Therapeutics: Agitation in the ED

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Acute agitation is a common presentation in the Emergency Department, with some studies citing that this accounts for 2.6% of total patient encounters. [1,3] The American Association for Emergency Psychiatry BETA project defines agitation as “an extreme form of arousal that is associated with increased verbal and motor activity.” [2] Patients who are acutely agitated can pose risk to themselves as well as staff. The treatment of agitation in the ED can protect patients and staff from harm as well as allow a medical workup to proceed in order to identify any underlying medical cause. [1] Agitation needs to be recognized quickly by ED personnel and managed while taking into account likely predisposing factors for each patient as well as co-morbidities.

Though psychiatric illness can be associated with presentation of acute agitation, experts reinforce that new onset agitation in a patient without clear history of psychiatric disease should be presumed to be from a medical etiology until shown otherwise. [2] All agitated patients should immediately have a POC glucose performed, and all women of child-bearing age should have a pregnancy test. [1]

NON-PHARMOCOLOGIC DE-ESCALATION TECHNIQUES

First-line interventions for acute agitation should utilize non-medication based techniques to de-escalate the situation. Verbal de-escalation should first be attempted, including re-orientation and successive attempts at a therapeutic alliance. [1] Noise and other distractions should be minimized as much as possible in the busy ED environment, and the patient may be provided with food, blankets, and other comfort items. [1] If these interventions are unsuccessful, a show of force can be utilized with the help of security staff, with a provider-led team when possible. In the case of pediatric patients, providers should take note whether family members are calming or exacerbating the child’s agitation, and steps can be taken to further involve family or separate as necessary. [4]

MEDICATIONS 

Some patients with agitation will require medication mediated sedation for safety and to facilitate medical evaluation. Studies have reported that sedation is given for agitation in 3-20 of every 1000 ED visits. [2] However, sedation related adverse events are somewhat common. In one Australian study, 15.9% of patients experienced a sedation related adverse event.5 These were most commonly hypoxia, airway obstruction, QTc prolongation, bradycardia, and hypotension. Certain patient factors were found to increase the odds of an adverse event, including age 65 or older, multiple sedative administrations within 60 minutes, and alcohol intoxication.[5] With this in mind, it is important to know the risks and benefits of various classes of medications frequently used for agitation in the Emergency Department.  

ROUTE OF ADMINISTRATION

If medication is required to manage agitation, administering drugs either PO or IV may be perceived as less threatening or traumatic by patients. [6] There have been multiple studies demonstrating the non-inferiority of oral methods when able, most frequently oral risperidone or olanzapine, sometimes combined with oral lorazepam, to typical IM medications such as haloperidol. [6] It is, however, important to remember that giving medications orally leaves open the possibility of drug diversion and if this is a concern, oral dissolving preparations are an option.[1]


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Benzodiazipines

First Generation Antipsychotics

Second Generation Antipsychotics

Antipsychotic medications are frequently used for sedation in acute agitation and are particularly helpful in patients with underlying psychosis. Both first- and second-generation drugs are frequently used, though each has different associated side effects and chances of causing extrapyramidal symptoms.

First Generation Antipsychotics

First generation antipsychotics have long been used in the treatment of agitation, and can be useful if sedation is needed in alcohol intoxicated patients or known psychosis. However, some first generation antipsychotics, particularly the phenothiazine group (eg chlorpromazine) have been known to lower seizure threshold, spur hypotension, and give more anticholinergic side effects. [7]  

Haloperidol

Haloperidol is a butyrophenone first generation antipsychotic that works on D2 dopamine receptors. [7] haloperidol can be administered PO, IV, or IM. Typical initial dosing is 2.5-10 mg, which may be repeated with a maximum dose of 20 mg per 24 hours. Average time to sedation is 25-28 minutes. With mean total time sedated 84-126 minutes. [1,8] The major risks associated with haloperidol include extrapyramidal side effects such as akathisia and dystonia. Risk of EPS can be minimized by adding an anticholinergic agent such as diphenhydramine or benztropine. [1] As with neuroleptics as a class, there is also a risk of QTc prolongation. [1,7] Haloperidol is particularly well-studied in treating agitation associated with alcohol intoxication, and may be the agent of choice in this setting. [7]

