Chapter 287: Acute Agitation

EDs are the portal of access to the healthcare system for most patients with acute agitation and acute behavioral or mental health disorders.¹ Agitation is one of the most common manifestations of mental health and behavioral disorders, dementia, and intoxication and withdrawal syndromes. The last consensus updates for acute agitation were published in 2006,² prior to the release of newer therapeutic agents and prior to the recognition of QT_c prolongation with acutely administered psychotropics. This review provides a general pharmacotherapeutic approach for acute agitation and acute behavioral emergencies.

Try to obtain vital signs, obtain a patient history and perform a physical examination, and obtain baseline laboratory data. Psychosis, mania, withdrawal syndromes, drug intoxication, delirium, or even depression and anxiety can cause psychomotor agitation, aggressive behaviors, or disorientation. Other causes of acute agitation include adverse effects of medications, pain, substance abuse, or worsening of a chronic underlying illness.

The most important goal in the care of the agitated patient is ensuring the safety of the patient and staff involved. Management of the patient's undifferentiated agitation ensures immediate safety and allows a more thorough evaluation for serious acute pathology.

Provide a sitter and try to address patient comfort needs. Decrease external stimuli by placing the patient in a quiet room. Remove potentially dangerous objects from the immediate environment. Use physical restraints if there is imminent harm to healthcare workers, other patients or visitors, or the patient him/herself.^1,2,3,4

When considering pharmacologic treatment options, assess the underlying diagnosis, presenting signs and symptoms, and potential risks/benefits of specific agents (Tables 287-1 and 287-2), and determine the proper dose and easiest mode of administration. Because the oral and parenteral routes are equivalent for some agents,^5,6,7,8 offer oral agents first, if appropriate and feasible. If repeated dosing is needed, try to wait 1 hour before the next dose to adequately assess patient behavior and medication effect. Generally, all antipsychotics have similar efficacy at comparable dosages and may be used to treat acute agitation.

The FDA recommends evaluating the QT_c interval prior to the use of many of these agents, because all antipsychotic agents carry a bolded warning for altered cardiac conduction and risk of fatal arrhythmias. In clinical situations in which rapid tranquilization is necessary, prior determination of the QT_c interval is usually impractical and often impossible. If an electrocardiogram is available from a prior hospital visit, review it for evidence of QT_c prolongation.

The QT interval is used as a surrogate marker for the potential development of abnormal cardiac conduction. In general, the QT_c interval is considered prolonged when it is ≥450 milliseconds in men and 460 milliseconds in women.⁹ Medication-induced QT_c prolongation is considered highly significant at ≥500 milliseconds.^9,10,11,12 Unfortunately, QT_c prolongation does not directly correlate with clinical risk of dysrhythmias or the development of the malignant arrhythmia torsade de pointes.

BENZODIAZEPINES

Of the benzodiazepines, lorazepam is the agent with the highest level of guideline and literature support for acute use and is considered first-line therapy in the treatment of undifferentiated agitation. Much of this preference is due to its availability for administration by the PO, IM, PR, or IV route; relatively quick onset of action; and lack of active hepatic metabolites. Benzodiazepines bind to benzodiazepine-1 receptors on the postsynaptic γ-aminobutyric-A receptor, which results in increased influx of chloride ions into the postsynaptic neuron, leading to hypoexcitability and neuronal stabilization.¹³

The initial dose of lorazepam for acute agitation is 2 milligrams, with repeated dosing, if needed, given at least 30 minutes after the initial dose. Cumulative studied dosage is 4 milligrams over 2 to 4 hours; however, dosage regimens of up to 8 milligrams have been described.^14,15,16 Onset of action is 0.5 to 1 hour, with a duration of 6 to 8 hours and a terminal half-life of 12.9 hours in adults that is extended to 15.9 hours in the elderly and up to 72 hours in patients with renal failure.

