Agitation

Etiology

The etiology of aggression or behavioral disturbance can be multifactorial, reflecting the interaction of precipitating factors and patient characteristics. Agitation, or extreme motor activity or inner restlessness, can be a normal physiological process related to specific situations, but it can also entail an underlying disease. Leading causes of agitation are a new environment, drug intoxication or withdrawal, alcohol in the system, and general medical conditions. Some of the common medical conditions leading to agitation are trauma (especially to the head), generalized infection, sepsis, dementia, delirium, exposure to toxins, electrolyte abnormalities, endocrine abnormalities, and a post-ictal state.[3] Mental health conditions like anxiety, depression, bipolar disorder, autism spectrum disorder, and substance use may lead to agitation.

Epidemiology

Establishing the epidemiology of aggression or behavioral disturbances can be challenging as it differs by age group, general reasons for aggression, confounding interactions, environmental factors, as well as also severity that cannot be objectively and uniformly measured. The most researched places where aggression occurs are long-term care facilities, where professionals can monitor a patient’s day-to-day behavioral changes. Hence, these facilities are ideal for research because confounding factors can be minimized. Agitation and aggressive behaviors are reported in 33% of community-dwelling patients with dementia and 80% of institutionalized patients with dementia. The younger age group (16 to 19 years) experienced more aggression than the older age group (20 to 26 years). Research indicates a range in prevalence for challenging behaviors, such as self-injury and aggression, of 10% to 20% of all people with intellectual disability. The probability of violent behavior among patients with mental disorders is greater than the probability in the general population. Historically, the consensus was that mental disorders led to aggression and violence. However, modern epidemiological studies have shown that mental disorders have a higher relative risk of aggression and violence, but they are not the sole reason for aggression. A study from Sweden showed that 1 out of 20 patients who have mental disease commit violent crimes including assaults. These findings have been replicated globally in various studies. A Finnish study found that patients with schizophrenia and reported alcohol use were about 25 times more likely (95% CI, 6.1-97.5) to commit violent crimes than mentally healthy patients. Aggression is a global problem that transcends cultures, races, and environments.[4][5]

Pathophysiology

Agitation is a nonspecific constellation of relatively unrelated behaviors that can be seen in various clinical situations, usually presenting as a fluctuating course. One of the biggest difficulties in delineating its pathophysiology is its episodic nature, no distinct clinical features, and a non-linear relationship with various neurotransmitters in the body. Multiple neurotransmitters have been postulated to be the cause of aggression. Dysregulations of dopaminergic, serotonergic, noradrenergic, androgenic, and GABAergic systems have been most widely studied. Agents that reduce dopaminergic or noradrenergic tone or increase serotonergic or GABAergic tone will attenuate agitation, often irrespective of etiology. Sheard et al hypothesized that serotonin 5-HT was a modulator of aggression, and this finding was validated by Asberg et al. In inmate populations, Sheard studied effects of lithium for 3 months and concluded that lithium (does have serotonergic activity) and could have a clinically useful effect on impulsive aggression not related to psychosis. It was Asberg and colleagues who studied cerebrospinal fluid (CSF) of depressed patients and concluded that patients with low levels of 5-HIAA, a breakdown product of serotonin, are more likely to commit suicide using more violent means. Further studies verified that low levels of 5-HIAA are significantly associated with more violent attempts. This led to more studies searching for other neurotransmitters involved in aggression.

Experimental studies in which 5-HT activity was manipulated and aggressive responding monitored have been conducted in research volunteers without documented psychopathology. Four studies in which brain 5-HT was putatively manipulated by tryptophan depletion, supplementation, or both reported data consistent with an inverse relationship between 5-HT activity and aggressive response in the laboratory. Based on animal studies, increased noradrenergic (NE) and dopaminergic (DA) activity could be hypothesized to facilitate aggressive responses in humans. NE pharmacological challenge studies in this field have been limited and include a positive correlation between the growth hormone response to the alpha 2-NE agonist clonidine and self-reported ‘‘irritability’’ (a type of aggression) in a limited sample of male personality-disordered and healthy volunteer test subjects. Testosterone has also been postulated to play a role in aggression, but aggression levels do not change during puberty when testosterone levels increase.