Droperidol

Droperidol is also a first-generation antipsychotic and analog of haloperidol. The starting dosing of droperidol for agitation is 2.5 to 5 mg IV or IM. Average time to sedation is 15-30 minutes. Droperidol has a short half-life of 2.3 hours, but effects may last up to 6-8 hours. [9] Droperidol had fallen out of favor in the setting of a black box warning for QTc prolongation associated with its use beginning in 2001. This warning is controversial, however, as it has been suggested that it was based on a small number of adverse events when droperidol was given at very high doses. [7] Indeed, one study demonstrated less adverse effects when up to 10 mg Droperidol was administered compared with midazolam. Another study failed to report even one adverse cardiac event after a decade of use of 5 mg droperidol in a psychiatric emergency department. [7] In addition to QTc prolongation, risks include extrapyramidal side effects.

Droperidol has subsequently been shown to be a safe choice for single agent sedation. In one study, fewer patients who received 5 mg droperidol required rescue sedative medications than those who received 5 mg haloperidol. Rescue sedation was considered the need for additional antipsychotic medication, benzodiazepines, or ketamine. [10] One study comparing droperidol, lorazepam, and ziprasidone (at both 10 and 20 mg doses), found that 5 mg droperidol was more effective in inducing adequate sedation. Droperidol was also associated with less incidence of respiratory depression in this study. [11]

For more droperidol discussion check out our ongoing Journal Club Podcast series deep dives

SECOND GENERATION ANTIPSYCHOTICS 

Multiple studies have shown efficacy to be similar between first and second generation antipsychotics. [1] Adverse events are relatively uncommon in both groups. Second generation drugs do have the added benefit of lower risk of QTc prolongation. [1] These drugs also have been shown to result in less sedation and fewer extrapyramidal symptoms compared to first generation drugs. [12]

Olanzapine

Olanzapine is available for treatment of agitation via IM or IV administration. The typical starting dose is 10 mg IM or 5-10 mg IV. Of note, olanzapine does require reconstitution in order to be administered IM, which may limit its utility in the severely agitated patient requiring rapid medication management. Olanzapine reaches peak concentration in 15-45 minutes and its half-life is 2-4 hours. [13]  

Olanzapine has less incidence of EPS than injectable haloperidol. [9] This drug has also demonstrated very rare incidence of QTc prolongation. [1] In one study, fewer patients who received 10 mg olanzapine required additional rescue sedation than those receiving 5 mg haloperidol. [10]  Another study demonstrated that more patients were adequately sedated at 15 minutes after administration of 10 mg olanzapine as compared to both 5 mg and 10 mg doses of haloperidol. [14] Rescue rates were found to be similar between olanzapine and droperidol. However, compared to droperidol, olanzapine also holds a lower risk of EPS and QTc effects. [10] If readily available, olanzapine may be a safer single agent for use in acute agitation as compared to first-generation neuroleptics.  

Multiple studies, however, have described adverse events when olanzapine is combined with benzodiazepines, so this combination should be avoided. [7] Olanzapine also has been found to have significant anticholinergic properties, and as such should be specifically avoided in patients who are thought to be agitated secondary to anticholinergic overdose. [13]

Ziprasidone

Ziprasidone is a second generation antipsychotic that is available for PO or IM administration. The typical IM dosing is 10-20 mg. Time to onset of effect is typically 15-20 minutes and ziprasidone reaches peak concentrations in 30-45 minutes. Its duration of effect is at least 4 hours. [13] Of note, ziprasidone also requires reconstitution for IM administration and thus may not rapidly be available for the severely agitated patient. Further, of the second-generation antipsychotics, ziprasidone has the highest risk for QTc prolongation. [15] Ziprasidone is also not recommended in children by some experts due to risk of cardiac effects or potential paradoxical reaction. [4]

Risperidone

Data for risperidone in acute agitation is limited. This medication is most typically administered orally in doses of 1-2 mg. It can be a good option in patients with underlying psychosis who are cooperative with oral medication. It may also be a useful agent in the elderly, and it is the agent of choice in pregnant patients if amenable to oral medication. [1] 

BENZODIAZEPINES

Benzodiazepines are another common choice of medication for rapid treatment of acute agitation in the Emergency Department. Benzodiazepines are often the agent of choice when sedating an undifferentiated patient without obvious delirium or psychiatric disease. [7] Benzodiazepines do carry a risk for creating a paradoxical reaction in patients, particularly the young and elderly. However, this is relatively rare, occurring in only about 1% of patients. [16,17] Flumazenil (benzodiazepine antagonist) has been demonstrated to manage these reactions without frequent adverse events. [17] Benzodiazepines also carry a risk for respiratory depression, especially in patients who have ingested other depressant medications, and should thus be avoided in this patient population. In withdrawal states of alcohol or benzodiazepines, this class is the first-lane management.

