation in the emergency setting) published a consensus statement outlining recommendations for the medical evaluation and triage of patients with agitation,[38] which was updated in 2019 [39] and 2023.[37] Evaluating a patient with agitation differs based on whether the setting is nonmedical or medical. A brief history and vital signs should be obtained as safety allows.

Immediate assessment for serious, possibly life-threatening conditions is recommended next. Symptoms that require immediate evaluation by a clinician include loss of memory, disorientation, severe headache, extreme muscle stiffness or weakness, heat intolerance, unintentional weight loss, new-onset psychosis, or difficulty breathing. Signs that require immediate evaluation by a clinician include any abnormal vital signs (blood pressure, pulse, oxygen saturation, or temperature), abnormal point-of-care glucose, any overt trauma, pupil asymmetry, slurred speech, incoordination, seizures, or hemiparesis.[38] In a nonmedical setting, any of these signs or symptoms should lead to transfer to an emergency department or immediate clinician evaluation in a medical setting.

In a nonmedical setting, if none of the above symptoms or signs are identified, assessing the level of agitation is recommended using psychometric scales such as the Overt Agitation Severity Scale (OASS) or the Behavioral Activity Rating Scale (BARS). Various screening tools and psychometric scales are available, and the choice of tool may depend on factors such as workflow, ease of use, setting, time constraints, and patient population. No current consensus favors one screening tool over another. Project BETA utilized BARS as a scale to triage patients.[38] An individual who is difficult to arouse or cannot be aroused (BARS 1) should be transferred to a medical emergency department. If an individual does not respond to de-escalation, they should be moved to an acute care facility for further evaluation. If de-escalation is successful (BARS 5 or 6), or if the patient presents with a BARS of 4 and the presentation is consistent with their known psychiatric condition, routine management is recommended.

History should be obtained from the patient and collateral sources (family, law enforcement, emergency medical services, and outpatient providers). This history should include details about previous agitation or violence, prior psychiatric hospitalizations, TBI, cognitive problems, borderline or antisocial personality disorder, interpersonal violence, and substance use.[37]

The physical examination should include an assessment of the heart, lungs, abdomen, skin, and neurological system, as well as a mental status examination.[38] For agitation due to a general medical condition, the examination should focus on head trauma, slurred speech, pupil asymmetry, motor problems, seizures, disorientation, hemiparesis, somnolence, muscle rigidity, myoclonus, and hyperreflexia.[38] In cases of agitation due to alcohol or substance withdrawal or intoxication, the physical examination should assess for the odor of alcohol and evidence of drug injection, such as track marks, hallucinations, and seizures.[38]

Evaluation

Identifying the etiology of agitation is a priority. Initially, a point-of-care glucose test, oxygen saturation measurement, and urine toxicology screen are useful. In cases of suspected substance intoxication or withdrawal, additional tests should include a urine toxicology screen, blood alcohol level, and liver function tests. When delirium is suspected, a complete blood count, comprehensive metabolic panel, urinalysis, urine toxicology screen, and head CT scan should be obtained to determine the etiology of delirium so the underlying cause can be treated.

Other tests to consider include:

• Pregnancy test: For all women of reproductive age.
• Ammonia: For hepatic encephalopathy.
• Creatinine kinase: For rhabdomyolysis, myopathy, and other muscle damage.
• Thyroid-stimulating hormone (TSH): For hypothyroidism or hyperthyroidism.
• Lactate: For sepsis.
• Acetaminophen and salicylate levels: For overdose.
• Urinalysis and urine culture: For urinary tract infection or ketosis.
• Lumbar puncture: For encephalitis or meningitis, syphilis, or cerebritis.
• Electrocardiogram (ECG): For QTc prolongation associated with overdose or cardiac disease.

Further laboratory testing and radiographic evaluation should be guided by the identified underlying etiology.[40] 

Treatment / Management

Treatment of an agitated patient should prioritize diagnosing and treating acute medical conditions while ensuring the safety of the patient, staff, and environment. Treatment recommendations should be guided by the underlying etiology of the agitation and the epidemiology of the local patient population.[41] This includes understanding the prevalence of specific substance use within the community and differentiating agitation resulting from intoxication or withdrawal.