Furthermore, aggression is not observed more in hypogonadal males when exogenous testosterone is administered, or in hirsute females where androgens levels can double. However, studies like the one by Rasanen et al. have shown that plasma testosterone levels are higher in aggressive individuals in the psychiatric and criminal populations. They also showed that male prisoners with personality disorders had a higher level of plasma testosterone compared to prisoners with schizophrenia. Cortisol, prolactin, and vasopressin have all been postulated to cause aggression, but research shows no conclusive results, Studies have shown that aggression is multifactorial and cannot be attributed to one cause.

History and Physical

During an episode of agitation, obtaining a history is difficult, and in most cases, counterproductive, as patients might retaliate, especially if they are psychotic. Individuals who are agitated do not want to talk about their history, but the initial evaluation is the most important tool that will help a clinician to determine the outcome of an episode. After approaching the patient, the clinician should seek to build rapport by verbal de-escalation using a calm tone and let the patient know that his or her needs will be cared for and the medical staff is there to help. Once the patients trust the clinician, they may discuss the patient's basic history. Questions should not be leading and assumptions may lead to sudden outbursts. Basic questions should focus on the probable cause of the agitation. If the patient has a medical condition that led to delirium, then the focus should be on orientation questions.

A mental status exam will be necessary. If the patient is agitated due to postictal confusion, then asking about a seizure history is appropriate. If agitation is due to psychosis, it is helpful to talk about the delusions or hallucinations. If the patient is disorganized, then empathy alone can calm the patient. Conducting a physical is appropriate once the patient is redirectable and not agitated. Before doing a physical, always ask them if it is okay for you to do a brief exam. If the patient consents, then approach them with care as patients can use stethoscopes, pens, badges, and anything they can get their hands on for assault. Therefore, it is most important to make sure that the patient is calm, not agitated, and not passive-aggressive before approaching them for a physical exam. The physical exam should be focused and brief.

Evaluation

With an agitated patient, the first thing to do is to make sure that the environment is safe. Note anything that can be used as a weapon, for example, chairs, food trays, and other things in the room. Observe any exit points in the examination room for easy egress and mentally prepare for possible physical attacks. Have staff nearby while talking to an agitated patient as things can escalate rather quickly, especially if the agitated person has a strong built. When engaging, try to keep a safe distance, 1 to 2 arm lengths is ideal. In some instances, physical assaults are unprovoked, and the individual interviewing the patient is not prepared for harmful outcomes. Clinicians should also be careful of their body language and any non-verbal communication. Clinicians should let patients know that they are listening to them and not simply there to dispense medication.[6][7][8]

The initial assessment of any agitated patient should be rapid and focused on limiting disruption of the environment as yelling and screaming will make the other patients agitated as well. In some cases, this may lead to physical fights among the other patients. Professionals should then decide whether verbal de-escalation is enough, or if more active treatments like medications, seclusion, or restraints are needed.

Treatment / Management

Treatment recommendations are outlined by the etiology of the agitation, with several alternatives for each category. Individuals involved in the direct care of agitated patients should know the epidemiology and what to expect in the patient population that they will be dealing with, for example, the most common self-harming behaviors and how to manage each of them. The proper management of an agitated patient is essential to keep staff safe and to ensure appropriate treatment for the patient. Treatment teams should be trained in managing any motor unrest and assaultive behaviors and how to tackle these situations with minimal necessary interventions. Such training includes Pro-Act (Professional Assault Crisis Training) that is being implemented globally. In some facilities, annual staff training is mandated to help individuals to develop critical thinking in the management of aggressive, behavioral patients. This ultimately reduces the use of unnecessary coercive or sedative treatments that are destructive to the doctor-patient relationship. Training in the management of agitated patients also tends to decrease the likelihood of staff and physicians fearing for their safety, and, hence, avoiding proper assessment.[9][10](B3)

The best way to initially engage agitated patients is through noncoercive de-escalation. De-escalation skills are usually involved in training but can only be improved with practice and real-life application. Clinicians can work on these skills through role-playing and impromptu scenarios. If the patient has a good rapport with a trained healthcare provider, this person should start the initial conversation as the patient already trusts them. The goal is to have the patient believe that their concerns are heard and appropriately addressed. It always helps to repeat what the patient is saying, so they know they are heard. The clinician should ask open-ended questions when trying to de-escalate a volatile situation. If this does not work, one may politely ask the patient if they are willing to take any medications to help them. Seclusion is another good method for calming as it reduces stimuli and the patient may calm down, but seclusion should never be forced. One should bear in mind that telling a patient to go to the quiet room is different than asking the patient if they would like to be in a quiet room. Whenever possible, patients should be offered a chance to calm down with physical restraints or medications. In specific, severe cases where verbal de-escalation has failed, or patient or staff safety is in question, involuntary medications become necessary. In more severe cases where everything else, including verbal de-escalation, medications, and seclusion, has failed, a patient will have to be restrained. Restraints are controversial, specifically because there are cases where unnecessary force led to patient deaths. Fortunately, these rates have decreased in recent years due to preemptive staff training. 