Lorazepam is effective in both undifferentiated and psychotic agitation, and 2 milligrams may be as effective 5 milligrams of haloperidol, with additive benefits when given in combination with other agents (except olanzapine).^5,14,17 The most common adverse effect of lorazepam or other benzodiazepines is sedation, and sedation is greater than that with haloperidol alone.^5,14 Lorazepam can cause respiratory depression and hypotension, particularly with repeated and high-dose administration. Another noTable adverse effect is paradoxical agitation, or activation or worsening of confusion, most commonly seen in patients with delirium and in the elderly.

TYPICAL, OR FIRST-GENERATION, ANTIPSYCHOTICS

Typical antipsychotics are also called first-generation or conventional antipsychotics, classic neuroleptics, or major tranquilizers. This class of drugs blocks dopamine receptors and is strongly associated with extrapyramidal symptoms, such as dystonias, akathisia or restlessness, and parkinsonism, and anticholinergic blockade (dry mouth, hypotension, glaucoma exacerbation, delirium). Typical antipsychotics are classified as low, intermediate, or high potency when compared to 100 milligrams of chlorpromazine (Thorazine^®). Low-potency typical antipsychotics tend to be more sedating and are associated with hypotension, dizziness, and anticholinergic symptoms. High-potency medications are less sedating but are associated with extrapyramidal symptoms (Table 287-3).

Agents commonly used for acute agitation within this class include haloperidol, fluphenazine, and chlorpromazine because these agents are available in multiple dosage forms and have decades of clinical and anecdotal data supporting their efficacy. Droperidol has historically been commonly used for agitation; however, U.S. Food and Drug Administration concerns of QT_c prolongation have limited its use for this purpose.

Adverse effects limiting the use of these medications in acute agitation include sedation, hypotension, risk of extrapyramidal symptoms, and QT_c prolongation and the risk of torsades de pointes. While all antipsychotics can increase the QT_c interval and risk of torsades de pointes, several agents within this first-generation subclass have been implicated for adverse outcomes. Among antipsychotics used for acute agitation, haloperidol and droperidol carry additional Food and Drug Administration warnings regarding QT_c prolongation, torsades de pointes, and sudden cardiac death.^18,19

Neuroleptic malignant syndrome, though rare, is a potentially life-threatening adverse effect that consists of a constellation of signs including altered mental status, hyperthermia, muscular rigidity, autonomic instability, and elevated creatinine phosphokinase. Contributing factors for neuroleptic malignant syndrome may include high dose, rapid dose escalation, use of a high-potency first-generation agent, history of previous neuromuscular malignant syndrome, agitation, or dehydration.²⁰

Common extrapyramidal symptoms encountered with the acute administration of first-generation agents include akathisia and the parkinsonian symptoms of tremor and gait disturbances. Acute dystonias, which occur less frequently but can be severe, include torticollis, laryngeal spasm, and oculogyric crisis. Acute dystonia is associated more frequently with the high-potency agents (e.g., fluphenazine, haloperidol, and droperidol). The mechanism of extrapyramidal symptoms is thought to be related to secondary acetylcholine dysregulation in response to decreased dopamine in the nigrostriatal pathway. Treat acute dystonias with anticholinergic agents such as IM or IV diphenhydramine (25 to 50 milligrams) or benztropine (2 milligrams). Coadministration of these agents with a typical IM antipsychotic to prevent dystonia and other extrapyramidal symptoms is also common practice. Be aware that diphenhydramine and benztropine carry their own risks of adverse reactions including sedation, constipation, and blurred vision.

Droperidol

Despite strong clinical evidence supporting efficacy in acute agitation, droperidol is no longer U.S. FDA–approved for this use.¹⁸ The FDA warning includes reports of death from QT_c prolongation even with use at low dosage and in patients with no cardiac risk factors. These risks led to removal of the drug from the European markets. Droperidol is still available in the United States and is Food and Drug Administration–approved for perioperative nausea and vomiting and is to be used only when other treatment methods fail. The maximum initial dosage is 2.5 milligrams given IV or IM, with repeat doses of 1.25 milligrams given until desired effect is achieved.

