In a beloved book from my childhood, Max wreaks havoc in his home life; while the surroundings of his bedroom turn into a mysterious jungle, he finds himself surrounded by creatures that meet his need for chaos in the begging of Where the Wild Things Are.
Working in Colorado, pre-hospital care has been brought into the media lately over two significant cases. The first being a few years old, with the death of Elijah McCain in Aurora in 2019, and more recently, the death of Hunter Barr in Colorado, in Colorado Springs. The bottom line, up front, I’m not here to get into police tactics or the politics of both of these cases. Both cases are educational points for pre-hospital providers and should be analyzed and Red Teamed by you as a provider and by your department.
Nor am I going into anything Ketamine. It’s a good tool and used in the right way; it’s been proven safe for the right reasons—end of that discussion at this present moment in time.
What I think is worth talking about is why discussing a plan with your team and other stakeholders who may be present on the scene is greatly important, as well as looking a little deeper into some of the pathologies and processes that patients may present within related scenarios.
My dive into this was sparked by a patient we had in our service on another shift. While watching these other events in the media, we had a call that started like many do in EMS these days: someone wasn’t acting right, they seemed to be altered, and there may be multiple substances involved. We have been having a lot of poly-pharm overdoses here lately, like, I may be missing nursing home calls it’s to that extent, a little maybe, but take it for what you will.
The pinnacle of one of my recent experiences was two cases in the same week that ended up being Serotonin Syndrome patients. I ended up digging into this and making a hypothesis that perhaps many of the Excited Delirium cases we see in EMS may be Serotonin Syndrome, or one of its look like, the more I have read, the more I feel like this may be the case. Maybe Excited Delirium is not real; perhaps we’ve messed up. There is interesting data out there. I also wonder if it is some other pathos we just are not connecting the dots on? 
Are we being Max, making our jungle out there, and not looking at more evidence-based approaches to the differential diagnosis of these patients that keep ending up on the front page of the evening paper?
Some of the differentials I have found are nothing I would have guessed. Serotonin Syndrome is probably underreported- because in minor to moderate symptoms are so vague that may not be recognized as Serotonin Syndrome patient (Nordstrom et al., 2016).
Serotonin Syndrome
The most basic definition I can distill down for you via the copper piping of my brain is that: Serotonin syndrome happens when there is an increased instance of central and peripheral serotonin (technically speaking, 5-hydroxytryptamine(Werneke et al., 2020a)).
Signs and symptoms are kind of generic when you look at them, and they fit a lot of the calls we get dispatched to: someone not acting right or altered at the 7-11. You get there, and your windshield triage shows someone clearly not acting right; maybe you can hear them talking, and it sounds less sensical than expected, and they are moving around funny or jittery. I don’t know about you, but that’s a pretty standard call every place I’ve worked. Its also important to note that most cases of the syndrome that have been documented have been on standard, therapeutic dosing regimens, and only about 10 percent have been contributed to overdoses.
What’s important to remember is to think past just what you’re seeing and putting together some solid differentials and treatment plans. Serotonin Syndrome usually is a triad of CNS issues, autonomic disturbances, and neuromuscular effects. Signs and symptoms of Serotonin Syndrome include:
- Cardiovascular System
- Tachycardia
- Hypo/hypertension
- Flushing
- Respiratory
- Tachypnoea
- Neurological
- Confusion
- Seizures
- Coma
- Agitation
- Restlessness
- CLONUS
- Hyperreflexia
- Incoordination
- Ataxia
- Rigidity
- Dilated pupils
- Metabolic
- Fever
- Acidosis
- Hematology
- DIC
- Renal Failure (Serotonin Syndrome CCC • LITFL • CCC Toxicology, n.d.)
Sounds like a total mess. It also sounds like things we see in Excited Delirium at the street level, too, doesn’t it? One of the kid differences in leading you down the correct differential diagnosis trail is bold up there.
