Multiple RCTs on ketamine for severe agitation

There has been a dramatic surge in the popularity of ketamine for the management of agitated delirium in emergency medicine. Considering the dangers such patients pose to themselves and the department, rapid acting ketamine makes a lot of sense, but evidence for the practice has been lacking. However, in the last few months, there have now been two RCTs published that look at ketamine for severe agitation.

Paper #1

Lin J, Figuerado Y, Montgomery A, Lee J, Cannis M, Norton VC, Calvo R, Sikand H. Efficacy of ketamine for initial control of acute agitation in the emergency department: A randomized study. Am J Emerg Med. 2021 Jun;44:306-311. doi: 10.1016/j.ajem.2020.04.013. PMID: 32340820

This is a single center, randomized, open-label, pilot study that enrolled adult emergency department patients with combative agitation (presenting an urgent danger to themselves and staff). They excluded patients based on published contraindications to ketamine: pregnancy, schizophrenia, angina, uncontrolled hypertension, heart failure, glaucoma/ocular injury, or thyroid disorder. (I don’t think all of these contraindications really matter. In the patients in whom ketamine is appropriate, there is no way you are getting this information anyway.) Patients were randomized to either ketamine or the combination of haloperidol and lorazepam. Ketamine was given as 4 mg/kg IM (max 500 mg) or 1 mg/kg IV. Haldodol was 10 mg IM or IV (with the option to decrease to 5 mg) and lorazepam was 2 mg IV or IM (with the option to decrease to 1 mg or omit). 

They randomized 93 patients, with a  mean age of 39 and 62% being male. Despite excluding a history of schizophrenia, about half of patients were ultimately found to have a prior history of psychiatric disease. (Again, you can’t get history from these patients, so don’t create a protocol that requires this information.) 95% of patients received the study drug intramuscularly. 60% of the haloperidol group received the full dose, but that means 40% received lower doses. This probably represents normal clinical practice, but could bias against haloperidol. For the primary outcome of adequate sedation (RASS less than or equal to 1) at 5 minutes, ketamine was successful in 22% of patients as compared to 0% of the haloperidol and lorazepam group (p=0.001). At 15 minutes, it was 66% versus 7%. Mean time to adequate sedation was 15 minutes with ketamine and 37 minutes with haloperidol plus lorazepam. Hypoxia (less than 92%) was higher with ketamine (21% vs 10%), although the difference was not statistically significant (p=0.24) and it was all short lived (there was one intubation in both groups). There was one death, which occured in the haloperidol and lorazepam group.

There are a number of problems with this trial. It is open-label and uses a relatively subjective outcome. Considering the popularity of ketamine, I would expect this to bias the results against haloperidol. Similarly, almost half the population didn’t receive the full dose of haloperidol, which may have been prudent, but introduces another source of bias. Although haloperidol and ativan are commonly used in North America, they are not the ideal comparison group. Droperidol is a better agent, and is what I would consider the baseline standard of care (even though I can’t get it in Canada.) Ultimately, though, the results of this trial are pretty believable. The combination of haldol and ativan works, but is incredibly slow. For severely agitated patients, waiting 30 minutes for control can result in really bad outcomes. Either option will need resuscitation level monitoring. For agitated delirium, I think this counts as evidence supporting ketamine, but is still pretty weak evidence that it really improves patient (and staff) important outcomes.

Paper #2

Barbic D, Andolfatto G, Grunau B, Scheuermeyer FX, Macewan B, Qian H, Wong H, Barbic SP, Honer WG. Rapid Agitation Control With Ketamine in the Emergency Department: A Blinded, Randomized Controlled Trial. Ann Emerg Med. 2021 Aug 2:S0196-0644(21)00433-9. doi: 10.1016/j.annemergmed.2021.05.023 PMID: 34353650

This is another single-center, randomized trial looking at IM ketamine in agitated patients. This trial was partially blinded (the nurse drawing up the medications was unblinded, but they tried to conceal the groups from everyone else). They enrolled patients aged 19-60 years with severe agitation (RASS 3 or more). They excluded patients in police custody, patients who were pregnant or breastfeeding, and those with allergies. The ketamine group received 5 mg/kg IM. The control group received haloperidol and midazolam, both dosed at 5 mg.

They enrolled 80 patients. Unfortunately, this was only about half their intended sample size, as research activities were halted due to COVID-19. The median age was 35 years, and 68% were men. The primary outcome, time to adequate sedation (RASS -1 or less), was faster in the ketamine group. The median time to sedation was 15 minutes with haloperidol and midazolam and 6 minutes with ketamine (actual difference 8.8 minutes, 95% CI 3.0-14.5). Use of rescue medications was the same. Serious adverse events were not statistically different, but were clearly higher with ketamine (13% versus 5%). Considering that these are very sick patients, the serious adverse events really don’t seem that bad – 2 cases of apnea, 1 laryngospasm, 1 dystonia, and 1 patient requiring oxygen, with no intubations or ICU use – but they are important.

This trial has some of the same limitations as the first. Perhaps the biggest limitation of both trials is their size. Small trials are adequate for assessing efficacy, but whether ketamine would be effective was never really a question for me. The real question is which approach is safer, and that will require much larger trials to determine. There were more adverse events in the ketamine group in both of these trials, but I consider the reported adverse events to be pretty mild, considering how sick these patients are. In order to catch arrhythmias, intubations, or deaths, we are going to need much larger trials. I also find it weird that neither trial comments on the safety of the staff. Staff injuries are common with these patients, and should almost certainly be considered as a safety outcome in these trials.

