By: Kelvy Levit, PGY3
Reviewed by: David Slattery, MD
Violence is rising at a concerning rate in emergency departments. According to a national survey by American College of Emergency Physicians’ (ACEP), almost 50% of emergency physicians and nearly 70% of emergency nurses report being physically assaulted at work. A troubling 97% of assailants were patients (1).
With these staggering statistics in mind, it’s important to not only have preventative measures in place, but also a management plan when dealing with agitated, combative, and altered patients.
Dealing with the agitated patient can be distressing to not only the emergency physician but also to the staff involved directly or indirectly. As providers, we are prone to cognitive errors during times of high stress. This blog will discuss the approach to the agitated patient to include verbal de-escalation techniques, options for chemical sedation, and an overview of the current literature supporting practice recommendations.
There is no one size that fits all. As EM providers, we’re used to having a stepwise approach to patient care. Managing these patients can be messy, intimidating, and often dangerous. The etiology of the patient’s agitation may be due to primary psychiatric illness, drugs, hypoxia, endocrine emergencies, central causes, or any combination of the above. Because of the patient’s altered mental status, it is vital to obtain critical historical information from pre-hospital personnel, family or friends. As we know, diagnostic and therapeutic considerations often occur simultaneously.
Your immediate goals when taking care of these patients are to:
Current experts recommend classifying patients into one of 3 levels of agitation when trying to determine the most appropriate approach (6).
Levels of Agitation
Examples of common patient presentations in this category include: elderly patients with dementia, schizophrenia, or other psychosis, decompensation with minimal symptoms, and those who present with intoxication. You have little to no concern of an organic etiology of their symptoms. These patients are generally cooperative and will behave if they have someone sit with them.
At this point you can also offer them medications which may decrease the chance of needing something intramuscular. Keep in mind, for the elderly patient, you may have to decrease dosages. Benzodiazepines and other sedative hypnotics should be used with caution in the elderly as they may worsen dementia and delirium related agitation. For antipsychotics, consider olanzapine 5 – 10 mg PO or Risperidone 2mg PO. For benzodiazepines, consider Lorazepam 1-2 mg PO. (3).
These are the loud, disruptive intoxicated patient. They typically make a scene but aren’t a danger to themselves and others. They usually can’t be verbally re-directed due to the inherit nature of their intoxicants. These are also patients that you can do a reasonable history and physical exam, and in the absence of any red-flag findings, the clinician may feel pretty confident that the patient just needs to be serially observed while they metabolize the alcohol or drug. These patients can typically be observed in an unmonitored bed. The classic “B52” (Benadryl 50mg + Haldol 5mg + Ativan 2mg) has historically been used for this category of agitation. Although this “agitation cocktail” works in many patients, we believe that there are better options. Ideally, the best pharmacologic sedative will be fast acting, have a short half-life, hemodynamically stable, and allow our patient to sleep and metabolize to freedom.
Droperidol is back on the market and this once commonly used medication is now gaining popularity again. It was initially approved by the USFDA for nausea, vomiting, anxiety and sedation. It is an effective and safe agent for undifferentiated agitation (9).
In 2001, the FDA issued a suspicious black box warning about droperidol, stating there was a significant risk of cardiac arrhythmias related to QT prolongation. This was incredibly surprising, as at the time, droperidol was a very popular antiemetic used for post-operative nausea and vomiting for thirty years. 277 cases were reported to the FDA. No one had noticed a problem until 71 adverse events were reported on the same day. Even more suspiciously, around this time, Ondansetron came on the market, also treating post-operative nausea and vomiting, except at a much more expensive price. Eventually, it stopped being produced in the US, except at Mayo Clinic, where they made their own. There have been many studies supporting the safety and efficacy of droperidol. An article by Jackson et al. reviews the 277 cases of adverse events associated with droperidol that were reported to the FDA (5). They did this by a written request to the FDA to provide any and all reports of cardiovascular events related to droperidol use that were part of the decision to place the black-box warning. They found that many of the reports were duplicates, leaving a total of only 65 individual cases. Of these cases, only 2 described adverse cardiovascular events possibly caused by droperidol in dosages used in the US. They also found that in addition to these reports, 2 European studies prompted the FDA to place its black box warning on droperidol. Both studies used droperidol in 50 to 100 times higher than those used in the US.
There have been numerous studies that have addressed the safety of droperidol.
Other studies have compared droperidol to midazolam or the combination of the two.
There have also been some studies that compare droperidol to ziprasidone or midazolam.