Midazolam

Midazolam is available for intranasal, IV, IM rectal, and oral routes of administration. [1,16] Typical initial dosing of midazolam in the ED begins at 2-5 mg IM or IV. Average time to sedation with this drug varies from 1-5 minutes IV to 13-18 minutes when given IM. The average total time of sedation ranges from 82-105 minutes. [1] In children, intranasal administration is more common. Intranasal administration of midazolam can produce rapid onset of sedation and time to peak concentration.[16]

Frequently, midazolam is preferred over lorazepam for its rapid onset of sedative effects.[1] Midazolam may also be preferred over antipsychotic agents for its rapid onset. Indeed, in one study, midazolam 5 mg IM produced adequate sedation at a time after administration of 15 minutes more frequently compared to both haloperidol and ziprasidone. [14] An added benefit of midazolam is its relatively short total time of sedation. Studies have also demonstrated faster time to arousal for patients who were given midazolam as compared to haloperidol and lorazepam. [8] Given the simple mechanism of action and rapid onset, midazolam is often the first choice in undifferentiated agitation.

Lorazepam

Lorazepam is available IV, IM, oral, as well as intranasal, which is commonly used in children. [1,16] Typical dosing is 0.5-2 mg IM or IV. The suggested interval for re-dosing is 30 minutes. Lorazepam is longer-acting compared to midazolam. [16] Lorazepam has an average time to adequate sedation of 32 minutes and patient’s average total sedation time is up to 217 minutes. [1]

Intranasal has been found to lead to more rapid absorption compared to IM, with sedating effects found at 5 minutes, vs. up to 15-30 minutes with IM. Intranasal dosing recommendations for children are 0.05-0.1 mg/kg divided in half with half administered to each nares with an atomization device. [16]

BENZODIAZEPINE AND NEUROLEPTIC COMBINATION

Providers will frequently use “5 & 5”, a combination of 5 mg haloperidol and 5 mg midazolam, or a B52, a combination of 50mg diphenhydramine, 5mg haloperidol and 2mg midazolam, both options for the sedation of agitated patients. Evidence supports this combination approach. For both haloperidol and droperidol, there is good evidence that the combination of these drugs with a benzodiazepine such as lorazepam or midazolam is more effective than either alone. [1,18] This increase in efficacy is not associated with an increase in adverse events. [1] Using a combination of both medications also frequently leads to a more rapid onset of sedation. Combining these medications may also lead to a reduction in side effects. [19]

Ketamine

Ketamine is exciting to explore in this setting because of its rapid onset and general preservation of airway reflexes. [20] In general, ketamine has an average time to onset of 2-3 minutes. [1] Intramuscular administration has a slightly slower onset (4-5 minutes) to effect compared to intravenous (1-2 minutes). [21] Sedative effect lasts anywhere from 5-30 minutes. [1] Ketamine is also reportedly safe at a wide range of doses. [20] Recommended dosing for agitation begins at 1-2 mg/kg IV or 4-6 mg/kg IM. [22,23,24] Given the dissociation that ketamine induces at these doses, it is important to remember you are functionally performing conscious sedation and should be prepared to secure the airway if need, provide sedation documentation, etc.

One study comparing ketamine (5 mg/kg IM) to haloperidol (10 mg IM) for agitation in the prehospital setting found a mean time to sedation of 5 minutes for ketamine vs. 17 for haloperidol. Significantly fewer patients required additional sedation in the ketamine group. [20] However, ketamine group did have higher complication and intubation rates, with 39% of patients receiving ketamine subsequently intubated. Of note, the indication for intubation was most commonly failure to protect airway. [20] Notably, other studies examining ketamine for agitation have not reported such high rates of intubation. In one prospective study examining ketamine, haloperidol, benzodiazepines, or combination haloperidol + benzodiazepine for acute agitation, ketamine was found to lead to a higher number of patients adequately sedated at 5, 10, and 15 minutes after administration. Each group had a low intubation rate. [1]