Haloperidol

Haloperidol also carries an additional warning from the U.S. FDA regarding QT_c prolongation, specifically related to IV administration, and by any route at dosages higher than recommended,²¹ most commonly defined as >35 milligrams/d or single doses of 20 milligrams or greater. Data supporting this warning include 73 cases of torsades de pointes, including 11 fatalities.¹⁹ It is also important to note that, while used in common practice, haloperidol is not Food and Drug Administration–approved for IV administration. If used IV, doses of 2 to 10 milligrams have been studied, with repeat dosing every 15 to 30 minutes as needed to achieve calming effects, and subsequent administration of 25% of the required bolus dosing. Use the lowest effective single and cumulative dose. Continuous cardiac monitoring should be maintained after IV dosing.

IM haloperidol is often used for acute agitation and is considered second only to lorazepam as standard-of-care therapy.²² Doses between 2.5 and 10 milligrams have been evaluated in clinical trials as either the primary medication or active comparator, with the most common dosage of 5 milligrams initially, with repeated dosing in 1 to 2 hours as needed. Coadministration with lorazepam has additive calming effects but a higher incidence of sedation.

Fluphenazine

Fluphenazine IM is an additional injectable, high-potency, first-generation antipsychotic option. Its efficacy is generally considered interchangeable with haloperidol.²³ The average dosing of IM fluphenazine is 2.5 to 5 milligrams per injection, with a recommended dosing range of 1.25 to 10 milligrams per injection.²²

Chlorpromazine

Chlorpromazine, a low-potency, first-generation antipsychotic agent, may also be administered PO or IM at doses of 12.5 to 25 milligrams initially, with repeat doses of 25 to 50 milligrams given if necessary to calm agitation.²⁴ Chlorpromazine may also be given IV, although this is seldom done in clinical practice for the treatment of acute agitation. While this agent does not carry a formal bolded U.S. FDA warning, its label still advises cardiac monitoring, because QT_c prolongation is a concern.²⁵ Additionally, frequent monitoring of vital signs and orthostatic blood pressure is recommended with acute administration because hypotension, tachycardia, and sedation are common and can be profound. These adverse effects limit the usefulness of this agent in acute agitation.

ATYPICAL, OR SECOND-GENERATION, ANTIPSYCHOTICS

Atypical antipsychotics are also called second-generation antipsychotics. These agents block dopamine receptors, but their precise action is not known. Atypical antipsychotics are less likely than typical antipsychotics to cause extrapyramidal symptoms or neuroleptic malignant syndrome and have lower rates of tardive dyskinesia. These features have served to propel them to first-line therapy within the field of psychiatry. Another advantage of atypical antipsychotics is the decreased need for coadministration of medications to combat adverse anticholinergic effects. Less need for concomitant benzodiazepines is also an advantage, especially in the elderly.

Several agents in this class can be given orally or IM. Oral disintegrating tablets of olanzapine and risperidone, oral solution of risperidone, and IM preparations of olanzapine, ziprasidone, and aripiprazole have all been studied specifically for use in acute agitation. Additionally, quetiapine is effective for agitation in delirious critical care patients.²⁶ Table 287-4 outlines dosage forms for the available options in this class.

Risperidone

Risperidone (Risperdal^®) has been studied in both ED and psychiatric settings for the treatment of acute agitation. It is not available as an IM preparation, but the oral liquid or rapid oral dispersible tablet (M-Tab^®) is comparable to IM haloperidol with and without concomitant lorazepam. It is effective beginning 30 to 60 minutes after administration and has lower rates of extrapyramidal symptoms and sedation than haloperidol.^6,7 It also has comparable efficacy to olanzapine PO and IM, but with a longer time to onset of effect.^8,27

Olanzapine

Olanzapine (Zyprexa^®) is available as a rapidly dissolving oral tablet (Zydis^®) and an IM preparation. It is as effective as haloperidol or risperidone, with less extrapyramidal symptoms than haloperidol, but with more hypotension than risperidone.^8,27,28 Olanzapine given either orally or IM has a faster onset of action than IM haloperidol or oral risperidone, with effect beginning within 15 minutes after administration.⁸