The best way to engage agitated patients is through noncoercive de-escalation, a complex intervention at the interface of psychotherapy, linguistic sciences, martial arts, the nursing profession, and law enforcement.[42] Patients may respond better to a particular healthcare provider for various reasons, in which case that provider can either lead or help facilitate the evaluation. Helping the patient feel that their concerns are being heard and addressed, and reflecting the patient's statements in their own words, can convey that the clinician is listening. Open-ended questions and active listening may de-escalate a volatile situation. If verbal de-escalation does not work, offering voluntary oral medications may be the next step. Seclusion may help calm the patient if excess environmental stimuli contribute to agitation. Patients should be allowed to self-regulate whenever possible without medications or physical restraints.(B3)

In cases where all other interventions have failed or if patient or staff safety is threatened, involuntary medications may be necessary. When medications must be used, the goal should be to calm the patient so that they may safely engage in the medical evaluation. Clinicians should try to avoid sedating the patient if possible; however, treating for safety remains the primary goal. If a patient does experience sedation after medication administration, the patient should be closely monitored. Sedation from medications may also assist in recovery from agitation in specific cases, such as acute mania, which is a disorder of the sleep-wake cycle.[43] In more severely agitated patients, especially those actively trying to hurt themselves or others, sedation may be emergently necessary. Using intramuscular injections for sedation can be termed a "chemical restraint" and is controversial.[9][44](B3)

If agitation is mild or moderate, allowing the patient a choice regarding medication options may help reduce agitation. Oral medication administration should be prioritized over parenteral administration, although oral medications take effect more slowly. Institutions may have guidelines for the use of preferred medications. Agitation secondary to alcohol intoxication is best treated with an antipsychotic medication, whereas agitation secondary to alcohol withdrawal is best treated with a benzodiazepine. Evidence suggests that patients with neurocognitive disorders with agitation benefit from group activity-based interventions (recreation therapy), resident interventions (massage and touch therapy and music therapy), and person-centered care.[45]  (B3)

If a patient is a danger to themselves or others, they may require physical restraints. When physical restraints are implemented, close monitoring of the patient is necessary to ensure safety. Traumatic rhabdomyolysis has been associated with prolonged physical restraints, especially in individuals actively fighting against the restraints.[46] In these cases, administering medications along with physical restraints may reduce the length of time restraints are needed and the subsequent risk of rhabdomyolysis. Other risks of physical restraints include pressure ulcers, asphyxiation, nerve and limb injuries, head injuries and intracranial hemorrhage, contractures, posttraumatic stress disorder, and reinforcement of past psychological traumas.[47] Physical restraints may also induce hostility from the patient toward staff and contribute to future aggression. Patients who are restrained are more likely to have longer lengths of stay, increased risk of falls, decline in physical function, and increased risk of psychiatric comorbidities.[48] Physical restraints are the last resort and should be avoided if possible.(B2)

Pharmacological Management of Severe Agitation

The 2024 American College of Emergency Physicians (ACEP) evidence-based clinical policy for the treatment of patients in the emergency department with severe agitation recommends treatment with a combination of droperidol and midazolam or an atypical antipsychotic medication in combination with midazolam (Level B recommendation). The ACEP also recommends haloperidol alone or in combination with lorazepam (Level B recommendation).[49] Midazolam appears to have a more rapid onset than lorazepam. Olanzapine may have a more favorable profile than other atypical antipsychotic medications but should not be administered with benzodiazepines due to the risk of hypotension, bradycardia, and respiratory depression.[49] In situations in the emergency department where the safety of the patient, bystanders, or staff is a concern, the ACEP recommends considering intravenous or intramuscular ketamine to rapidly treat severe agitation (Level C recommendation), noting the risks of laryngospasm and hypersalivation with an infrequent need for intubation due to these adverse effects.[49]

According to the ACEP review, due to the lack of evidence, no recommendations can be made regarding the use of specific agents in out-of-hospital settings or for patients aged 65 or older.[49] Both typical and atypical antipsychotic medications have black box warnings indicating that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. The ACEP acknowledges that droperidol carries a black box warning for QT prolongation, requiring ECG monitoring of the QT interval before administration and continuing for 2 to 3 hours after completing treatment. However, the ACEP review demonstrated an overall favorable safety profile for droperidol when used for sedation of agitated patients in the emergency department.[49]

The Society of Critical Care Medicine (SCCM) 2018 Practice Guidelines suggest not routinely using haloperidol to treat delirium, as the evidence indicates that the use of haloperidol or an atypical antipsychotic medication is not associated with a shorter duration of delirium, mechanical ventilation, ICU length of stay, or decreased mortality. Despite the lack of evidence, short-term use of haloperidol or an atypical antipsychotic medication may be considered for agitated patients who may physically harm themselves or others. The SCCM conditionally recommends using dexmedetomidine for delirium in mechanically ventilated adults where agitation is precluding weaning/extubation.[35]  (A1)

