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Definitions and EtiologyTop
Physicians may encounter agitated patients in emergency rooms, on inpatient units, and in nursing home settings. Agitation may be expressed in many ways. Patients may be uncooperative, angry, threatening, or they may express their agitation through behavior with restlessness, pacing, self-injurious behavior, and violence. Agitation may be a reflection of an underlying medical disorder, psychiatric disorder, substance use disorder, or a maladaptive response to a challenging environment. In a hospital setting, agitated and violent behavior may occur in patients with delirium, dementia, personality disorders, substance intoxication and withdrawal, and in those with serious mental illnesses, such as schizophrenia and bipolar disorder. Appropriate assessment and treatment are needed to ensure agitation is resolved in a manner that ensures the safety of the patient and health-care workers and promotes the patient’s engagement in treatment. For patients with agitation due to primary psychiatric or substance use disorders, the clinical encounter may be their first presentation to medical professionals for conditions that will likely require ongoing treatment. How the physician manages the encounter and the resultant experience of the patient may have a lasting impact on the patient’s willingness to engage with health-care professionals in the future.
There are a number of factors that increase the risk that individuals in the general population will be violent. These include being male, having a lifetime history of violence or criminal behavior, being of late teen or young adult age, alcohol and drug intoxication or withdrawal, delirium, and mental illness. In individuals with mental illness, the risk of violence is greatly increased by concurrent substance abuse, personality disorders, and recent medication nonadherence. In patients with psychotic disorders, the presence of persecutory delusions, command hallucinations, and low intellectual functioning also contribute to the risk of violence.
When assessing an agitated patient, it is critical to be aware of the goals that need to be achieved in the interaction:
1) Safety—of yourself, the agitated patient, other patients, and hospital staff.
2) Careful assessment of the patient to ensure that any urgent medical problems contributing to the agitation are identified in order to minimize morbidity and mortality.
3) Determination of medical or surgical referrals that are required for further investigation and management of the patient.
4) Reducing the patient’s distress.
In most cases agitation can be de-escalated with verbal interventions and support. When these are not effective, pharmacologic intervention may be required. A number of steps should be taken when initiating contact with an agitated patient. Make sure that:
1) The patient has been searched for any objects that could be dangerous, including weapons.
2) You have someone accompany you if you feel uncomfortable or intimidated.
3) The door to the examination room is kept open.
4) You are positioned so that you maintain a safe distance from the patient and can safely leave the room.
5) You have a clear plan for how to get urgent help if needed.
6) You convey a sense of calm, reassurance, and being in control when you approach the patient.
Restraint and seclusion may be required for highly agitated patients (see Medical Practice and the Law). Restraints are more commonly available in medical settings, with seclusion being an additional option in psychiatric settings. For violent patients, the use of restraints eliminates the risks to staff of entering a seclusion room with a patient who remains violent. Major international efforts have been focused on reducing and eliminating the use of restraint and seclusion in psychiatric settings, as these techniques are traumatic for patients and are associated with physical risk to staff and medical risks to patients. The latter include complications that may be severe and potentially life-threatening, including fractures, rhabdomyolysis, strangulation, asphyxia, deep vein thrombosis, and pulmonary embolism.
The management of an agitated patient, irrespective of etiology, begins with a focused assessment that will include vital signs, appropriate history, physical and mental state examination, and laboratory testing (see Psychiatric Examination). In some cases a more complete medical assessment may need to be delayed until acute agitation is resolved. Once a rapid focused assessment is obtained, an individualized intervention can be made based on the patient’s medical and psychiatric history, physical and mental status examination, and results of any laboratory investigations.
The specific goals of pharmacologic intervention need to be identified. These include calming the patient, ensuring safety, addressing the underlying cause of agitation, and facilitating completion of the medical evaluation needed to inform the patient’s clinical management. Giving patients some control over the route of administration of medications prescribed for agitation often helps to calm them. Offering patients sedating medication in the form of pills, rapidly dissolving tablets, or liquid formulations should be considered as the first choice for all but the most agitated patients, as these are experienced as less threatening than injectable medications.