Hypotension with IM olanzapine is a serious adverse effect and has led to fatalities in patients coadministered benzodiazepines or chlorpromazine.²⁹ The product information for olanzapine warns against coadministration with benzodiazepines, because life-threatening sedation and hypotension can occur 1 hour after administration of lorazepam 2 milligrams IM.³⁰ While recommendations differ, it is best to wait 1 to 2 hours between administering benzodiazepines with IM olanzapine, and if coadministering with oral olanzapine, monitor blood pressure frequently.

Ziprasidone

Ziprasidone (Geodon^®) is available in an IM preparation and has been compared with haloperidol for the treatment of patients with bipolar disorder or schizophrenia. Doses of 20 milligrams IM are comparable to 5 milligrams of IM haloperidol.^31,32 A potential barrier to use for ziprasidone is its effects on QT_c prolongation. In a direct-comparative study, IM ziprasidone was found to increase QT_c approximately 9 to 14 milliseconds longer than four other antipsychotic agents, including haloperidol.³³ As a result, ziprasidone is contraindicated in patients with a known history of QT_c prolongation, recent myocardial infarction, or uncompensated heart failure, or who are taking other medications known to prolong the QT_c interval. If possible, magnesium and potassium levels should be obtained and corrected prior to administration of ziprasidone, and the drug should be discontinued in patients with a QT_c >500 milliseconds.^31,32,33 This warning has limited its use for acute agitation in the ED.

Aripiprazole

IM aripiprazole (Abilify^®) is effective for acute agitation when compared with IM haloperidol, with onset of response within 1 hour. Patients treated with aripiprazole had lower rates of extrapyramidal symptoms when compared with patients treated with haloperidol, but a higher incidence of headache.^34,35 No studies have researched the utility of oral aripiprazole in the management of acute agitation. The dose of IM aripiprazole is 9.75 milligrams per injection, with a maximum dose of 30 milligrams per day. Aripiprazole is not recommended for use in children or adolescents with acute agitation due to an increased rate of akathisia in this patient group.³⁶

Quetiapine

Quetiapine is an atypical antipsychotic that has shown benefits for agitation associated with delirium in a critical care population.³⁷ Dosing ranges from 12.5 to 200 milligrams twice daily, and the most common adverse effects include somnolence and hypotension. Quetiapine has not been studied specifically for the treatment of undifferentiated or psychotic agitation in adults. Dosage forms are limited to oral tablets.

ANTIHISTAMINES

The most commonly used antihistamines for the treatment of agitation include diphenhydramine and hydroxyzine. Diphenhydramine is available in both liquid and parenteral dosage forms, but carries a higher rate of sedation and anticholinergic burden than hydroxyzine or other agents for agitation. Efficacy most supports the use of antihistamines in the treatment of anxiety in pediatric and adolescent patients, but antihistamines may be used as a single agent or adjunctive therapy in a generally agitated patient, particularly if the symptoms are anxiety driven.³⁸

ANTICONVULSANTS

Anticonvulsants have been studied as agents for agitation, particularly in the acutely aggressive patient, as well as for anxiety. Gabapentin has shown some efficacy as adjunctive therapy of agitation in patients with major mental illnesses,³⁹ as well as some benefits in anxiety or agitation associated with dementia. Overall efficacy, however, is considered to be modest.⁴⁰ In patients with bipolar disorder, it is reasonable to consider valproic acid/divalproex as a treatment option for agitation because it can be "loaded" (i.e., dosed in a fashion that promotes efficacy for bipolar agitation quickly) and often produces calm and sedation as adverse effects.⁴¹ Other anticonvulsants indicated for bipolar disorder such as carbamazepine or lamotrigine must be titrated to effect to avoid Stevens-Johnson syndrome and other adverse effects, therefore limiting their use in acute agitation associated with bipolar disorder. The same limitation applies for lithium as well, rendering it ineffective in acute symptom management.