The severely agitated patient is one that is classified as a danger to themselves and to others around them. They are unable to be re-directed verbally and present with hyperactivity, violence, and extreme levels of strength. These patients usually fall into the category of “excited delirium”. Excited delirium is not a pathophysiologic disease entity. It is a description of the way these patients behave. The concept of excited delirium is useful to remind us that the dangerously agitated patient is at high risk for sudden death if they aren’t treated quickly and appropriately. The priority in these patients is to obtain immediate control of the situation in order to identify reversible life-threatening conditions. The agent that has been gaining popularity due to its efficacy and reliability is dissociative dose ketamine. However, patients with excited delirium tranquilized with dissociated dose ketamine are high risk for decompensation. Consider this a procedural sedation and all that entails. These are medical resuscitation cases and ultimately may require intubation. Ketamine dissociated patients have the potential to develop hypoventilation and apnea from a variety of mechanisms: Laryngospasm, airway malpositioning, obstruction, hypersalivation, and central apnea. Unfortunately, strictly from an evidence-based medicine perspective, there isn’t a substantial amount of evidence. Although most of the case series, cohorts, and observational data seem promising, most of it is low level evidence.
Riddell et al performed a single-center, prospective, observational study examining agitation levels in acutely agitated emergency department patients between the ages of 18 and 65 who required sedation medication for acute agitation (14). Pregnant women, prisoners, and persons in police custody were excluded along with those triaged to a low acuity zone of the ED. These were severely agitated patients requiring care in a high acuity treatment area with available cardiorespiratory monitoring. This study’s primary objective was to compare the time to a defined reduction in agitation scores for ketamine vs benzodiazepines (midazolam or lorazepam) and haloperidol, alone or in combination. Due to the observational nature of the study, medication dosages were not uniform. They did, however, use current published dosage recommendations of ketamine 4-6mg intramuscular (IM) or 1-2 mg/kg intravenous (IV), haloperidol 5-10mg IM, midazolam 5-10mg IM or 5mg IV, and lorazepam 1-2mg IM or IV. Secondary objectives were to compare rates of medication redosing, vital sign changes, and adverse events in the different treatment groups. Providers measured agitation levels on a previously validated 6-point sedation scale at 0, 10, and 15 minutes after receiving sedation. They assessed the incidence of adverse events, repeat or rescue medication dosing, and changes in vital signs. 98 patients met eligibility criteria with the study cohort being mostly male. 33 received lorazepam, 24 received ketamine, 19 received midazolam, 14 received Haldol, and 10 received a combination of medications There were no significant differences based on race, stated use of substances, or previous psychiatric history. Based on agitation scores, more patients in the ketamine group were no longer agitated than the other medication groups at 5,10, and 15 minutes after receiving medication. Patients receiving ketamine had similar rates of redosing, changes in vital signs, and adverse events to the other groups. Of note, there were 2 intubations in the ketamine group (8.7%) and 1 in each other groups. This goes to show how severely agitated these patients were across the board. The main limitations of this study are: It’s underpowered to look at anything but time to sedation, physicians were unblinded, they are assessing subjective outcomes, the dosing was not uniform, and there was an element of selection bias. Ultimately, the study shows us that ketamine can be used to quickly sedate highly agitated patients but can’t really comment of the safety or which patients might benefit most.
Another study by Lin et al compares ketamine to haloperidol plus lorazepam for behavioral disturbance in the emergency department (15). This was the first randomized, prospective clinical trial that sought out to determine the efficacy and safety of ketamine compared to parenteral haloperidol plus lorazepam for initial control of acute agitation. Patients were randomized to ketamine (4mg/kg IM or 1mg/kg IV) or haloperidol/lorazepam (haloperidol 5-10mg IM or IV + lorazepam 1-2 mg IM or IV). The primary outcome was adequate sedation within 5 minutes, as defined by a documented Richmond Agitation and Sedation Scale score <0 or nursing narrative documentation. Secondary outcomes included sedation within 15 minutes, time to sedation, and safety. A total of 93 patients were enrolled. Patients were excluded from the study if they were younger than 18 years old, pregnant, previous diagnosis of schizophrenia, angina, uncontrolled hypertension, heart failure, glaucoma/ocular injury or thyroid disorder. These exclusion criteria were based off the published guidelines on the use of ketamine for dissociative sedation. Prior to arrival, paramedics have standing orders for midazolam 5mg IM once as needed for agitation. If they received midazolam prior to randomization, were hypoxic, at risk for respiratory depression, or were overtly intoxicated, physicians had the option to either omit or lower the dose of lorazepam to 1mg. Physicians also had the option to lower the dose of haloperidol to 5mg for patients weighing less than 60kg, age greater than 80 years, or in the presence of significant medical comorbidities. A total of 44 patients were randomized to receive ketamine and 49 patients were randomized to receive haloperidol plus lorazepam. The majority of the patients (93%) enrolled in the study were administered medications intramuscularly, most commonly for a diagnosis of acute agitated delirium or acute agitation. Of the patients who received haloperidol/lorazepam arm, 61% received the goal dose of 10mg and 2mg respectively. Across both groups, the most common intoxicants were found to be methamphetamines, alcohol, or cannabinoids. Significantly more patients who received ketamine compared to haloperidol/lorazepam were sedated within 5 min (22% vs 0%, p = 0.001) and 15 min (66% vs 7%, p < 0.001). The median time to sedation in patients who received ketamine compared to haloperidol/lorazepam was 15 vs 36 min respectively (p < 0.001). In terms of safety, hypertension and tachycardia were significantly more common with ketamine (33% and 34% vs 11% and 11%), and there was a non-statistically significant difference in hypoxia (21% vs 10%) but no difference across arms in QTc prolongation, hypotension, nausea, and hypersalivation. No emergence reactions were documented in this trial. Some study limitations included that 7 patients were excluded after randomization and no information is given on the other medications patients might have received. Enrolling physicians might have excluded certain high-risk cohorts which may lead to selection bias. The study personnel were not blinded to a highly subjective primary outcome. Doses were frequently lowered in the haloperidol/lorazepam arm. They concluded that patients receiving ketamine for combative agitation was significantly more effective than haloperidol/lorazepam for initial control of acute agitation and is not associated with any significant adverse effects. However, the study’s small sample size, use of a convenience sample of patients, and nonblinded design limits the applicability of the results.