During restraining, when staff members physically intervene to subdue a patient, the patient's idea that violence is necessary to resolve the conflict is reinforced. Furthermore, patients who are restrained are more likely to be admitted to a psychiatric hospital and have longer inpatient lengths of stay. The Joint Commission and the Centers for Medicare and Medicaid Services consider low-restraint rates a key quality indicator. Staff and patients are less likely to be hurt when physical confrontation is averted.

When medications must be used, the goal should not be to overly sedate the patient, but to calm them to a point at which they can engage in a conversation. In more severely agitated patients, especially patients actively trying to hurt themselves by biting, hitting their heads, or punching walls, sedation may be necessary. If agitation is mild or moderate, medical options should be left to the patient to give them a sense of control and say in the matter. Second-Generation antipsychotic medications are preferred, but consensus can vary among facilities. If, however, the patient is agitated and coming off alcohol then the consensus is to use benzodiazepines instead of antipsychotics. Haloperidol (first-generation antipsychotic) with lorazepam (short-acting benzodiazepine) is an extensively used combination, and there have been numerous studies indicating that haloperidol is as effective as a second-generation antipsychotic either with or without lorazepam. Commonly used second-generation antipsychotic medications like olanzapine, ziprasidone, quetiapine, and risperidone are all equally effective, and it is more a matter of avoiding side effects that lead a physician to choose one medication over another. In all cases, intravenous medications should be used only as a last resort.

Pharmacological Consensus of the Management of Acute Agitation

In all cases, seclusion and restraints are the last resort and should be avoided.

For acute agitation requiring rapid management in the emergency department, the American College of Emergency Physicians (ACEP) clinical policy for management recommends the use of benzodiazepines (lorazepam or midazolam) or conventional antipsychotic (droperidol or haloperidol). The addition of benzodiazepines to antipsychotics has not consistently shown improved control of agitation and increases the risk of side effects, including oversedation and respiratory depression. One of the most common medications in the emergency department is butyrophenones (haloperidol and droperidol). Haloperidol and droperidol have been compared with droperidol alone. The result is more rapid control of agitation and/or less need for subsequent dosing. The FDA placed a “black box” warning on droperidol, and later haloperidol, over fears of Torsades de Pointes-inducing QT prolongation. The ACEP Clinical Policy on the management of adult psychiatric patients continues to include droperidol as a recommended treatment option despite the FDA warning as studies have shown conflicting data on droperidol increasing QT interval. Other antipsychotics agents like ziprasidone and olanzapine are marketed as being as effective as the typical antipsychotics with less sedation and fewer extrapyramidal symptoms, but studies have shown that these medications tend to have a slower onset and need more repeated dosing.

For agitation in adult patients with psychiatric conditions, the consensus is to use antipsychotic first or second-generation monotherapy for both management of agitation and initial drug therapy for patients with known mental illness for which antipsychotics are indicated. World Federation of Societies of Biological Psychiatry (WFSBP) recommends that the goal of rapid calming without over-sedating as well as involving patients in the selection of oral or injectable medication to help calm them. Again, this gives patients some sense of control. In mildly agitated patients, oral medications are preferred over intramuscular medications. However, in moderate or severe agitation choosing oral versus injectable medications is a clinical decision. Clinicians should reserve intravenous medications as a last resort. For mild-to-moderate agitation, and when rapid effects of medication are needed, clinicians should consider inhaled formulations of antipsychotics. Furthermore, they should avoid the concomitant use of intramuscular olanzapine and benzodiazepines due to possible dangerous effects induced by the interaction of these 2 medications (for example, hypotension, bradycardia, and respiratory depression). Elderly, agitated patients should be treated with lower doses (usually between 25% and 50% of the standard adult dose).