α₂-AGONISTS

Clonidine, a centrally acting α₂-agonist, has historically been tried to combat acute agitation. Unfortunately, hypotension and bradycardia, along with mixed data for efficacy in this patient group, limit its use. However, the sedative agent dexmedetomidine, also an α₂-agonist, has gained attention for use in acute agitation in the intensive care unit setting.⁴² It is currently under investigation for use in alcohol detoxification in intensive care unit patients as well. It is further hypothesized that the potential benefits of quetiapine and risperidone may be, in part, due to their alpha-agonist effects.³⁷ Although clonidine and dexmedetomidine are potentially of benefit, the current literature supports limiting them to adjunctive or alternative strategies.

Acute agitation is acutely treated with either benzodiazepines or antipsychotic medications, or both. For children and adolescents or for adjunctive use, consider antihistamines. Agent-specific information is found in Tables 287-3, 287-4, 287-5, 287-6.

Table 287-2 provides guidelines for pharmacotherapy in special circumstances and special populations.

THE ELDERLY PATIENT

No pharmacologic therapy has proven optimal for agitation in the elderly patient presenting to the ED with or without dementia. Nonpharmacologic therapies such as reorientation to surroundings; offering food, water, and bathroom facilities; and making sure the patient has his or her hearing aids and glasses are important. If medication is needed, select an agent based on its adverse effect profile at the lowest effective dose and least invasive route of administration. For delirium, treat the underlying disease processes.

Most atypical antipsychotics have not been investigated in the elderly for treatment of agitation in the ED setting, but small studies have investigated the safety and efficacy of IM ziprasidone and IM olanzapine in this group. Data for 15 patients aged 65 to 87 who received at least one dose of 20 milligrams of IM ziprasidone showed outcomes similar to those in patients treated with lorazepam and haloperidol together, or with physical restraints, with no spontaneous reports of adverse effects or changes in electrocardiogram parameters.^43,44 In a single study of agitated inpatients or nursing home residents with comorbid Alzheimer's disease, acute agitation decreased from 2 to 20 hours after a dose of 2.5 or 5 milligrams of IM olanzapine, with somnolence reported as the predominant adverse effect.⁴⁴ However, systematic evaluation of specific atypical antipsychotics in elderly patients with dementia showed minimal efficacy, even when used for up to 27 weeks.⁴⁵

Overall, elderly patients are more susceptible to extrapyramidal symptoms, sedation, and confusion than younger populations, and, if treatment with an antipsychotic agent is warranted, initial dosing should be lower than that in the general adult population. Suggested dosing ranges are described in Table 287-7 based on the data available for treatment of agitation (acute or chronic) in elderly patients.

Unfortunately, all antipsychotic agents carry a Black Box warning because their use increases all-cause mortality in the elderly, especially in those with dementia. Benzodiazepines should be used with caution, because they can cause paradoxical disinhibition and increased agitation in elderly patients, even at doses as low as 1 milligram of lorazepam.⁴⁵ If a benzodiazepine is used, consider a short-acting, glucuronidated agent such as lorazepam, oxazepam, or temazepam to minimize prolonged benzodiazepine effects. Antihistamines have strong anticholinergic effects and can induce or worsen delirium in this patient group, and thus are generally avoided.⁴⁵

CHILDREN

The mainstays of therapy in children are antihistamines and benzodiazepines. If an antipsychotic regimen is needed, chlorpromazine, haloperidol, risperidone, olanzapine, or IM ziprasidone may be used.^36,38 Dosing information from these guidelines is presented in Table 287-8 for patients aged 6 to 18 years.^36,38

ACUTE WITHDRAWAL OR INTOXICATION SYNDROMES

Withdrawal or intoxication from substances can often lead to acute agitation, resulting in the potential for violence. History is often lacking, so it is necessary to treat without knowing the offending substance.

