The Agitated Patient

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I don’t know if this has happened to you yet.  It happened to me on my first shift as an intern.  I hadn’t laid hand on a stethoscope in months.  I had just unloaded the cardboard boxes from my rental truck into my new place.  As I was settling in to my first few patient encounters one of our nurses approached me to say that a patient had been brought into our area that was extremely agitated.  I looked up to see a man being held down by multiple police officers, thrashing and swearing.  

“What can I give him?” She said.

“How about a hug?” I replied.

Both my nurse and my patient did not respond well to this.

Some assistance with a needle was required, but frankly I had very little experience with pharmacologic restraint at that time.  Fortunately, our nursing staff was more than able to educate me on some starting points for patients of this particular ilk. For the rest of us, in the attached podcast Dr. Stettler and I discuss the approach to the agitated patient as well as what drugs may be helpful in providing safe sedation.  Some important highlights from the episode include:

  • When the patient is agitated, re-address the reason why the patient has been brought to the emergency department in the first place.  If the patient did not show up agitated but has become so during their stay, often the agitation is related to a decompensation of their medical condition (think: worsening respiratory status, sepsis run amok, etc.)

  • If no rectifiable medical problem can be found, re-direction and attempts at de-escalation are certainly worthwhile, however, if the patient isn’t able to be talked down within a minute or so, it’s not likely going to happen

  • If the patient is significantly intoxicated, you may be able to de-escalate the patient at bedside, however, this process may become prohibitively time intensive as their agitation may return each time you are not at their side to talk them down

A portion of this episode centers on which drugs to use to provide chemical sedation for a patient when it is needed.  In Dr. Stettler’s experience he has found good success with a combination of intramuscular midazolam and haloperidol, starting doses of 5-10 mg and 10 mg, respectively.  The reasoning for this combination approach is for that of rapidity of onset in addition to avoidance of significant respiratory depression.  One study analyzed the effect of high-dose midazolam sedation for patients in the emergency department suspected to be suffering from psychostimulant induced agitation1.  Enrolled patients received intramuscular or intravenous doses of midazolam, 10 mg at a time, performed every 10 minutes up to four doses, titrated to “drowsiness”.  Of 62 patients in the study, 55 received adequate sedation after two doses (20 mg), with two thirds of all patients only requiring one dose.  However, four of these patients experienced significant respiratory depression requiring airway adjuncts (either nasopharyngeal or oral airway, none required intubation).  Of interest, these patients requiring respiratory support were those in the one or two dose category.  Those that received three or four doses of midazolam did not have such events.  Though there are certainly limitations to this study, there are also many inferences that could be made.  While benzodiazepines may certainly be effective at providing sedation, their potential for respiratory depression is a cause for concern.  Furthermore, Dr. Stettler brings up the interesting point of the concern for synergistic respiratory depression from ethanol or other substances should larger quantities of benzodiazepines be utilized. 

In order to combat this potential for morbidity, adding an antipsychotic to a benzodiazepine can be a helpful way to augment sedation while safely distributing side effect profiles.  Haloperidol is suggested in our podcast as an effective agent.  There are some who advocate for usage of a second generation antipsychotic in this instance, the main reasons for which are secondary to the increased incidence of side effects, most notably extrapyramidal symptoms or EPS (dystonia, akathisia, tardive dyskinesia, etc.) and prolongation of the QT interval. In our department an agent that I have used with good results has been ziprasidone (Geodon) 20 mg IM.  However, this is a medication that requires reconstitution, i.e. adding 2-3 minutes of preparation before it is able to be administered.  Depending on the circumstance those 2-3 minutes could be very important.  So if you give haloperidol will your patients’ hearts explode and their tongues stick out forever?

We’re looking at you, Joker.

In a randomized single blind trial2 58 patients with schizophrenia or schizoaffective disorder being treated with antipsychotic medication were randomized for trial dosage of either haloperidol or ziprasidone with the goal to measure their effect on the QT interval following administration.  After a 10 day taper and washout of current antipsychotic medication patients received either 20 mg of ziprasidone followed 4 hours later by 30 mg or 7.5 mg haloperidol followed 4 hours later by 10 mg.  Serial EKGs were performed over the subsequent 48 hours to monitor QTc.  On average the patient’s QTc interval changed between 5 and 15 milliseconds, with the greatest change in all treatment groups being in one patient after the second dose of haloperidol at 19.2 milliseconds.  Of note, no patient crossed 480 milliseconds on QTc, avoiding any concerning threshold at 500 milliseconds for potential degeneration into torsades de pointes.  What does that all mean?  Granted, limitations of the study include funding from Pfizer, single blind, etc., however, a relatively small bump in the QTc interval of only 5-15 milliseconds is certainly reassuring when these medications are being administered without knowledge of a patient’s baseline EKG status.

