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

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