When I first started looking into this more, I felt like there were many low-hanging answers here unless my patient was taking SSRIs, or maybe MAOIs. Worry not; there’s more to it because things are never that simple. Potential common medications that may cause Serotonin Syndrome are as follows:
- SSRIs, SNRIS, TACSs, MAOI, and Lithium
- Opiate Analgesics
- Anti-emetics (Zofran and Metoclopramide)
- Antibiotics (Zyvox)
- Sumatriptan
- OTC Cold/Flu meds like Dextromethorphan
- Drugs: of abuse, such as MDMA, LSD, and cocaine
- St John’s Wort and Methylene Blue. (Nillas, 2021)
I’m not sure about you, but the more I read about what may cause this syndrome, at normal dosing levels, I can only start putting puzzle pieces together that we have to be seeing it more than we realize in the field, and maybe it is what we’re labeling as Excited Delirium.
Differential Diagnosis rules here, and it’s essential to quickly develop a possible one as you pull up on scene, progress from the window triage you have done, and maybe get some history from a bystander, LEO, mental health worker, or even the patient. The list that could be through your head may include the following:
- Neuroleptic malignant syndrome (NMS)
- Anticholinergic toxicity
- Malignant hyperthermia
- Intoxication from other sympathomimetic agents
- Opioid withdrawal
- Sepsis
- Meningitis/encephalitis
- Heatstroke
- Delirium tremens
- Thyroid storm (Chodakowski, n.d.)
That’s…well, a lot. Fear not, though; there are three published tools out there, each with their variability in making a clinical diagnosis for Serotonin Syndrome: Strenbach criteria, Radomski criteria, and Hunter criteria (Werneke et al., 2020b). All three have a specific list of symptoms and the need for some type of serotonin antagonist.
Strenbach’s Criteria is as follows: You have ruled out all other potential causes/differential diagnosis first. The criteria needs: the addition of or increase in a serotonergic agent in a medication regime and at least three of the following symptoms:
- Mental status changes (confusion, hypomania)
- Agitation
- Myoclonus
- Hyperreflexia
- Diaphoresis
- Shivering
- Tremor
- Diarrhea
- Incoordination
- Fever
In comparison, Radomski’s criteria breaks things down into Major and Minor symptoms. More importantly, you have to have already ruled out other differential diagnoses, such as withdrawal, sepsis, and metabolic issues. Beyond having a known serotonergic agent aboard, you also needed four major or three major plus minor symptoms on top of the known serotonin agent increase:
- Mental
- Major
- Consciousness impartment
- Elevated mood
- Semi-coma/coma
- Minor
- Restless
- Insomnia
- Major
- Neurological
- Major
- Myoclonus
- Tremor
- Shivering
- Rigidity
- Minor
- Uncoordination
- Dilated Pupils
- Akathisia
- Hyperreflexia
- Vegetative
- Major
- Fever
- Sweating
- Minor
- Tachycardia (Werneke et al., 2020b)
- Major
- Major
Lastly is Hunter’s Criteria, which varies the most in qualifications, requiring the presence of a serotonergic agent and either symptom/symptom constellation:
- Spontaneous clonus
- Inducible clonus and agitation or diaphoresis
- Ocular clonus and agitation or diaphoresis
- Tremor and hyperreflexia
- Hypertonic and temperature > 38 Celsius and ocular clonus/inducible clonus (Werneke et al., 2020b)
Hunter’s Criteria has some differences from the prior two and focuses significantly on the concept that the patient under assessment needed to have some clonus to identify them as having Serotonin Syndrome. Hunter’s Criteria is said to be more sensitive than Sternbach’s (84% v 75%) and was more specific (97% v 96%). The big take-home here in identifying Serotonin Syndrome is the presence of clonus in any form (Dunkley et al., 2003).