How about all the EPS reported from use with haloperidol?  A meta-analysis published in 20083 examined the risk for extrapyramidal symptoms in intramuscular administration among different antipsychotic agents.  At first, their analysis compares second generation antipsychotics (i.e. ziprasidone) against haloperidol alone head to head, the results of which do show a trend of more favorable side effect profile in the second generation group.  They found that of patients receiving haloperidol alone, 4.7% experienced some sort of dystonic reaction, compared to that of 0.6% of those receiving second generation antipsychotics alone.  However, they further clarify that all of these studies were “industry funded”.  They followed their initial analysis with a second analysis integrating an additional study which compared the use of second generation antipsychotics versus haloperidol plus promethazine, the promethazine being added for its anticholinergic properties to prevent extrapyramidal symptoms.  Surprisingly, they found that none of the patients receiving the combination of haloperidol and promethazine experienced the dystonic reactions described previously.  They imply that other medications such as diphenhydramine could be used to prevent side effects with a presumed similar efficacy.  Furthermore, the point is made of the significant cost disparity between the two groups.  At the time of their publication they noted that a single dose of 20 mg of ziprasidone cost near $12, while a single dose of haloperidol and promethazine or diphenhydramine each cost less than $1.  Even so, we do plenty in the emergency department that costs much, much more.  The important consideration to reiterate is that of time.  In our emergency department, ziprasidone may take a few minutes to get ready.  If that is time that is available and safe, it is certainly an appropriate option.  However, for the patient struggling with multiple bodies piled on top of them, consider it best to remedy that situation as soon as possible.

But is there anything else we can use?  For an awesome podcast with a lot more information click here: http://blog.ercast.org/art-chemical-takedown/ .  Dr. Rob Orman gathers the input from emergency providers around the world and what their go-to cocktail is for dealing with the agitated patient.  A favorite drug of many is that of droperidol.  Although no longer available at our institution, there are anecdotal comments (many of them yearning) regarding its efficacy in the agitated patient.  One study4 in Australia compared the use of haloperidol to droperidol head to head in a randomized double blind trial in a psychiatry ward.  Intramuscular administration of 10 mg of either drug in this study was found to have no difference in median time to sedation, with droperidol requiring less rescue dosing than haloperidol.  Concerns about QT prolongation with this drug may have led to its untimely demise at some institutions, however, one study5 reports a “rigorous review” of 35 articles meeting criteria for safety profile of droperidol and have found that intramuscular dosing up to 10 mg seems to have no difference in safety as compared to other commonly used drugs.

For some more interesting reading take a look at the use of IM ketamine for sedation in the agitated patient6,7, coming soon to an emergency department near you? 

Pretty please? With droperidol on top?

References

  1. Spain, David, et al. "Safety and effectiveness of high‐dose midazolam for severe behavioural disturbance in an emergency department with suspected psychostimulant‐affected patients." Emergency Medicine Australasia 20.2 (2008): 112-120.
  2. Miceli, Jeffrey J., et al. “Effects of high-dose ziprasidone and haloperidol on the QTc interval after intramuscular administration: a randomized, single-blind, parallel-group study in patients with schizophrenia or schizoaffective disorder.” Clinical therapeutics 32.3 (2010): 472-491.
  3. Satterthwaite, Theodore D., et al. “A meta-analysis of the risk of acute extrapyramidal symptoms with intramuscular antipsychotics for the treatment of agitation.” The Journal of clinical psychiatry 69.12 (2008): 1869.
  4. Calver, Leonie, et al. "Droperidol v. haloperidol for sedation of aggressive behaviour in acute mental health: randomised controlled trial." The British Journal of Psychiatry 206.3 (2015): 223-228.
  5. Perkins, Jack, et al. "Safety of Droperidol Use in the Emergency Department." The Journal of emergency medicine (2015).
  6. Keseg, David, et al. "The Use of Prehospital Ketamine for Control of Agitation in a Metropolitan Firefighter-based EMS System." Prehospital Emergency Care19.1 (2015): 110-115.
  7. Hopper, Austin B., et al. "Ketamine Use for Acute Agitation in the Emergency Department." The Journal of emergency medicine (2015).