Of note, this study divided the ketamine dose up, such that there was a maximum of 4 mL per injection site. I think this would make Reuben Strayer mad. He has cited that IM injections of up to 20 mL are safe and effective, and every extra needle increases the chance of needle stick injuries. (And the increased risk is almost certainly not linear. It is much easier to keep track of a single person with a single needle than it is to keep track of multiple needles.) For more on this, see the EMCrit podcast with Reuben: https://emcrit.org/emcrit/dangerous-and-disruptive/

Thoughts

We now have some RCT evidence that partially supports the use of ketamine for severely agitated patients. This would be bigger news if everyone wasn’t already using ketamine for these patients.

However, it is important to note that neither of these trials is a clear win for ketamine. There appears to be a bit of a trade off, with ketamine providing more rapid sedation, but also more adverse events. In our most agitated patients, rapid sedation is really important for the safety of both the patient and the staff, and probably warrants the adverse events reported. (However, neither of these trials actually demonstrated an improvement in safety, which is something future trials should probably look at.) However, I worry about indication creep. If people start using ketamine for patients with less severe agitation, the harms could easily outweigh the benefits.

I must emphasize: time to sedation is a surrogate outcome. We think that rapidly sedating these patients will be important to improve safety, but that is an unproven logical step. Ideally, future trials would measure safety directly, rather than using time as a surrogate.

However, demonstrating an improvement in safety will be difficult, and will be dependent on trials selecting appropriate patients. It is actually pretty rare for patients to be so agitated that ketamine is required. Most patients can be managed with verbal de-escalation and oral medications, if one has the patience and skills for such an approach. (Listen to basically anything by Reuban strayer if you want to become a master in managing agitation in emergency medicine.) If a trial enrolls patients with less severe agitation, ketamine will be overkill. Unfortunately, RCTs looking only at the most severe agitated delirium patients are very hard to accomplish.

The fact that both of these trials occurred in an emergency department means that the sickest patients were almost certainly excluded. The sickest, most agitated patients never make it to an emergency department. It is impossible to transport them. EMS and police manage these patients in the field. This is an essential point when trying to extrapolate these results. These patients can seem overwhelming in an emergency department, with a full team and almost endless resources. Trying to safely manage the same patients in the field with just a couple of paramedics is much harder, and time to control is much more important. In an emergency department, we need to reserve this treatment for the sickest patients. Waiting 20 minutes for droperidol or haloperidol to work is completely appropriate for the vast majority of patients we see. However, the threshold is lower for paramedics, because 20 minutes in the field can be much more dangerous. Ultimately, I think ketamine for agitation is primarily a prehospital treatment. Patients who have already been safely transported to the ED are rarely agitated enough to require immediate sedation with ketamine.

Whatever option we use in the ED, it is essential to recognize these patients as critically ill. People often confuse the role of study protocols and clinical protocols. For example, when trying to implement intranasal fentanyl, I have been severely hindered because the studies all check vital signs every 15 minutes after administration. This is clearly not necessary. (We don’t follow this protocol when providing IV morphine, so why would we have a stricter protocol for an intranasal opioid?) We often do things in studies that are completely unnecessary in clinical practice, because the role of studies is to gather data, and therefore closer monitoring is required. However, I personally think the monitoring requirements in these studies are critical. In the RACKED trial, “all potential patients were treated in a trauma bed with full cardiopulmonary monitoring and resuscitation capabilities.” Whether you choose ketamine, droperidol, or a combination of haloperidol and a benzodiazepine, I think it is essential to recognize these severely agitated patients as critically ill, and to redirect them to a resuscitation area for close monitoring and urgent investigations.

Ultimately, I tend to agree with Reuben Strayer’s take on ketamine for agitation. If the patient is so sick that you would consider intubating for safety, ketamine is a brilliant option. However, the patient must be given the same attention they would have received had they been intubated. They need a resuscitation room, 1 to 1 nursing, urgent investigations, and preparations for advanced airway management. If you don’t think your patient warrants this degree of attention, then ketamine is probably the wrong agent to choose.

Bottom line

There are now 2 RCTs that demonstrate that ketamine will result in more rapid sedation than haloperidol plus a benzodiazepine, but that seems to come at the cost of an increase in adverse events. Ketamine makes sense in carefully selected patients, and may be particularly helpful in the prehospital setting. Regardless of sedative choice, agitated delirium is an emergency that warrants our full attention.

Other FOAMed

EMCrit 279 – The Decision to use Ketamine – Disruptive and Dangerous with Reub Strayer

Podcast 185 – Disruption, Danger and Droperidol by Reub Strayer

Emergency Medicine Updates: Emergency Management of the Agitated Patient

Emergency Medicine Updates: Jon Cole on Ketamine for Agitation\

The Evolution of Ketamine for Severe Agitation – REBEL EM

EM Cases Ep 115 Emergency Management of the Agitated Patient

Approach to altered mental status

References

Barbic D, Andolfatto G, Grunau B, Scheuermeyer FX, Macewan B, Qian H, Wong H, Barbic SP, Honer WG. Rapid Agitation Control With Ketamine in the Emergency Department: A Blinded, Randomized Controlled Trial. Ann Emerg Med. 2021 Aug 2:S0196-0644(21)00433-9. doi: 10.1016/j.annemergmed.2021.05.023 PMID: 34353650

Lin J, Figuerado Y, Montgomery A, Lee J, Cannis M, Norton VC, Calvo R, Sikand H. Efficacy of ketamine for initial control of acute agitation in the emergency department: A randomized study. Am J Emerg Med. 2021 Jun;44:306-311. doi: 10.1016/j.ajem.2020.04.013. PMID: 32340820