The American Psychiatric Association (APA) Practice Guideline (2016) recommends considering nonemergency antipsychotic medication only for managing "severe, dangerous, and/or significantly distressing agitation or psychosis."[50] In addition, the APA recommends reviewing the clinical response to nonpharmacological interventions before using nonemergency antipsychotics for agitation and constantly assessing the benefit-to-harm ratio.(A1)

Identifying drugs that may contribute to agitation is the first step in the pharmacological treatment of patients with neurocognitive disorders. Anticholinergic drugs may cause delirium, antipsychotic medications may cause neuroleptic malignant syndrome, serotonergic drugs may cause serotonin syndrome, and stimulants may cause hyperarousal. Cholinesterase inhibitors and memantine may reduce agitation in people with Alzheimer disease or Lewy body disease.[45](B3)

The International Psychogeriatric Association (IPA) consensus algorithm (2024) emphasizes the importance of ongoing psychosocial interventions for patients with neurocognitive disorders and agitation. IPA suggests various pharmacological treatments based on severity and circumstances, noting that there are no FDA-approved medications specifically for agitation in the United States.[45] Agitation that occurs at night or with "sundowning" can be treated with trazodone or dual orexin receptor antagonists such as suvorexant and lemborexant. Mild-to-moderate agitation or agitation with mood features can be treated with citalopram. In contrast, moderate-to-severe agitation can be treated with atypical antipsychotic medications (avoided in patients with Lewy body disease or Parkinson disease), carbamazepine, gabapentin, prazosin, dextromethorphan/quinidine, nabilone, or a combination of these medications. If agitation is extreme, intramuscular olanzapine or aripiprazole, or electroconvulsive therapy can reduce agitation. For patients with neurocognitive disorders with pain, such as hospice patients, morphine, delta-9-tetracannabinol, dronabinol, and cannabidiol can be beneficial.[45]    (B3)

Benzodiazepines are the first-line therapy for agitated patients with alcohol withdrawal or central nervous system stimulant toxicity from cocaine or amphetamines.[41] The American Society of Addiction Medicine (ASAM) recommends avoiding antipsychotic monotherapy for agitation in alcohol withdrawal, as it may lead to delirium tremens and an increased risk of complicated withdrawal.[51] Antipsychotic medications also reduce the seizure threshold.[52] The World Federation of Societies of Biological Psychiatry (WFSBP) recommends that for agitation associated with alcohol intoxication rather than withdrawal, antipsychotics are preferred over benzodiazepines, which can potentiate the effects of alcohol and increase the risk of respiratory depression.[41](A1)

In patients with autism spectrum disorder and agitation, risperidone and aripiprazole are the only FDA-approved medications.[53] Both medications have been studied primarily in children and adolescents, and further research is needed to confirm their effectiveness. Risperidone was approved by the FDA in 2007 for patients aged 5 to 17, following short-term trials demonstrating benefits in reducing aggression, self-injury, temper tantrums, and mood swings, with over 90% of participants aged 12 or younger. Aripiprazole is also FDA-approved for treating irritability associated with autism spectrum disorder in children and adolescents aged 6 to 17.(A1)

Differential Diagnosis

The differential diagnoses of agitation can be broadly classified as physical illness and delirium, neurocognitive disorders, substance use and withdrawal, and psychiatric and developmental conditions (see Table below).[54]

Table. Examples of Differential Diagnoses of Agitation

Reference for the Table.[37]

Prognosis

Agitation is a medical and psychiatric emergency with a broad differential diagnosis. The prognosis depends on the swift identification of the underlying cause, prompt treatment, and maintaining a safe environment to prevent injury to patients, bystanders, and staff. In the short term, reducing stress, improving sleep quality, and addressing the patient's needs can often lead to better outcomes. Agitation related to substance use may resolve with detoxification and treatment of withdrawal symptoms. Patients with altered mental status who exhibit generalized slowing on electroencephalogram may have a worse prognosis.[55] In the ICU, agitated patients with delirium tend to have a worse prognosis compared to those without agitation.[56]

Complications

Agitation is a medical and psychiatric emergency that heightens the risk of injury to patients, bystanders, and staff. Complications associated with agitation include falls, removal of indwelling catheters and tubes, and restraint-related injuries. Physical restraints can lead to dislocations, fractures, skin abrasions, head injuries, and rhabdomyolysis, especially if individuals remain agitated and resist the restraints. The use of sedating medications in conjunction with physical restraints can help mitigate these risks.