Benzodiazepines are considered the preferred treatment of agitation for the patient with alcohol or substance abuse. Benzodiazepines are beneficial for short-term sedation and cessation of agitation. They are associated with fewer cardiac and extrapyramidal side effects; however, be cautious of sedation and respiratory depression in an intoxicated patient. Of the benzodiazepines, lorazepam is the favored agent due to its lack of hepatic metabolites, rapid and complete IM absorption, and quick onset of action. Lorazepam may be given PO, IV, or IM. For agitation, using lorazepam "as needed" is as effective as a scheduled regimen. A typical starting dose is lorazepam 1 milligram PO, IV, or IM and repeating as needed. Higher doses may be required in a very agitated patient. In an elderly patient, considering a lower starting dose of lorazepam (0.5 milligram PO, IV, or IM once) and assessing efficacy is appropriate.

Acute Withdrawal Syndromes

Withdrawal syndromes may result from the abrupt discontinuation of various substances including alcohol, opiates, benzodiazepines, and other prescription medications or illicit drugs. Intoxicated patients often present to the ED confused, agitated, combative, and disoriented. The goals of therapy are rapid reduction in agitation, maintaining patient and staff safety, and avoiding excessive sedation. Try to decrease external stimuli by providing a quiet room. The ED staff should communicate a safe and respectful attitude and remove any potentially dangerous objects from the patient's room.

Alcohol Withdrawal The abrupt discontinuation of alcohol can lead to delirium tremens and withdrawal seizures, which may be fatal. The Clinical Institute Withdrawal Assessment Scale for Alcohol, Revised is often used to assess symptom severity.⁴⁶ The severity of alcohol withdrawal syndrome and history of complications will determine whether the patient can be managed with "symptom-triggered" or "as-needed" medication administration or a fixed-schedule detoxification (Table 287-9).

Benzodiazepine Withdrawal Treatment of agitation secondary to benzodiazepine withdrawal is very similar to the treatment of alcohol withdrawal. A slow taper of the benzodiazepine is recommended. Consider switching short or intermediate half-life drugs to an equivalent dose of diazepam (multiply triazolam dose by 20, alprazolam dose by 10, and lorazepam dose by 5), and then taper. A recommended tapering strategy is to decrease the dose by 25% the first week, by 25% the second week, and then by 12.5% every 7 days.⁴⁷

Opiate Withdrawal Opiate withdrawal is not fatal but can result in agitation and combative behavior. Benzodiazepines are the treatment of choice in patients with acute agitation from opiate withdrawal. Because patients often have polysubstance abuse, benzodiazepines will provide a sedative effect as well as prevent possible withdrawal seizures from alcohol or benzodiazepine withdrawal. Other options for managing symptoms of opiate withdrawal are discussed in chapters 186 and 292.

Acute Intoxication Syndromes

Intoxication can occur from alcohol, prescription medications, hallucinogens, synthetic drugs, and a variety of drugs of abuse. Stimulants include prescription medications (e.g., methylphenidate, dextroamphetamine) and illicit substances (e.g., cocaine, methamphetamine). Hallucinogens, as categorized by the Substance Abuse and Mental Health Services Administration, include lysergic acid diethylamide (LSD or "acid"), phencyclidine (PCP), peyote, mescaline, psilocybin mushrooms, and methylenedioxymethamphetamine (MDMA or "ecstasy"). Synthetic drugs are easily obtained and are not detected on traditional drug screens. Herbal marijuana, commonly known as K2 or Spice, is a combination of synthetic cannabinoids and plant material. Marijuana alternatives are often sold as incense and potpourri and may induce anxiety, paranoia, agitation, delusions, and psychosis. Synthetic cathinones, or "bath salts," produce amphetamine-like euphoria, increased talkativeness, increased energy, and sexual arousal. Supportive care and benzodiazepines are first steps in the management of agitation from suspected acute intoxication. However, for severe agitation impacting patient and staff safety that is not controlled with benzodiazepines, antipsychotics such as haloperidol or droperidol may be the only effective therapeutic options.