The choice of specific medications for the agitated patient is determined by the etiology of agitation. The causes of agitation can be classified into 3 broad categories: primary medical disorders (most commonly delirium), substance intoxication or withdrawal, and those due to primary psychiatric disorders. Two broad categories of tranquilizing agents generally used in the acute management of agitation are benzodiazepines and antipsychotic medications. Benzodiazepines potentiate the effects of endogenous gamma-aminobutyric acid (GABA), the most abundant inhibitory neurotransmitter. The agents include lorazepam, diazepam, and clonazepam. Benzodiazepines are available for oral use (in pill form, rapidly dissolving sublingual tablets, and liquid formulations) and for IM and IV injections. Antipsychotic medications act by blocking dopamine D2 receptors in the brain. Both first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) are used for managing agitation and are available in a range of oral and injectable formulations. Depending on the etiology of agitation and degree of tranquilization required, benzodiazepines and antipsychotics may be used individually or in combination.
1. Agitation due to a primary medical disorder: Delirium is a medical emergency for which it is critical that the underlying etiology be identified and treated. Achieving these goals may well require that the patient’s agitation be resolved. If it is clear that the delirium is not due to alcohol or benzodiazepine withdrawal, benzodiazepines should be avoided as they may worsen delirium and, when given parenterally, may lead to respiratory depression and hypotension. Benzodiazepines should also be avoided in elderly patients considered to be at high risk of developing delirium. Antipsychotic medications are preferred for the management of agitated patients with delirium, and both FGAs and SGAs have been used for this indication. SGAs are generally associated with a lower risk of acute extrapyramidal symptoms (EPSs) (ie, acute dystonia, parkinsonism, and akathisia) than FGAs. Risperidone (1-2 mg) or olanzapine (5-10 mg) are SGAs that can be given in rapidly dissolving tablets or pill form. Haloperidol (1-2 mg) is the most commonly used FGA for acute agitation. It has minimal anticholinergic activity and low potential for causing hypotension. Haloperidol can increase QTc intervals, as can all other antipsychotics to varying degrees; cases of torsade de pointes have been reported with its use. When IM injections are required, olanzapine (5-10 mg) and haloperidol (2-5 mg) are the SGA and FGA, respectively, that have been most studied. The increased likelihood of anticholinergic effects with olanzapine should be weighed against the higher risk of acute EPSs with haloperidol. These risks will vary with dose and age of the patient (youths and the elderly being at higher risk for EPSs).
Patients with acute agitation of medical etiology who are psychotic in the absence of delirium should also be managed with antipsychotic medication. If the agitated medical patient is neither delirious nor psychotic, benzodiazepines are recommended. Lorazepam (1-2 mg orally, sublingually, IM, or IV), diazepam (5-10 mg orally), or clonazepam (0.5-1 mg orally) are commonly used.
2. Agitation due to substance intoxication or withdrawal: The emergency management of the agitated intoxicated patient will vary depending on the cause of intoxication. Agitation due to acute alcohol intoxication should be treated with antipsychotics, as benzodiazepines can contribute to the risk of respiratory depression. Haloperidol has been used extensively for this indication. It is critical that alcohol withdrawal be distinguished from alcohol intoxication, as benzodiazepines—not antipsychotics—are indicated in the management of agitated patients who are in alcohol withdrawal.
Patients agitated as a result of being intoxicated with stimulants (eg, cocaine, amphetamine, methamphetamine) should be treated with benzodiazepines. Stimulants can also induce acute psychotic symptoms, in which case antipsychotics may be required.