Too long? Didn’t read? (TLDR)… I got it. Here’s the simple answer, the other likely diagnosis is Neuroleptic Malignant Syndrome, which can be diagnosed if there was a dopamine antagonist taken or a recent cessation of dopamine agonist medication, combined with fever and muscle rigidity. Serotonin Syndrome comes on fast, fast onset, fast movements, and fast resolution; in contrast, NMS comes on slow, with slow movement and resolution.
Treatment for Serotonin Syndrome is largely supportive:
- Stop the agent causing the syndrome, if possible
- Treat hyperthermia: external and internal cooling measures
- RSI may be needed, Vecuronium is preferred over Succinylcholine due to the risk of hyperkalemia
- Treat agitation with Benzos, which will lower the risk of lactic acidosis and rhabdomyolysis
- Treatment of hyper or hypotension with appropriate pharmaceutical interventions.
- Have a Plan: discuss with your entire team what you think is going on, collect data to help your assessment from bystanders and the surrounding area. Have a takedown plan if it comes to it. Include your EMS team, LE, Fire, whoever is going to be involved. Take it from best case to worst case and think about discussing it in front of the LE’s body cam. If you’re doing the right thing, you might as well document it.
I get this has been a somewhat heavy read. I think it’s worth discussing, though. Much like Max in Where the Wild Things Are, maybe we did get too into Excited Delirium. Do we still have combative, hypermetabolic patients that are violent, a safety issue, and challenging to take care of totally, but maybe we need to come at it from a different approach. There is evidence that Excited Delirium may only be deadly to the patient when aggressive restraint is used (Strömmer et al., 2020).
Whatever you decide to call it, whatever differential diagnosis you may come to out in the field on this obscure, difficult to manage patients, I urge you to have a plan. Discuss it, game it for weaknesses, avoid asphyxiation at all costs if you must have a takedown, and be ready to treat all the things that could go wrong.
Chodakowski, J. (n.d.). Serotonin Syndrome — NUEM Blog. Nuemblog. Retrieved June 24, 2021, from https://www.nuemblog.com/blog/serotonin-syndrome
Dunkley, E. J. C., Isbister, G. K., Sibbritt, D., Dawson, A. H., & Whyte, I. M. (2003). The hunter serotonin toxicity criteria: Simple and accurate diagnostic decision rules for serotonin toxicity. QJM – Monthly Journal of the Association of Physicians, 96(9), 635–642. https://doi.org/10.1093/qjmed/hcg109
Nillas, A. (2021). emDOCs.net – Emergency Medicine EducationPush-Serotonin Syndrome – emDOCs.net – Emergency Medicine Education. EmDocs. http://www.emdocs.net/em3am-serotonin-syndrome/
Nordstrom, K., Vilke, G. M., & Wilson, M. P. (2016). Psychiatric Emergencies for Clinicians: Emergency Department Management of Serotonin Syndrome. Journal of Emergency Medicine, 50(1), 89–91. https://doi.org/10.1016/j.jemermed.2015.07.046
Serotonin Syndrome CCC • LITFL • CCC Toxicology. (n.d.). Retrieved June 17, 2021, from https://litfl.com/serotonin-syndrome-ccc/
Strömmer, E. M. F., Leith, W., Zeegers, M. P., & Freeman, M. D. (2020). The role of restraint in fatal excited delirium: a research synthesis and pooled analysis. In Forensic Science, Medicine, and Pathology (Vol. 16, Issue 4, pp. 680–692). Springer. https://doi.org/10.1007/s12024-020-00291-8
Werneke, U., Truedson-Martiniussen, P., Wikström, H., & Ott, M. (2020a). Serotonin syndrome: a clinical review of current controversies. J. Integr. Neurosci, 19(4), 719–727. https://doi.org/10.31083/j.jin.2020.04.314
Werneke, U., Truedson-Martiniussen, P., Wikström, H., & Ott, M. (2020b). Serotonin syndrome: a clinical review of current controversies. J. Integr. Neurosci, 19(4), 719–727. https://doi.org/10.31083/j.jin.2020.04.314