For patients with delirium, especially those in the elderly population, haloperidol twice daily has shown the most benefit. Some studies have also demonstrated that using quetiapine twice-daily dosing decreases the duration of delirium, however, the efficacy of using second-generation antipsychotic versus first-generation medications remains debatable.

For patients with dementia, the American Psychiatric Association 2016 practice guideline recommends consideration of nonemergency antipsychotic medication only for the management of severe, dangerous, and/or significantly distressing agitation or psychosis. They recommend that reviewing the clinical response to nonpharmacologic intervention prior to using any nonemergency antipsychotics for agitation and always assessing the benefit to harm ratio.

In patients whose primary agitation is due to alcohol intoxication or withdrawal, the World Federation of Societies of Biological Psychiatry (WFSBP) recommends benzodiazepines as the preferred over treatment with antipsychotics. American Society of Addiction Medicine (ASAM) recommends that antipsychotics alone can lead to delirium tremens due to increased risk of seizures, and hence, using benzodiazepines is ideal. However, using a combination antipsychotic with benzodiazepines should be considered if agitation, disturbed thinking, or perceptual disturbances are not adequately controlled. Benzodiazepines are considered first-line therapy for agitated patients with alcohol withdrawal or central nervous system (CNS) stimulant toxicity, including amphetamines. World Federation of Societies of Biological Psychiatry (WFSBP) also recommends that for agitation associated with alcohol intoxication, antipsychotics be used instead of medicating with benzodiazepines.

In patients with autism spectrum disorder, using risperidone or aripiprazole decreases repetitive and challenging behaviors,  like headbanging. Risperidone was FDA approved in 2007 after 3 short-term trials showed some benefit in patients with symptoms of aggression toward others, deliberate self-injury, temper tantrums, and quickly changing moods, but only in patients ages 5 to 17 years old. Of note, over 90% of the patients in the trial were younger than 12 years old. Aripiprazole is also FDA approved for treating irritability in 6-17-year-old children and adolescents with autism spectrum disorder. 

Differential Diagnosis

Leading causes of agitation from a general medical condition include head trauma which may accompany symptoms of headaches, loss of consciousness, acute mental changes, and somnolence.

Delirium is a common cause of agitation and can be attributed to many medical issues most commonly caused by infections or metabolic/electrolyte derangements. Delirium is characterized by waxing and waning cognition leading to spontaneous agitation in confused states. Speech, attention, orientation, and level of consciousness all vary during the episode. Hallucinations, mostly auditory in nature may accompany delirium.

Dementia leads to gradual, or rarely, sudden changes in memory, intellectual abilities, and cognition, leading to increased confusion and agitation. Ongoing medical causes leading to delirium can complicate this. In most cases, the course is progressive, and accurate history from collaterals can be useful. It is helpful to do a mental status exam on a regular basis, and in some cases where dementia or delirium is severe, doing these mental exams 2 to 3 times a day as a patient's cognition tends to vary throughout the day. Having multiple data sets from mental exams will give clinicians a better picture of how the patient is doing.

Psychosis can be from a myriad of related mental or postpartum disorders, certain medications, illicit drugs, sleep deprivation, and medical conditions. Psychosis in psychiatry is seen as a symptom of personality disorders, schizo-spectrum disorders, severe depression, or bipolar disorder. Patients may have delusions, hallucinations, disorganized speech or behavior, and negative symptoms such as anhedonia, apathy, blunted affect, isolation, and impaired attention. It is interesting that patients with acute psychosis are usually fully alert and oriented, but actively psychotic.

Drug intoxication or withdrawal will cause acute severe agitation that is usually short-lived. Patients respond well to treatment in these cases, but drugs like PCP can induce a mania-like state that is difficult to manage. Obtaining a urinary drug screen (UDS) and blood alcohol level is useful in suspected cases of synthetic or designer drug use. A conventional UDS will be negative; therefore, a clinician should obtain an extended UDS which covers most designer drugs.

Prognosis

The prognosis will depend on the underlying cause of the agitation. Limiting stress, improved sleep quality, meeting needs can often lead to improved outcomes. Preventive strategies can thus be useful in improving outcomes. Psychiatric and medical causes of agitation often respond to medications. The long-term outlook varies depending on the etiology.

Complications

Agitation increases the risk of injury to patients and staff. Other complications include falls, removal of indwelling catheters and tubes, and restraint-related injuries.