3. Agitation due to a primary psychiatric disorder: In the emergency setting, agitation due to an underlying psychiatric disorder occurs most commonly in patients who are experiencing psychosis (hallucinations, paranoid ideation, delusions) due to schizophrenia or a manic episode of bipolar disorder. As discussed above, both FGAs and SGAs can be used for managing acute agitation in a psychotic patient. Antipsychotic medications can bring about measurable improvement in overall symptoms within 2 hours and in psychotic symptoms within 24 hours.Evidence 1High Quality of Evidence (high confidence that we know true effects of the intervention). Kapur S, Arenovich T, Agid O, Zipursky R, Lindborg S, Jones B. Evidence for onset of antipsychotic effects within the first 24 hours of treatment. Am J Psychiatry. 2005 May;162(5):939-46. PubMed PMID: 15863796. SGAs are associated with a lower risk of EPSs than haloperidol and are generally considered to be first-line agents. Risperidone has been shown to be safe and effective in the management of acute agitation and is available in pill, rapidly dissolving tablet, and liquid forms. Liquid risperidone (2 mg) used in combination with oral lorazepam (2 mg) has been shown to be as effective as the combination of IM haloperidol (5 mg) and IM lorazepam (2 mg).Evidence 2High Quality of Evidence (high confidence that we know true effects of the intervention). Currier GW, Chou JC, Feifel D, et al. Acute treatment of psychotic agitation: a randomized comparison of oral treatment with risperidone and lorazepam versus intramuscular treatment with haloperidol and lorazepam. J Clin Psychiatry. 2004 Mar;65(3):386-94. PubMed PMID: 15096079. Risperidone is not available for acute IM injections; the long-acting injectable forms of risperidone and its primary metabolite, paliperidone, are not used in the management of acute agitation. Oral olanzapine has been shown to be as effective as oral risperidone in acutely agitated patients and is available in both pill and rapidly dissolving tablet forms. In Canada, olanzapine is the only SGA available for acute IM injections for those patients who will not accept oral medications. IM olanzapine given in a dose of 5 to 10 mg has been shown to be as effective as IM haloperidol 7.5 mg in the management of acute agitation. Olanzapine is associated with a lower risk of acute dystonic reactions than haloperidol but with a slightly higher frequency of hypotension.Evidence 3Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision and some indirectness (only one dose of haloperidol tested against several doses of olanzapine). Wright P, Birkett M, David SR, et al. Double-blind, placebo-controlled comparison of intramuscular olanzapine and intramuscular haloperidol in the treatment of acute agitation in schizophrenia. Am J Psychiatry. 2001 Jul;158(7):1149-51. PubMed PMID: 11431240. Breier A, Meehan K, Birkett M, et al. A double-blind, placebo-controlled dose-response comparison of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia. Arch Gen Psychiatry. 2002 May;59(5):441-8. PubMed PMID: 11982448. Parenteral benzodiazepines should not be administered within an hour before or after IM olanzapine due to the risk of hypotension and cardiorespiratory depression that have been associated with reported fatalities.
The FGA most commonly used and most extensively studied for the management of agitation is haloperidol. It is available for oral, IM, and IV administration. The combination of IM haloperidol (5 mg) and IM lorazepam (2 mg) given concomitantly reduces agitation more quickly than either drug administered alone.Evidence 4Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision and indirectness. Battaglia J, Moss S, Rush J, et al. Haloperidol, lorazepam, or both for psychotic agitation? A multicenter, prospective, double-blind, emergency department study. Am J Emerg Med. 1997 Jul;15(4):335-40. PubMed PMID: 9217519. When acute dystonic reactions (eg, oculogyric crisis, torticollis, opisthotonus) do occur, IM benztropine 2 mg should be given immediately. Subsequent doses of haloperidol can be accompanied by oral or IM doses of benztropine in order to prevent further dystonic reactions. Acute akathisia (objective or subjective motor restlessness) is extremely distressing and can be managed with IM or oral benzodiazepines. Haloperidol, like other antipsychotics, is associated with prolongation of the QTc interval and, in rare cases, torsade de pointes. The risk is thought to be greatest with the use of higher doses and IV administration.