The use of ketamine in the prehospital setting has also been studied. Cole et al. conducted an observational open-label, prospective study, coordinated at the Minnesota Poison Control System (16). The primary objective of this study was to determine if haloperidol or ketamine was superior for the treatment of severe prehospital acute undifferentiated agitation. Specifically, they hypothesized that in patients with severe agitation presenting to their EMS system, 5mg/kg of IM ketamine would be superior to 10mg of IM haloperidol, with time to adequate sedation. Secondary outcomes included need for redosing in the prehospital environment, the rate of adverse side effects, and rates of intubation between ketamine and haloperidol. They defined severe agitation as an Altered Mental Status Scale (AMSS) score of +2 or +3. Prehospital and ED providers were unblinded to which medication the patients received. All patients in the EMS system with severe acute undifferentiated agitation subsequently transported to the study hospital were included in the study. Exclusion criteria included obviously gravid women, patients less than 18 years of age, patients with “profound agitation”, defined as an AMSS score of +4. Their reasoning behind the last criteria was that they deemed it “unethical and unwise” to withhold ketamine from the most profoundly agitated patients at any time for both patient and caregiver safety. In terms of interventions, for the first 3 months of the study, the standard EMS operating procedure (SOP) for severely agitated patients was to treat acute undifferentiated agitation with 10mg of IM haloperidol. For the next 6 months, the SOP was changed to 5mg/kg of IM ketamine. For the final 3 months, the SOP was returned to haloperidol. A total of 146 patients were enrolled. 64 received ketamine and 82 received haloperidol. In terms of results, they found that time to adequate sedation was significantly faster in the ketamine group. Median time to adequate sedation was 5 min for ketamine and 17 min for haloperidol (p<0.0001, difference 12 min, 95% CI: 9-15). 95% of patients in the ketamine group achieved adequate sedation pre-hospital compared to 65% of patients in the haloperidol group. (p<0.0001, difference 0.3, 95% CI O.18-0.42). 5% of patients in the ketamine arm required additional sedation prehospital whereas 20% of patients in the haloperidol group required a second injection prehospital. Intubation rate was significantly higher in the ketamine group; 39% of patients receiving ketamine were intubated vs 4% of patients receiving haloperidol (p<0.0001, difference 35%, 95% CI 23-48%). No intubations occurred prehospital. These authors report a strikingly high rate of intubations for patients receiving ketamine. They report that “not protecting the airway” was the most common indication for intubation. They speculate that the receiving emergency physicians were either uncomfortable with a dissociated patient or may have misapplied the often-quoted axiom of “GCS less than 8 intubate”. A patient dissociated from ketamine cannot be evaluated properly by GCS. Their complication rates from ketamine administration appear to also be higher than previously reported studies. The procedural sedation literature suggests apnea occurs with a recommended dose of IM ketamine at 4-5 mg/kg, at a rate closer to 0.8% and often transient (9). Their observed rate was much higher at 12%. The comment that the etiology is unclear and may be a reflection of co-intoxication, most commonly with ethanol. The primary limitations of the study are its lack of randomization and blinding. They excluded patients with an AMSS score of +4, which is the exact population of interest, especially when considering excited delirium. The small sample size cannot be applied to the general population. In conclusion, they found that ketamine was superior to haloperidol in terms of time to adequate sedation, however, given the high intubation rate that was observed, risks vs benefits need to be considered. I believe this is an important reminder that these patients can be very sick, quickly decompensate, and should be viewed as a procedural sedation and medical resuscitation, along with all that entails.
In conclusion, agitated patients can present on a spectrum from slightly disruptive to dangerous and violent. An organized approach is important for your own safety, the safety of the staff and the patient. Selecting medications for chemical sedation can be difficult. Each patient’s presentation, co-morbidities, co-intoxicants, and psychiatric background needs to be considered prior to picking an agent. Hopefully this blog allows you to review some of the most pertinent studies for chemical sedation of the agitated patient in the emergency department.
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