Ketamine may increase acute agitation in patients with schizophrenia, and should be avoided in this group. [1,21] Though there is a concern for emergence reactions, these have only been noted to occur in 10-20% of patients receiving ketamine sedation, and are typically easily treated with benzodiazepines. [21] Other adverse events that have been noted in various studies include hypersalivation, vomiting, laryngospasm, tachycardia, and hypertension. [22]

While the onset of ketamine is rapid, it loses effect over a shorter period of time than other agents and require rescue medication or redosing. [1] In one study, over half of patients required additional medication in order to resolve agitation following ketamine. This suggests that ketamine may be best to gain rapid control of severe agitation, but not as a single agent for the entire patient visit. [21]

PHYSICAL RESTRAINTS

Studies suggest that physical restraints are utilized in over half of all acutely agitated patients. [1] However, putting patients in physical restraints may lead to injury for both patients and staff members. For example, in patients that continue to fight against restraints, muscle breakdown and resulting rhabdomyolysis may be seen. There have also been reports of asphyxiation, strangulation, and other consequences to physical restraint use. [1] In most patients, particularly ones with continued fighting through restraints, chemical sedation should be added for safety. Soft cloth and locked leather restraints are most commonly used. A specific risk of soft cloth restraints is the possibility of inadvertent tightening around the extremities, leading to circulation compromise. [1] 

Once placed in restraints, patients should be frequently reminded of the behaviors that would lead to restraint removal, and providers should make efforts to continue verbal de-escalation. According to the Centers for Medicare and Medicaid Services guidelines, adult patients should not remain restrained for more than 4 consecutive hours. For teen and adolescent patients, two hours is the recommended limit. For children under 9 years old, a limit of one hour is suggested. [1]

SPECIAL POPULATIONS:

Elderly Patients

Elderly patients in the ED may have altered mentation in close to 40% of visits. Of those, nearly 25% have an element of delirium. [1] However, delirium is only associated with an agitated presentation about 1/3 of the time and when present providers need to be particularly vigilant, as this is associated with high morbidity and mortality. [1]

In elderly populations, there is an increased risk associated with medication interactions due to high incidence of polypharmacy. [1] Also, as many elderly patients may be taking other QTc prolonging medications, the risk of QTc prolongation should be given extra thought when administering antipsychotic medications. However, antipsychotics are still usually considered first line in this group, as benzodiazepines are associated with poor outcomes. [1] Experts have recommended starting with no more than half of the typical starting dose for agitation treatment in this group. Due to the likelihood of concomitant decreased metabolism and excretion of drugs in the elderly, re-dosing should also be taken more slowly. [1]

Pediatric Patients

In recent years, pediatric emergency department visits for psychiatric or behavioral concerns now represent about 5% of total visits. [1]  The initial evaluation of agitated children needs to include rapid assessment of vitals signs as well as a POC glucose, similar to adult patients. An additional consideration in children is hydration status, as agitation frequently correlates with dehydration. [13]

In pediatric patients who present to the ED for psychiatric care or evaluation, between 6-10% require restraint for safety and to facilitate treatment. [4] Pediatric patients with autism experience even higher levels of restraint and sedation than those without. [25] However, there have also been at least 30 pediatric deaths recorded in the US related to restraint use in children, so this intervention should not be taken lightly. [4]

In children who require medication-based management of agitation, PO administration should always be attempted first, with IV administration being preferred over IM when required. [4] For children already prescribed psychiatric medications at home and who are in need of pharmacologic management of agitation, consider an extra full or half dose of their medication. [4] Diphenhydramine is also an option for agitation in children, and families may feel more comfortable and familiar with this medication. [4,25] This medication is particularly useful in young children, those with anxiety predominant symptoms, and those with no psychiatric history. This medication, along with benzodiazepines, should be avoided when delirium is suspected, as both of these medications can also cause paradoxical activating reactions. [4,17] The risk of this sort of reaction is particularly high in children with developmental disabilities or autism. Alpha-2 agonists such as clonidine are also an option to create a calming effect in children, but do require blood pressure monitoring.[4]

If delirium is suspected and in severe cases of agitation, neuroleptics are the agent of choice, and second generation neuroleptics are preferred. [4] Risperidone has the most robust evidence supporting its use for aggressive behavior, but is only available in oral formulation.[25] Among IM preparations, olanzapine may be the safest choice in children to avoid the risk of EPS. [1,4] Ziprasidone, though popular for use in adults, should be avoided in children due to the risk for activating this population. [4]

A second dose of the same medication should generally be used in children instead of two separate drugs, as children are at greater risk for adverse drug interactions. The exception to this is the combination of lorazepam and haloperidol. If agitation is thought to be due to intoxication with an unknown substance, lorazepam is the safest option. This may be combined with haloperidol if necessary. [4]

Pregnant Patients

In pregnancy, psychiatric conditions may be exacerbated by medication dosing changes or cessation. Even the pregnancy itself may cause worsening of previously well-managed mental health conditions. [1] Medication choice in pregnancy can be difficult from a safety perspective.

Risperidone is recommended as the first line treatment for acute agitation in pregnancy, as it has no known teratogenic effects. [1] However, risperidone is only available in oral formulation. Other options include haloperidol, which has been associated with increased risk of fetal limb defects, but this risk is small and seen typically with longterm use of the drug. [1] Similarly, benzodiazepines have a possible associated risk of malformations and cleft lip when taken for a prolonged period of time, especially in the first trimester. However, they are likely another relatively safe choice in the acute setting. [1] It has been suggested that benzodiazepines should be considered second-line. There is very little data regarding olanzapine and ziprasidone in pregnancy, so these medications are best avoided. [26]

Physical restraints also pose increased risk in pregnancy, particularly in later pregnancy, due to the chance of IVC compression. If physical restraint is necessary, the patient should be placed in left lateral decubitus or have their right side supported in order to avoid this. [1]

Intoxicated Patients

Over 80% of episodes of acute agitation in the ED are thought to be in the presence of drug and alcohol intoxication. [1,20] Benzodiazepines are the drug of choice for stimulant intoxication. [7] Antipsychotics are preferred over benzodiazepines when alcohol is suspected as the cause of agitation, as they are able to provide sedation quickly but with less additive respiratory depression.7,9

One study examined ED length of stay for patients with alcohol intoxication who received either parenteral droperidol, haloperidol, or olanzapine for sedation. Droperidol had the shortest length of stay when used as monotherapy. No difference in ED LOS was noted between haloperidol and olanzapine. [9] Olanzapine has less risk of EPS and demonstrated similar LOS to haloperidol, so may be preferred agent if droperidol is not an option. Ziprasidone has previously been shown to have a similar ED LOS to droperidol, so may be an option in this population as well.9 However, some experts suggest haloperidol may still be the medication of choice in alcohol intoxication, as it is the most well-studied in this context. [7]

Delirious Patients

In delirious patients in whom delirium is not thought to be due to either alcohol or benzodiazepine withdrawal, second generation antipsychotics are the drugs of choice. [7]

Known Psychiatric Patients

In patients with known psychiatric illness with psychosis and agitation, antipsychotic medications are preferred to treat agitation, as they also address the underlying dopaminergic psychosis. [7] Second generation antipsychotics offer advantages in side effects and duration of action over haloperidol in acute psychosis with agitation if time allows their administration. These drugs are even preferred over combination haloperidol and benzodiazepine. The medication with the most evidence backing safety and efficacy in this setting is oral risperidone, if this will be accepted by the patient. Otherwise, olanzapine or ziprasidone are preferred. [7] If the initial antipsychotic administered does not control the patient’s agitation, a benzodiazepine addition is preferred to further antipsychotic administration of either the same or different antipsychotic. [7]

Undifferentiated Patients

There is no perfect evidence to support the choice of one agent over another in the entirely undifferentiated patient. However, experts have suggested benzodiazepines may be the drug of choice when etiology of agitation is unknown and patient is non-delirious and without evidence of psychosis. [7]

Summary

The acutely agitated patient is common in the Emergency Department, however the underlying physiology and possible intoxicants rarely are uniform. This creates a plethora of possible agitation presentations, each requiring a sedation plan unique to the individual. While this post hopes to add specificity and evidence to your choice, remember that each patient needs a chance at environmental calming, redirection, and if sedation is needed, adequate monitoring and frequent reassessment so we can indeed do no harm.

 Post by Courtney Kein, MD

Dr. Kein is a PGY-1 in Emergency Medicine at the University of Cincinnati

Peer Editing and Post by Michael Gleimer, MD and Ryan LaFollette, MD

Dr. Gleimer is a PGY-4 in Emergency Medicine at the University of Cincinnati and Dr. LaFollette is an Assistant Program Director at UC

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